Sample records for abnormal fronto-striatal connectivity

  1. FRONTO-STRIATAL FUNCTIONAL CONNECTIVITY DURING RESPONSE INHIBITION IN ALCOHOL DEPENDENCE

    PubMed Central

    Courtney, Kelly E.; Ghahremani, Dara G.; Ray, Lara A.

    2013-01-01

    Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the µ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing a Stop Signal Task (SST). The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction (PPI) analyses. Analyses revealed greater alcohol dependence severity associated with weaker functional connectivity between the putamen and prefrontal regions (e.g., the anterior insula, anterior cingulate, and medial prefrontal cortex) during response inhibition. Further, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses. PMID:23240858

  2. Relationships between changes in Sustained Fronto-Striatal Connectivity and Positive Affect with Antidepressant Treatment in Major Depression

    PubMed Central

    Heller, Aaron S.; Johnstone, Tom; Light, Sharee; Peterson, Michael J.; Kolden, Gregory G.; Kalin, Ned H.; Davidson, Richard J.

    2012-01-01

    Objective Deficits in positive affect and their neural bases have been associated with major depression. However, whether reductions in positive affect result solely from an overall reduction in nucleus accumbens activity and fronto-striatal connectivity or the additional inability to sustain engagement over time of this network is unknown. Accordingly, we sought to determine whether treatment-induced changes in the ability to sustain nucleus accumbens activity and fronto-striatal connectivity during the regulation of positive affect are associated with gains in positive affect. Method Using fMRI, we assessed the ability to sustain activity in reward-related networks when attempting to increase positive emotion during performance of an emotion regulation paradigm in 21 depressed patients prior to, and after 2 months of antidepressant treatment. 14 healthy control subjects were scanned over the same interval. Results After 2 months of treatment, self-reported positive affect increased. Those patients demonstrating the largest increases in sustained nucleus accumbens activity over the 2 months were those demonstrating the largest increases in positive affect. In addition, those patients demonstrating the largest increases in sustained fronto-striatal connectivity were also those demonstrating the largest increases in positive affect when controlling for negative affect. Healthy controls showed none of these associations. Conclusions Treatment induced changes in the sustained engagement of fronto-striatal circuitry tracks the experience of positive emotion in daily life. Studies examining reduced positive affect in a variety of psychiatric disorders might benefit from examining the temporal dynamics of brain activity when attempting to understand changes in daily positive affect. PMID:23223803

  3. Abnormal fronto-striatal activation as a marker of threshold and subthreshold Bulimia Nervosa.

    PubMed

    Cyr, Marilyn; Yang, Xiao; Horga, Guillermo; Marsh, Rachel

    2018-04-01

    This study aimed to determine whether functional disturbances in fronto-striatal control circuits characterize adolescents with Bulimia Nervosa (BN) spectrum eating disorders regardless of clinical severity. FMRI was used to assess conflict-related brain activations during performance of a Simon task in two samples of adolescents with BN symptoms compared with healthy adolescents. The BN samples differed in the severity of their clinical presentation, illness duration and age. Multi-voxel pattern analyses (MVPAs) based on machine learning were used to determine whether patterns of fronto-striatal activation characterized adolescents with BN spectrum disorders regardless of clinical severity, and whether accurate classification of less symptomatic adolescents (subthreshold BN; SBN) could be achieved based on patterns of activation in adolescents who met DSM5 criteria for BN. MVPA classification analyses revealed that both BN and SBN adolescents could be accurately discriminated from healthy adolescents based on fronto-striatal activation. Notably, the patterns detected in more severely ill BN compared with healthy adolescents accurately discriminated less symptomatic SBN from healthy adolescents. Deficient activation of fronto-striatal circuits can characterize BN early in its course, when clinical presentations are less severe, perhaps pointing to circuit-based disturbances as useful biomarker or risk factor for the disorder, and a tool for understanding its developmental trajectory, as well as the development of early interventions. © 2018 Wiley Periodicals, Inc.

  4. Fronto-striatal circuits in response-inhibition: Relevance to addiction

    PubMed Central

    Morein-Zamir, Sharon; Robbins, Trevor W.

    2015-01-01

    Disruptions to inhibitory control are believed to contribute to multiple aspects of drug abuse, from preexisting vulnerability in at-risk individuals, through escalation to dependence, to promotion of relapse in chronic users. Paradigms investigating the suppression of actions have been investigated in animal and human research on drug addiction. Rodent research has focused largely on impulsive behaviors, often gauged by premature responding, as a viable model highlighting the relevant role of dopamine and other neurotransmitters primarily in the striatum. Human research on action inhibition in stimulant dependence has highlighted impaired performance and largely prefrontal cortical abnormalities as part of a broader pattern of cognitive abnormalities. Animal and human research implicate inhibitory difficulties mediated by fronto-striatal circuitry both preceding and as a result of excessive stimulus use. In this regard, response-inhibition has proven a useful cognitive function to gauge the integrity of fronto-striatal systems and their role in contributing to impulsive and compulsive features of drug dependence. This article is part of a Special Issue entitled SI:Addiction circuits. PMID:25218611

  5. Dermatoglyphic asymmetries and fronto-striatal dysfunction in young-adults reporting non-clinical psychosis

    PubMed Central

    Mittal, Vijay A.; Dean, Derek J.; Pelletier, Andrea

    2012-01-01

    Objective Growing evidence indicates that non-clinical psychotic-like experiences occur in otherwise healthy individuals, suggesting that psychosis may occur on a continuum. However, little is know about how the diathesis for formal psychosis maps on to individuals at the non-clinical side of this continuum. Our current understanding of the pathophysiology of schizophrenia implicates certain key factors such as early developmental abnormalities and fronto-striatal dysfunction. To date, no studies have examined these core factors in the context of non-clinical psychosis. Method A total of 221 young adults were assessed for distressing attenuated positive symptoms (DAPS), dermatoglyphic asymmetries (a marker of early developmental insult), and procedural memory (a proxy for fronto-striatal function). Results Participants reporting DAPS (n=16; 7.2%) and no-DAPS (n=205; 92.7%) were split into two groups. The DAPS group showed significantly elevated depression, elevated dermatoglyphic asymmetries, and a pattern of procedural learning consistent with other studies with formally psychotic patients. Conclusion The results indicate that the non-clinical side of the psychosis continuum also shares key vulnerability factors implicated in schizophrenia, suggesting that both early developmental disruption and abnormalities in fronto-striatal function are core aspects underlying the disorder. PMID:22519833

  6. Altered Functional Connectivity of Fronto-Cingulo-Striatal Circuits during Error Monitoring in Adolescents with a History of Childhood Abuse

    PubMed Central

    Hart, Heledd; Lim, Lena; Mehta, Mitul A.; Curtis, Charles; Xu, Xiaohui; Breen, Gerome; Simmons, Andrew; Mirza, Kah; Rubia, Katya

    2018-01-01

    Childhood maltreatment is associated with error hypersensitivity. We examined the effect of childhood abuse and abuse-by-gene (5-HTTLPR, MAOA) interaction on functional brain connectivity during error processing in medication/drug-free adolescents. Functional connectivity was compared, using generalized psychophysiological interaction (gPPI) analysis of functional magnetic resonance imaging (fMRI) data, between 22 age- and gender-matched medication-naïve and substance abuse-free adolescents exposed to severe childhood abuse and 27 healthy controls, while they performed an individually adjusted tracking stop-signal task, designed to elicit 50% inhibition failures. During inhibition failures, abused participants relative to healthy controls exhibited reduced connectivity between right and left putamen, bilateral caudate and anterior cingulate cortex (ACC), and between right supplementary motor area (SMA) and right inferior and dorsolateral prefrontal cortex. Abuse-related connectivity abnormalities were associated with longer abuse duration. No group differences in connectivity were observed for successful inhibition. The findings suggest that childhood abuse is associated with decreased functional connectivity in fronto-cingulo-striatal networks during error processing. Furthermore that the severity of connectivity abnormalities increases with abuse duration. Reduced connectivity of error detection networks in maltreated individuals may be linked to constant monitoring of errors in order to avoid mistakes which, in abusive contexts, are often associated with harsh punishment. PMID:29434543

  7. Fronto-striatal contribution to lexical set-shifting.

    PubMed

    Simard, France; Joanette, Yves; Petrides, Michael; Jubault, Thomas; Madjar, Cécile; Monchi, Oury

    2011-05-01

    Fronto-striatal circuits in set-shifting have been examined in neuroimaging studies using the Wisconsin Card Sorting Task (WCST) that requires changing the classification rule for cards containing visual stimuli that differ in color, shape, and number. The present study examined whether this fronto-striatal contribution to the planning and execution of set-shifts is similar in a modified sorting task in which lexical rules are applied to word stimuli. Young healthy adults were scanned with functional magnetic resonance imaging while performing the newly developed lexical version of the WCST: the Wisconsin Word Sorting Task. Significant activation was found in a cortico-striatal loop that includes area 47/12 of the ventrolateral prefrontal cortex (PFC), and the caudate nucleus during the planning of a set-shift, and in another that includes the posterior PFC and the putamen during the execution of a set-shift. However, in the present lexical task, additional activation peaks were observed in area 45 of the ventrolateral PFC area during both matching periods. These results provide evidence that the functional contributions of the various fronto-striatal loops are not dependent on the modality of the information to be manipulated but rather on the specific executive processes required.

  8. Contribution of fronto-striatal regions to emotional valence and repetition under cognitive conflict.

    PubMed

    Chun, Ji-Won; Park, Hae-Jeong; Kim, Dai Jin; Kim, Eosu; Kim, Jae-Jin

    2017-07-01

    Conflict processing mediated by fronto-striatal regions may be influenced by emotional properties of stimuli. This study aimed to examine the effects of emotion repetition on cognitive control in a conflict-provoking situation. Twenty-one healthy subjects were scanned using functional magnetic resonance imaging while performing a sequential cognitive conflict task composed of emotional stimuli. The regional effects were analyzed according to the repetition or non-repetition of cognitive congruency and emotional valence between the preceding and current trials. Post-incongruence interference in error rate and reaction time was significantly smaller than post-congruence interference, particularly under repeated positive and non-repeated positive, respectively, and post-incongruence interference, compared to post-congruence interference, increased activity in the ACC, DLPFC, and striatum. ACC and DLPFC activities were significantly correlated with error rate or reaction time in some conditions, and fronto-striatal connections were related to the conflict processing heightened by negative emotion. These findings suggest that the repetition of emotional stimuli adaptively regulates cognitive control and the fronto-striatal circuit may engage in the conflict adaptation process induced by emotion repetition. Both repetition enhancement and repetition suppression of prefrontal activity may underlie the relationship between emotion and conflict adaptation. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania

    PubMed Central

    Altinay, Murat I.; Hulvershorn, Leslie A.; Karne, Harish; Beall, Erik B.

    2016-01-01

    Abstract Bipolar disorder (BP) is characterized by periods of depression (BPD) and (hypo)mania (BPM), but the underlying state-related brain circuit abnormalities are not fully understood. Striatal functional activation and connectivity abnormalities have been noted in BP, but consistent findings have not been reported. To further elucidate striatal abnormalities in different BP states, this study investigated differences in resting-state functional connectivity of six striatal subregions in BPD, BPM, and healthy control (HC) subjects. Ninety medication-free subjects (30 BPD, 30 BPM, and 30 HC), closely matched for age and gender, were scanned using 3T functional magnetic resonance imaging (fMRI) acquired at resting state. Correlations of low-frequency blood oxygen level dependent signal fluctuations for six previously described striatal subregions were used to obtain connectivity maps of each subregion. Using a factorial design, main effects for differences between groups were obtained and post hoc pairwise group comparisons performed. BPD showed increased connectivity of the dorsal caudal putamen with somatosensory areas such as the insula and temporal gyrus. BPM group showed unique increased connectivity between left dorsal caudate and midbrain regions, as well as increased connectivity between ventral striatum inferior and thalamus. In addition, both BPD and BPM exhibited widespread functional connectivity abnormalities between striatal subregions and frontal cortices, limbic regions, and midbrain structures. In summary, BPD exhibited connectivity abnormalities of associative and somatosensory subregions of the putamen, while BPM exhibited connectivity abnormalities of associative and limbic caudate. Most other striatal subregion connectivity abnormalities were common to both groups and may be trait related. PMID:26824737

  10. Mechanisms mediating parallel action monitoring in fronto-striatal circuits.

    PubMed

    Beste, Christian; Ness, Vanessa; Lukas, Carsten; Hoffmann, Rainer; Stüwe, Sven; Falkenstein, Michael; Saft, Carsten

    2012-08-01

    Flexible response adaptation and the control of conflicting information play a pivotal role in daily life. Yet, little is known about the neuronal mechanisms mediating parallel control of these processes. We examined these mechanisms using a multi-methodological approach that integrated data from event-related potentials (ERPs) with structural MRI data and source localisation using sLORETA. Moreover, we calculated evoked wavelet oscillations. We applied this multi-methodological approach in healthy subjects and patients in a prodromal phase of a major basal ganglia disorder (i.e., Huntington's disease), to directly focus on fronto-striatal networks. Behavioural data indicated, especially the parallel execution of conflict monitoring and flexible response adaptation was modulated across the examined cohorts. When both processes do not co-incide a high integrity of fronto-striatal loops seems to be dispensable. The neurophysiological data suggests that conflict monitoring (reflected by the N2 ERP) and working memory processes (reflected by the P3 ERP) differentially contribute to this pattern of results. Flexible response adaptation under the constraint of high conflict processing affected the N2 and P3 ERP, as well as their delta frequency band oscillations. Yet, modulatory effects were strongest for the N2 ERP and evoked wavelet oscillations in this time range. The N2 ERPs were localized in the anterior cingulate cortex (BA32, BA24). Modulations of the P3 ERP were localized in parietal areas (BA7). In addition, MRI-determined caudate head volume predicted modulations in conflict monitoring, but not working memory processes. The results show how parallel conflict monitoring and flexible adaptation of action is mediated via fronto-striatal networks. While both, response monitoring and working memory processes seem to play a role, especially response selection processes and ACC-basal ganglia networks seem to be the driving force in mediating parallel conflict

  11. Aberrant striatal functional connectivity in children with autism.

    PubMed

    Di Martino, Adriana; Kelly, Clare; Grzadzinski, Rebecca; Zuo, Xi-Nian; Mennes, Maarten; Mairena, Maria Angeles; Lord, Catherine; Castellanos, F Xavier; Milham, Michael P

    2011-05-01

    Models of autism spectrum disorders (ASD) as neural disconnection syndromes have been predominantly supported by examinations of abnormalities in corticocortical networks in adults with autism. A broader body of research implicates subcortical structures, particularly the striatum, in the physiopathology of autism. Resting state functional magnetic resonance imaging has revealed detailed maps of striatal circuitry in healthy and psychiatric populations and vividly captured maturational changes in striatal circuitry during typical development. Using resting state functional magnetic resonance imaging, we examined striatal functional connectivity (FC) in 20 children with ASD and 20 typically developing children between the ages of 7.6 and 13.5 years. Whole-brain voxelwise statistical maps quantified within-group striatal FC and between-group differences for three caudate and three putamen seeds for each hemisphere. Children with ASD mostly exhibited prominent patterns of ectopic striatal FC (i.e., functional connectivity present in ASD but not in typically developing children), with increased functional connectivity between nearly all striatal subregions and heteromodal associative and limbic cortex previously implicated in the physiopathology of ASD (e.g., insular and right superior temporal gyrus). Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD. Secondary analyses revealed ASD-related hyperconnectivity between the pons and insula cortex. Examination of FC of striatal networks in children with ASD revealed abnormalities in circuits involving early developing areas, such as the brainstem and insula, with a pattern of increased FC in ectopic circuits that likely reflects developmental derangement rather than immaturity of functional circuits. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Altered striatal intrinsic functional connectivity in pediatric anxiety

    PubMed Central

    Dorfman, Julia; Benson, Brenda; Farber, Madeline; Pine, Daniel; Ernst, Monique

    2016-01-01

    Anxiety disorders are among the most common psychiatric disorders of adolescence. Behavioral and task-based imaging studies implicate altered reward system function, including striatal dysfunction, in adolescent anxiety. However, no study has yet examined alterations of the striatal intrinsic functional connectivity in adolescent anxiety disorders. The current study examines striatal intrinsic functional connectivity (iFC), using six bilateral striatal seeds, among 35 adolescents with anxiety disorders and 36 healthy comparisons. Anxiety is associated with abnormally low iFC within the striatum (e.g., between nucleus accumbens and caudate nucleus), and between the striatum and prefrontal regions, including subgenual anterior cingulate cortex, posterior insula and supplementary motor area. The current findings extend prior behavioral and task-based imaging research, and provide novel data implicating decreased striatal iFC in adolescent anxiety. Alterations of striatal neurocircuitry identified in this study may contribute to the perturbations in the processing of motivational, emotional, interoceptive, and motor information seen in pediatric anxiety disorders. This pattern of the striatal iFC perturbations can guide future research on specific mechanisms underlying anxiety. PMID:27004799

  13. Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia.

    PubMed

    Horga, Guillermo; Cassidy, Clifford M; Xu, Xiaoyan; Moore, Holly; Slifstein, Mark; Van Snellenberg, Jared X; Abi-Dargham, Anissa

    2016-08-01

    Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographic organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of antidopaminergic medication. To examine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission. In this multimodal, case-control study, we obtained resting-state functional magnetic resonance imaging data from 18 unmedicated patients with schizophrenia and 24 matched healthy controls from the New York State Psychiatric Institute. A subset of these (12 and 17, respectively) underwent positron emission tomography with the dopamine D2 receptor radiotracer carbon 11-labeled FLB457 before and after amphetamine administration. Data were acquired between June 16, 2011, and February 25, 2014. Data analysis was performed from September 1, 2014, to January 11, 2016. Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, the association between the multivariate striatal connectivity pattern and extrastriatal baseline D2 receptor binding potential and its change after amphetamine administration, and the association between the multivariate connectivity pattern and the severity of positive symptoms evaluated with the Positive and Negative Syndrome Scale. Of the patients with schizophrenia (mean [SEM] age, 35.6 [11.8] years), 9 (50%) were male and 9

  14. Possible roles for fronto-striatal circuits in reading disorder

    PubMed Central

    Hancock, Roeland; Richlan, Fabio; Hoeft, Fumiko

    2016-01-01

    Several studies have reported hyperactivation in frontal and striatal regions in individuals with reading disorder (RD) during reading-related tasks. Hyperactivation in these regions is typically interpreted as a form of neural compensation and related to articulatory processing. Fronto-striatal hyperactivation in RD can however, also arise from fundamental impairment in reading related processes, such as phonological processing and implicit sequence learning relevant to early language acquisition. We review current evidence for the compensation hypothesis in RD and apply large-scale reverse inference to investigate anatomical overlap between hyperactivation regions and neural systems for articulation, phonological processing, implicit sequence learning. We found anatomical convergence between hyperactivation regions and regions supporting articulation, consistent with the proposed compensatory role of these regions, and low convergence with phonological and implicit sequence learning regions. Although the application of large-scale reverse inference to decode function in a clinical population should be interpreted cautiously, our findings suggest future lines of research that may clarify the functional significance of hyperactivation in RD. PMID:27826071

  15. Reduced frontal cortical thickness and increased caudate volume within fronto-striatal circuits in young adult smokers.

    PubMed

    Li, Yangding; Yuan, Kai; Cai, Chenxi; Feng, Dan; Yin, Junsen; Bi, Yanzhi; Shi, Sha; Yu, Dahua; Jin, Chenwang; von Deneen, Karen M; Qin, Wei; Tian, Jie

    2015-06-01

    Smoking during early adulthood results in neurophysiological and brain structural changes that may promote nicotine dependence later in life. Previous studies have revealed the important roles of fronto-striatal circuits in the pathology of nicotine dependence; however, few studies have focused on both cortical thickness and subcortical striatal volume differences between young adult smokers and nonsmokers. Twenty-seven young male adult smokers and 22 age-, education- and gender-matched nonsmokers were recruited in the present study. The cortical thickness and striatal volume differences of young adult smokers and age-matched nonsmokers were investigated in the present study and then correlated with pack-years and Fagerström Test for Nicotine Dependence (FTND). The following results were obtained: (1) young adult smokers showed significant cortical thinning in the frontal cortex (left caudal anterior cingulate cortex (ACC), right lateral orbitofrontal cortex (OFC)), left insula, left middle temporal gyrus, right inferior parietal lobule, and right parahippocampus; (2) in regards to subcortical striatal volume, the volume of the right caudate was larger in young adult smokers than nonsmokers; and (3) the cortical thickness of the right dorsolateral prefrontal cortex (DLPFC) and OFC were associated with nicotine dependence severity (FTND) and cumulative amount of nicotine intake (pack-years) in smokers, respectively. This study revealed reduced frontal cortical thickness and increased caudate volume in the fronto-striatal circuits in young adult smokers compared to nonsmokers. These deficits suggest an imbalance between cognitive control (reduced protection factors) and reward drive behaviours (increased risk factors) associated with nicotine addiction and relapse. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Abnormalities in fronto-striatal connectivity within language networks relate to differences in grey-matter heterogeneity in Asperger syndrome☆

    PubMed Central

    Radulescu, Eugenia; Minati, Ludovico; Ganeshan, Balaji; Harrison, Neil A.; Gray, Marcus A.; Beacher, Felix D.C.C.; Chatwin, Chris; Young, Rupert C.D.; Critchley, Hugo D.

    2013-01-01

    Asperger syndrome (AS) is an Autism Spectrum Disorder (ASD) characterised by qualitative impairment in the development of emotional and social skills with relative preservation of general intellectual abilities, including verbal language. People with AS may nevertheless show atypical language, including rate and frequency of speech production. We previously observed that abnormalities in grey matter homogeneity (measured with texture analysis of structural MR images) in AS individuals when compared with controls are also correlated with the volume of caudate nucleus. Here, we tested a prediction that these distributed abnormalities in grey matter compromise the functional integrity of brain networks supporting verbal communication skills. We therefore measured the functional connectivity between caudate nucleus and cortex during a functional neuroimaging study of language generation (verbal fluency), applying psycho-physiological interaction (PPI) methods to test specifically for differences attributable to grey matter heterogeneity in AS participants. Furthermore, we used dynamic causal modelling (DCM) to characterise the causal directionality of these differences in interregional connectivity during word production. Our results revealed a diagnosis-dependent influence of grey matter heterogeneity on the functional connectivity of the caudate nuclei with right insula/inferior frontal gyrus and anterior cingulate, respectively with the left superior frontal gyrus and right precuneus. Moreover, causal modelling of interactions between inferior frontal gyri, caudate and precuneus, revealed a reliance on bottom-up (stimulus-driven) connections in AS participants that contrasted with a dominance of top-down (cognitive control) connections from prefrontal cortex observed in control participants. These results provide detailed support for previously hypothesised central disconnectivity in ASD and specify discrete brain network targets for diagnosis and therapy in ASD

  17. Altered fronto-striatal functions in the Gdi1-null mouse model of X-linked Intellectual Disability.

    PubMed

    Morè, Lorenzo; Künnecke, Basil; Yekhlef, Latefa; Bruns, Andreas; Marte, Antonella; Fedele, Ernesto; Bianchi, Veronica; Taverna, Stefano; Gatti, Silvia; D'Adamo, Patrizia

    2017-03-06

    RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder.

    PubMed

    Naaijen, Jilly; Zwiers, Marcel P; Amiri, Houshang; Williams, Steven C R; Durston, Sarah; Oranje, Bob; Brandeis, Daniel; Boecker-Schlier, Regina; Ruf, Matthias; Wolf, Isabella; Banaschewski, Tobias; Glennon, Jeffrey C; Franke, Barbara; Buitelaar, Jan K; Lythgoe, David J

    2017-11-01

    Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8-13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model. Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. In addition, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared with controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.

  19. Creative cognition and dopaminergic modulation of fronto-striatal networks: Integrative review and research agenda.

    PubMed

    Boot, Nathalie; Baas, Matthijs; van Gaal, Simon; Cools, Roshan; De Dreu, Carsten K W

    2017-07-01

    Creative cognition is key to human functioning yet the underlying neurobiological mechanisms are sparsely addressed and poorly understood. Here we address the possibility that creative cognition is a function of dopaminergic modulation in fronto-striatal brain circuitries. It is proposed that (i) creative cognition benefits from both flexible and persistent processing, (ii) striatal dopamine and the integrity of the nigrostriatal dopaminergic pathway is associated with flexible processing, while (iii) prefrontal dopamine and the integrity of the mesocortical dopaminergic pathway is associated with persistent processing. We examine this possibility in light of studies linking creative ideation, divergent thinking, and creative problem-solving to polymorphisms in dopamine receptor genes, indirect markers and manipulations of the dopaminergic system, and clinical populations with dysregulated dopaminergic activity. Combined, studies suggest a functional differentiation between striatal and prefrontal dopamine: moderate (but not low or high) levels of striatal dopamine benefit creative cognition by facilitating flexible processes, and moderate (but not low or high) levels of prefrontal dopamine enable persistence-driven creativity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Reduced functional connectivity of fronto-parietal sustained attention networks in severe childhood abuse

    PubMed Central

    Mehta, Mitul A.; Chatzieffraimidou, Antonia; Curtis, Charles; Xu, Xiaohui; Breen, Gerome; Simmons, Andrew; Mirza, Kah; Rubia, Katya

    2017-01-01

    Childhood maltreatment is associated with attention deficits. We examined the effect of childhood abuse and abuse-by-gene (5-HTTLPR, MAOA, FKBP5) interaction on functional brain connectivity during sustained attention in medication/drug-free adolescents. Functional connectivity was compared, using generalised psychophysiological interaction (gPPI) analysis of functional magnetic resonance imaging (fMRI) data, between 21 age-and gender-matched adolescents exposed to severe childhood abuse and 27 healthy controls, while they performed a parametrically modulated vigilance task requiring target detection with a progressively increasing load of sustained attention. Behaviourally, participants exposed to childhood abuse had increased omission errors compared to healthy controls. During the most challenging attention condition abused participants relative to controls exhibited reduced connectivity, with a left-hemispheric bias, in typical fronto-parietal attention networks, including dorsolateral, rostromedial and inferior prefrontal and inferior parietal regions. Abuse-related connectivity abnormalities were exacerbated in individuals homozygous for the risky C-allele of the single nucleotide polymorphism rs3800373 of the FK506 Binding Protein 5 (FKBP5) gene. Findings suggest that childhood abuse is associated with decreased functional connectivity in fronto-parietal attention networks and that the FKBP5 genotype moderates neurobiological vulnerability to abuse. These findings represent a first step towards the delineation of abuse-related neurofunctional connectivity abnormalities, which hopefully will facilitate the development of specific treatment strategies for victims of childhood maltreatment. PMID:29190830

  1. An fMRI investigation of the fronto-striatal learning system in women who exhibit eating disorder behaviors

    PubMed Central

    Celone, Kim A.; Thompson-Brenner, Heather; Ross, Robert S.; Pratt, Elizabeth M.; Stern, Chantal E.

    2013-01-01

    In the present study, we sought to examine whether the fronto-striatal learning system, which has been implicated in bulimia nervosa, would demonstrate altered BOLD activity during probabilistic category learning in women who met subthreshold criteria for bulimia nervosa (Sub-BN). Sub-BN, which falls within the clinical category of Eating Disorder Not Otherwise Specified (EDNOS), is comprised of individuals who demonstrate recurrent binge eating, efforts to minimize their caloric intake and caloric retention, and elevated levels of concern about shape, weight, and/or eating, but just fail to meet the diagnostic threshold for bulimia nervosa (BN). fMRI data were collected from eighteen women with subthreshold-BN (Sub-BN) and nineteen healthy control women group-matched for age, education and body mass index (MC) during the weather prediction task. Sub-BN participants demonstrated increased caudate nucleus and dorsolateral prefrontal cortex (DLPFC) activation during the learning of probabilistic categories. Though the two subject groups did not differ in behavioral performance, over the course of learning, Sub-BN participants showed a dynamic pattern of brain activity differences when compared to matched control participants. Regions implicated in episodic memory, including the medial temporal lobe (MTL), retrosplenial cortex, middle frontal gyrus, and anterior and posterior cingulate cortex showed decreased activity in the Sub-BN participants compared to MCs during early learning which was followed by increased involvement of the DLPFC during later learning. These findings demonstrate that women with Sub-BN demonstrate differences in fronto-striatal learning system activity, as well as a distinct functional pattern between fronto-striatal and MTL learning systems during the course of implicit probabilistic category learning. PMID:21419229

  2. Altered fronto-cerebellar connectivity in alcohol-naïve youth with a family history of alcoholism

    PubMed Central

    Herting, Megan M.; Fair, Damien; Nagel, Bonnie J.

    2011-01-01

    Fronto-cerebellar connections are thought to be involved in higher-order cognitive functioning. It is suspected that damage to this network may contribute to cognitive deficits in chronic alcoholics. However, it remains to be elucidated if fronto-cerebellar circuitry is altered in high-risk individuals even prior to alcohol use onset. The current study used functional connectivity MRI (fcMRI) to examine fronto-cerebellar circuitry in 13 alcohol-naïve, at-risk youth with a family history of alcoholism (FH+) and 14 age-matched controls. In addition, we examined how white matter microstructure, as evidenced by fractional anisotropy (FA) related to fcMRI. FH+ youth showed significantly reduced functional connectivity between bilateral anterior prefrontal cortices and contralateral cerebellar seed regions compared to controls. We found that this reduction in connectivity significantly correlated with reduced FA in the anterior limb of the internal capsule and the superior longitudinal fasciculus. Taken together, our findings reflect associated aberrant functional and structural connectivity in substance-naïve FH+ adolescents, perhaps suggesting an identifiable neurophenotypic precursor to substance use. Given the role of frontal and cerebellar brain regions in subserving executive functioning, the presence of premorbid abnormalities in fronto-cerebellar circuitry may heighten the risk for developing an alcohol use disorder in FH+ youth through atypical control processing. PMID:20970506

  3. Real-time parallel processing of grammatical structure in the fronto-striatal system: a recurrent network simulation study using reservoir computing.

    PubMed

    Hinaut, Xavier; Dominey, Peter Ford

    2013-01-01

    Sentence processing takes place in real-time. Previous words in the sentence can influence the processing of the current word in the timescale of hundreds of milliseconds. Recent neurophysiological studies in humans suggest that the fronto-striatal system (frontal cortex, and striatum--the major input locus of the basal ganglia) plays a crucial role in this process. The current research provides a possible explanation of how certain aspects of this real-time processing can occur, based on the dynamics of recurrent cortical networks, and plasticity in the cortico-striatal system. We simulate prefrontal area BA47 as a recurrent network that receives on-line input about word categories during sentence processing, with plastic connections between cortex and striatum. We exploit the homology between the cortico-striatal system and reservoir computing, where recurrent frontal cortical networks are the reservoir, and plastic cortico-striatal synapses are the readout. The system is trained on sentence-meaning pairs, where meaning is coded as activation in the striatum corresponding to the roles that different nouns and verbs play in the sentences. The model learns an extended set of grammatical constructions, and demonstrates the ability to generalize to novel constructions. It demonstrates how early in the sentence, a parallel set of predictions are made concerning the meaning, which are then confirmed or updated as the processing of the input sentence proceeds. It demonstrates how on-line responses to words are influenced by previous words in the sentence, and by previous sentences in the discourse, providing new insight into the neurophysiology of the P600 ERP scalp response to grammatical complexity. This demonstrates that a recurrent neural network can decode grammatical structure from sentences in real-time in order to generate a predictive representation of the meaning of the sentences. This can provide insight into the underlying mechanisms of human cortico-striatal

  4. Abnormal fronto-parietal white matter organisation in the superior longitudinal fasciculus branches in autism spectrum disorders.

    PubMed

    Fitzgerald, Jacqueline; Leemans, Alexander; Kehoe, Elizabeth; O'Hanlon, Erik; Gallagher, Louise; McGrath, Jane

    2018-03-01

    Core features of autism spectrum disorder (ASD) may be underpinned by disrupted functional and structural neural connectivity. Abnormal fronto-parietal functional connectivity has been widely reported in the literature; this may be underpinned by disrupted microstructural organisation of white matter. The superior longitudinal fasciculus (SLF) is a major fronto-parietal white matter tract, the structure of which has been little studied in ASD. The fronto-parietal projections of this tract (SLF I, II and III) are thought to play an important role in a number of cognitive functions including attention and visuospatial processing. To date, the isolation of the fronto-parietal branches of the SLF has been hampered by limitations of traditional tractography approaches. Constrained spherical deconvolution (CSD)-based tractography is an advanced approach that allows valid isolation of the fronto-parietal branches of the SLF. Diffusion MRI data were acquired from 45 participants with ASD and 45 age- and IQ-matched controls. The SLF I, II and III branches were isolated using CSD-based tractography in ExploreDTI. Significantly greater fractional anisotropy (FA) was observed in the right SLF II relative to controls. The ASD group also showed greater linear diffusion coefficient in the left SLF I and the right SLF II. In the SLF II, the ASD group had significantly greater right lateralisation of FA in comparison with the control group. The clinical and functional implications of increased FA in white matter are poorly understood; however, it is possible that this increased white matter organisation in the SLF in ASD may contribute to relative processing advantages in the condition. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  5. Stimulant treatment history predicts frontal-striatal structural connectivity in adolescents with attention-deficit/hyperactivity disorder.

    PubMed

    Schweren, L J S; Hartman, C A; Zwiers, M P; Heslenfeld, D J; Franke, B; Oosterlaan, J; Buitelaar, J K; Hoekstra, P J

    2016-04-01

    Diffusion tensor imaging (DTI) has revealed white matter abnormalities in individuals with attention-deficit/hyperactivity disorder (ADHD). Stimulant treatment may affect such abnormalities. The current study investigated associations between long-term stimulant treatment and white matter integrity within the frontal-striatal and mesolimbic pathways, in a large sample of children, adolescents and young adults with ADHD. Participants with ADHD (N=172; mean age 17, range 9-26) underwent diffusion-weighted MRI scanning, along with an age- and gendermatched group of 96 control participants. Five study-specific white matter tract masks (orbitofrontal-striatal, orbitofrontal-amygdalar, amygdalar-striatal, dorsolateral-prefrontal-striatal and medialprefrontal-striatal) were created. First we analyzed case-control differences in fractional anisotropy (FA) and mean diffusivity (MD) within each tract. Second, FA and MD in each tract was predicted from cumulative stimulant intake within the ADHD group. After correction for multiple testing, participants with ADHD showed reduced FA in the orbitofrontal-striatal pathway (p=0.010, effect size=0.269). Within the ADHD group, higher cumulative stimulant intake was associated with lower MD in the same pathway (p=0.011, effect size=-0.164), but not with FA. The association between stimulant treatment and orbitofrontal-striatal MD was of modest effect size. It fell short of significance after adding ADHD severity or ADHD type to the model (p=0.036 and p=0.094, respectively), while the effect size changed little. Our findings are compatible with stimulant treatment enhancing orbitofrontal-striatal white matter connectivity, and emphasize the importance of the orbitofrontal cortex and its connections in ADHD. Longitudinal studies including a drug-naïve baseline assessment are needed to distinguish between-subject variability in ADHD severity from treatment effects. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  6. Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

    PubMed Central

    de Leeuw, Max; Kahn, René S.; Vink, Matthijs

    2015-01-01

    Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia. PMID:25368371

  7. Real-Time Parallel Processing of Grammatical Structure in the Fronto-Striatal System: A Recurrent Network Simulation Study Using Reservoir Computing

    PubMed Central

    Hinaut, Xavier; Dominey, Peter Ford

    2013-01-01

    Sentence processing takes place in real-time. Previous words in the sentence can influence the processing of the current word in the timescale of hundreds of milliseconds. Recent neurophysiological studies in humans suggest that the fronto-striatal system (frontal cortex, and striatum – the major input locus of the basal ganglia) plays a crucial role in this process. The current research provides a possible explanation of how certain aspects of this real-time processing can occur, based on the dynamics of recurrent cortical networks, and plasticity in the cortico-striatal system. We simulate prefrontal area BA47 as a recurrent network that receives on-line input about word categories during sentence processing, with plastic connections between cortex and striatum. We exploit the homology between the cortico-striatal system and reservoir computing, where recurrent frontal cortical networks are the reservoir, and plastic cortico-striatal synapses are the readout. The system is trained on sentence-meaning pairs, where meaning is coded as activation in the striatum corresponding to the roles that different nouns and verbs play in the sentences. The model learns an extended set of grammatical constructions, and demonstrates the ability to generalize to novel constructions. It demonstrates how early in the sentence, a parallel set of predictions are made concerning the meaning, which are then confirmed or updated as the processing of the input sentence proceeds. It demonstrates how on-line responses to words are influenced by previous words in the sentence, and by previous sentences in the discourse, providing new insight into the neurophysiology of the P600 ERP scalp response to grammatical complexity. This demonstrates that a recurrent neural network can decode grammatical structure from sentences in real-time in order to generate a predictive representation of the meaning of the sentences. This can provide insight into the underlying mechanisms of human cortico-striatal

  8. Connectivity-based parcellation reveals distinct cortico-striatal connectivity fingerprints in Autism Spectrum Disorder.

    PubMed

    Balsters, Joshua H; Mantini, Dante; Wenderoth, Nicole

    2018-04-15

    Autism Spectrum Disorder (ASD) has been associated with abnormal synaptic development causing a breakdown in functional connectivity. However, when measured at the macro scale using resting state fMRI, these alterations are subtle and often difficult to detect due to the large heterogeneity of the pathology. Recently, we outlined a novel approach for generating robust biomarkers of resting state functional magnetic resonance imaging (RS-fMRI) using connectivity based parcellation of gross morphological structures to improve single-subject reproducibility and generate more robust connectivity fingerprints. Here we apply this novel approach to investigating the organization and connectivity strength of the cortico-striatal system in a large sample of ASD individuals and typically developed (TD) controls (N=130 per group). Our results showed differences in the parcellation of the striatum in ASD. Specifically, the putamen was found to be one single structure in ASD, whereas this was split into anterior and posterior segments in an age, IQ, and head movement matched TD group. An analysis of the connectivity fingerprints revealed that the group differences in clustering were driven by differential connectivity between striatum and the supplementary motor area, posterior cingulate cortex, and posterior insula. Our approach for analysing RS-fMRI in clinical populations has provided clear evidence that cortico-striatal circuits are organized differently in ASD. Based on previous task-based segmentations of the striatum, we believe that the anterior putamen cluster present in TD, but not in ASD, likely contributes to social and language processes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Increased resting state functional connectivity in the fronto-parietal and default mode network in anorexia nervosa

    PubMed Central

    Boehm, Ilka; Geisler, Daniel; King, Joseph A.; Ritschel, Franziska; Seidel, Maria; Deza Araujo, Yacila; Petermann, Juliane; Lohmeier, Heidi; Weiss, Jessika; Walter, Martin; Roessner, Veit; Ehrlich, Stefan

    2014-01-01

    The etiology of anorexia nervosa (AN) is poorly understood. Results from functional brain imaging studies investigating the neural profile of AN using cognitive and emotional task paradigms are difficult to reconcile. Task-related imaging studies often require a high level of compliance and can only partially explore the distributed nature and complexity of brain function. In this study, resting state functional connectivity imaging was used to investigate well-characterized brain networks potentially relevant to understand the neural mechanisms underlying the symptomatology and etiology of AN. Resting state functional magnetic resonance imaging data was obtained from 35 unmedicated female acute AN patients and 35 closely matched healthy controls female participants (HC) and decomposed using spatial group independent component analyses (ICA). Using validated templates, we identified components covering the fronto-parietal “control” network, the default mode network (DMN), the salience network, the visual and the sensory-motor network. Group comparison revealed an increased functional connectivity between the angular gyrus and the other parts of the fronto-parietal network in patients with AN in comparison to HC. Connectivity of the angular gyrus was positively associated with self-reported persistence in HC. In the DMN, AN patients also showed an increased functional connectivity strength in the anterior insula in comparison to HC. Anterior insula connectivity was associated with self-reported problems with interoceptive awareness. This study, with one of the largest sample to date, shows that acute AN is associated with abnormal brain connectivity in two major resting state networks (RSN). The finding of an increased functional connectivity in the fronto-parietal network adds novel support for the notion of AN as a disorder of excessive cognitive control, whereas the elevated functional connectivity of the anterior insula with the DMN may reflect the high

  10. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I.

    PubMed

    Harting, Inga; Neumaier-Probst, Eva; Seitz, Angelika; Maier, Esther M; Assmann, Birgit; Baric, Ivo; Troncoso, Monica; Mühlhausen, Chris; Zschocke, Johannes; Boy, Nikolas P S; Hoffmann, Georg F; Garbade, Sven F; Kölker, Stefan

    2009-07-01

    In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises--in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities

  11. Impulsive-antisocial dimension of psychopathy linked to enlargement and abnormal functional connectivity of the striatum.

    PubMed

    Korponay, Cole; Pujara, Maia; Deming, Philip; Philippi, Carissa; Decety, Jean; Kosson, David S; Kiehl, Kent A; Koenigs, Michael

    2017-03-01

    Psychopathy is a mental health disorder characterized by callous and impulsive antisocial behavior, and is associated with a high incidence of violent crime, substance abuse, and recidivism. Recent studies suggest that the striatum may be a key component of the neurobiological basis for the disorder, though structural findings have been mixed and functional connectivity of the striatum in psychopathy has yet to be fully examined. We performed a multimodal neuroimaging study of striatum volume and functional connectivity in psychopathy, using a large sample of adult male prison inmates ( N =124). We conducted volumetric analyses in striatal subnuclei, and subsequently assessed resting-state functional connectivity in areas where volume was related to psychopathy severity. Total PCL-R and Factor 2 scores (which index the impulsive/antisocial traits of psychopathy) were associated with larger striatal subnuclei volumes and increased volume in focal areas throughout the striatum, particularly in the nucleus accumbens and putamen bilaterally. Furthermore, at many of the striatal areas where volume was positively associated with Factor 2 scores, psychopathy severity was also associated with abnormal functional connectivity with other brain regions, including dorsolateral prefrontal cortex, ventral midbrain and other areas of the striatum. The results were not attributable to age, race, IQ, substance use history, or intracranial volume. These findings associate the impulsive/antisocial dimension of psychopathy with enlarged striatal subnuclei and aberrant functional connectivity between the striatum and other brain regions. Furthermore, the co-localization of volumetric and functional connectivity findings suggests that these neural abnormalities may be pathophysiologically linked.

  12. Impulsive-antisocial dimension of psychopathy linked to enlargement and abnormal functional connectivity of the striatum

    PubMed Central

    Korponay, Cole; Pujara, Maia; Deming, Philip; Philippi, Carissa; Decety, Jean; Kosson, David S.; Kiehl, Kent A.; Koenigs, Michael

    2016-01-01

    Background Psychopathy is a mental health disorder characterized by callous and impulsive antisocial behavior, and is associated with a high incidence of violent crime, substance abuse, and recidivism. Recent studies suggest that the striatum may be a key component of the neurobiological basis for the disorder, though structural findings have been mixed and functional connectivity of the striatum in psychopathy has yet to be fully examined. Methods We performed a multimodal neuroimaging study of striatum volume and functional connectivity in psychopathy, using a large sample of adult male prison inmates (N=124). We conducted volumetric analyses in striatal subnuclei, and subsequently assessed resting-state functional connectivity in areas where volume was related to psychopathy severity. Results Total PCL-R and Factor 2 scores (which index the impulsive/antisocial traits of psychopathy) were associated with larger striatal subnuclei volumes and increased volume in focal areas throughout the striatum, particularly in the nucleus accumbens and putamen bilaterally. Furthermore, at many of the striatal areas where volume was positively associated with Factor 2 scores, psychopathy severity was also associated with abnormal functional connectivity with other brain regions, including dorsolateral prefrontal cortex, ventral midbrain and other areas of the striatum. The results were not attributable to age, race, IQ, substance use history, or intracranial volume. Conclusion These findings associate the impulsive/antisocial dimension of psychopathy with enlarged striatal subnuclei and aberrant functional connectivity between the striatum and other brain regions. Furthermore, the co-localization of volumetric and functional connectivity findings suggests that these neural abnormalities may be pathophysiologically linked. PMID:28367514

  13. Cocaine addiction is associated with abnormal prefrontal function, increased striatal connectivity and sensitivity to monetary incentives, and decreased connectivity outside the human reward circuit.

    PubMed

    Vaquero, Lucía; Cámara, Estela; Sampedro, Frederic; Pérez de Los Cobos, José; Batlle, Francesca; Fabregas, Josep Maria; Sales, Joan Artur; Cervantes, Mercè; Ferrer, Xavier; Lazcano, Gerardo; Rodríguez-Fornells, Antoni; Riba, Jordi

    2017-05-01

    Cocaine addiction has been associated with increased sensitivity of the human reward circuit to drug-related stimuli. However, the capacity of non-drug incentives to engage this network is poorly understood. Here, we characterized the functional sensitivity to monetary incentives and the structural integrity of the human reward circuit in abstinent cocaine-dependent (CD) patients and their matched controls. We assessed the BOLD response to monetary gains and losses in 30 CD patients and 30 healthy controls performing a lottery task in a magnetic resonance imaging scanner. We measured brain gray matter volume (GMV) using voxel-based morphometry and white matter microstructure using voxel-based fractional anisotropy (FA). Functional data showed that, after monetary incentives, CD patients exhibited higher activation in the ventral striatum than controls. Furthermore, we observed an inverted BOLD response pattern in the prefrontal cortex, with activity being highest after unexpected high gains and lowest after losses. Patients showed increased GMV in the caudate and the orbitofrontal cortex, increased white matter FA in the orbito-striatal pathway but decreased FA in antero-posterior association bundles. Abnormal activation in the prefrontal cortex correlated with GMV and FA increases in the orbitofrontal cortex. While functional abnormalities in the ventral striatum were inversely correlated with abstinence duration, structural alterations were not. In conclusion, results suggest abnormal incentive processing in CD patients with high salience for rewards and punishments in subcortical structures but diminished prefrontal control after adverse outcomes. They further suggest that hypertrophy and hyper-connectivity within the reward circuit, to the expense of connectivity outside this network, characterize cocaine addiction. © 2016 Society for the Study of Addiction.

  14. Cortical connectivity in fronto-temporal focal epilepsy from EEG analysis: A study via graph theory.

    PubMed

    Vecchio, Fabrizio; Miraglia, Francesca; Curcio, Giuseppe; Della Marca, Giacomo; Vollono, Catello; Mazzucchi, Edoardo; Bramanti, Placido; Rossini, Paolo Maria

    2015-06-01

    It is believed that effective connectivity and optimal network structure are essential for proper information processing in the brain. Indeed, functional abnormalities of the brain are found to be associated with pathological changes in connectivity and network structures. The aim of the present study was to explore the interictal network properties of EEG signals from temporal lobe structures in the context of fronto-temporal lobe epilepsy. To complete this aim, the graph characteristics of the EEG data of 17 patients suffering from focal epilepsy of the fronto-temporal type, recorded during interictal periods, were examined and compared in terms of the affected versus the unaffected hemispheres. EEG connectivity analysis was performed using eLORETA software in 15 fronto-temporal regions (Brodmann Areas BAs 8, 9, 10, 11, 20, 21, 22, 37, 38, 41, 42, 44, 45, 46, 47) on both affected and unaffected hemispheres. The evaluation of the graph analysis parameters, such as 'global' (characteristic path length) and 'local' connectivity (clustering coefficient) showed a statistically significant interaction among side (affected and unaffected hemisphere) and Band (delta, theta, alpha, beta, gamma). Duncan post hoc testing showed an increase of the path length in the alpha band in the affected hemisphere with respect to the unaffected one, as evaluated by an inter-hemispheric marker. The affected hemisphere also showed higher values of local connectivity in the alpha band. In general, an increase of local and global graph theory parameters in the alpha band was found in the affected hemisphere. It was also demonstrated that these effects were more evident in drug-free patients than in those undergoing pharmacological therapy. The increased measures in the affected hemisphere of both functional local segregation and global integration could result from the combination of overlapping mechanisms, including reactive neuroplastic changes seeking to maintain constant integration

  15. Developmental Alterations of Frontal-Striatal-Thalamic Connectivity in Obsessive-Compulsive Disorder

    ERIC Educational Resources Information Center

    Fitzgerald, Kate Dimond; Welsh, Robert C.; Stern, Emily R.; Angstadt, Mike; Hanna, Gregory L.; Abelson, James L.; Taylor, Stephan F.

    2011-01-01

    Objective: Pediatric obsessive-compulsive disorder is characterized by abnormalities of frontal-striatal-thalamic circuitry that appear near illness onset and persist over its course. Distinct frontal-striatal-thalamic loops through cortical centers for cognitive control (anterior cingulate cortex) and emotion processing (ventral medial frontal…

  16. Segregated Fronto-Cerebellar Circuits Revealed by Intrinsic Functional Connectivity

    PubMed Central

    Buckner, Randy L.

    2009-01-01

    Multiple, segregated fronto-cerebellar circuits have been characterized in nonhuman primates using transneuronal tracing techniques including those that target prefrontal areas. Here, we used functional connectivity MRI (fcMRI) in humans (n = 40) to identify 4 topographically distinct fronto-cerebellar circuits that target 1) motor cortex, 2) dorsolateral prefrontal cortex, 3) medial prefrontal cortex, and 4) anterior prefrontal cortex. All 4 circuits were replicated and dissociated in an independent data set (n = 40). Direct comparison of right- and left-seeded frontal regions revealed contralateral lateralization in the cerebellum for each of the segregated circuits. The presence of circuits that involve prefrontal regions confirms that the cerebellum participates in networks important to cognition including a specific fronto-cerebellar circuit that interacts with the default network. Overall, the extent of the cerebellum associated with prefrontal cortex included a large portion of the posterior hemispheres consistent with a prominent role of the cerebellum in nonmotor functions. We conclude by providing a provisional map of the topography of the cerebellum based on functional correlations with the frontal cortex. PMID:19592571

  17. Fronto-temporal connectivity predicts cognitive empathy deficits and experiential negative symptoms in schizophrenia.

    PubMed

    Abram, Samantha V; Wisner, Krista M; Fox, Jaclyn M; Barch, Deanna M; Wang, Lei; Csernansky, John G; MacDonald, Angus W; Smith, Matthew J

    2017-03-01

    Impaired cognitive empathy is a core social cognitive deficit in schizophrenia associated with negative symptoms and social functioning. Cognitive empathy and negative symptoms have also been linked to medial prefrontal and temporal brain networks. While shared behavioral and neural underpinnings are suspected for cognitive empathy and negative symptoms, research is needed to test these hypotheses. In two studies, we evaluated whether resting-state functional connectivity between data-driven networks, or components (referred to as, inter-component connectivity), predicted cognitive empathy and experiential and expressive negative symptoms in schizophrenia subjects. Study 1: We examined associations between cognitive empathy and medial prefrontal and temporal inter-component connectivity at rest using a group-matched schizophrenia and control sample. We then assessed whether inter-component connectivity metrics associated with cognitive empathy were also related to negative symptoms. Study 2: We sought to replicate the connectivity-symptom associations observed in Study 1 using an independent schizophrenia sample. Study 1 results revealed that while the groups did not differ in average inter-component connectivity, a medial-fronto-temporal metric and an orbito-fronto-temporal metric were related to cognitive empathy. Moreover, the medial-fronto-temporal metric was associated with experiential negative symptoms in both schizophrenia samples. These findings support recent models that link social cognition and negative symptoms in schizophrenia. Hum Brain Mapp 38:1111-1124, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. L-Dopa Modulates Functional Connectivity in Striatal Cognitive and Motor Networks: A Double-Blind Placebo-Controlled Study

    PubMed Central

    Kelly, Clare; de Zubicaray, Greig; Di Martino, Adriana; Copland, David A.; Reiss, Philip T.; Klein, Donald F.; Castellanos, F. Xavier; Milham, Michael P.; McMahon, Katie

    2010-01-01

    Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 healthy young adults. We examined the FC of 6 striatal regions-of-interest previously shown to elicit networks known to be associated with motivational, cognitive and motor subdivisions of the caudate and putamen (Di Martino et al., Cerebral Cortex, 2008). In addition to replicating the previously demonstrated patterns of striatal FC, we observed robust effects of L-dopa. Specifically, L-dopa increased FC in motor pathways connecting the putamen ROIs with the cerebellum and brainstem. While L-dopa also increased FC between the inferior ventral striatum and ventrolateral prefrontal cortex, it disrupted ventral striatal and dorsal caudate FC with the default mode network. These alterations in FC are consistent with studies that have demonstrated dopaminergic modulation of cognitive and motor striatal networks in healthy participants. Recent studies have demonstrated altered resting state FC in several conditions believed to be characterized by abnormal dopaminergic neurotransmission. Our findings suggest that the application of similar experimental pharmacological manipulations in such populations may further our understanding of the role of dopaminergic neurotransmission in those conditions. PMID:19494158

  19. Neural alterations of fronto-striatal circuitry during reward anticipation in euthymic bipolar disorder.

    PubMed

    Schreiter, S; Spengler, S; Willert, A; Mohnke, S; Herold, D; Erk, S; Romanczuk-Seiferth, N; Quinlivan, E; Hindi-Attar, C; Banzhaf, C; Wackerhagen, C; Romund, L; Garbusow, M; Stamm, T; Heinz, A; Walter, H; Bermpohl, F

    2016-11-01

    Bipolar disorder (BD), with the hallmark symptoms of elevated and depressed mood, is thought to be characterized by underlying alterations in reward-processing networks. However, to date the neural circuitry underlying abnormal responses during reward processing in BD remains largely unexplored. The aim of this study was to investigate whether euthymic BD is characterized by aberrant ventral striatal (VS) activation patterns and altered connectivity with the prefrontal cortex in response to monetary gains and losses. During functional magnetic resonance imaging 20 euthymic BD patients and 20 age-, gender- and intelligence quotient-matched healthy controls completed a monetary incentive delay paradigm, to examine neural processing of reward and loss anticipation. A priori defined regions of interest (ROIs) included the VS and the anterior prefrontal cortex (aPFC). Psychophysiological interactions (PPIs) between these ROIs were estimated and tested for group differences for reward and loss anticipation separately. BD participants, relative to healthy controls, displayed decreased activation selectively in the left and right VS during anticipation of reward, but not during loss anticipation. PPI analyses showed decreased functional connectivity between the left VS and aPFC in BD patients compared with healthy controls during reward anticipation. This is the first study showing decreased VS activity and aberrant connectivity in the reward-processing circuitry in euthymic, medicated BD patients during reward anticipation. Our findings contrast with research supporting a reward hypersensitivity model of BD, and add to the body of literature suggesting that blunted activation of reward processing circuits may be a vulnerability factor for mood disorders.

  20. Fronto-limbic effective connectivity as possible predictor of antidepressant response to SSRI administration.

    PubMed

    Vai, Benedetta; Bulgarelli, Chiara; Godlewska, Beata R; Cowen, Philip J; Benedetti, Francesco; Harmer, Catherine J

    2016-12-01

    The timely selection of the optimal treatment for depressed patients is critical to improve remission rates. The detection of pre-treatment variables able to predict differential treatment response may provide novel approaches for treatment selection. Selective serotonin reuptake inhibitors (SSRIs) modulate the fronto-limbic functional response and connectivity, an effect preceding the overt clinical antidepressant effects. Here we investigated whether the cortico-limbic connectivity associated with emotional bias measured before SSRI administration predicts the efficacy of antidepressant treatment in MDD patients. fMRI and Dynamic Causal Modeling (DCM) were combined to study if effective connectivity might differentiate healthy controls (HC) and patients affected by major depression who later responded (RMDD, n=21), or failed to respond (nRMDD, n=12), to 6 weeks of escitalopram administration. Sixteen DCMs exploring connectivity between anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), Amygdala (Amy), and fusiform gyrus (FG) were constructed. Analyses revealed that nRMDD had reduced endogenous connectivity from Amy to VLPFC and to ACC, with an increased connectivity and modulation of the ACC to Amy connectivity when processing of fearful emotional stimuli compared to HC. RMDD and HC did not significantly differ among themselves. Pre-treatment effective connectivity in fronto-limbic circuitry could be an important factor affecting antidepressant response, and highlight the mechanisms which may be involved in recovery from depression. These results suggest that fronto-limbic connectivity might provide a neural biomarker to predict the clinical outcome to SSRIs administration in major depression. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  1. Normative development of ventral striatal resting state connectivity in humans.

    PubMed

    Fareri, Dominic S; Gabard-Durnam, Laurel; Goff, Bonnie; Flannery, Jessica; Gee, Dylan G; Lumian, Daniel S; Caldera, Christina; Tottenham, Nim

    2015-09-01

    Incentives play a crucial role in guiding behavior throughout our lives, but perhaps no more so than during the early years of life. The ventral striatum is a critical piece of an incentive-based learning circuit, sharing robust anatomical connections with subcortical (e.g., amygdala, hippocampus) and cortical structures (e.g., medial prefrontal cortex (mPFC), insula) that collectively support incentive valuation and learning. Resting-state functional connectivity (rsFC) is a powerful method that provides insight into the development of the functional architecture of these connections involved in incentive-based learning. We employed a seed-based correlation approach to investigate ventral striatal rsFC in a cross-sectional sample of typically developing individuals between the ages of 4.5 and 23-years old (n=66). Ventral striatal rsFC with the mPFC showed regionally specific linear age-related changes in connectivity that were associated with age-related increases in circulating testosterone levels. Further, ventral striatal connectivity with the posterior hippocampus and posterior insula demonstrated quadratic age-related changes characterized by negative connectivity in adolescence. Finally, across this age range, the ventral striatum demonstrated positive coupling with the amygdala beginning during childhood and remaining consistently positive across age. In sum, our findings suggest that normative ventral striatal rsFC development is dynamic and characterized by early establishment of connectivity with medial prefrontal and limbic structures supporting incentive-based learning, as well as substantial functional reorganization with later developing regions during transitions into and out of adolescence. Copyright © 2015. Published by Elsevier Inc.

  2. Parkinsonism is associated to fronto-caudate disconnectivity and cognition in schizophrenia.

    PubMed

    Molina, Vicente; Lubeiro, Alba; Blanco, Jorge; Blanco, José A; Rodríguez, Margarita; Rodríguez-Campos, Alicia; de Luis-García, Rodrigo

    2018-07-30

    The present work studies the possible relation of parkinsonism and fronto-caudate dysconnectivity, as well as its relation to cognition in schizophrenia patients. We assessed parkinsonism using Simpson-Angus scale and prefronto-caudate connectivity using diffusion magnetic resonance in 22 schizophrenia patients (11 first-episodes) and 14 healthy controls. Fractional anisotropy was calculated for the white matter tracts directly linking rostral middle prefrontal (RMPF) and superior medial prefrontal (SMPF) regions with caudate nucleus. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia Scale (BACS). Total parkinsonism scores were negatively related to fractional anisotropy in the right SMPF-caudate tract in patients, which was also found in the first-episode patients alone, but not in controls. Parkinsonism was also inversely associated in patients to performance in social cognition, verbal memory, working memory and performance speed tests. In conclusion, our data support the involvement of fronto-striatal dysconnectivity in parkinsonism in schizophrenia. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Reductions in Cortico-Striatal Hyperconnectivity Accompany Successful Treatment of Obsessive-Compulsive Disorder with Dorsomedial Prefrontal rTMS

    PubMed Central

    Dunlop, Katharine; Woodside, Blake; Olmsted, Marion; Colton, Patricia; Giacobbe, Peter; Downar, Jonathan

    2016-01-01

    Obsessive-compulsive disorder (OCD) is a disabling illness with high rates of nonresponse to conventional treatments. OCD pathophysiology is believed to involve abnormalities in cortico-striatal-thalamic-cortical circuits through regions such as dorsomedial prefrontal cortex (dmPFC) and ventral striatum. These regions may constitute therapeutic targets for neuromodulation treatments, such as repetitive transcranial magnetic stimulation (rTMS). However, the neurobiological predictors and correlates of successful rTMS treatment for OCD are unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) to identify neural predictors and correlates of response to 20–30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls as baseline comparators. A region of interest in the dmPFC was used to generate whole-brain functional connectivity maps pre-treatment and post treatment. Ten of 20 patients met the response criteria (⩾50% improvement on Yale-Brown Obsessive-Compulsive Scale, YBOCS); response to dmPFC-rTMS was sharply bimodal. dmPFC-rTMS responders had higher dmPFC-ventral striatal connectivity at baseline. The degree of reduction in this connectivity, from pre- to post-treatment, correlated to the degree of YBOCS symptomatic improvement. Baseline clinical and psychometric data did not predict treatment response. In summary, reductions in fronto-striatal hyperconnectivity were associated with treatment response to dmPFC-rTMS in OCD. This finding is consistent with previous fMRI studies of deep brain stimulation in OCD, but opposite to previous reports on mechanisms of dmPFC-rTMS in major depression. fMRI could prove useful in predicting the response to dmPFC-rTMS in OCD. PMID:26440813

  4. Reductions in Cortico-Striatal Hyperconnectivity Accompany Successful Treatment of Obsessive-Compulsive Disorder with Dorsomedial Prefrontal rTMS.

    PubMed

    Dunlop, Katharine; Woodside, Blake; Olmsted, Marion; Colton, Patricia; Giacobbe, Peter; Downar, Jonathan

    2016-04-01

    Obsessive-compulsive disorder (OCD) is a disabling illness with high rates of nonresponse to conventional treatments. OCD pathophysiology is believed to involve abnormalities in cortico-striatal-thalamic-cortical circuits through regions such as dorsomedial prefrontal cortex (dmPFC) and ventral striatum. These regions may constitute therapeutic targets for neuromodulation treatments, such as repetitive transcranial magnetic stimulation (rTMS). However, the neurobiological predictors and correlates of successful rTMS treatment for OCD are unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) to identify neural predictors and correlates of response to 20-30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls as baseline comparators. A region of interest in the dmPFC was used to generate whole-brain functional connectivity maps pre-treatment and post treatment. Ten of 20 patients met the response criteria (⩾50% improvement on Yale-Brown Obsessive-Compulsive Scale, YBOCS); response to dmPFC-rTMS was sharply bimodal. dmPFC-rTMS responders had higher dmPFC-ventral striatal connectivity at baseline. The degree of reduction in this connectivity, from pre- to post-treatment, correlated to the degree of YBOCS symptomatic improvement. Baseline clinical and psychometric data did not predict treatment response. In summary, reductions in fronto-striatal hyperconnectivity were associated with treatment response to dmPFC-rTMS in OCD. This finding is consistent with previous fMRI studies of deep brain stimulation in OCD, but opposite to previous reports on mechanisms of dmPFC-rTMS in major depression. fMRI could prove useful in predicting the response to dmPFC-rTMS in OCD.

  5. Abnormal brain structure implicated in stimulant drug addiction.

    PubMed

    Ersche, Karen D; Jones, P Simon; Williams, Guy B; Turton, Abigail J; Robbins, Trevor W; Bullmore, Edward T

    2012-02-03

    Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual's health and social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.

  6. Early Math Achievement and Functional Connectivity in the Fronto-Parietal Network

    PubMed Central

    Emerson, Robert W.; Cantlon, Jessica F.

    2011-01-01

    In this study we test the hypothesis that the functional connectivity of the frontal and parietal regions that children recruit during a basic numerical task (matching Arabic numerals to arrays of dots) is predictive of their math test scores (TEMA-3; Ginsburg 2003). Specifically, we tested 4- to 11-year-old children on a matching task during fMRI to localize a fronto-parietal network that responds more strongly during numerical matching than matching faces, words, or shapes. We then tested the functional connectivity between those regions during an independent task: natural viewing of an educational video that included math topics. Using this novel natural viewing method, we found that the connectivity between frontal and parietal regions during task-independent free-viewing of educational material is correlated with children's basic number matching ability, as well as their scores on the standardized test of mathematical ability (the TEMA). The correlation between children's mathematics scores and fronto-parietal connectivity is math-specific in the sense that it is independent of children's verbal IQ scores. Moreover, a control network, selective for faces, showed no correlation with mathematics performance. Finally, brain regions that correlate with subjects’ overall response times in the matching task do not account for our number- and math-related effects. We suggest that the functional intersection of number-related frontal and parietal regions is math-specific. PMID:22682903

  7. Inferior fronto-temporo-occipital connectivity: a missing link between maltreated girls and neglectful mothers

    PubMed Central

    León, Inmaculada; Góngora, Daylin; Hernández-Cabrera, Juan A.; Byrne, Sonia; Bobes, María A.

    2016-01-01

    The neurobiological alterations resulting from adverse childhood experiences that subsequently may lead to neglectful mothering are poorly understood. Maternal neglect of an infant’s basic needs is the most prevalent type of child maltreatment. We tested white matter alterations in neglectful mothers, the majority of whom had also suffered maltreatment in their childhood, and compared them to a matched control group. The two groups were discriminated by a structural brain connectivity pattern comprising inferior fronto-temporo-occipital connectivity, which constitutes a major portion of the face-processing network and was indexed by fewer streamlines in neglectful mothers. Mediation and regression analyses showed that fewer streamlines in the right inferior longitudinal fasciculus tract (ILF-R) predicted a poorer quality of mother–child emotional availability observed during cooperative play and that effect depended on the respective interactions with left and right inferior fronto-occipital fasciculi (IFO-R/L), with no significant impact of psychopathological and cognitive conditions. Volume alteration in ILF-R but not in IFO-L modulated the impact of having been maltreated on emotional availability. The findings suggest the altered inferior fronto-temporal-occipital connectivity, affecting emotional visual processing, as a possible common neurological substrate linking a history of childhood maltreatment with maternal neglect. PMID:27342834

  8. Striatal connectivity changes following gambling wins and near-misses: Associations with gambling severity.

    PubMed

    van Holst, Ruth J; Chase, Henry W; Clark, Luke

    2014-01-01

    Frontostriatal circuitry is implicated in the cognitive distortions associated with gambling behaviour. 'Near-miss' events, where unsuccessful outcomes are proximal to a jackpot win, recruit overlapping neural circuitry with actual monetary wins. Personal control over a gamble (e.g., via choice) is also known to increase confidence in one's chances of winning (the 'illusion of control'). Using psychophysiological interaction (PPI) analyses, we examined changes in functional connectivity as regular gamblers and non-gambling participants played a slot-machine game that delivered wins, near-misses and full-misses, and manipulated personal control. We focussed on connectivity with striatal seed regions, and associations with gambling severity, using voxel-wise regression. For the interaction term of near-misses (versus full-misses) by personal choice (participant-chosen versus computer-chosen), ventral striatal connectivity with the insula, bilaterally, was positively correlated with gambling severity. In addition, some effects for the contrast of wins compared to all non-wins were observed at an uncorrected (p < .001) threshold: there was an overall increase in connectivity between the striatal seeds and left orbitofrontal cortex and posterior insula, and a negative correlation for gambling severity with the connectivity between the right ventral striatal seed and left anterior cingulate cortex. These findings corroborate the 'non-categorical' nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling.

  9. Sex differences in effective fronto-limbic connectivity during negative emotion processing.

    PubMed

    Lungu, Ovidiu; Potvin, Stéphane; Tikàsz, Andràs; Mendrek, Adrianna

    2015-12-01

    In view of the greater prevalence of depression and anxiety disorders in women than in men, functional magnetic resonance imaging (fMRI) studies have examined sex-differences in brain activations during emotion processing. Comparatively, sex-differences in brain connectivity received little attention, despite evidence for important fronto-limbic connections during emotion processing across sexes. Here, we investigated sex-differences in fronto-limbic connectivity during negative emotion processing. Forty-six healthy individuals (25 women, 21 men) viewed negative, positive and neutral images during an fMRI session. Effective connectivity between significantly activated regions was examined using Granger causality and psychophysical interaction analyses. Sex steroid hormones and feminine-masculine traits were also measured. Subjective ratings of negative emotional images were higher in women than in men. Across sexes, significant activations were observed in the dorso-medial prefrontal cortex (dmPFC) and the right amygdala. Granger connectivity from right amygdala was significantly greater than that from dmPFC during the 'high negative' condition, an effect driven by men. Magnitude of this effect correlated negatively with highly negative image ratings and feminine traits and positively with testosterone levels. These results highlight critical sex differences in brain connectivity during negative emotion processing and point to the fact that both biological (sex steroid hormones) and psychosocial (gender role and identity) variables contribute to them. As the dmPFC is involved in social cognition and action planning, and the amygdala-in threat detection, the connectivity results suggest that compared to women, men have a more evaluative, rather than purely affective, brain response during negative emotion processing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. The BACHD Rat Model of Huntington Disease Shows Signs of Fronto-Striatal Dysfunction in Two Operant Conditioning Tests of Short-Term Memory.

    PubMed

    Clemensson, Erik Karl Håkan; Clemensson, Laura Emily; Riess, Olaf; Nguyen, Huu Phuc

    2017-01-01

    The BACHD rat is a recently developed transgenic animal model of Huntington disease, a progressive neurodegenerative disorder characterized by extensive loss of striatal neurons. Cognitive impairments are common among patients, and characterization of similar deficits in animal models of the disease is therefore of interest. The present study assessed the BACHD rats' performance in the delayed alternation and the delayed non-matching to position test, two Skinner box-based tests of short-term memory function. The transgenic rats showed impaired performance in both tests, indicating general problems with handling basic aspects of the tests, while short-term memory appeared to be intact. Similar phenotypes have been found in rats with fronto-striatal lesions, suggesting that Huntington disease-related neuropathology might be present in the BACHD rats. Further analyses indicated that the performance deficit in the delayed alternation test might be due to impaired inhibitory control, which has also been implicated in Huntington disease patients. The study ultimately suggests that the BACHD rats might suffer from neuropathology and cognitive impairments reminiscent of those of Huntington disease patients.

  11. Abnormal Superior Temporal Connectivity During Fear Perception in Schizophrenia

    PubMed Central

    Leitman, David I.; Loughead, James; Wolf, Daniel H.; Ruparel, Kosha; Kohler, Christian G.; Elliott, Mark A.; Bilker, Warren B.; Gur, Raquel E.; Gur, Ruben C.

    2008-01-01

    Patients with schizophrenia have difficulty in decoding facial affect. A study using event–related functional neuroimaging indicated that errors in fear detection in schizophrenia are associated with paradoxically higher activation in the amygdala and an associated network implicated in threat detection. Furthermore, this exaggerated activation to fearful faces correlated with severity of flat affect. These findings suggest that abnormal threat detection processing may reflect disruptions between nodes that comprise the affective appraisal circuit. Here we examined connectivity within this network by determining the pattern of intercorrelations among brain regions (regions of interest) significantly activated during fear identification in both healthy controls and patients using a novel procedure CORANOVA. This analysis tests differences in the interregional correlation strength between schizophrenia and healthy controls. Healthy subjects' task activation was principally characterized by robust correlations between medial structures like thalamus (THA) and amygdala (AMY) and middle frontal (MF), inferior frontal (IF), and prefrontal cortical (PFC) regions. In contrast, schizophrenia patients displayed no significant correlations between the medial regions and either MF or IF. Further, patients had significantly higher correlations between occipital lingual gyrus and superior temporal gyrus than healthy subjects. These between-group connectivity differences suggest that schizophrenia threat detection impairment may stem from abnormal stimulus integration. Such abnormal integration may disrupt the evaluation of threat within fronto-cortical regions. PMID:18550592

  12. Abnormal brain activation during working memory in children with prenatal exposure to drugs of abuse: the effects of methamphetamine, alcohol, and polydrug exposure.

    PubMed

    Roussotte, Florence F; Bramen, Jennifer E; Nunez, S Christopher; Quandt, Lorna C; Smith, Lynne; O'Connor, Mary J; Bookheimer, Susan Y; Sowell, Elizabeth R

    2011-02-14

    Structural and metabolic abnormalities in fronto-striatal structures have been reported in children with prenatal methamphetamine (MA) exposure. The current study was designed to quantify functional alterations to the fronto-striatal circuit in children with prenatal MA exposure using functional magnetic resonance imaging (fMRI). Because many women who use MA during pregnancy also use alcohol, a known teratogen, we examined 50 children (age range 7-15), 19 with prenatal MA exposure, 15 of whom had concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but no MA exposure (ALC group), and 18 unexposed controls (CON group). We hypothesized that MA exposed children would demonstrate abnormal brain activation during a visuospatial working memory (WM) "N-Back" task. As predicted, the MAA group showed less activation than the CON group in many brain areas, including the striatum and frontal lobe in the left hemisphere. The ALC group showed less activation than the MAA group in several regions, including the right striatum. We found an inverse correlation between performance and activity in the striatum in both the CON and MAA groups. However, this relationship was significant in the caudate of the CON group but not the MAA group, and in the putamen of the MAA group but not the CON group. These findings suggest that structural damage in the fronto-striatal circuit after prenatal MA exposure leads to decreased recruitment of this circuit during a WM challenge, and raise the possibility that a rewiring of cortico-striatal networks may occur in children with prenatal MA exposure. Copyright © 2010 Elsevier Inc. All rights reserved.

  13. Striatal connectivity changes following gambling wins and near-misses: Associations with gambling severity

    PubMed Central

    van Holst, Ruth J.; Chase, Henry W.; Clark, Luke

    2014-01-01

    Frontostriatal circuitry is implicated in the cognitive distortions associated with gambling behaviour. ‘Near-miss’ events, where unsuccessful outcomes are proximal to a jackpot win, recruit overlapping neural circuitry with actual monetary wins. Personal control over a gamble (e.g., via choice) is also known to increase confidence in one's chances of winning (the ‘illusion of control’). Using psychophysiological interaction (PPI) analyses, we examined changes in functional connectivity as regular gamblers and non-gambling participants played a slot-machine game that delivered wins, near-misses and full-misses, and manipulated personal control. We focussed on connectivity with striatal seed regions, and associations with gambling severity, using voxel-wise regression. For the interaction term of near-misses (versus full-misses) by personal choice (participant-chosen versus computer-chosen), ventral striatal connectivity with the insula, bilaterally, was positively correlated with gambling severity. In addition, some effects for the contrast of wins compared to all non-wins were observed at an uncorrected (p < .001) threshold: there was an overall increase in connectivity between the striatal seeds and left orbitofrontal cortex and posterior insula, and a negative correlation for gambling severity with the connectivity between the right ventral striatal seed and left anterior cingulate cortex. These findings corroborate the ‘non-categorical’ nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling. PMID:25068112

  14. The extended fronto-striatal model of obsessive compulsive disorder: convergence from event-related potentials, neuropsychology and neuroimaging

    PubMed Central

    Melloni, Margherita; Urbistondo, Claudia; Sedeño, Lucas; Gelormini, Carlos; Kichic, Rafael; Ibanez, Agustin

    2012-01-01

    In this work, we explored convergent evidence supporting the fronto-striatal model of obsessive-compulsive disorder (FSMOCD) and the contribution of event-related potential (ERP) studies to this model. First, we considered minor modifications to the FSMOCD model based on neuroimaging and neuropsychological data. We noted the brain areas most affected in this disorder -anterior cingulate cortex (ACC), basal ganglia (BG), and orbito-frontal cortex (OFC) and their related cognitive functions, such as monitoring and inhibition. Then, we assessed the ERPs that are directly related to the FSMOCD, including the error-related negativity (ERN), N200, and P600. Several OCD studies present enhanced ERN and N2 responses during conflict tasks as well as an enhanced P600 during working memory (WM) tasks. Evidence from ERP studies (especially regarding ERN and N200 amplitude enhancement), neuroimaging and neuropsychological findings suggests abnormal activity in the OFC, ACC, and BG in OCD patients. Moreover, additional findings from these analyses suggest dorsolateral prefrontal and parietal cortex involvement, which might be related to executive function (EF) deficits. Thus, these convergent results suggest the existence of a self-monitoring imbalance involving inhibitory deficits and executive dysfunctions. OCD patients present an impaired ability to monitor, control, and inhibit intrusive thoughts, urges, feelings, and behaviors. In the current model, this imbalance is triggered by an excitatory role of the BG (associated with cognitive or motor actions without volitional control) and inhibitory activity of the OFC as well as excessive monitoring of the ACC to block excitatory impulses. This imbalance would interact with the reduced activation of the parietal-DLPC network, leading to executive dysfunction. ERP research may provide further insight regarding the temporal dynamics of action monitoring and executive functioning in OCD. PMID:23015786

  15. Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: Link to impulsivity in methamphetamine users

    PubMed Central

    Kohno, Milky; Okita, Kyoji; Morales, Angelica M.; Robertson, Chelsea; Dean, Andy C.; Ghahremani, Dara G.; Sabb, Fred; Mandelkern, Mark A.; Bilder, Robert M.; London, Edythe D.

    2015-01-01

    Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC), and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between midbrain and striatum, orbitofrontal cortex, and insula in methamphetamine-dependent participants but a positive relationship in the control group. In Study 2, an interaction of group with RSFC on impulsivity was observed. Methamphetamine-dependent participants users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals. PMID:26830141

  16. Anticipation-related brain connectivity in bipolar and unipolar depression: a graph theory approach

    PubMed Central

    Almeida, Jorge R. C.; Stiffler, Richelle; Lockovich, Jeanette C.; Aslam, Haris A.; Phillips, Mary L.

    2016-01-01

    that loss anticipation was characterized by denser top-down fronto-striatal and fronto-parietal connectivity in healthy control subjects, by bottom-up striatal-frontal connectivity in MDD, and by sparse connectivity lacking fronto-striatal connections in BDD. Win anticipation was characterized by dense connectivity of medial frontal with striatal and lateral frontal cortical regions in BDD, by sparser bottom-up striatum-medial frontal cortex connectivity in MDD, and by sparse connectivity in healthy control subjects. In summary, this is the first study to demonstrate that BDD and MDD with comparable levels of current depression differed from each other and healthy control subjects in density of connections, connectivity path length, and connectivity direction as a function of win or loss anticipation. These findings suggest that different neurobiological mechanisms may underlie aberrant anticipation processes in BDD and MDD, and that distinct therapeutic strategies may be required for these individuals to improve coping strategies during expectation of positive and negative outcomes. PMID:27368345

  17. Abnormal prefrontal cortex resting state functional connectivity and severity of internet gaming disorder.

    PubMed

    Jin, Chenwang; Zhang, Ting; Cai, Chenxi; Bi, Yanzhi; Li, Yangding; Yu, Dahua; Zhang, Ming; Yuan, Kai

    2016-09-01

    Internet Gaming Disorder (IGD) among adolescents has become an important public concern and gained more and more attention internationally. Recent studies focused on IGD and revealed brain abnormalities in the IGD group, especially the prefrontal cortex (PFC). However, the role of PFC-striatal circuits in pathology of IGD remains unknown. Twenty-five adolescents with IGD and 21 age- and gender-matched healthy controls were recruited in our study. Voxel-based morphometric (VBM) and functional connectivity analysis were employed to investigate the abnormal structural and resting-state properties of several frontal regions in individuals with online gaming addiction. Relative to healthy comparison subjects, IGD subjects showed significant decreased gray matter volume in PFC regions including the bilateral dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and the right supplementary motor area (SMA) after controlling for age and gender effects. We chose these regions as the seeding areas for the resting-state analysis and found that IGD subjects showed decreased functional connectivity between several cortical regions and our seeds, including the insula, and temporal and occipital cortices. Moreover, significant decreased functional connectivity between some important subcortical regions, i.e., dorsal striatum, pallidum, and thalamus, and our seeds were found in the IGD group and some of those changes were associated with the severity of IGD. Our results revealed the involvement of several PFC regions and related PFC-striatal circuits in the process of IGD and suggested IGD may share similar neural mechanisms with substance dependence at the circuit level.

  18. Distinct fronto-striatal couplings reveal the double-faced nature of response-outcome relations in instruction-based learning.

    PubMed

    Ruge, Hannes; Wolfensteller, Uta

    2015-06-01

    Higher species commonly learn novel behaviors by evaluating retrospectively whether actions have yielded desirable outcomes. By relying on explicit behavioral instructions, only humans can use an acquisition shortcut that prospectively specifies how to yield intended outcomes under the appropriate stimulus conditions. A recent and largely unexplored hypothesis suggests that striatal areas interact with lateral prefrontal cortex (LPFC) when novel behaviors are learned via explicit instruction, and that regional subspecialization exists for the integration of differential response-outcome contingencies into the current task model. Behaviorally, outcome integration during instruction-based learning has been linked to functionally distinct performance indices. This includes (1) compatibility effects, measured in a postlearning test procedure probing the encoding strength of outcome-response (O-R) associations, and (2) increasing response slowing across learning, putatively indicating active usage of O-R associations for the online control of goal-directed action. In the present fMRI study, we examined correlations between these behavioral indices and the dynamics of fronto-striatal couplings in order to mutually constrain and refine the interpretation of neural and behavioral measures in terms of separable subprocesses during outcome integration. We found that O-R encoding strength correlated with LPFC-putamen coupling, suggesting that the putamen is relevant for the formation of both S-R habits and habit-like O-R associations. By contrast, response slowing as a putative index of active usage of O-R associations correlated with LPFC-caudate coupling. This finding highlights the relevance of the caudate for the online control of goal-directed action also under instruction-based learning conditions, and in turn clarifies the functional relevance of the behavioral slowing effect.

  19. Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons

    PubMed Central

    Pappas, Samuel S; Darr, Katherine; Holley, Sandra M; Cepeda, Carlos; Mabrouk, Omar S; Wong, Jenny-Marie T; LeWitt, Tessa M; Paudel, Reema; Houlden, Henry; Kennedy, Robert T; Levine, Michael S; Dauer, William T

    2015-01-01

    Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model. DOI: http://dx.doi.org/10.7554/eLife.08352.001 PMID:26052670

  20. A neurobehavioral examination of individuals with high-functioning autism and Asperger's disorder using a fronto-striatal model of dysfunction.

    PubMed

    Rinehart, Nicole J; Bradshaw, John L; Tonge, Bruce J; Brereton, Avril V; Bellgrove, Mark A

    2002-06-01

    The repetitive, stereotyped, and obsessive behaviors that characterize autism may in part be attributable to disruption of the region of the fronto-striatal system, which mediates executive abilities. Neuropsychological testing has shown that children with autism exhibit set-shifting deficiencies on tests such as the Wisconsin Card Sorting task but show normal inhibitory ability on variants of the Stroop color-word test. According to Minshew and Goldstein's multiple primary deficit theory, the complexity of the executive functioning task is important in determining the performance of individuals with autism. This study employed a visual-spatial task (with a Stroop-type component) to examine the integrity of executive functioning, in particular inhibition, in autism (n = 12) and Asperger's disorder (n = 12) under increasing levels of cognitive complexity. Whereas the Asperger's disorder group performed similarly to age- and IQ-matched control participants, even at the higher levels of cognitive complexity, the high-functioning autism group displayed inhibitory deficits specifically associated with increasing cognitive load.

  1. Abnormal Connectional Fingerprint in Schizophrenia: A Novel Network Analysis of Diffusion Tensor Imaging Data.

    PubMed

    Edwin Thanarajah, Sharmili; Han, Cheol E; Rotarska-Jagiela, Anna; Singer, Wolf; Deichmann, Ralf; Maurer, Konrad; Kaiser, Marcus; Uhlhaas, Peter J

    2016-01-01

    The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal-frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder.

  2. Anticipation-related brain connectivity in bipolar and unipolar depression: a graph theory approach.

    PubMed

    Manelis, Anna; Almeida, Jorge R C; Stiffler, Richelle; Lockovich, Jeanette C; Aslam, Haris A; Phillips, Mary L

    2016-09-01

    loss anticipation was characterized by denser top-down fronto-striatal and fronto-parietal connectivity in healthy control subjects, by bottom-up striatal-frontal connectivity in MDD, and by sparse connectivity lacking fronto-striatal connections in BDD. Win anticipation was characterized by dense connectivity of medial frontal with striatal and lateral frontal cortical regions in BDD, by sparser bottom-up striatum-medial frontal cortex connectivity in MDD, and by sparse connectivity in healthy control subjects. In summary, this is the first study to demonstrate that BDD and MDD with comparable levels of current depression differed from each other and healthy control subjects in density of connections, connectivity path length, and connectivity direction as a function of win or loss anticipation. These findings suggest that different neurobiological mechanisms may underlie aberrant anticipation processes in BDD and MDD, and that distinct therapeutic strategies may be required for these individuals to improve coping strategies during expectation of positive and negative outcomes. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Activating Developmental Reserve Capacity Via Cognitive Training or Non-invasive Brain Stimulation: Potentials for Promoting Fronto-Parietal and Hippocampal-Striatal Network Functions in Old Age

    PubMed Central

    Passow, Susanne; Thurm, Franka; Li, Shu-Chen

    2017-01-01

    Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate

  4. Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia.

    PubMed

    Simonyan, Kristina; Berman, Brian D; Herscovitch, Peter; Hallett, Mark

    2013-09-11

    Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.

  5. Abnormal Striatal Dopaminergic Neurotransmission during Rest and Task Production in Spasmodic Dysphonia

    PubMed Central

    Berman, Brian D.; Herscovitch, Peter; Hallett, Mark

    2013-01-01

    Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia–thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [11C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder. PMID:24027271

  6. Convergent evidence for abnormal striatal synaptic plasticity in dystonia

    PubMed Central

    Peterson, David A.; Sejnowski, Terrence J.; Poizner, Howard

    2010-01-01

    Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor “use” may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes

  7. Retinotopic patterns of background connectivity between V1 and fronto-parietal cortex are modulated by task demands

    PubMed Central

    Griffis, Joseph C.; Elkhetali, Abdurahman S.; Burge, Wesley K.; Chen, Richard H.; Visscher, Kristina M.

    2015-01-01

    Attention facilitates the processing of task-relevant visual information and suppresses interference from task-irrelevant information. Modulations of neural activity in visual cortex depend on attention, and likely result from signals originating in fronto-parietal and cingulo-opercular regions of cortex. Here, we tested the hypothesis that attentional facilitation of visual processing is accomplished in part by changes in how brain networks involved in attentional control interact with sectors of V1 that represent different retinal eccentricities. We measured the strength of background connectivity between fronto-parietal and cingulo-opercular regions with different eccentricity sectors in V1 using functional MRI data that were collected while participants performed tasks involving attention to either a centrally presented visual stimulus or a simultaneously presented auditory stimulus. We found that when the visual stimulus was attended, background connectivity between V1 and the left frontal eye fields (FEF), left intraparietal sulcus (IPS), and right IPS varied strongly across different eccentricity sectors in V1 so that foveal sectors were more strongly connected than peripheral sectors. This retinotopic gradient was weaker when the visual stimulus was ignored, indicating that it was driven by attentional effects. Greater task-driven differences between foveal and peripheral sectors in background connectivity to these regions were associated with better performance on the visual task and faster response times on correct trials. These findings are consistent with the notion that attention drives the configuration of task-specific functional pathways that enable the prioritized processing of task-relevant visual information, and show that the prioritization of visual information by attentional processes may be encoded in the retinotopic gradient of connectivty between V1 and fronto-parietal regions. PMID:26106320

  8. Origin and Properties of Striatal Local Field Potential Responses to Cortical Stimulation: Temporal Regulation by Fast Inhibitory Connections

    PubMed Central

    Galiñanes, Gregorio L.; Braz, Barbara Y.; Murer, Mario Gustavo

    2011-01-01

    Evoked striatal field potentials are seldom used to study corticostriatal communication in vivo because little is known about their origin and significance. Here we show that striatal field responses evoked by stimulating the prelimbic cortex in mice are reduced by more than 90% after infusing the AMPA receptor antagonist CNQX close to the recording electrode. Moreover, the amplitude of local field responses and dPSPs recorded in striatal medium spiny neurons increase in parallel with increasing stimulating current intensity. Finally, the evoked striatal fields show several of the basic known properties of corticostriatal transmission, including paired pulse facilitation and topographical organization. As a case study, we characterized the effect of local GABAA receptor blockade on striatal field and multiunitary action potential responses to prelimbic cortex stimulation. Striatal activity was recorded through a 24 channel silicon probe at about 600 µm from a microdialysis probe. Intrastriatal administration of the GABAA receptor antagonist bicuculline increased by 65±7% the duration of the evoked field responses. Moreover, the associated action potential responses were markedly enhanced during bicuculline infusion. Bicuculline enhancement took place at all the striatal sites that showed a response to cortical stimulation before drug infusion, but sites showing no field response before bicuculline remained unresponsive during GABAA receptor blockade. Thus, the data demonstrate that fast inhibitory connections exert a marked temporal regulation of input-output transformations within spatially delimited striatal networks responding to a cortical input. Overall, we propose that evoked striatal fields may be a useful tool to study corticostriatal synaptic connectivity in relation to behavior. PMID:22163020

  9. Abnormal fronto-limbic engagement in incarcerated stimulant users during moral processing.

    PubMed

    Fede, Samantha J; Harenski, Carla L; Schaich Borg, Jana; Sinnott-Armstrong, Walter; Rao, Vikram; Caldwell, Brendan M; Nyalakanti, Prashanth K; Koenigs, Michael R; Decety, Jean; Calhoun, Vince D; Kiehl, Kent A

    2016-09-01

    Stimulant use is a significant and prevalent problem, particularly in criminal populations. Previous studies found that cocaine and methamphetamine use is related to impairment in identifying emotions and empathy. Stimulant users also have abnormal neural structure and function of the ventromedial prefrontal cortex (vmPFC), amygdala, and anterior (ACC) and posterior cingulate (PCC), regions implicated in moral decision-making. However, no research has studied the neural correlates of stimulant use and explicit moral processing in an incarcerated population. Here, we examine how stimulant use affects sociomoral processing that might contribute to antisocial behavior. We predicted that vmPFC, amygdala, PCC, and ACC would show abnormal neural response during a moral processing task in incarcerated methamphetamine and cocaine users. Incarcerated adult males (N = 211) were scanned with a mobile MRI system while completing a moral decision-making task. Lifetime drug use was assessed. Neural responses during moral processing were compared between users and non-users. The relationship between duration of use and neural function was also examined. Incarcerated stimulant users showed less amygdala engagement than non-users during moral processing. Duration of stimulant use was negatively associated with activity in ACC and positively associated with vmPFC response during moral processing. These results suggest a dynamic pattern of fronto-limbic moral processing related to stimulant use with deficits in both central motive and cognitive integration elements of biological moral processes theory. This increases our understanding of how drug use relates to moral processing in the brain in an ultra-high-risk population.

  10. Reduced Activation in Lateral Prefrontal Cortex and Anterior Cingulate during Attention and Cognitive Control Functions in Medication-Naive Adolescents with Depression Compared to Controls

    ERIC Educational Resources Information Center

    Halari, Rozmin; Simic, Mima; Pariante, Carmine M.; Papadopoulos, Andrew; Cleare, Anthony; Brammer, Michael; Fombonne, Eric; Rubia, Katya

    2009-01-01

    Background: There is increasing recognition of major depressive disorder (MDD) in adolescence. In adult MDD, abnormalities of fronto-striatal and fronto-cingulate circuitries mediating cognitive control functions have been implicated in the pathogenesis and been related to problems with controlling negative thoughts. No neuroimaging studies of…

  11. Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling

    PubMed Central

    Lee, Yeunkum; Kim, Sun Gyun; Lee, Bokyoung; Zhang, Yinhua; Kim, Yoonhee; Kim, Shinhyun; Kim, Eunjoon; Kang, Hyojin; Han, Kihoon

    2017-01-01

    Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD). Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream regulators of mTORC1

  12. Motor and cortico-striatal-thalamic connectivity alterations in intrauterine growth restriction.

    PubMed

    Eixarch, Elisenda; Muñoz-Moreno, Emma; Bargallo, Nuria; Batalle, Dafnis; Gratacos, Eduard

    2016-06-01

    .409 ± 0.046; P = .016) in both networks were observed in the intrauterine growth restriction group, with no differences in number of streamlines. More importantly, strong specific correlation was found between tractography-related metrics and its relative function in both networks in intrauterine growth restricted children. Motor network metrics were correlated specifically with motor scale results (fractional anisotropy: rho = 0.857; integrity: rho = 0.740); cortico-striatal-thalamic network metrics were correlated with cognitive (fractional anisotropy: rho = 0.793; integrity, rho = 0.762) and socioemotional scale (fractional anisotropy: rho = 0.850; integrity: rho = 0.877). These results support the existence of altered brain connectivity in intrauterine growth restriction demonstrated by altered connectivity in motor and cortico-striatal-thalamic networks, with reduced fractional anisotropy and integrity. The specific correlation between tractography-related metrics and neurodevelopmental outcomes in intrauterine growth restriction shows the potential to use this approach to develop imaging biomarkers to predict specific neurodevelopmental outcome in infants who are at risk because of intrauterine growth restriction and other prenatal diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

    PubMed Central

    Peça, João; Feliciano, Cátia; Ting, Jonathan T.; Wang, Wenting; Wells, Michael F.; Venkatraman, Talaignair N.; Lascola, Christopher D.; Fu, Zhanyan; Feng, Guoping

    2011-01-01

    Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice. PMID:21423165

  14. Abnormal interhemispheric connectivity in male psychopathic offenders.

    PubMed

    Hoppenbrouwers, Sylco S; De Jesus, Danilo R; Sun, Yinming; Stirpe, Tania; Hofman, Dennis; McMaster, Jeff; Hughes, Ginny; Daskalakis, Zafiris J; Schutter, Dennis J L G

    2014-01-01

    Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders.

  15. Striatal changes in Parkinson disease: An investigation of morphology, functional connectivity and their relationship to clinical symptoms.

    PubMed

    Owens-Walton, Conor; Jakabek, David; Li, Xiaozhen; Wilkes, Fiona A; Walterfang, Mark; Velakoulis, Dennis; van Westen, Danielle; Looi, Jeffrey C L; Hansson, Oskar

    2018-05-30

    We sought to investigate morphological and resting state functional connectivity changes to the striatal nuclei in Parkinson disease (PD) and examine whether changes were associated with measures of clinical function. Striatal nuclei were manually segmented on 3T-T1 weighted MRI scans of 74 PD participants and 27 control subjects, quantitatively analysed for volume, shape and also functional connectivity using functional MRI data. Bilateral caudate nuclei and putamen volumes were significantly reduced in the PD cohort compared to controls. When looking at left and right hemispheres, the PD cohort had significantly smaller left caudate nucleus and right putamen volumes compared to controls. A significant correlation was found between greater atrophy of the caudate nucleus and poorer cognitive function, and between greater atrophy of the putamen and more severe motor symptoms. Resting-state functional MRI analysis revealed altered functional connectivity of the striatal structures in the PD group. This research demonstrates that PD involves atrophic changes to the caudate nucleus and putamen that are linked to clinical dysfunction. Our work reveals important information about a key structure-function relationship in the brain and provides support for caudate nucleus and putamen atrophy as neuroimaging biomeasures in PD. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Noradrenaline transporter blockade increases fronto-parietal functional connectivity relevant for working memory.

    PubMed

    Hernaus, Dennis; Casales Santa, Marta Ma; Offermann, Jan Stefan; Van Amelsvoort, Thérèse

    2017-04-01

    Experimental animal work has demonstrated that dopamine and noradrenaline play an essential role in modulating prefrontal cortex-mediated networks underlying working memory performance. Studies of functional connectivity have been instrumental in extending such notions to humans but, so far, have almost exclusively focussed on pharmacological agents with a predominant dopaminergic mechanism of action. Here, we investigate the effect of a single dose of atomoxetine 60mg, a noradrenaline transporter inhibitor, on working memory performance and associated functional connectivity during an n-back task in 19 healthy male volunteers. Atomoxetine increased functional connectivity between right anterior insula and dorsolateral prefrontal cortex, precentral gyrus, posterior parietal cortex and precuneus during the high-working memory load condition of the n-back task. Increased atomoxetine-induced insula-dorsolateral prefrontal cortex functional connectivity during this condition correlated with decreased reaction time variability and was furthermore predicted by working memory capacity. These results show for the first time that noradrenaline transporter blockade-induced increases in cortical catecholamines accentuate fronto-parietal working memory-related network integrity. The observation of significant inter-subject variability in response to atomoxetine has implications for inverted-U frameworks of dopamine and noradrenaline function, which could be useful to predict drug effects in clinical disorders with variable treatment response. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  17. Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

    PubMed Central

    Bhattacharyya, Sagnik; Falkenberg, Irina; Martin-Santos, Rocio; Atakan, Zerrin; Crippa, Jose A; Giampietro, Vincent; Brammer, Mick; McGuire, Philip

    2015-01-01

    There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli. PMID:25249057

  18. Cannabinoid modulation of functional connectivity within regions processing attentional salience.

    PubMed

    Bhattacharyya, Sagnik; Falkenberg, Irina; Martin-Santos, Rocio; Atakan, Zerrin; Crippa, Jose A; Giampietro, Vincent; Brammer, Mick; McGuire, Philip

    2015-05-01

    There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli.

  19. Brain Events Underlying Episodic Memory Changes in Aging: A Longitudinal Investigation of Structural and Functional Connectivity.

    PubMed

    Fjell, Anders M; Sneve, Markus H; Storsve, Andreas B; Grydeland, Håkon; Yendiki, Anastasia; Walhovd, Kristine B

    2016-03-01

    Episodic memories are established and maintained by close interplay between hippocampus and other cortical regions, but degradation of a fronto-striatal network has been suggested to be a driving force of memory decline in aging. We wanted to directly address how changes in hippocampal-cortical versus striatal-cortical networks over time impact episodic memory with age. We followed 119 healthy participants (20-83 years) for 3.5 years with repeated tests of episodic verbal memory and magnetic resonance imaging for quantification of functional and structural connectivity and regional brain atrophy. While hippocampal-cortical functional connectivity predicted memory change in young, changes in cortico-striatal functional connectivity were related to change in recall in older adults. Within each age group, effects of functional and structural connectivity were anatomically closely aligned. Interestingly, the relationship between functional connectivity and memory was strongest in the age ranges where the rate of reduction of the relevant brain structure was lowest, implying selective impacts of the different brain events on memory. Together, these findings suggest a partly sequential and partly simultaneous model of brain events underlying cognitive changes in aging, where different functional and structural events are more or less important in various time windows, dismissing a simple uni-factorial view on neurocognitive aging. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Abnormal interhemispheric connectivity in male psychopathic offenders

    PubMed Central

    Hoppenbrouwers, Sylco S.; De Jesus, Danilo R.; Sun, Yinming; Stirpe, Tania; Hofman, Dennis; McMaster, Jeff; Hughes, Ginny; Daskalakis, Zafiris J.; Schutter, Dennis J.L.G.

    2014-01-01

    Background Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. Methods We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. Results We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. Limitations The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. Conclusion To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders. PMID:23937798

  1. Motor tics evoked by striatal disinhibition in the rat

    PubMed Central

    Bronfeld, Maya; Yael, Dorin; Belelovsky, Katya; Bar-Gad, Izhar

    2013-01-01

    Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS). Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure—the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons' collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration, and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1–4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders. PMID:24065893

  2. Novelty modulates human striatal activation and prefrontal-striatal effective connectivity during working memory encoding.

    PubMed

    Geiger, Lena S; Moessnang, Carolin; Schäfer, Axel; Zang, Zhenxiang; Zangl, Maria; Cao, Hengyi; van Raalten, Tamar R; Meyer-Lindenberg, Andreas; Tost, Heike

    2018-05-11

    The functional role of the basal ganglia (BG) in the gating of suitable motor responses to the cortex is well established. Growing evidence supports an analogous role of the BG during working memory encoding, a task phase in which the "input-gating" of relevant materials (or filtering of irrelevant information) is an important mechanism supporting cognitive capacity and the updating of working memory buffers. One important aspect of stimulus relevance is the novelty of working memory items, a quality that is understudied with respect to its effects on corticostriatal function and connectivity. To this end, we used functional magnetic resonance imaging (fMRI) in 74 healthy volunteers performing an established Sternberg working memory task with different task phases (encoding vs. retrieval) and degrees of stimulus familiarity (novel vs. previously trained). Activation analyses demonstrated a highly significant engagement of the anterior striatum, in particular during the encoding of novel working memory items. Dynamic causal modeling (DCM) of corticostriatal circuit connectivity identified a selective positive modulatory influence of novelty encoding on the connection from the dorsolateral prefrontal cortex (DLPFC) to the anterior striatum. These data extend prior research by further underscoring the relevance of the BG for human cognitive function and provide a mechanistic account of the DLPFC as a plausible top-down regulatory element of striatal function that may facilitate the "input-gating" of novel working memory materials.

  3. Cell Assembly Dynamics of Sparsely-Connected Inhibitory Networks: A Simple Model for the Collective Activity of Striatal Projection Neurons.

    PubMed

    Angulo-Garcia, David; Berke, Joshua D; Torcini, Alessandro

    2016-02-01

    Striatal projection neurons form a sparsely-connected inhibitory network, and this arrangement may be essential for the appropriate temporal organization of behavior. Here we show that a simplified, sparse inhibitory network of Leaky-Integrate-and-Fire neurons can reproduce some key features of striatal population activity, as observed in brain slices. In particular we develop a new metric to determine the conditions under which sparse inhibitory networks form anti-correlated cell assemblies with time-varying activity of individual cells. We find that under these conditions the network displays an input-specific sequence of cell assembly switching, that effectively discriminates similar inputs. Our results support the proposal that GABAergic connections between striatal projection neurons allow stimulus-selective, temporally-extended sequential activation of cell assemblies. Furthermore, we help to show how altered intrastriatal GABAergic signaling may produce aberrant network-level information processing in disorders such as Parkinson's and Huntington's diseases.

  4. The mouse cortico-striatal projectome

    PubMed Central

    Hintiryan, Houri; Foster, Nicholas N.; Bowman, Ian; Bay, Maxwell; Song, Monica Y.; Gou, Lin; Yamashita, Seita; Bienkowski, Michael S.; Zingg, Brian; Zhu, Muye; Yang, X. William; Shih, Jean C.; Toga, Arthur W.; Dong, Hong-Wei

    2017-01-01

    Different cortical areas are organized into distinct intra-cortical subnetworks. How descending pathways from the entire cortex interact subcortically as a network remains unclear. Here, we report an open-access comprehensive mesoscale cortico-striatal projectome—a detailed connectivity projection map from the entire cerebral cortex to the dorsal striatum or caudoputamen (CP) in rodents. Based on these projections, we use novel computational neuroanatomical tools to identify 29 distinct functional striatal domains. Further, we characterize different cortico-striatal networks and how they reconfigure across the rostral-caudal extent of the CP. The workflow was also applied to select cortico-striatal connections in two different mouse models of disconnection syndromes to demonstrate its utility in characterizing circuitry-specific connectopathies. Together, this work provides the structural basis for studying the functional diversity of the dorsal striatum and disruptions of cortico-basal ganglia networks across a broad range of disorders. PMID:27322419

  5. Ventral striatal network connectivity reflects reward learning and behavior in patients with Parkinson's disease.

    PubMed

    Petersen, Kalen; Van Wouwe, Nelleke; Stark, Adam; Lin, Ya-Chen; Kang, Hakmook; Trujillo-Diaz, Paula; Kessler, Robert; Zald, David; Donahue, Manus J; Claassen, Daniel O

    2018-01-01

    A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward-driven behaviors, which can result in life-altering morbidity. The mesocorticolimbic dopamine network guides reward-motivated behavior; however, its role in this treatment-related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward-learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD-fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex-matched PD patients with (n = 19) or without (n = 18) ICB. An incentive-based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole-brain voxelwise analyses and region-of-interest-based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala-to-midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum-to-subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment-avoidance learning. These data indicate that PD-ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward-based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509-521, 2018. © 2017

  6. Regional vulnerability of longitudinal cortical association connectivity: Associated with structural network topology alterations in preterm children with cerebral palsy.

    PubMed

    Ceschin, Rafael; Lee, Vince K; Schmithorst, Vince; Panigrahy, Ashok

    2015-01-01

    Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior-anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior-anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal-thalamic-striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with

  7. Abnormalities of functional brain networks in pathological gambling: a graph-theoretical approach

    PubMed Central

    Tschernegg, Melanie; Crone, Julia S.; Eigenberger, Tina; Schwartenbeck, Philipp; Fauth-Bühler, Mira; Lemènager, Tagrid; Mann, Karl; Thon, Natasha; Wurst, Friedrich M.; Kronbichler, Martin

    2013-01-01

    Functional neuroimaging studies of pathological gambling (PG) demonstrate alterations in frontal and subcortical regions of the mesolimbic reward system. However, most investigations were performed using tasks involving reward processing or executive functions. Little is known about brain network abnormalities during task-free resting state in PG. In the present study, graph-theoretical methods were used to investigate network properties of resting state functional magnetic resonance imaging data in PG. We compared 19 patients with PG to 19 healthy controls (HCs) using the Graph Analysis Toolbox (GAT). None of the examined global metrics differed between groups. At the nodal level, pathological gambler showed a reduced clustering coefficient in the left paracingulate cortex and the left juxtapositional lobe (supplementary motor area, SMA), reduced local efficiency in the left SMA, as well as an increased node betweenness for the left and right paracingulate cortex and the left SMA. At an uncorrected threshold level, the node betweenness in the left inferior frontal gyrus was decreased and increased in the caudate. Additionally, increased functional connectivity between fronto-striatal regions and within frontal regions has also been found for the gambling patients. These findings suggest that regions associated with the reward system demonstrate reduced segregation but enhanced integration while regions associated with executive functions demonstrate reduced integration. The present study makes evident that PG is also associated with abnormalities in the topological network structure of the brain during rest. Since alterations in PG cannot be explained by direct effects of abused substances on the brain, these findings will be of relevance for understanding functional connectivity in other addictive disorders. PMID:24098282

  8. Functional brain imaging across development.

    PubMed

    Rubia, Katya

    2013-12-01

    The developmental cognitive neuroscience literature has grown exponentially over the last decade. This paper reviews the functional magnetic resonance imaging (fMRI) literature on brain function development of typically late developing functions of cognitive and motivation control, timing and attention as well as of resting state neural networks. Evidence shows that between childhood and adulthood, concomitant with cognitive maturation, there is progressively increased functional activation in task-relevant lateral and medial frontal, striatal and parieto-temporal brain regions that mediate these higher level control functions. This is accompanied by progressively stronger functional inter-regional connectivity within task-relevant fronto-striatal and fronto-parieto-temporal networks. Negative age associations are observed in earlier developing posterior and limbic regions, suggesting a shift with age from the recruitment of "bottom-up" processing regions towards "top-down" fronto-cortical and fronto-subcortical connections, leading to a more mature, supervised cognition. The resting state fMRI literature further complements this evidence by showing progressively stronger deactivation with age in anti-correlated task-negative resting state networks, which is associated with better task performance. Furthermore, connectivity analyses during the resting state show that with development increasingly stronger long-range connections are being formed, for example, between fronto-parietal and fronto-cerebellar connections, in both task-positive networks and in task-negative default mode networks, together with progressively lesser short-range connections, suggesting progressive functional integration and segregation with age. Overall, evidence suggests that throughout development between childhood and adulthood, there is progressive refinement and integration of both task-positive fronto-cortical and fronto-subcortical activation and task-negative deactivation, leading to

  9. Fronto-Temporal Connectivity Predicts ECT Outcome in Major Depression.

    PubMed

    Leaver, Amber M; Wade, Benjamin; Vasavada, Megha; Hellemann, Gerhard; Joshi, Shantanu H; Espinoza, Randall; Narr, Katherine L

    2018-01-01

    Electroconvulsive therapy (ECT) is arguably the most effective available treatment for severe depression. Recent studies have used MRI data to predict clinical outcome to ECT and other antidepressant therapies. One challenge facing such studies is selecting from among the many available metrics, which characterize complementary and sometimes non-overlapping aspects of brain function and connectomics. Here, we assessed the ability of aggregated, functional MRI metrics of basal brain activity and connectivity to predict antidepressant response to ECT using machine learning. A radial support vector machine was trained using arterial spin labeling (ASL) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) metrics from n = 46 (26 female, mean age 42) depressed patients prior to ECT (majority right-unilateral stimulation). Image preprocessing was applied using standard procedures, and metrics included cerebral blood flow in ASL, and regional homogeneity, fractional amplitude of low-frequency modulations, and graph theory metrics (strength, local efficiency, and clustering) in BOLD data. A 5-repeated 5-fold cross-validation procedure with nested feature-selection validated model performance. Linear regressions were applied post hoc to aid interpretation of discriminative features. The range of balanced accuracy in models performing statistically above chance was 58-68%. Here, prediction of non-responders was slightly higher than for responders (maximum performance 74 and 64%, respectively). Several features were consistently selected across cross-validation folds, mostly within frontal and temporal regions. Among these were connectivity strength among: a fronto-parietal network [including left dorsolateral prefrontal cortex (DLPFC)], motor and temporal networks (near ECT electrodes), and/or subgenual anterior cingulate cortex (sgACC). Our data indicate that pattern classification of multimodal fMRI metrics can successfully predict ECT

  10. Time Processing in Children with Tourette's Syndrome

    ERIC Educational Resources Information Center

    Vicario, Carmelo Mario; Martino, Davide; Spata, Felice; Defazio, Giovanni; Giacche, Roberta; Martino, Vito; Rappo, Gaetano; Pepi, Anna Maria; Silvestri, Paola Rosaria; Cardona, Francesco

    2010-01-01

    Background: Tourette syndrome (TS) is characterized by dysfunctional connectivity between prefrontal cortex and sub-cortical structures, and altered meso-cortical and/or meso-striatal dopamine release. Since time processing is also regulated by fronto-striatal circuits and modulated by dopaminergic transmission, we hypothesized that time…

  11. Diminished fronto-striatal activity during processing of monetary rewards and losses in pathological gambling

    PubMed Central

    Balodis, Iris M.; Kober, Hedy; Worhunsky, Patrick D.; Stevens, Michael C.; Pearlson, Godfrey D.; Potenza, Marc N.

    2012-01-01

    Background Mesocorticolimbic neurocircuitry and impulsivity have both been implicated in pathological gambling (PG) and in reward processing. However, the neural underpinnings of specific phases of reward and loss processing in PG and their relationships to impulsivity remain only partially understood. The present functional magnetic resonance imaging study examined brain activity associated with different phases of reward and loss processing in PG. Given an inverse relationship between ventral striatal recruitment during anticipation of monetary rewards and impulsivity in alcohol dependence, the current study explored whether a similar association might also be present in PG. Methods Fourteen adults with PG and 14 control comparison (CC) participants performed the Monetary Incentive Delay Task (MIDT) to identify brain activation changes associated with reward/loss prospect, reward/loss anticipation and reward/loss notification. Impulsivity was assessed separately using the Barratt Impulsiveness Scale. Results Relative to the CC group, the PG group exhibited significantly reduced activity in the ventromedial prefrontal cortex, insula and ventral striatum during several phases, including the prospect and anticipation phases of both gain and losses. Activity in the ventral striatum correlated inversely with levels of impulsivity in PG participants, consistent with prior findings in alcohol dependence. Conclusions Relatively decreased activity in cortico-striatal neurocircuitry during multiple phases of reward processing suggests consistent alterations in neurocircuitry underlying incentive valuation and loss prediction. Together with findings in alcohol dependence, these results suggest that impulsive tendencies in addictions may be reflected in diminished ventral striatal activations to reward anticipation and may represent targets for treatment development in addictions. PMID:22336565

  12. Striatal Circuits as a Common Node for Autism Pathophysiology

    PubMed Central

    Fuccillo, Marc V.

    2016-01-01

    Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains—deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD

  13. Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.

    PubMed

    Wang, Xiaoming; Bey, Alexandra L; Katz, Brittany M; Badea, Alexandra; Kim, Namsoo; David, Lisa K; Duffney, Lara J; Kumar, Sunil; Mague, Stephen D; Hulbert, Samuel W; Dutta, Nisha; Hayrapetyan, Volodya; Yu, Chunxiu; Gaidis, Erin; Zhao, Shengli; Ding, Jin-Dong; Xu, Qiong; Chung, Leeyup; Rodriguiz, Ramona M; Wang, Fan; Weinberg, Richard J; Wetsel, William C; Dzirasa, Kafui; Yin, Henry; Jiang, Yong-Hui

    2016-05-10

    Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Δe4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.

  14. Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism

    PubMed Central

    Wang, Xiaoming; Bey, Alexandra L.; Katz, Brittany M.; Badea, Alexandra; Kim, Namsoo; David, Lisa K.; Duffney, Lara J.; Kumar, Sunil; Mague, Stephen D.; Hulbert, Samuel W.; Dutta, Nisha; Hayrapetyan, Volodya; Yu, Chunxiu; Gaidis, Erin; Zhao, Shengli; Ding, Jin-Dong; Xu, Qiong; Chung, Leeyup; Rodriguiz, Ramona M.; Wang, Fan; Weinberg, Richard J.; Wetsel, William C.; Dzirasa, Kafui; Yin, Henry; Jiang, Yong-hui

    2016-01-01

    Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22−/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs. PMID:27161151

  15. Dynamic Changes of Striatal and Extrastriatal Abnormalities in Glutaric Aciduria Type I

    ERIC Educational Resources Information Center

    Harting, Inga; Neumaier-Probst, Eva; Seitz, Angelika; Maier, Esther M.; Assmann, Birgit; Baric, Ivo; Troncoso, Monica; Muhlhausen, Chris; Zschocke, Johannes; Boy, Nikolas P. S.; Hoffmann, Georg F.; Garbade, Sven F.; Kolker, Stefan

    2009-01-01

    In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as…

  16. Cortico-striatal language pathways dynamically adjust for syntactic complexity: A computational study.

    PubMed

    Szalisznyó, Krisztina; Silverstein, David; Teichmann, Marc; Duffau, Hugues; Smits, Anja

    2017-01-01

    A growing body of literature supports a key role of fronto-striatal circuits in language perception. It is now known that the striatum plays a role in engaging attentional resources and linguistic rule computation while also serving phonological short-term memory capabilities. The ventral semantic and the dorsal phonological stream dichotomy assumed for spoken language processing also seems to play a role in cortico-striatal perception. Based on recent studies that correlate deep Broca-striatal pathways with complex syntax performance, we used a previously developed computational model of frontal-striatal syntax circuits and hypothesized that different parallel language pathways may contribute to canonical and non-canonical sentence comprehension separately. We modified and further analyzed a thematic role assignment task and corresponding reservoir computing model of language circuits, as previously developed by Dominey and coworkers. We examined the models performance under various parameter regimes, by influencing how fast the presented language input decays and altering the temporal dynamics of activated word representations. This enabled us to quantify canonical and non-canonical sentence comprehension abilities. The modeling results suggest that separate cortico-cortical and cortico-striatal circuits may be recruited differently for processing syntactically more difficult and less complicated sentences. Alternatively, a single circuit would need to dynamically and adaptively adjust to syntactic complexity. Copyright © 2016. Published by Elsevier Inc.

  17. Functional neural networks underlying response inhibition in adolescents and adults.

    PubMed

    Stevens, Michael C; Kiehl, Kent A; Pearlson, Godfrey D; Calhoun, Vince D

    2007-07-19

    This study provides the first description of neural network dynamics associated with response inhibition in healthy adolescents and adults. Functional and effective connectivity analyses of whole brain hemodynamic activity elicited during performance of a Go/No-Go task were used to identify functionally integrated neural networks and characterize their causal interactions. Three response inhibition circuits formed a hierarchical, inter-dependent system wherein thalamic modulation of input to premotor cortex by fronto-striatal regions led to response suppression. Adolescents differed from adults in the degree of network engagement, regional fronto-striatal-thalamic connectivity, and network dynamics. We identify and characterize several age-related differences in the function of neural circuits that are associated with behavioral performance changes across adolescent development.

  18. Abnormal brain activation in excoriation (skin-picking) disorder: evidence from an executive planning fMRI study

    PubMed Central

    Odlaug, Brian L.; Hampshire, Adam; Chamberlain, Samuel R.; Grant, Jon E.

    2016-01-01

    Background Excoriation (skin-picking) disorder (SPD) is a relatively common psychiatric condition whose neurobiological basis is unknown. Aims To probe the function of fronto-striatal circuitry in SPD. Method Eighteen participants with SPD and 15 matched healthy controls undertook an executive planning task (Tower of London) during functional magnetic resonance imaging (fMRI). Activation during planning was compared between groups using region of interest and whole-brain permutation cluster approaches. Results The SPD group exhibited significant functional underactivation in a cluster encompassing bilateral dorsal striatum (maximal in right caudate), bilateral anterior cingulate and right medial frontal regions. These abnormalities were, for the most part, outside the dorsal planning network typically activated by executive planning tasks. Conclusions Abnormalities of neural regions involved in habit formation, action monitoring and inhibition appear involved in the pathophysiology of SPD. Implications exist for understanding the basis of excessive grooming and the relationship of SPD with putative obsessive–compulsive spectrum disorders. PMID:26159604

  19. Multimodal Neuroimaging of Fronto-limbic Structure and Function Associated with Suicide Attempts in Adolescents and Young Adults with Bipolar Disorder

    PubMed Central

    Johnston, Jennifer A. Y.; Wang, Fei; Liu, Jie; Blond, Benjamin N.; Wallace, Amanda; Liu, Jiacheng; Spencer, Linda; Cox Lippard, Elizabeth T.; Purves, Kirstin L.; Landeros-Weisenberger, Angeli; Hermes, Eric; Pittman, Brian; Zhang, Sheng; King, Robert; Martin, Andrés; Oquendo, Maria A.; Blumberg, Hilary P.

    2018-01-01

    Objective Bipolar disorder is associated with high risk for suicide behavior that often develops in adolescence/young adulthood. Elucidation of involved neural systems is critical for prevention. This study of adolescents/young adults with bipolar disorder with and without history of suicide attempts combines structural, diffusion tensor and functional magnetic resonance imaging methods to investigate implicated abnormalities in structural and functional connectivity within fronto-limbic systems. Method Participants with bipolar disorder included 26 with a prior suicide attempt and 42 without attempts. Regional gray matter volume, white matter integrity and functional connectivity during processing of emotional stimuli were compared between groups and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors. Results Compared to the non-attempter group, the attempter group showed reductions in gray matter volume in orbitofrontal cortex, hippocampus and cerebellum; white matter integrity in uncinate fasciculus, ventral frontal and right cerebellum regions; and amygdala functional connectivity to left ventral and right rostral prefrontal cortex (p<0.05, corrected). In exploratory analyses, among attempters, right rostral prefrontal connectivity was negatively correlated with suicidal ideation (p<0.05), and left ventral prefrontal connectivity was negatively correlated with attempt lethality (p<0.05). Conclusions Adolescent/young adult suicide attempters with bipolar disorder demonstrate less gray matter volume and decreased structural and functional connectivity in a ventral fronto-limbic neural system subserving emotion regulation. Among suicide attempters, reductions in amygdala-prefrontal functional connectivity may be associated with severity of suicide ideation and attempt lethality. PMID:28135845

  20. Impaired development of cortico-striatal synaptic connectivity in a cell culture model of Huntington's disease.

    PubMed

    Buren, Caodu; Parsons, Matthew P; Smith-Dijak, Amy; Raymond, Lynn A

    2016-03-01

    Huntington's disease (HD) is a genetically inherited neurodegenerative disease caused by a mutation in the gene encoding the huntingtin protein. This mutation results in progressive cell death that is particularly striking in the striatum. Recent evidence indicates that early HD is initially a disease of the synapse, in which subtle alterations in synaptic neurotransmission, particularly at the cortico-striatal (C-S) synapse, can be detected well in advance of cell death. Here, we used a cell culture model in which striatal neurons are co-cultured with cortical neurons, and monitored the development of C-S connectivity up to 21days in vitro (DIV) in cells cultured from either the YAC128 mouse model of HD or the background strain, FVB/N (wild-type; WT) mice. Our data demonstrate that while C-S connectivity in WT co-cultures develops rapidly and continuously from DIV 7 to 21, YAC128 C-S connectivity shows no significant growth from DIV 14 onward. Morphological and electrophysiological data suggest that a combination of pre- and postsynaptic mechanisms contribute to this effect, including a reduction in both the postsynaptic dendritic arborization and the size and replenishment rate of the presynaptic readily releasable pool of excitatory vesicles. Moreover, a chimeric culture strategy confirmed that the most robust impairment in C-S connectivity was only observed when mutant huntingtin was expressed both pre- and postsynaptically. In all, our data demonstrate a progressive HD synaptic phenotype in this co-culture system that may be exploited as a platform for identifying promising therapeutic strategies to prevent early HD-associated synaptopathy. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Reduced activation in lateral prefrontal cortex and anterior cingulate during attention and cognitive control functions in medication-naïve adolescents with depression compared to controls.

    PubMed

    Halari, Rozmin; Simic, Mima; Pariante, Carmine M; Papadopoulos, Andrew; Cleare, Anthony; Brammer, Michael; Fombonne, Eric; Rubia, Katya

    2009-03-01

    There is increasing recognition of major depressive disorder (MDD) in adolescence. In adult MDD, abnormalities of fronto-striatal and fronto-cingulate circuitries mediating cognitive control functions have been implicated in the pathogenesis and been related to problems with controlling negative thoughts. No neuroimaging studies of cognitive control functions, however, exist in paediatric depression. This study investigated whether medication-naïve adolescents with MDD show abnormal brain activation of fronto-striatal and fronto-cingulate networks when performing tasks of attentional and cognitive control. Event-related functional magnetic resonance imaging was used to compare brain activation between 21 medication-naïve adolescents with a first-episode of MDD aged 14-17 years and 21 healthy adolescents, matched for handedness, age, sex, demographics and IQ. Activation paradigms were tasks of selective attention (Simon task), attentional switching (Switch task), and motor response inhibition and error detection (Stop task). In all three tasks, adolescents with depression compared to healthy controls demonstrated reduced activation in task-relevant right dorsolateral (DLPFC), inferior prefrontal cortex (IFC) and anterior cingulate gyrus (ACG). Additional areas of relatively reduced activation were in the parietal lobes during the Stop and Switch tasks, putamen, insula and temporal lobes during the Switch task and precuneus during the Simon task. This study shows first evidence that medication-naïve adolescents with MDD are characterised by abnormal function in ACG and right lateral prefrontal cortex during tasks of attention and performance monitoring, suggesting an early pathogenesis of these functional abnormalities attributed to MDD.

  2. Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke

    PubMed Central

    Inman, Cory S.; James, G. Andrew; Hamann, Stephan; Rajendra, Justin K.; Pagnoni, Giuseppe; Butler, Andrew J.

    2011-01-01

    Previous brain imaging work suggests that stroke alters the effective connectivity (the influence neural regions exert upon each other) of motor execution networks. The present study examines the intrinsic effective connectivity of top-down motor control in stroke survivors (n=13) relative to healthy participants (n=12). Stroke survivors exhibited significant deficits in motor function, as assessed by the Fugl-Meyer Motor Assessment. We used structural equation modeling (SEM) of resting-state fMRI data to investigate the relationship between motor deficits and the intrinsic effective connectivity between brain regions involved in motor control and motor execution. An exploratory adaptation of SEM determined the optimal model of motor execution effective connectivity in healthy participants, and confirmatory SEM assessed stroke survivors’ fit to that model. We observed alterations in spontaneous resting-state effective connectivity from fronto-parietal guidance systems to the motor network in stroke survivors. More specifically, diminished connectivity was found in connections from the superior parietal cortex to primary motor cortex and supplementary motor cortex. Furthermore, the paths demonstrated large individual variance in stroke survivors but less variance in healthy participants. These findings suggest that characterizing the deficits in resting-state connectivity of top-down processes in stroke survivors may help optimize cognitive and physical rehabilitation therapies by individually targeting specific neural pathway. PMID:21839174

  3. ADHD- and Medication-Related Brain Activation Effects in Concordantly Affected Parent-Child Dyads with ADHD

    ERIC Educational Resources Information Center

    Epstein, Jeffery N.; Casey, B. J.; Tonev, Simon T.; Davidson, Matthew C.; Reiss, Allan L.; Garrett, Amy; Hinshaw, Stephen P.; Greenhill, Laurence L.; Glover, Gary; Shafritz, Keith M.; Vitolo, Alan; Kotler, Lisa A.; Jarrett, Matthew A.; Spicer, Julie

    2007-01-01

    Background: Several studies have documented fronto-striatal dysfunction in children and adolescents with attention deficit/hyperactivity disorder (ADHD) using response inhibition tasks. Our objective was to examine functional brain abnormalities among youths and adults with ADHD and to examine the relations between these neurobiological…

  4. Intensive reasoning training alters patterns of brain connectivity at rest

    PubMed Central

    Mackey, Allyson P.; Miller Singley, Alison T.; Bunge, Silvia A.

    2013-01-01

    Patterns of correlated activity among brain regions reflect functionally relevant networks that are widely assumed to be stable over time. We hypothesized that if these correlations reflect the prior history of co-activation of brain regions, then a marked shift in cognition could alter the strength of coupling between these regions. We sought to test whether intensive reasoning training in humans would result in tighter coupling among regions in the lateral fronto-parietal network, as measured with resting-state fMRI (rs-fMRI). Rather than designing an artificial training program, we studied individuals who were preparing for a standardized test that places heavy demands on relational reasoning, the Law School Admissions Test (LSAT). LSAT questions require test-takers to group or sequence items according to a set of complex rules. We recruited young adults who were enrolled in an LSAT course that offers 70 hours of reasoning instruction (n=25), and age- and IQ-matched controls intending to take the LSAT in the future (n=24). Rs-fMRI data were collected for all subjects during two scanning sessions separated by 90 days. An analysis of pairwise correlations between brain regions implicated in reasoning showed that fronto-parietal connections were strengthened, along with parietal-striatal connections. These findings provide strong evidence for neural plasticity at the level of large-scale networks supporting high-level cognition. PMID:23486950

  5. In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.

    PubMed

    Thomas, Elizabeth A; Coppola, Giovanni; Tang, Bin; Kuhn, Alexandre; Kim, SoongHo; Geschwind, Daniel H; Brown, Timothy B; Luthi-Carter, Ruth; Ehrlich, Michelle E

    2011-03-15

    Huntington's disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neurons.

  6. Atypical Activations of Fronto-Cerebellar Regions During Forethought in Parents of Children With ADHD.

    PubMed

    Rapin, Lucile; Poissant, Hélène; Mendrek, Adrianna

    2017-10-01

    Although several studies suggest heritability of ADHD, only a few investigations of possible associations between people at risk and neural abnormalities in ADHD exist. In this study, we tested whether parents of children with ADHD would show atypical patterns of cerebral activations during forethought, a feature of working memory. Using Functional Magnetic Resonance Imaging (fMRI), we compared 12 parents of children with ADHD and 9 parents of control children during a forethought task. Parents of children with ADHD exhibited significantly increased neural activations in the posterior lobes of the cerebellum and in the left inferior frontal gyrus, relative to parents of control children. These findings are consistent with previous reports in children and suggest the fronto-cerebellar circuit's abnormalities during forethought in parents of children with ADHD. Future studies of people at risk of ADHD are needed to fully understand the extent of the fronto-cerebellar heritability.

  7. Striatal activation and frontostriatal connectivity during non-drug reward anticipation in alcohol dependence.

    PubMed

    Becker, Alena; Kirsch, Martina; Gerchen, Martin Fungisai; Kiefer, Falk; Kirsch, Peter

    2017-05-01

    According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol-associated cues, diminished motivation to pursue non-drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non-drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol-dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task-related brain activation and connectivity. Alcohol-dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit. © 2016 Society for the Study of Addiction.

  8. Effects of Fronto-Temporal Transcranial Direct Current Stimulation on Auditory Verbal Hallucinations and Resting-State Functional Connectivity of the Left Temporo-Parietal Junction in Patients With Schizophrenia

    PubMed Central

    Mondino, Marine; Jardri, Renaud; Suaud-Chagny, Marie-Françoise; Saoud, Mohamed; Poulet, Emmanuel; Brunelin, Jérôme

    2016-01-01

    Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring. PMID:26303936

  9. PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency

    PubMed Central

    Xu, Benjamin; Sandrini, Marco; Wang, Wen-tung; Smith, Jason F.; Sarlls, Joelle E.; Awosika, Oluwole; Butman, John A.; Horwitz, Barry; Cohen, Leonardo G.

    2016-01-01

    Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right pre-supplementary motor area (preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex (rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white-matter microstructure along the preSMA – rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. PMID:27144466

  10. Alterations in Striatal Circuits Underlying Addiction-Like Behaviors.

    PubMed

    Kim, Hyun Jin; Lee, Joo Han; Yun, Kyunghwa; Kim, Joung-Hun

    2017-06-30

    Drug addiction is a severe psychiatric disorder characterized by the compulsive pursuit of drugs of abuse despite potential adverse consequences. Although several decades of studies have revealed that psychostimulant use can result in extensive alterations of neural circuits and physiology, no effective therapeutic strategies or medicines for drug addiction currently exist. Changes in neuronal connectivity and regulation occurring after repeated drug exposure contribute to addiction-like behaviors in animal models. Among the involved brain areas, including those of the reward system, the striatum is the major area of convergence for glutamate, GABA, and dopamine transmission, and this brain region potentially determines stereotyped behaviors. Although the physiological consequences of striatal neurons after drug exposure have been relatively well documented, it remains to be clarified how changes in striatal connectivity underlie and modulate the expression of addiction-like behaviors. Understanding how striatal circuits contribute to addiction-like behaviors may lead to the development of strategies that successfully attenuate drug-induced behavioral changes. In this review, we summarize the results of recent studies that have examined striatal circuitry and pathway-specific alterations leading to addiction-like behaviors to provide an updated framework for future investigations.

  11. Cerebral Correlates of Abnormal Emotion Conflict Processing in Euthymic Bipolar Patients: A Functional MRI Study.

    PubMed

    Favre, Pauline; Polosan, Mircea; Pichat, Cédric; Bougerol, Thierry; Baciu, Monica

    2015-01-01

    Patients with bipolar disorder experience cognitive and emotional impairment that may persist even during the euthymic state of the disease. These persistent symptoms in bipolar patients (BP) may be characterized by disturbances of emotion regulation and related fronto-limbic brain circuitry. The present study aims to investigate the modulation of fronto-limbic activity and connectivity in BP by the processing of emotional conflict. Fourteen euthymic BP and 13 matched healthy subjects (HS) underwent functional magnetic resonance imaging (fMRI) while performing a word-face emotional Stroop task designed to dissociate the monitoring/generation of emotional conflict from its resolution. Functional connectivity was determined by means of psychophysiological interaction (PPI) approach. Relative to HS, BP were slower to process incongruent stimuli, reflecting higher amount of behavioral interference during emotional Stroop. Furthermore, BP showed decreased activation of the right dorsolateral prefrontal cortex (DLPFC) during the monitoring and a lack of bilateral amygdala deactivation during the resolution of the emotional conflict. In addition, during conflict monitoring, BP showed abnormal positive connectivity between the right DLPFC and several regions of the default mode network. Overall, our results highlighted dysfunctional processing of the emotion conflict in euthymic BP that may be subtended by abnormal activity and connectivity of the DLPFC during the conflict monitoring, which, in turn, leads to failure of amygdala deactivation during the resolution of the conflict. Emotional dysregulation in BP may be underpinned by a lack of top-down cognitive control and a difficulty to focus on the task due to persistent self-oriented attention.

  12. Connection between the striatal neurokinin-1 receptor and nitric oxide formation during methamphetamine exposure.

    PubMed

    Wang, Jing; Xu, Wenjing; Ali, Syed F; Angulo, Jesus A

    2008-10-01

    Methamphetamine (METH) is a widely used "club drug" that produces neural damage in the brain, including the loss of some neurons. METH-induced striatal neuronal loss has been attenuated by pretreatment with the neurokinin-1 receptor antagonist WIN-51,708 in mice. Using a histologic method, we have observed the internalization of the neurokinin-1 receptor into endosomes in the striatal somatostatin/NPY/nitric oxide synthase interneurons. To investigate the role of this interneuron in the striatal cell death induced by METH, we assessed by immunohistochemistry the number of striatal nitric oxide synthase-positive neurons in the presence of METH at 8 and 16 hours after systemic injection of a bolus of METH (30 mg/kg, i.p.). We found the number of striatal nitric oxide synthase-positive neurons unchanged at these time points after METH. In a separate experiment we measured the levels of striatal 3-nitrotyrosine (3-NT) by HPLC (high-pressure liquid chromatography) as an indirect index of nitric oxide synthesis. METH increased the levels of 3-nitrotyrosine in the striatum and this increase was significantly attenuated by pretreatment with a selective neurokinin-1 receptor antagonist. These observations suggest a causal relationship between the neurokinin-1 receptor and the activation of neuronal nitric oxide synthase that warrants further investigation.

  13. Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders.

    PubMed

    Arnsten, Amy F T; Rubia, Katya

    2012-04-01

    This article aims to review basic and clinical studies outlining the roles of prefrontal cortical (PFC) networks in the behavior and cognitive functions that are compromised in childhood neurodevelopmental disorders and how these map into the neuroimaging evidence of circuit abnormalities in these disorders. Studies of animals, normally developing children, and patients with neurodevelopmental disorders were reviewed, with focus on neuroimaging studies. The PFC provides "top-down" regulation of attention, inhibition/cognitive control, motivation, and emotion through connections with posterior cortical and subcortical structures. Dorsolateral and inferior PFC regulate attention and cognitive/inhibitory control, whereas orbital and ventromedial structures regulate motivation and affect. PFC circuitries are very sensitive to their neurochemical environment, and small changes in the underlying neurotransmitter systems, e.g. by medications, can produce large effects on mediated function. Neuroimaging studies of children with neurodevelopmental disorders show altered brain structure and function in distinctive circuits respecting this organization. Children with attention-deficit/hyperactivity disorder show prominent abnormalities in the inferior PFC and its connections to striatal, cerebellar, and parietal regions, whereas children with conduct disorder show alterations in the paralimbic system, comprising ventromedial, lateral orbitofrontal, and superior temporal cortices together with specific underlying limbic regions, regulating motivation and emotion control. Children with major depressive disorder show alterations in ventral orbital and limbic activity, particularly in the left hemisphere, mediating emotions. Finally, children with obsessive-compulsive disorder appear to have a dysregulation in orbito-fronto-striatal inhibitory control pathways, but also deficits in dorsolateral fronto-parietal systems of attention. Altogether, there is a good correspondence

  14. Effects of Fronto-Temporal Transcranial Direct Current Stimulation on Auditory Verbal Hallucinations and Resting-State Functional Connectivity of the Left Temporo-Parietal Junction in Patients With Schizophrenia.

    PubMed

    Mondino, Marine; Jardri, Renaud; Suaud-Chagny, Marie-Françoise; Saoud, Mohamed; Poulet, Emmanuel; Brunelin, Jérôme

    2016-03-01

    Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20 min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

  15. Corticostriatal connectivity fingerprints: Probability maps based on resting-state functional connectivity.

    PubMed

    Jaspers, Ellen; Balsters, Joshua H; Kassraian Fard, Pegah; Mantini, Dante; Wenderoth, Nicole

    2017-03-01

    Over the last decade, structure-function relationships have begun to encompass networks of brain areas rather than individual structures. For example, corticostriatal circuits have been associated with sensorimotor, limbic, and cognitive information processing, and damage to these circuits has been shown to produce unique behavioral outcomes in Autism, Parkinson's Disease, Schizophrenia and healthy ageing. However, it remains an open question how abnormal or absent connectivity can be detected at the individual level. Here, we provide a method for clustering gross morphological structures into subregions with unique functional connectivity fingerprints, and generate network probability maps usable as a baseline to compare individual cases against. We used connectivity metrics derived from resting-state fMRI (N = 100), in conjunction with hierarchical clustering methods, to parcellate the striatum into functionally distinct clusters. We identified three highly reproducible striatal subregions, across both hemispheres and in an independent replication dataset (N = 100) (dice-similarity values 0.40-1.00). Each striatal seed region resulted in a highly reproducible distinct connectivity fingerprint: the putamen showed predominant connectivity with cortical and cerebellar sensorimotor and language processing areas; the ventromedial striatum cluster had a distinct limbic connectivity pattern; the caudate showed predominant connectivity with the thalamus, frontal and occipital areas, and the cerebellum. Our corticostriatal probability maps agree with existing connectivity data in humans and non-human primates, and showed a high degree of replication. We believe that these maps offer an efficient tool to further advance hypothesis driven research and provide important guidance when investigating deviant connectivity in neurological patient populations suffering from e.g., stroke or cerebral palsy. Hum Brain Mapp 38:1478-1491, 2017. © 2016 Wiley Periodicals, Inc.

  16. Striatal norepinephrine efflux in l-DOPA-induced dyskinesia.

    PubMed

    Ostock, Corinne Y; Bhide, Nirmal; Goldenberg, Adam A; George, Jessica A; Bishop, Christopher

    2018-03-01

    l-DOPA remains the primary treatment for Parkinson's disease (PD). Unfortunately, its therapeutic benefits are compromised by the development of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID). The norepinephrine (NE) system originating in the locus coeruleus is profoundly affected in PD and known to influence dopamine (DA) signaling. However, the effect of noradrenergic loss on l-DOPA-induced striatal monoamine efflux and Parkinsonian motor behavior remains controversial and is frequently overlooked in traditional animal models of LID. Thus, the current study sought to determine whether degeneration of the DA and/or NE system(s) altered l-DOPA-induced striatal monoamine efflux in hemiparkinsonian rats with additional NE loss induced by the potent NE-toxin α DA beta hydroxylase (DBH)-saporin. Sham-, DA-, NE-, and dual DA + NE-lesioned rats were treated with l-DOPA (6 mg/kg, s.c.) for 2 weeks. Thereafter, l-DOPA-mediated striatal monoamine efflux was measured with in vivo microdialysis, and concurrent AIMs testing occurred to determine responsiveness to l-DOPA. Noradrenergic lesions exacerbated parkinsonian motor deficits but did not significantly alter LID expression or corresponding l-DOPA-induced striatal monoamine efflux. Interestingly, l-DOPA-induced striatal NE efflux rather than DA efflux, corresponded more closely with dyskinesia severity. Moreover, marked reductions in striatal NE tissue concentration did not appear to impact l-DOPA-induced striatal NE efflux. The current study implicates l-DOPA-induced striatal NE as an important factor in LID expression and demonstrates the importance of developing treatment strategies that co-modulate the NE and DA systems. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency.

    PubMed

    Xu, Benjamin; Sandrini, Marco; Wang, Wen-Tung; Smith, Jason F; Sarlls, Joelle E; Awosika, Oluwole; Butman, John A; Horwitz, Barry; Cohen, Leonardo G

    2016-09-01

    Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right presupplementary motor area (preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex (rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white-matter microstructure along the preSMA-rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. Hum Brain Mapp 37:3236-3249, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study.

    PubMed

    Reinstein, Eyal; Pariani, Mitchel; Bannykh, Serguei; Rimoin, David L; Schievink, Wouter I

    2013-04-01

    We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.

  19. White matter microstructural abnormalities in the frontal lobe of adults with antisocial personality disorder.

    PubMed

    Sundram, Frederick; Deeley, Quinton; Sarkar, Sagari; Daly, Eileen; Latham, Richard; Craig, Michael; Raczek, Malgorzata; Fahy, Tom; Picchioni, Marco; Barker, Gareth J; Murphy, Declan G M

    2012-02-01

    Antisocial personality disorder (ASPD) and psychopathy involve significant interpersonal and behavioural impairments. However, little is known about their underlying neurobiology and in particular, abnormalities in white matter (WM) microstructure. A preliminary diffusion tensor magnetic resonance imaging (DT-MRI) study of adult psychopaths employing tractography revealed abnormalities in the right uncinate fasciculus (UF) (Craig et al., 2009), indicating fronto-limbic disconnectivity. However, it is not clear whether WM abnormalities are restricted to this tract or are or more widespread, including other tracts which are involved in connectivity with the frontal lobe. We performed whole brain voxel-based analyses on WM fractional anisotropy (FA) and mean diffusivity (MD) maps acquired with DT-MRI to compare 15 adults with ASPD and healthy age, handedness and IQ-matched controls. Also, within ASPD subjects we related differences in FA and MD to measures of psychopathy. Significant WM FA reduction and MD increases were found respectively in ASPD subjects relative to controls. FA was bilaterally reduced in the genu of corpus callosum while in the right frontal lobe FA reduction was found in the UF, inferior fronto-occipital fasciculus (IFOF), anterior corona radiata and anterior limb and genu of the internal capsule. These differences negatively correlated with measures of psychopathy. Also in the right frontal lobe, increased MD was found in the IFOF and UF, and the corpus callosum and anterior corona radiata. There was a significant positive correlation between MD and psychopathy scores. The present study confirms a previous report of reduced FA in the UF. Additionally, we report for the first time, FA deficits in tracts involved in interhemispheric as well as frontal lobe connectivity in conjunction with MD increases in the frontal lobe. Hence, we provide evidence of significant WM microstructural abnormalities in frontal brain regions in ASPD and psychopathy

  20. Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions

    PubMed Central

    Klug, Jason R; Engelhardt, Max D; Cadman, Cara N; Li, Hao; Smith, Jared B; Ayala, Sarah; Williams, Elora W; Hoffman, Hilary

    2018-01-01

    Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior. PMID:29714166

  1. Individual Differences in Adult Reading Are Associated with Left Temporo-parietal to Dorsal Striatal Functional Connectivity

    PubMed Central

    Achal, Sanjay; Hoeft, Fumiko; Bray, Signe

    2016-01-01

    Reading skills vary widely in both children and adults, with a number of factors contributing to this variability. The most prominent factor may be related to efficiency of storage, representation, or retrieval of speech sounds. This phonological hypothesis is supported by findings of reduced activation in poor readers in left hemisphere ventro-lateral prefrontal and temporo-parietal phonological processing regions. Less well explained by phonological theories are reported hyperactivation in prefrontal, striatal, and insular regions. This study investigated functional connectivity of a core phonological processing region, the temporo-parietal junction (TPJ), in relation to reading skill in an adult community sample. We hypothesized that connectivity between TPJ and regions implicated in meta-analyses of reading disorder would correlate with individual differences in reading. Forty-four adults aged 30–54, ranging in reading ability, underwent resting fMRI scans. Data-driven connectivity clustering was used to identify TPJ subregions for seed-based connectivity analyses. Correlations were assessed between TPJ connectivity and timed-pseudoword reading (decoding) ability. We found a significant correlation wherein greater left supramarginal gyrus to anterior caudate connectivity was associated with weaker decoding. This suggests that hyperactivation of the dorsal striatum, reported in poor readers during reading tasks, may reflect compensatory or inefficient overintegration into attention networks. PMID:26400921

  2. Whole-brain structural connectivity in dyskinetic cerebral palsy and its association with motor and cognitive function.

    PubMed

    Ballester-Plané, Júlia; Schmidt, Ruben; Laporta-Hoyos, Olga; Junqué, Carme; Vázquez, Élida; Delgado, Ignacio; Zubiaurre-Elorza, Leire; Macaya, Alfons; Póo, Pilar; Toro, Esther; de Reus, Marcel A; van den Heuvel, Martijn P; Pueyo, Roser

    2017-09-01

    Dyskinetic cerebral palsy (CP) has long been associated with basal ganglia and thalamus lesions. Recent evidence further points at white matter (WM) damage. This study aims to identify altered WM pathways in dyskinetic CP from a standardized, connectome-based approach, and to assess structure-function relationship in WM pathways for clinical outcomes. Individual connectome maps of 25 subjects with dyskinetic CP and 24 healthy controls were obtained combining a structural parcellation scheme with whole-brain deterministic tractography. Graph theoretical metrics and the network-based statistic were applied to compare groups and to correlate WM state with motor and cognitive performance. Results showed a widespread reduction of WM volume in CP subjects compared to controls and a more localized decrease in degree (number of links per node) and fractional anisotropy (FA), comprising parieto-occipital regions and the hippocampus. However, supramarginal gyrus showed a significantly higher degree. At the network level, CP subjects showed a bilateral pathway with reduced FA, comprising sensorimotor, intraparietal and fronto-parietal connections. Gross and fine motor functions correlated with FA in a pathway comprising the sensorimotor system, but gross motor also correlated with prefrontal, temporal and occipital connections. Intelligence correlated with FA in a network with fronto-striatal and parieto-frontal connections, and visuoperception was related to right occipital connections. These findings demonstrate a disruption in structural brain connectivity in dyskinetic CP, revealing general involvement of posterior brain regions with relative preservation of prefrontal areas. We identified pathways in which WM integrity is related to clinical features, including but not limited to the sensorimotor system. Hum Brain Mapp 38:4594-4612, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Cognition and Resting-State Functional Connectivity in Schizophrenia

    PubMed Central

    Sheffield, Julia M; Barch, Deanna M

    2015-01-01

    Individuals with schizophrenia consistently display deficits in a multitude of cognitive domains, but the neurobiological source of these cognitive impairments remains unclear. By analyzing the functional connectivity of resting-state functional magnetic resonance imaging (rs-fcMRI) data in clinical populations like schizophrenia, research groups have begun elucidating abnormalities in the intrinsic communication between specific brain regions, and assessing relationships between these abnormalities and cognitive performance in schizophrenia. Here we review studies that have reported analysis of these brain-behavior relationships. Through this systematic review we found that patients with schizophrenia display abnormalities within and between regions comprising 1) the cortico-cerebellar-striatal-thalamic loop and 2) task-positive and task-negative cortical networks. Importantly, we did not observe unique relationships between specific functional connectivity abnormalities and distinct cognitive domains, suggesting that the observed functional systems may underlie mechanisms that are shared across cognitive abilities, the disturbance of which could contribute to the “generalized” cognitive deficit found in schizophrenia. We also note several areas of methodological change that we believe will strengthen this literature. PMID:26698018

  4. Functional Connectivity and Quantitative EEG in Women with Alcohol Use Disorders: A Resting-State Study.

    PubMed

    Herrera-Díaz, Adianes; Mendoza-Quiñones, Raúl; Melie-Garcia, Lester; Martínez-Montes, Eduardo; Sanabria-Diaz, Gretel; Romero-Quintana, Yuniel; Salazar-Guerra, Iraklys; Carballoso-Acosta, Mario; Caballero-Moreno, Antonio

    2016-05-01

    This study was aimed at exploring the electroencephalographic features associated with alcohol use disorders (AUD) during a resting-state condition, by using quantitative EEG and Functional Connectivity analyses. In addition, we explored whether EEG functional connectivity is associated with trait impulsivity. Absolute and relative powers and Synchronization Likelihood (SL) as a measure of functional connectivity were analyzed in 15 AUD women and fifteen controls matched in age, gender and education. Correlation analysis between self-report impulsivity as measured by the Barratt impulsiveness Scale (BIS-11) and SL values of AUD patients were performed. Our results showed increased absolute and relative beta power in AUD patients compared to matched controls, and reduced functional connectivity in AUD patients predominantly in the beta and alpha bands. Impaired connectivity was distributed at fronto-central and occipito-parietal regions in the alpha band, and over the entire scalp in the beta band. We also found that impaired functional connectivity particularly in alpha band at fronto-central areas was negative correlated with non-planning dimension of impulsivity. These findings suggest that functional brain abnormalities are present in AUD patients and a disruption of resting-state EEG functional connectivity is associated with psychopathological traits of addictive behavior.

  5. DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding.

    PubMed

    Sambataro, Fabio; Fazio, Leonardo; Taurisano, Paolo; Gelao, Barbara; Porcelli, Annamaria; Mancini, Marina; Sinibaldi, Lorenzo; Ursini, Gianluca; Masellis, Rita; Caforio, Grazia; Di Giorgio, Annabella; Niccoli-Asabella, Artor; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

    2013-01-01

    The default mode network (DMN) comprises a set of brain regions with "increased" activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([(123)I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.

  6. DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding

    PubMed Central

    Sambataro, Fabio; Fazio, Leonardo; Taurisano, Paolo; Gelao, Barbara; Porcelli, Annamaria; Mancini, Marina; Sinibaldi, Lorenzo; Ursini, Gianluca; Masellis, Rita; Caforio, Grazia; Di Giorgio, Annabella; Niccoli-Asabella, Artor; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

    2013-01-01

    The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling. PMID:21976709

  7. Striatal hyper-sensitivity during stress in remitted individuals with recurrent depression

    PubMed Central

    Admon, Roee; Holsen, Laura M.; Aizley, Harlyn; Remington, Anne; Whitfield-Gabrieli, Susan; Goldstein, Jill M.; Pizzagalli, Diego A.

    2014-01-01

    Background Increased sensitivity to stress and dysfunctional reward processing are two primary characteristics of Major Depressive Disorder (MDD) that may persist following remission. Preclinical work has established the pivotal role of the striatum in mediating both stress and reward responses. Human neuroimaging studies have corroborated these preclinical findings and highlighted striatal dysfunction in MDD in response to reward, but have yet to investigate striatal function during stress, in particular in individuals with recurrent depression. Methods Thirty three remitted individuals with a history of recurrent MDD (rMDD) and 35 matched healthy controls underwent a validated mild psychological stress task involving viewing of negative stimuli during fMRI. Cortisol and anxiety levels were assessed throughout scanning. Stress-related activation was investigated in three striatal regions: caudate, nucleus accumbens (Nacc), and putamen. Psychophysiological interaction (PPI) analyses probed connectivity of those regions with central structures of the neural stress circuitry, the amygdala and hippocampus. Results The task increased cortisol and anxiety levels, although to a greater extent in rMDD than healthy controls. In response to the negative stimuli, rMDD individuals, but not controls, also exhibited significantly potentiated caudate, Nacc, and putamen activations, as well as increased caudate-amygdala and caudate-hippocampus connectivity. Conclusions Findings highlight striatal hyper-sensitivity in response to a mild psychological stress in rMDD, as manifested by hyper-activation and hyper-connectivity with the amygdala and hippocampus. Striatal hyper-sensitivity during stress might thus constitute a trait mark of depression, providing a potential neural substrate for the interaction between stress and reward dysfunction in MDD. PMID:25483401

  8. Striatal dysfunction increases basal ganglia output during motor cortex activation in parkinsonian rats.

    PubMed

    Belluscio, Mariano A; Riquelme, Luis A; Murer, M Gustavo

    2007-05-01

    During movement, inhibitory neurons in the basal ganglia output nuclei show complex modulations of firing, which are presumptively driven by corticostriatal and corticosubthalamic input. Reductions in discharge should facilitate movement by disinhibiting thalamic and brain stem nuclei while increases would do the opposite. A proposal that nigrostriatal dopamine pathway degeneration disrupts trans-striatal pathways' balance resulting in sustained overactivity of basal ganglia output nuclei neurons and Parkinson's disease clinical signs is not fully supported by experimental evidence, which instead shows abnormal synchronous oscillatory activity in animal models and patients. Yet, the possibility that variation in motor cortex activity drives transient overactivity in output nuclei neurons in parkinsonism has not been explored. In Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions, approximately 50% substantia nigra pars reticulata (SNpr) units show abnormal cortically driven slow oscillations of discharge. Moreover, these units selectively show abnormal responses to motor cortex stimulation consisting in augmented excitations of an odd latency, which overlapped that of inhibitory responses presumptively mediated by the trans-striatal direct pathway in control rats. Delivering D1 or D2 dopamine agonists into the striatum of parkinsonian rats by reverse microdialysis reduced these abnormal excitations but had no effect on pathological oscillations. The present study establishes that dopamine-deficiency related changes of striatal function contribute to producing abnormally augmented excitatory responses to motor cortex stimulation in the SNpr. If a similar transient overactivity of basal ganglia output were driven by motor cortex input during movement, it could contribute to impeding movement initiation or execution in Parkinson's disease.

  9. Motor Deficits and Decreased Striatal Dopamine Receptor 2 Binding Activity in the Striatum-Specific Dyt1 Conditional Knockout Mice

    PubMed Central

    Yokoi, Fumiaki; Dang, Mai Tu; Li, Jianyong; Standaert, David G.; Li, Yuqing

    2011-01-01

    DYT1 early-onset generalized dystonia is a hyperkinetic movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Recently, significant progress has been made in studying pathophysiology of DYT1 dystonia using targeted mouse models. Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 knock-down (KD) mice exhibit motor deficits and alterations of striatal dopamine metabolisms, while Dyt1 knockout (KO) and Dyt1 ΔGAG homozygous KI mice show abnormal nuclear envelopes and neonatal lethality. However, it has not been clear whether motor deficits and striatal abnormality are caused by Dyt1 mutation in the striatum itself or the end results of abnormal signals from other brain regions. To identify the brain region that contributes to these phenotypes, we made a striatum-specific Dyt1 conditional knockout (Dyt1 sKO) mouse. Dyt1 sKO mice exhibited motor deficits and reduced striatal dopamine receptor 2 (D2R) binding activity, whereas they did not exhibit significant alteration of striatal monoamine contents. Furthermore, we also found normal nuclear envelope structure in striatal medium spiny neurons (MSNs) of an adult Dyt1 sKO mouse and cerebral cortical neurons in cerebral cortex-specific Dyt1 conditional knockout (Dyt1 cKO) mice. The results suggest that the loss of striatal torsinA alone is sufficient to produce motor deficits, and that this effect may be mediated, at least in part, through changes in D2R function in the basal ganglia circuit. PMID:21931745

  10. Self-face recognition shares brain regions active during proprioceptive illusion in the right inferior fronto-parietal superior longitudinal fasciculus III network.

    PubMed

    Morita, Tomoyo; Saito, Daisuke N; Ban, Midori; Shimada, Koji; Okamoto, Yuko; Kosaka, Hirotaka; Okazawa, Hidehiko; Asada, Minoru; Naito, Eiichi

    2017-04-21

    Proprioception is somatic sensation that allows us to sense and recognize position, posture, and their changes in our body parts. It pertains directly to oneself and may contribute to bodily awareness. Likewise, one's face is a symbol of oneself, so that visual self-face recognition directly contributes to the awareness of self as distinct from others. Recently, we showed that right-hemispheric dominant activity in the inferior fronto-parietal cortices, which are connected by the inferior branch of the superior longitudinal fasciculus (SLF III), is associated with proprioceptive illusion (awareness), in concert with sensorimotor activity. Herein, we tested the hypothesis that visual self-face recognition shares brain regions active during proprioceptive illusion in the right inferior fronto-parietal SLF III network. We scanned brain activity using functional magnetic resonance imaging while twenty-two right-handed healthy adults performed two tasks. One was a proprioceptive illusion task, where blindfolded participants experienced a proprioceptive illusion of right hand movement. The other was a visual self-face recognition task, where the participants judged whether an observed face was their own. We examined whether the self-face recognition and the proprioceptive illusion commonly activated the inferior fronto-parietal cortices connected by the SLF III in a right-hemispheric dominant manner. Despite the difference in sensory modality and in the body parts involved in the two tasks, both tasks activated the right inferior fronto-parietal cortices, which are likely connected by the SLF III, in a right-side dominant manner. Here we discuss possible roles for right inferior fronto-parietal activity in bodily awareness and self-awareness. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  11. Abnormal functional connectivity during visuospatial processing is associated with disrupted organisation of white matter in autism

    PubMed Central

    McGrath, Jane; Johnson, Katherine; O'Hanlon, Erik; Garavan, Hugh; Leemans, Alexander; Gallagher, Louise

    2013-01-01

    Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD) but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were (1) to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM) in ASD and (2) to examine the relationships between aberrant neural connectivity and behavior in ASD. Twenty-two individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD) based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19) and five paired regions: left caudate head, left caudate body, left uncus, left thalamus, and left cuneus. Measures of WM microstructural organization were extracted from these tracts. Fractional anisotropy (FA) reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant WM microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute (1) to abnormal functional connectivity and (2) to atypical visuospatial processing in ASD. PMID:24133425

  12. Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA.

    PubMed

    Iwabuchi, Sarina J; Raschke, Felix; Auer, Dorothee P; Liddle, Peter F; Lankappa, Sudheer T; Palaniyappan, Lena

    2017-02-01

    Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e.g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e.g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Subcomponents and Connectivity of the Inferior Fronto-Occipital Fasciculus Revealed by Diffusion Spectrum Imaging Fiber Tracking

    PubMed Central

    Wu, Yupeng; Sun, Dandan; Wang, Yong; Wang, Yibao

    2016-01-01

    The definitive structure and functional role of the inferior fronto-occipital fasciculus (IFOF) are still controversial. In this study, we aimed to investigate the connectivity, asymmetry, and segmentation patterns of this bundle. High angular diffusion spectrum imaging (DSI) analysis was performed on 10 healthy adults and a 90-subject DSI template (NTU-90 Atlas). In addition, a new tractography approach based on the anatomic subregions and two regions of interest (ROI) was evaluated for the fiber reconstructions. More widespread anterior-posterior connections than previous “standard” definition of the IFOF were found. This distinct pathway demonstrated a greater inter-subjects connective variability with a maximum of 40% overlap in its central part. The statistical results revealed no asymmetry between the left and right hemispheres and no significant differences existed in distributions of the IFOF according to sex. In addition, five subcomponents within the IFOF were identified according to the frontal areas of originations. As the subcomponents passed through the anterior floor of the external capsule, the fibers radiated to the posterior terminations. The most common connection patterns of the subcomponents were as follows: IFOF-I, from frontal polar cortex to occipital pole, inferior occipital lobe, middle occipital lobe, superior occipital lobe, and pericalcarine; IFOF-II, from orbito-frontal cortex to occipital pole, inferior occipital lobe, middle occipital lobe, superior occipital lobe, and pericalcarine; IFOF-III, from inferior frontal gyrus to inferior occipital lobe, middle occipital lobe, superior occipital lobe, occipital pole, and pericalcarine; IFOF-IV, from middle frontal gyrus to occipital pole, and inferior occipital lobe; IFOF-V, from superior frontal gyrus to occipital pole, inferior occipital lobe, and middle occipital lobe. Our work demonstrates the feasibility of high resolution diffusion tensor tractography with sufficient sensitivity

  14. Prolonged striatal disinhibition as a chronic animal model of tic disorders.

    PubMed

    Vinner, Esther; Israelashvili, Michal; Bar-Gad, Izhar

    2017-12-01

    Experimental findings and theoretical models have associated Tourette syndrome with abnormal striatal inhibition. The expression of tics, the hallmark symptom of this disorder, has been transiently induced in non-human primates and rodents by the injection of GABA A antagonists into the striatum, leading to temporary disinhibition. The novel chronic model of tic expression utilizes mini-osmotic pumps implanted subcutaneously in the rat's back for prolonged infusion of bicuculline into the dorsolateral striatum. Tics were expressed on the contralateral side to the infusion over a period of multiple days. Tic expression was stable, and maintained similar properties throughout the infusion period. Electrophysiological recordings revealed the existence of tic-related local field potential spikes and individual neuron activity changes that remained stable throughout the infusion period. The striatal disinhibition model provides a unique combination of face validity (tic expression) and construct validity (abnormal striatal inhibition) but is limited to sub-hour periods. The new chronic model extends the period of tic expression to multiple days and thus enables the study of tic dynamics and the effects of behavior and pharmacological agents on tic expression. The chronic model provides similar behavioral and neuronal correlates of tics as the acute striatal disinhibition model but over prolonged periods of time, thus providing a unique, basal ganglia initiated model of tic expression. Chronic expression of symptoms is the key to studying the time varying properties of Tourette syndrome and the effects of multiple internal and external factors on this disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Aversive disinhibition of behavior and striatal signaling in social avoidance.

    PubMed

    Ly, Verena; Cools, Roshan; Roelofs, Karin

    2014-10-01

    Social avoidance is a major factor contributing to the development and maintenance of anxiety and depressive symptoms. Converging evidence suggests that social avoidance is associated with abnormal aversive processing and hyperactive amygdala signaling. However, what are the consequences of such abnormal aversive processing for action and for the neural mechanisms implementing action is unclear. Existing literature is conflicting, pointing at either enhanced or reduced action inhibition. We investigated the interaction between aversion and action in social avoidance by comparing the effects of aversive vs appetitive faces on a go/no-go task and associated striatal signals in 42 high and low socially avoidant individuals. We combined fMRI with a novel probabilistic learning task, in which emotional valence (angry and happy faces) and optimal response (go- and no-go-responses) were manipulated independently. High compared with low socially avoidant individuals showed reduced behavioral inhibition (proportion no-go-responses) for angry relative to happy faces. This behavioral disinhibition correlated with greater striatal signal during no-go-responses for angry relative to happy faces. The results suggest that social avoidant coping style is accompanied by disinhibition of action and striatal signal in the context of social threat. The findings concur with recent theorizing about aversive disinhibition and affective disorders. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  16. Prefrontal and Striatal Glutamate Differently Relate to Striatal Dopamine: Potential Regulatory Mechanisms of Striatal Presynaptic Dopamine Function?

    PubMed

    Gleich, Tobias; Deserno, Lorenz; Lorenz, Robert Christian; Boehme, Rebecca; Pankow, Anne; Buchert, Ralph; Kühn, Simone; Heinz, Andreas; Schlagenhauf, Florian; Gallinat, Jürgen

    2015-07-01

    Theoretical and animal work has proposed that prefrontal cortex (PFC) glutamate inhibits dopaminergic inputs to the ventral striatum (VS) indirectly, whereas direct VS glutamatergic afferents have been suggested to enhance dopaminergic inputs to the VS. In the present study, we aimed to investigate relationships of glutamate and dopamine measures in prefrontostriatal circuitries of healthy humans. We hypothesized that PFC and VS glutamate, as well as their balance, are differently associated with VS dopamine. Glutamate concentrations in the left lateral PFC and left striatum were assessed using 3-Tesla proton magnetic resonance spectroscopy. Striatal presynaptic dopamine synthesis capacity was measured by fluorine-18-l-dihydroxyphenylalanine (F-18-FDOPA) positron emission tomography. First, a negative relationship was observed between glutamate concentrations in lateral PFC and VS dopamine synthesis capacity (n = 28). Second, a positive relationship was revealed between striatal glutamate and VS dopamine synthesis capacity (n = 26). Additionally, the intraindividual difference between PFC and striatal glutamate concentrations correlated negatively with VS dopamine synthesis capacity (n = 24). The present results indicate an involvement of a balance in PFC and striatal glutamate in the regulation of VS dopamine synthesis capacity. This notion points toward a potential mechanism how VS presynaptic dopamine levels are kept in a fine-tuned range. A disruption of this mechanism may account for alterations in striatal dopamine turnover as observed in mental diseases (e.g., in schizophrenia). The present work demonstrates complementary relationships between prefrontal and striatal glutamate and ventral striatal presynaptic dopamine using human imaging measures: a negative correlation between prefrontal glutamate and presynaptic dopamine and a positive relationship between striatal glutamate and presynaptic dopamine are revealed. The results may reflect a regulatory role

  17. The neurobiology of schizotypy: Fronto-striatal prediction error signal correlates with delusion-like beliefs in healthy people

    PubMed Central

    Corlett, P.R.; Fletcher, P.C.

    2012-01-01

    Healthy people sometimes report experiences and beliefs that are strikingly similar to the symptoms of psychosis in their bizarreness and the apparent lack of evidence supporting them. An important question is whether this represents merely a superficial resemblance or whether there is a genuine and deep similarity indicating, as some have suggested, a continuum between odd but healthy beliefs and the symptoms of psychotic illness. We sought to shed light on this question by determining whether the neural marker for prediction error - previously shown to be altered in early psychosis – is comparably altered in healthy individuals reporting schizotypal experiences and beliefs. We showed that non-clinical schizotypal experiences were significantly correlated with aberrant frontal and striatal prediction error signal. This correlation related to the distress associated with the beliefs. Given our previous observations that patients with first episode psychosis show altered neural responses to prediction error and that this alteration, in turn, relates to the severity of their delusional ideation, our results provide novel evidence in support of the view that schizotypy relates to psychosis at more than just a superficial descriptive level. However, the picture is a complex one in which the experiences, though associated with altered striatal responding, may provoke distress but may nonetheless be explained away, while an additional alteration in frontal cortical responding may allow the beliefs to become more delusion-like: intrusive and distressing. PMID:23079501

  18. Perceptual alternation in obsessive compulsive disorder--implications for a role of the cortico-striatal circuitry in mediating awareness.

    PubMed

    Li, C S; Chen, M C; Yang, Y Y; Chang, H L; Liu, C Y; Shen, S; Chen, C Y

    2000-06-15

    Mounting evidence suggests that obsessive compulsive disorder (OCD) results from functional aberrations of the fronto-striatal circuitry. However, empirical studies of the behavioral manifestations of OCD have been relatively lacking. The present study employs a behavioral task that allows a quantitative measure of how alternative percepts are formed from one moment to another, a process mimicking the brain state in which different thoughts and imageries compete for access to awareness. Eighteen patients with OCD, 12 with generalized anxiety disorder, and 18 normal subjects participated in the experiment, in which they viewed one of the three Schröder staircases and responded by pressing a key to each perceptual reversal. The results demonstrate that the patients with OCD have a higher perceptual alternation rate than the normal controls. Moreover, the frequency of perceptual alternation is significantly correlated with the Yale-Brown obsessive compulsive and the Hamilton anxiety scores. The increase in the frequency of perceptual reversals cannot easily be accounted for by learning or by different patterns of eye fixations on the task. These results provide further evidence that an impairment of the inhibitory function of the cortico-striatal circuitry might underlie the etiology of OCD. The implications of the results for a general role of the cortico-striatal circuitry in mediating awareness are discussed.

  19. Connectivity and functional profiling of abnormal brain structures in pedophilia

    PubMed Central

    Poeppl, Timm B.; Eickhoff, Simon B.; Fox, Peter T.; Laird, Angela R.; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

    2015-01-01

    Despite its 0.5–1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multi-modal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. PMID:25733379

  20. Connectivity and functional profiling of abnormal brain structures in pedophilia.

    PubMed

    Poeppl, Timm B; Eickhoff, Simon B; Fox, Peter T; Laird, Angela R; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

    2015-06-01

    Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. © 2015 Wiley Periodicals, Inc.

  1. Probabilistic diffusion tractography and graph theory analysis reveal abnormal white matter structural connectivity networks in drug-naive boys with attention deficit/hyperactivity disorder.

    PubMed

    Cao, Qingjiu; Shu, Ni; An, Li; Wang, Peng; Sun, Li; Xia, Ming-Rui; Wang, Jin-Hui; Gong, Gao-Lang; Zang, Yu-Feng; Wang, Yu-Feng; He, Yong

    2013-06-26

    Attention-deficit/hyperactivity disorder (ADHD), which is characterized by core symptoms of inattention and hyperactivity/impulsivity, is one of the most common neurodevelopmental disorders of childhood. Neuroimaging studies have suggested that these behavioral disturbances are associated with abnormal functional connectivity among brain regions. However, the alterations in the structural connections that underlie these behavioral and functional deficits remain poorly understood. Here, we used diffusion magnetic resonance imaging and probabilistic tractography method to examine whole-brain white matter (WM) structural connectivity in 30 drug-naive boys with ADHD and 30 healthy controls. The WM networks of the human brain were constructed by estimating inter-regional connectivity probability. The topological properties of the resultant networks (e.g., small-world and network efficiency) were then analyzed using graph theoretical approaches. Nonparametric permutation tests were applied for between-group comparisons of these graphic metrics. We found that both the ADHD and control groups showed an efficient small-world organization in the whole-brain WM networks, suggesting a balance between structurally segregated and integrated connectivity patterns. However, relative to controls, patients with ADHD exhibited decreased global efficiency and increased shortest path length, with the most pronounced efficiency decreases in the left parietal, frontal, and occipital cortices. Intriguingly, the ADHD group showed decreased structural connectivity in the prefrontal-dominant circuitry and increased connectivity in the orbitofrontal-striatal circuitry, and these changes significantly correlated with the inattention and hyperactivity/impulsivity symptoms, respectively. The present study shows disrupted topological organization of large-scale WM networks in ADHD, extending our understanding of how structural disruptions of neuronal circuits underlie behavioral disturbances in

  2. Sex differences of gray matter morphology in cortico-limbic-striatal neural system in major depressive disorder.

    PubMed

    Kong, Lingtao; Chen, Kaiyuan; Womer, Fay; Jiang, Wenyan; Luo, Xingguang; Driesen, Naomi; Liu, Jie; Blumberg, Hilary; Tang, Yanqing; Xu, Ke; Wang, Fei

    2013-06-01

    Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). The cortico-limbic-striatal neural system, including the prefrontal cortex, amygdala, hippocampus, and striatum, have shown sexually dimorphic morphological features and have been implicated in the dysfunctional regulation of mood and emotion in MDD. In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in the regional distribution of gray matter (GM) morphological abnormalities in medication-naïve participants with MDD. Participants included 29 medication-naïve individuals with MDD (16 females and 13 males) and 33 healthy controls (HC) (17 females and 16 males). Gray matter morphology of the cortico-limbic-striatal neural system was examined using voxel-based morphometry analyzes of high-resolution structural magnetic resonance imaging scans. The main effect of diagnosis and interaction effect of diagnosis by sex on GM morphology were statistically significant (p < 0.05, corrected) in the left ventral prefrontal cortex, right amygdala, right hippocampus and bilateral caudate when comparing the MDD and HC groups. Posthoc analyzes showed that females with MDD had significant GM decreases in limbic regions (p < 0.05, corrected), compared to female HC; while males with MDD demonstrated significant GM reduction in striatal regions, (p < 0.05, corrected), compared to HC males. The observed sex-related patterns of abnormalities within the cortico-limbic-strial neural system, such as predominant prefrontal-limbic abnormalities in MDD females vs. predominant prefrontal-striatal abnormalities in MDD males, suggest differences in neural circuitry that may mediate sex differences in the clinical presentation of MDD and potential targets for sex-differentiated treatment of the disorder. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Abnormal Connectional Fingerprint in Schizophrenia: A Novel Network Analysis of Diffusion Tensor Imaging Data

    PubMed Central

    Edwin Thanarajah, Sharmili; Han, Cheol E.; Rotarska-Jagiela, Anna; Singer, Wolf; Deichmann, Ralf; Maurer, Konrad; Kaiser, Marcus; Uhlhaas, Peter J.

    2016-01-01

    The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal–frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder. PMID:27445870

  4. Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania.

    PubMed

    Dandash, Orwa; Yücel, Murat; Daglas, Rothanthi; Pantelis, Christos; McGorry, Patrick; Berk, Michael; Fornito, Alex

    2018-03-06

    Mood disturbances seen in first-episode mania (FEM) are linked to disturbed functional connectivity of the striatum. Lithium and quetiapine are effective treatments for mania but their neurobiological effects remain largely unknown. We conducted a single-blinded randomized controlled maintenance trial in 61 FEM patients and 30 healthy controls. Patients were stabilized for a minimum of 2 weeks on lithium plus quetiapine then randomly assigned to either lithium (serum level 0.6 mmol/L) or quetiapine (dosed up to 800 mg/day) treatment for 12 months. Resting-state fMRI was acquired at baseline, 3 months (patient only) and 12 months. The effects of treatment group, time and their interaction, on striatal functional connectivity were assessed using voxel-wise general linear modelling. At baseline, FEM patients showed reduced connectivity in the dorsal (p = 0.05) and caudal (p = 0.008) cortico-striatal systems when compared to healthy controls at baseline. FEM patients also showed increased connectivity in a circuit linking the ventral striatum with the medial orbitofrontal cortex, cerebellum and thalamus (p = 0.02). Longitudinally, we found a significant interaction between time and treatment group, such that lithium was more rapid, compared to quetiapine, in normalizing abnormally increased functional connectivity, as assessed at 3-month and 12-month follow-ups. The results suggest that FEM is associated with reduced connectivity in dorsal and caudal corticostriatal systems, as well as increased functional connectivity of ventral striatal systems. Lithium appears to act more rapidly than quetiapine in normalizing hyperconnectivity of the ventral striatum with the cerebellum. The study was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12607000639426). http://www.anzctr.org.au.

  5. Abnormal network connectivity in frontotemporal dementia: evidence for prefrontal isolation.

    PubMed

    Farb, Norman A S; Grady, Cheryl L; Strother, Stephen; Tang-Wai, David F; Masellis, Mario; Black, Sandra; Freedman, Morris; Pollock, Bruce G; Campbell, Karen L; Hasher, Lynn; Chow, Tiffany W

    2013-01-01

    Degraded social function, disinhibition, and stereotypy are defining characteristics of frontotemporal dementia (FTD), manifesting in both the behavioral variant of frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Recent neuroimaging research also associates FTD with alterations in the brain's intrinsic connectivity networks. The present study explored the relationship between neural network connectivity and specific behavioral symptoms in FTD. Resting-state functional magnetic resonance imaging was employed to investigate neural network changes in bvFTD and SD. We used independent components analysis (ICA) to examine changes in frontolimbic network connectivity, as well as several metrics of local network strength, such as the fractional amplitude of low-frequency fluctuations, regional homogeneity, and seed-based functional connectivity. For each analysis, we compared each FTD subgroup to healthy controls, characterizing general and subtype-unique network changes. The relationship between abnormal connectivity in FTD and behavior disturbances was explored. Across multiple analytic approaches, both bvFTD and SD were associated with disrupted frontolimbic connectivity and elevated local connectivity within the prefrontal cortex. Even after controlling for structural atrophy, prefrontal hyperconnectivity was robustly associated with apathy scores. Frontolimbic disconnection was associated with lower disinhibition scores, suggesting that abnormal frontolimbic connectivity contributes to positive symptoms in dementia. Unique to bvFTD, stereotypy was associated with elevated default network connectivity in the right angular gyrus. The behavioral variant was also associated with marginally higher apathy scores and a more diffuse pattern of prefrontal hyperconnectivity than SD. The present findings support a theory of FTD as a disorder of frontolimbic disconnection leading to unconstrained prefrontal connectivity. Prefrontal hyperconnectivity may

  6. Decreased integrity of the fronto-temporal fibers of the left inferior occipito-frontal fasciculus associated with auditory verbal hallucinations in schizophrenia.

    PubMed

    Oestreich, Lena K L; McCarthy-Jones, Simon; Whitford, Thomas J

    2016-06-01

    Auditory verbal hallucinations (AVH) have been proposed to result from altered connectivity between frontal speech production regions and temporal speech perception regions. Whilst the dorsal language pathway, serviced by the arcuate fasciculus, has been extensively studied in relation to AVH, the ventral language pathway, serviced by the inferior occipito-frontal fasciculus (IOFF) has been rarely studied in relation to AVH. This study examined whether structural changes in anatomically defined subregions of the IOFF were associated with AVH in patients with schizophrenia. Diffusion tensor imaging scans and clinical data were obtained from the Australian Schizophrenia Research Bank for 113 schizophrenia patients, of whom 39 had lifetime experience of AVH (18 had current AVH, 21 had remitted AVH), 74 had no lifetime experience of AVH, and 40 healthy controls. Schizophrenia patients with a lifetime experience of AVH exhibited reduced fractional anisotropy (FA) in the fronto-temporal fibers of the left IOFF compared to both healthy controls and schizophrenia patients without AVH. In contrast, structural abnormalities in the temporal and occipital regions of the IOFF were observed bilaterally in both patient groups, relative to the healthy controls. These results suggest that while changes in the structural integrity of the bilateral IOFF are associated with schizophrenia per se, integrity reductions in the fronto-temporal fibers of the left IOFF may be specifically associated with AVH.

  7. DTI-measured white matter abnormalities in adolescents with Conduct Disorder

    PubMed Central

    Haney-Caron, Emily; Caprihan, Arvind; Stevens, Michael C.

    2013-01-01

    Emerging research suggests that antisocial behavior in youth is linked to abnormal brain white matter microstructure, but the extent of such anatomical connectivity abnormalities remain largely untested because previous Conduct Disorder (CD) studies typically have selectively focused on specific frontotemporal tracts. This study aimed to replicate and extend previous frontotemporal diffusion tensor imaging (DTI) findings to determine whether noncomorbid CD adolescents have white matter microstructural abnormalities in major white matter tracts across the whole brain. Seventeen CD-diagnosed adolescents recruited from the community were compared to a group of 24 non-CD youth which did not differ in average age (12–18) or gender proportion. Tract-based spatial statistics (TBSS) fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) measurements were compared between groups using FSL nonparametric two-sample t test, clusterwise whole-brain corrected, p<.05. CD FA and AD deficits were widespread, but unrelated to gender, verbal ability, or CD age of onset. CD adolescents had significantly lower FA and AD values in frontal lobe and temporal lobe regions, including frontal lobe anterior/superior corona radiata, and inferior longitudinal and fronto-occpital fasciculi passing through the temporal lobe. The magnitude of several CD FA deficits was associated with number of CD symptoms. Because AD, but not RD, differed between study groups, abnormalities of axonal microstructure in CD rather than myelination are suggested. This study provides evidence that adolescent antisocial disorder is linked to abnormal white matter microstructure in more than just the uncinate fasciulcus as identified in previous DTI studies, or frontotemporal brain structures as suggested by functional neuroimaging studies. Instead, neurobiological risk specific to antisociality in adolescence is linked to microstructural abnormality in numerous long-range white matter

  8. Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate

    PubMed Central

    Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

    2017-01-01

    The central extended amygdala (CEA) has been conceptualized as a ‘macrosystem’ that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the ‘limbic-associative’ striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning. PMID:28220796

  9. Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.

    PubMed

    Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

    2017-07-01

    The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.

  10. Abnormal Functional Connectivity in Autism Spectrum Disorders during Face Processing

    ERIC Educational Resources Information Center

    Kleinhans, Natalia M.; Richards, Todd; Sterling, Lindsey; Stegbauer, Keith C.; Mahurin, Roderick; Johnson, L. Clark; Greenson, Jessica; Dawson, Geraldine; Aylward, Elizabeth

    2008-01-01

    Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning…

  11. Clonazepam increases in vivo striatal extracellular glucose in diabetic rats after glucose overload.

    PubMed

    Gomez, Rosane; Barros, Helena M T

    2003-12-01

    Hyperglycemia modulates brain function, including neuronal excitability, neurotransmitter release and behavioral changes. There may be connections between the GABAergic system, glucose sensing neurons and glucose in the neuronal environment that shed light on the mechanism by which GABA(A) agents influence depressive behavior in diabetic rats submitted to the forced swimming test. We aimed to investigate whether clonazepam (CNZ), a GABA(A) receptor positive modulator, modifies in vivo striatal extracellular glucose levels in diabetic rats under fasting condition or after oral glucose overload. Streptozotocin diabetic and nondiabetic rats were submitted to in vivo striatal microdialysis. Perfusate samples were collected at baseline, during fasting and following administration of CNZ (0.25 mg/kg) and oral glucose overload. Blood glucose and striatal extracellular glucose were measured simultaneously at several time points. Fasting striatal glucose levels were higher in diabetic than in nondiabetic rats and the differences between these animals were maintained after glucose overload. The increases in extracellular striatal glucose after glucose overload were around 40% and blood to brain transference was decreased in diabetics. CNZ treatment paradoxically increased striatal glucose after glucose overload in diabetic rats, which may mark the dysfunction in brain glucose homeostasis.

  12. Fronto-Parietal Network Reconfiguration Supports the Development of Reasoning Ability

    PubMed Central

    Wendelken, Carter; Ferrer, Emilio; Whitaker, Kirstie J.; Bunge, Silvia A.

    2016-01-01

    The goal of this fMRI study was to examine how well developmental improvements in reasoning ability can be explained by changes in functional connectivity between specific nodes in prefrontal and parietal cortices. To this end, we examined connectivity within the lateral fronto-parietal network (LFPN) and its relation to reasoning ability in 132 children and adolescents aged 6–18 years, 56 of whom were scanned twice over the course of 1.5 years. Developmental changes in strength of connections within the LFPN were most prominent in late childhood and early adolescence. Reasoning ability was related to functional connectivity between left rostrolateral prefrontal cortex (RLPFC) and inferior parietal lobule (IPL), but only among 12–18-year olds. For 9–11-year olds, reasoning ability was most strongly related to connectivity between left and right RLPFC; this relationship was mediated by working memory. For 6–8-year olds, significant relationships between connectivity and performance were not observed; in this group, processing speed was the primary mediator of improvement in reasoning ability. We conclude that different connections best support reasoning at different points in development and that RLPFC-IPL connectivity becomes an important predictor of reasoning during adolescence. PMID:25824536

  13. Abnormal Striatal BOLD Responses to Reward Anticipation and Reward Delivery in ADHD

    PubMed Central

    Furukawa, Emi; Bado, Patricia; Tripp, Gail; Mattos, Paulo; Wickens, Jeff R.; Bramati, Ivanei E.; Alsop, Brent; Ferreira, Fernanda Meireles; Lima, Debora; Tovar-Moll, Fernanda; Sergeant, Joseph A.; Moll, Jorge

    2014-01-01

    Altered reward processing has been proposed to contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The neurobiological mechanism underlying this alteration remains unclear. We hypothesize that the transfer of dopamine release from reward to reward-predicting cues, as normally observed in animal studies, may be deficient in ADHD. Functional magnetic resonance imaging (fMRI) was used to investigate striatal responses to reward-predicting cues and reward delivery in a classical conditioning paradigm. Data from 14 high-functioning and stimulant-naïve young adults with elevated lifetime symptoms of ADHD (8 males, 6 females) and 15 well-matched controls (8 males, 7 females) were included in the analyses. During reward anticipation, increased blood-oxygen-level-dependent (BOLD) responses in the right ventral and left dorsal striatum were observed in controls, but not in the ADHD group. The opposite pattern was observed in response to reward delivery; the ADHD group demonstrated significantly greater BOLD responses in the ventral striatum bilaterally and the left dorsal striatum relative to controls. In the ADHD group, the number of current hyperactivity/impulsivity symptoms was inversely related to ventral striatal responses during reward anticipation and positively associated with responses to reward. The BOLD response patterns observed in the striatum are consistent with impaired predictive dopamine signaling in ADHD, which may explain altered reward-contingent behaviors and symptoms of ADHD. PMID:24586543

  14. Altered cingulo-striatal function underlies reward drive deficits in schizophrenia.

    PubMed

    Park, Il Ho; Chun, Ji Won; Park, Hae-Jeong; Koo, Min-Seong; Park, Sunyoung; Kim, Seok-Hyeong; Kim, Jae-Jin

    2015-02-01

    Amotivation in schizophrenia is assumed to involve dysfunctional dopaminergic signaling of reward prediction or anticipation. It is unclear, however, whether the translation of neural representation of reward value to behavioral drive is affected in schizophrenia. In order to examine how abnormal neural processing of response valuation and initiation affects incentive motivation in schizophrenia, we conducted functional MRI using a deterministic reinforcement learning task with variable intervals of contingency reversals in 20 clinically stable patients with schizophrenia and 20 healthy controls. Behaviorally, the advantage of positive over negative reinforcer in reinforcement-related responsiveness was not observed in patients. Patients showed altered response valuation and initiation-related striatal activity and deficient rostro-ventral anterior cingulate cortex activation during reward approach initiation. Among these neural abnormalities, rostro-ventral anterior cingulate cortex activation was correlated with positive reinforcement-related responsiveness in controls and social anhedonia and social amotivation subdomain scores in patients. Our findings indicate that the central role of the anterior cingulate cortex is in translating action value into driving force of action, and underscore the role of the cingulo-striatal network in amotivation in schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Preliminary fMRI findings on the effects of event rate in adults with ADHD.

    PubMed

    Kooistra, Libbe; van der Meere, Jaap J; Edwards, Jodi D; Kaplan, Bonnie J; Crawford, Susan; Goodyear, Bradley G

    2010-05-01

    Inhibition problems in attention deficit hyperactivity disorder (ADHD) are sensitive to stimulus event rate. This pilot study explores the neural basis of this increased susceptibility to event rate in ADHD. Event-related functional magnetic resonance imaging was used in conjunction with the administration of a fast (1.5 s) and a slow (7 s) Go/No-Go task. Brain activity patterns and reaction times of ten young male adults with ADHD (two of whom were in partial remission) and ten healthy male controls were compared. The ADHD group responded slower than controls with greater variability but with similar number of errors. Accurate response inhibition in the ADHD group in the slow condition was associated with widespread fronto-striatal activation, including the thalamus. For correct Go trials only, the ADHD group compared with controls showed substantial under-activation in the slow condition. The observed abnormal brain activation in the slow condition in adults with ADHD supports a fronto-striatal etiology, and underlines a presumed activation regulation deficit. Larger sample sizes to further validate these preliminary findings are needed.

  16. A previously undescribed autosomal recessive multiple congenital anomalies/mental retardation (MCA/MR) syndrome with fronto-nasal dysostosis, cleft lip/palate, limb hypoplasia, and postaxial poly-syndactyly: acro-fronto-facio-nasal dysostosis syndrome.

    PubMed

    Richieri-Costa, A; Colletto, G M; Gollop, T R; Masiero, D

    1985-04-01

    We describe two sibs born to a consanguineous couple. Among other clinical findings both have mental retardation, short stature, facial and skeletal abnormalities characterized by hypertelorism, broad notched nasal tip, cleft lip/palate, campto-brachy-poly-syndactyly, fibular hypoplasia, and marked anomalies of foot structures. Facial signs of the reported patients resemble those present in the fronto-nasal "dysplasia" syndrome; however, the whole clinical picture in the present patients suggests a true MCA/MR syndrome, most likely inherited as an autosomal recessive trait. Clinical and genetic aspects of the present family are discussed.

  17. Striatal dopamine release and impaired reinforcement learning in adults with 22q11.2 deletion syndrome.

    PubMed

    van Duin, Esther D A; Kasanova, Zuzana; Hernaus, Dennis; Ceccarini, Jenny; Heinzel, Alexander; Mottaghy, Felix; Mohammadkhani-Shali, Siamak; Winz, Oliver; Frank, Michael; Beck, Merrit C H; Booij, Jan; Myin-Germeys, Inez; van Amelsvoort, Thérèse

    2018-06-01

    22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk for developing psychosis. The catechol-O-methyltransferase (COMT) gene is located in the deleted region and involved in dopamine (DA) breakdown. Impaired reinforcement learning (RL) is a recurrent feature in psychosis and thought to be related to abnormal striatal DA function. This study aims to examine RL and the potential association with striatal DA-ergic neuromodulation in 22q11DS. Twelve non-psychotic adults with 22q11DS and 16 healthy controls (HC) were included. A dopamine D 2/3 receptor [ 18 F]fallypride positron emission tomography (PET) scan was acquired while participants performed a modified version of the probabilistic stimulus selection task. RL-task performance was significantly worse in 22q11DS compared to HC. There were no group difference in striatal nondisplaceable binding potential (BP ND ) and task-induced DA release. In HC, striatal task-induced DA release was positively associated with task performance, but no such relation was found in 22q11DS subjects. Moreover, higher caudate nucleus task-induced DA release was found in COMT Met hemizygotes relative to Val hemizygotes. This study is the first to show impairments in RL in 22q11DS. It suggests that potentially motivational impairments are not only present in psychosis, but also in this genetic high risk group. These deficits may be underlain by abnormal striatal task-induced DA release, perhaps as a consequence of COMT haplo-insufficiency. Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.

  18. Development of a selective left-hemispheric fronto-temporal network for processing syntactic complexity in language comprehension.

    PubMed

    Xiao, Yaqiong; Friederici, Angela D; Margulies, Daniel S; Brauer, Jens

    2016-03-01

    The development of language comprehension abilities in childhood is closely related to the maturation of the brain, especially the ability to process syntactically complex sentences. Recent studies proposed that the fronto-temporal connection within left perisylvian regions, supporting the processing of syntactically complex sentences, is still immature at preschool age. In the current study, resting state functional magnetic resonance imaging data were acquired from typically developing 5-year-old children and adults to shed further light on the brain functional development. Children additionally performed a behavioral syntactic comprehension test outside the scanner. The amplitude of low-frequency fluctuations was analyzed in order to identify the functional correlation networks of language-relevant brain regions. Results showed an intrahemispheric correlation between left inferior frontal gyrus (IFG) and left posterior superior temporal sulcus (pSTS) in adults, whereas an interhemispheric correlation between left IFG and its right-hemispheric homolog was predominant in children. Correlation analysis between resting-state functional connectivity and sentence processing performance in 5-year-olds revealed that local connectivity within the left IFG is associated with competence of processing syntactically simple canonical sentences, while long-range connectivity between IFG and pSTS in left hemisphere is associated with competence of processing syntactically relatively more complex non-canonical sentences. The present developmental data suggest that a selective left fronto-temporal connectivity network for processing complex syntax is already in functional connection at the age of 5 years when measured in a non-task situation. The correlational findings provide new insight into the relationship between intrinsic functional connectivity and syntactic language abilities in preschool children. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights

  19. Approaching a network connectivity-driven classification of the psychosis continuum: a selective review and suggestions for future research.

    PubMed

    Schmidt, André; Diwadkar, Vaibhav A; Smieskova, Renata; Harrisberger, Fabienne; Lang, Undine E; McGuire, Philip; Fusar-Poli, Paolo; Borgwardt, Stefan

    2014-01-01

    Brain changes in schizophrenia evolve along a dynamic trajectory, emerging before disease onset and proceeding with ongoing illness. Recent investigations have focused attention on functional brain interactions, with experimental imaging studies supporting the disconnection hypothesis of schizophrenia. These studies have revealed a broad spectrum of abnormalities in brain connectivity in patients, particularly for connections integrating the frontal cortex. A critical point is that brain connectivity abnormalities, including altered resting state connectivity within the fronto-parietal (FP) network, are already observed in non-help-seeking individuals with psychotic-like experiences. If we consider psychosis as a continuum, with individuals with psychotic-like experiences at the lower and psychotic patients at the upper ends, individuals with psychotic-like experiences represent a key population for investigating the validity of putative biomarkers underlying the onset of psychosis. This paper selectively addresses the role played by FP connectivity in the psychosis continuum, which includes patients with chronic psychosis, early psychosis, clinical high risk, genetic high risk, as well as the general population with psychotic experiences. We first discuss structural connectivity changes among the FP pathway in each domain in the psychosis continuum. This may provide a basis for us to gain an understanding of the subsequent changes in functional FP connectivity. We further indicate that abnormal FP connectivity may arise from glutamatergic disturbances of this pathway, in particular from abnormal NMDA receptor-mediated plasticity. In the second part of this paper we propose some concepts for further research on the use of network connectivity in the classification of the psychosis continuum. These concepts are consistent with recent efforts to enhance the role of data in driving the diagnosis of psychiatric spectrum diseases.

  20. Approaching a network connectivity-driven classification of the psychosis continuum: a selective review and suggestions for future research

    PubMed Central

    Schmidt, André; Diwadkar, Vaibhav A.; Smieskova, Renata; Harrisberger, Fabienne; Lang, Undine E.; McGuire, Philip; Fusar-Poli, Paolo; Borgwardt, Stefan

    2015-01-01

    Brain changes in schizophrenia evolve along a dynamic trajectory, emerging before disease onset and proceeding with ongoing illness. Recent investigations have focused attention on functional brain interactions, with experimental imaging studies supporting the disconnection hypothesis of schizophrenia. These studies have revealed a broad spectrum of abnormalities in brain connectivity in patients, particularly for connections integrating the frontal cortex. A critical point is that brain connectivity abnormalities, including altered resting state connectivity within the fronto-parietal (FP) network, are already observed in non-help-seeking individuals with psychotic-like experiences. If we consider psychosis as a continuum, with individuals with psychotic-like experiences at the lower and psychotic patients at the upper ends, individuals with psychotic-like experiences represent a key population for investigating the validity of putative biomarkers underlying the onset of psychosis. This paper selectively addresses the role played by FP connectivity in the psychosis continuum, which includes patients with chronic psychosis, early psychosis, clinical high risk, genetic high risk, as well as the general population with psychotic experiences. We first discuss structural connectivity changes among the FP pathway in each domain in the psychosis continuum. This may provide a basis for us to gain an understanding of the subsequent changes in functional FP connectivity. We further indicate that abnormal FP connectivity may arise from glutamatergic disturbances of this pathway, in particular from abnormal NMDA receptor-mediated plasticity. In the second part of this paper we propose some concepts for further research on the use of network connectivity in the classification of the psychosis continuum. These concepts are consistent with recent efforts to enhance the role of data in driving the diagnosis of psychiatric spectrum diseases. PMID:25628553

  1. The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

    PubMed Central

    Colon-Perez, Luis M; Tran, Kelvin; Thompson, Khalil; Pace, Michael C; Blum, Kenneth; Goldberger, Bruce A; Gold, Mark S; Bruijnzeel, Adriaan W; Setlow, Barry; Febo, Marcelo

    2016-01-01

    The abuse of ‘bath salts' has raised concerns because of their adverse effects, which include delirium, violent behavior, and suicide ideation in severe cases. The bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) has been closely linked to these and other adverse effects. The abnormal behavioral pattern produced by acute high-dose MDPV intake suggests possible disruptions of neural communication between brain regions. Therefore, we determined if MDPV exerts disruptive effects on brain functional connectivity, particularly in areas of the prefrontal cortex. Male rats were imaged following administration of a single dose of MDPV (0.3, 1.0, or 3.0 mg/kg) or saline. Resting state brain blood oxygenation level-dependent (BOLD) images were acquired at 4.7 T. To determine the role of dopamine transmission in MDPV-induced changes in functional connectivity, a group of rats received the dopamine D1/D2 receptor antagonist cis-flupenthixol (0.5 mg/kg) 30 min before MDPV. MDPV dose-dependently reduced functional connectivity. Detailed analysis of its effects revealed that connectivity between frontal cortical and striatal areas was reduced. This included connectivity between the prelimbic prefrontal cortex and other areas of the frontal cortex and the insular cortex with hypothalamic, ventral, and dorsal striatal areas. Although the reduced connectivity appeared widespread, connectivity between these regions and somatosensory cortex was not as severely affected. Dopamine receptor blockade did not prevent the MDPV-induced decrease in functional connectivity. The results provide a novel signature of MDPV's in vivo mechanism of action. Reduced brain functional connectivity has been reported in patients suffering from psychosis and has been linked to cognitive dysfunction, audiovisual hallucinations, and negative affective states akin to those reported for MDPV-induced intoxication. The present results suggest that disruption of functional connectivity

  2. Fronto-parietal and cingulo-opercular network integrity and cognition in health and schizophrenia

    PubMed Central

    Sheffield, Julia M; Repovs, Grega; Harms, Michael P.; Carter, Cameron S.; Gold, James M.; MacDonald, Angus W.; Ragland, J. Daniel; Silverstein, Steven M.; Godwin, Douglass; Barch, Deanna M

    2015-01-01

    Growing evidence suggests that coordinated activity within specific functional brain networks supports cognitive ability, and that abnormalities in brain connectivity may underlie cognitive deficits observed in neuropsychiatric diseases, such as schizophrenia. Two functional networks, the fronto-parietal network (FPN) and cingulo-opercular network (CON), are hypothesized to support top-down control of executive functioning, and have therefore emerged as potential drivers of cognitive impairment in disease-states. Graph theoretic analyses of functional connectivity data can characterize network topology, allowing the relationships between cognitive ability and network integrity to be examined. In the current study we applied graph analysis to pseudo-resting state data in 54 healthy subjects and 46 schizophrenia patients, and measured overall cognitive ability as the shared variance in performance from tasks of episodic memory, verbal memory, processing speed, goal maintenance, and visual integration. We found that, across all participants, cognitive ability was significantly positively associated with the local and global efficiency of the whole brain, FPN, and CON, but not with the efficiency of a comparison network, the auditory network. Additionally, the participation coefficient of the right anterior insula, a major hub within the CON, significantly predicted cognition, and this relationship was independent of CON global efficiency. Surprisingly, we did not observe strong evidence for group differences in any of our network metrics. These data suggest that functionally efficient task control networks support better cognitive ability in both health and schizophrenia, and that the right anterior insula may be a particularly important hub for successful cognitive performance across both health and disease. PMID:25979608

  3. Fronto-Parietal Network Reconfiguration Supports the Development of Reasoning Ability.

    PubMed

    Wendelken, Carter; Ferrer, Emilio; Whitaker, Kirstie J; Bunge, Silvia A

    2016-05-01

    The goal of this fMRI study was to examine how well developmental improvements in reasoning ability can be explained by changes in functional connectivity between specific nodes in prefrontal and parietal cortices. To this end, we examined connectivity within the lateral fronto-parietal network (LFPN) and its relation to reasoning ability in 132 children and adolescents aged 6-18 years, 56 of whom were scanned twice over the course of 1.5 years. Developmental changes in strength of connections within the LFPN were most prominent in late childhood and early adolescence. Reasoning ability was related to functional connectivity between left rostrolateral prefrontal cortex (RLPFC) and inferior parietal lobule (IPL), but only among 12-18-year olds. For 9-11-year olds, reasoning ability was most strongly related to connectivity between left and right RLPFC; this relationship was mediated by working memory. For 6-8-year olds, significant relationships between connectivity and performance were not observed; in this group, processing speed was the primary mediator of improvement in reasoning ability. We conclude that different connections best support reasoning at different points in development and that RLPFC-IPL connectivity becomes an important predictor of reasoning during adolescence. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Nature or nurture? Determining the heritability of human striatal dopamine function: an [18F]-DOPA PET study.

    PubMed

    Stokes, Paul R A; Shotbolt, Paul; Mehta, Mitul A; Turkheimer, Eric; Benecke, Aaf; Copeland, Caroline; Turkheimer, Federico E; Lingford-Hughes, Anne R; Howes, Oliver D

    2013-02-01

    Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.

  5. Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an [18F]-DOPA PET Study

    PubMed Central

    Stokes, Paul R A; Shotbolt, Paul; Mehta, Mitul A; Turkheimer, Eric; Benecke, Aaf; Copeland, Caroline; Turkheimer, Federico E; Lingford-Hughes, Anne R; Howes, Oliver D

    2013-01-01

    Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions. PMID:23093224

  6. Striatal MPP+ levels do not necessarily correlate with striatal dopamine levels after MPTP treatment in mice.

    PubMed

    Vaglini, F; Fascetti, F; Tedeschi, D; Cavalletti, M; Fornai, F; Corsini, G U

    1996-06-01

    The present study offers confirmation of the fact that an MAO-B inhibitor, (-) deprenyl and a DA uptake blocker, GBR-12909, prevent MPTP-induced striatal DA decrease. This protective effect is accompanied by an almost complete prevention of MPP+ production induced by (-) deprenyl and an accelerated MPP+ clearance induced by GBR-12909 within the striatum. Similarly, the MPTP toxicity enhancers, DDC and acetaldehyde, both increase striatal MPP+ levels, as previously reported. On the contrary, the treatment with MK 801, although uneffective in preventing the long-term MPTP-induced striatal DA decrease, causes an increase in the striatal amount of MPP+. In a similar way, the administration of nicotine in combination with MPTP produces a significant increase in the levels of striatal MPP+, which does not elicit any effect on striatal DA. The effect of clonidine is consistent with these results and in sharp contrast with the current belief that a direct relationship exists between striatal MPP+ concentrations and the degree of MPTP-induced depletion of striatal DA. In this study, using different treatments, we failed to confirm the correlation between MPP+ striatal levels and dopaminergic lesions after MPTP administration in mice. We suggest that this correlation is not a rule and exceptions may depend on a different compartimentalization of the toxic metabolite.

  7. Changes in regional and temporal patterns of activity associated with aging during the performance of a lexical set-shifting task.

    PubMed

    Martins, Ruben; Simard, France; Provost, Jean-Sebastien; Monchi, Oury

    2012-06-01

    Some older individuals seem to use compensatory mechanisms to maintain high-level performance when submitted to cognitive tasks. However, whether and how these mechanisms affect fronto-striatal activity has never been explored. The purpose of this study was to investigate how aging affects brain patterns during the performance of a lexical analog of the Wisconsin Card Sorting Task, which has been shown to strongly depend on fronto-striatal activity. In the present study, both younger and older individuals revealed significant fronto-striatal loop activity associated with planning and execution of set-shifts, though age-related striatal activity reduction was observed. Most importantly, while the younger group showed the involvement of a "cognitive loop" during the receiving negative feedback period (which indicates that a set-shift will be required to perform the following trial) and the involvement of a "motor loop" during the matching after negative feedback period (when the set-shift must be performed), older participants showed significant activation of both loops during the matching after negative feedback period only. These findings are in agreement with the "load-shift" model postulated by Velanova et al. (Velanova K, Lustig C, Jacoby LL, Buckner RL. 2007. Evidence for frontally mediated controlled processing differences in older adults. Cereb Cortex. 17:1033-1046.) and indicate that the model is not limited to memory retrieval but also applies to executive processes relying on fronto-striatal regions.

  8. Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale

    PubMed Central

    Khan, Sheraz; Michmizos, Konstantinos; Tommerdahl, Mark; Ganesan, Santosh; Kitzbichler, Manfred G.; Zetino, Manuel; Garel, Keri-Lee A.; Herbert, Martha R.; Hämäläinen, Matti S.

    2015-01-01

    Functional connectivity is abnormal in autism, but the nature of these abnormalities remains elusive. Different studies, mostly using functional magnetic resonance imaging, have found increased, decreased, or even mixed pattern functional connectivity abnormalities in autism, but no unifying framework has emerged to date. We measured functional connectivity in individuals with autism and in controls using magnetoencephalography, which allowed us to resolve both the directionality (feedforward versus feedback) and spatial scale (local or long-range) of functional connectivity. Specifically, we measured the cortical response and functional connectivity during a passive 25-Hz vibrotactile stimulation in the somatosensory cortex of 20 typically developing individuals and 15 individuals with autism, all males and right-handed, aged 8–18, and the mu-rhythm during resting state in a subset of these participants (12 per group, same age range). Two major significant group differences emerged in the response to the vibrotactile stimulus. First, the 50-Hz phase locking component of the cortical response, generated locally in the primary (S1) and secondary (S2) somatosensory cortex, was reduced in the autism group (P < 0.003, corrected). Second, feedforward functional connectivity between S1 and S2 was increased in the autism group (P < 0.004, corrected). During resting state, there was no group difference in the mu-α rhythm. In contrast, the mu-β rhythm, which has been associated with feedback connectivity, was significantly reduced in the autism group (P < 0.04, corrected). Furthermore, the strength of the mu-β was correlated to the relative strength of 50 Hz component of the response to the vibrotactile stimulus (r = 0.78, P < 0.00005), indicating a shared aetiology for these seemingly unrelated abnormalities. These magnetoencephalography-derived measures were correlated with two different behavioural sensory processing scores (P < 0.01 and P < 0.02 for the autism

  9. Task-Rest Modulation of Basal Ganglia Connectivity in Mild to Moderate Parkinson’s Disease

    PubMed Central

    Müller-Oehring, Eva M.; Sullivan, Edith V.; Pfefferbaum, Adolf; Huang, Neng C.; Poston, Kathleen L.; Bronte-Stewart, Helen M.; Schulte, Tilman

    2014-01-01

    Parkinson’s disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG–cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen–medial parietal and pallidum–occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate–supramarginal gyrus and pallidum–inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal–cortical connectivity, specifically between caudate–prefrontal, caudate–precuneus, and putamen–motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance. PMID:25280970

  10. Role of contingency in striatal response to incentive in adolescents with anxiety.

    PubMed

    Benson, Brenda E; Guyer, Amanda E; Nelson, Eric E; Pine, Daniel S; Ernst, Monique

    2015-03-01

    This study examines the effect of contingency on reward function in anxiety. We define contingency as the aspect of a situation in which the outcome is determined by one's action-that is, when there is a direct link between one's action and the outcome of the action. Past findings in adolescents with anxiety or at risk for anxiety have revealed hypersensitive behavioral and neural responses to higher value rewards with correct performance. This hypersensitivity to highly valued (salient) actions suggests that the value of actions is determined not only by outcome magnitude, but also by the degree to which the outcome is contingent on correct performance. Thus, contingency and incentive value might each modulate reward responses in unique ways in anxiety. Using fMRI with a monetary reward task, striatal response to cue anticipation is compared in 18 clinically anxious and 20 healthy adolescents. This task manipulates orthogonally reward contingency and incentive value. Findings suggest that contingency modulates the neural response to incentive magnitude differently in the two groups. Specifically, during the contingent condition, right-striatal response tracks incentive value in anxious, but not healthy, adolescents. During the noncontingent condition, striatal response is bilaterally stronger to low than to high incentive in anxious adolescents, while healthy adolescents exhibit the expected opposite pattern. Both contingency and reward magnitude differentiate striatal activation in anxious versus healthy adolescents. These findings may reflect exaggerated concern about performance and/or alterations of striatal coding of reward value in anxious adolescents. Abnormalities in reward function in anxiety may have treatment implications.

  11. Striatal FoxP2 Is Actively Regulated during Songbird Sensorimotor Learning

    PubMed Central

    Teramitsu, Ikuko; Poopatanapong, Amy; Torrisi, Salvatore; White, Stephanie A.

    2010-01-01

    Background Mutations in the FOXP2 transcription factor lead to language disorders with developmental onset. Accompanying structural abnormalities in cortico-striatal circuitry indicate that at least a portion of the behavioral phenotype is due to organizational deficits. We previously found parallel FoxP2 expression patterns in human and songbird cortico/pallio-striatal circuits important for learned vocalizations, suggesting that FoxP2's function in birdsong may generalize to speech. Methodology/Principal Findings We used zebra finches to address the question of whether FoxP2 is additionally important in the post-organizational function of these circuits. In both humans and songbirds, vocal learning depends on auditory guidance to achieve and maintain optimal vocal output. We tested whether deafening prior to or during the sensorimotor phase of song learning disrupted FoxP2 expression in song circuitry. As expected, the songs of deafened juveniles were abnormal, however basal FoxP2 levels were unaffected. In contrast, when hearing or deaf juveniles sang for two hours in the morning, FoxP2 was acutely down-regulated in the striatal song nucleus, area X. The extent of down-regulation was similar between hearing and deaf birds. Interestingly, levels of FoxP2 and singing were correlated only in hearing birds. Conclusions/Significance Hearing appears to link FoxP2 levels to the amount of vocal practice. As juvenile birds spent more time practicing than did adults, their FoxP2 levels are likely to be low more often. Behaviorally-driven reductions in the mRNA encoding this transcription factor could ultimately affect downstream molecules that function in vocal exploration, especially during sensorimotor learning. PMID:20062527

  12. Global connectivity of prefrontal cortex predicts cognitive control and intelligence

    PubMed Central

    Cole, Michael W.; Yarkoni, Tal; Repovs, Grega; Anticevic, Alan; Braver, Todd S.

    2012-01-01

    Control of thought and behavior is fundamental to human intelligence. Evidence suggests a fronto-parietal brain network implements such cognitive control across diverse contexts. We identify a mechanism – global connectivity – by which components of this network might coordinate control of other networks. A lateral prefrontal cortex (LPFC) region’s activity was found to predict performance in a high control demand working memory task, and also to exhibit high global connectivity. Critically, global connectivity in this LPFC region, involving connections both within and outside the fronto-parietal network, showed a highly selective relationship with individual differences in fluid intelligence. These findings suggest LPFC is a global hub with a brain-wide influence that facilitates the ability to implement control processes central to human intelligence. PMID:22745498

  13. The association of children's mathematic abilities with both adults' cognitive abilities and intrinsic fronto-parietal networks is altered in preterm-born individuals.

    PubMed

    Bäuml, J G; Meng, C; Daamen, M; Baumann, N; Busch, B; Bartmann, P; Wolke, D; Boecker, H; Wohlschläger, A; Sorg, C; Jaekel, Julia

    2017-03-01

    Mathematic abilities in childhood are highly predictive for long-term neurocognitive outcomes. Preterm-born individuals have an increased risk for both persistent cognitive impairments and long-term changes in macroscopic brain organization. We hypothesized that the association of childhood mathematic abilities with both adulthood general cognitive abilities and associated fronto-parietal intrinsic networks is altered after preterm delivery. 72 preterm- and 71 term-born individuals underwent standardized mathematic and IQ testing at 8 years and resting-state fMRI and full-scale IQ testing at 26 years of age. Outcome measure for intrinsic networks was intrinsic functional connectivity (iFC). Controlling for IQ at age eight, mathematic abilities in childhood were significantly stronger positively associated with adults' IQ in preterm compared with term-born individuals. In preterm-born individuals, the association of children's mathematic abilities and adults' fronto-parietal iFC was altered. Likewise, fronto-parietal iFC was distinctively linked with preterm- and term-born adults' IQ. Results provide evidence that preterm birth alters the link of mathematic abilities in childhood and general cognitive abilities and fronto-parietal intrinsic networks in adulthood. Data suggest a distinct functional role of intrinsic fronto-parietal networks for preterm individuals with respect to mathematic abilities and that these networks together with associated children's mathematic abilities may represent potential neurocognitive targets for early intervention.

  14. Abnormal Neural Connectivity in Schizophrenia and fMRI-Brain-Computer Interface as a Potential Therapeutic Approach

    PubMed Central

    Ruiz, Sergio; Birbaumer, Niels; Sitaram, Ranganatha

    2012-01-01

    Considering that single locations of structural and functional abnormalities are insufficient to explain the diverse psychopathology of schizophrenia, new models have postulated that the impairments associated with the disease arise from a failure to integrate the activity of local and distributed neural circuits: the “abnormal neural connectivity hypothesis.” In the last years, new evidence coming from neuroimaging have supported and expanded this theory. However, despite the increasing evidence that schizophrenia is a disorder of neural connectivity, so far there are no treatments that have shown to produce a significant change in brain connectivity, or that have been specifically designed to alleviate this problem. Brain-Computer Interfaces based on real-time functional Magnetic Resonance Imaging (fMRI-BCI) are novel techniques that have allowed subjects to achieve self-regulation of circumscribed brain regions. In recent studies, experiments with this technology have resulted in new findings suggesting that this methodology could be used to train subjects to enhance brain connectivity, and therefore could potentially be used as a therapeutic tool in mental disorders including schizophrenia. The present article summarizes the findings coming from hemodynamics-based neuroimaging that support the abnormal connectivity hypothesis in schizophrenia, and discusses a new approach that could address this problem. PMID:23525496

  15. Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine.

    PubMed

    Aarts, Esther; van Holstein, Mieke; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

    2015-02-01

    Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3'-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD.

  16. Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine

    PubMed Central

    Aarts, Esther; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

    2015-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3′-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD. PMID:25485641

  17. Thalamocortical functional connectivity in Lennox-Gastaut syndrome is abnormally enhanced in executive-control and default-mode networks.

    PubMed

    Warren, Aaron E L; Abbott, David F; Jackson, Graeme D; Archer, John S

    2017-12-01

    To identify abnormal thalamocortical circuits in the severe epilepsy of Lennox-Gastaut syndrome (LGS) that may explain the shared electroclinical phenotype and provide potential treatment targets. Twenty patients with a diagnosis of LGS (mean age = 28.5 years) and 26 healthy controls (mean age = 27.6 years) were compared using task-free functional magnetic resonance imaging (MRI). The thalamus was parcellated according to functional connectivity with 10 cortical networks derived using group-level independent component analysis. For each cortical network, we assessed between-group differences in thalamic functional connectivity strength using nonparametric permutation-based tests. Anatomical locations were identified by quantifying spatial overlap with a histologically informed thalamic MRI atlas. In both groups, posterior thalamic regions showed functional connectivity with visual, auditory, and sensorimotor networks, whereas anterior, medial, and dorsal thalamic regions were connected with networks of distributed association cortex (including the default-mode, anterior-salience, and executive-control networks). Four cortical networks (left and right executive-control network; ventral and dorsal default-mode network) showed significantly enhanced thalamic functional connectivity strength in patients relative to controls. Abnormal connectivity was maximal in mediodorsal and ventrolateral thalamic nuclei. Specific thalamocortical circuits are affected in LGS. Functional connectivity is abnormally enhanced between the mediodorsal and ventrolateral thalamus and the default-mode and executive-control networks, thalamocortical circuits that normally support diverse cognitive processes. In contrast, thalamic regions connecting with primary and sensory cortical networks appear to be less affected. Our previous neuroimaging studies show that epileptic activity in LGS is expressed via the default-mode and executive-control networks. Results of the present study suggest that

  18. Cortical ionotropic glutamate receptor antagonism protects against methamphetamine-induced striatal neurotoxicity.

    PubMed

    Gross, N B; Duncker, P C; Marshall, J F

    2011-12-29

    Binge administration of the psychostimulant drug, methamphetamine (mAMPH), produces long-lasting structural and functional abnormalities in the striatum. mAMPH binges produce nonexocytotic release of dopamine (DA), and mAMPH-induced activation of excitatory afferent inputs to cortex and striatum is evidenced by elevated extracellular glutamate (GLU) in both regions. The mAMPH-induced increases in DA and GLU neurotransmission are thought to combine to injure striatal DA nerve terminals of mAMPH-exposed brains. Systemic pretreatment with either competitive or noncompetitive N-methyl-D-aspartic acid (NMDA) antagonists protects against mAMPH-induced striatal DA terminal damage, but the locus of these antagonists' effects has not been determined. Here, we applied either the NMDA receptor antagonist, (dl)-amino-5-phosphonovaleric acid (AP5), or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, dinitroquinoxaline-2,3-dione (DNQX), directly to the dura mater over frontoparietal cortex to assess their effects on mAMPH-induced cortical and striatal immediate-early gene (c-fos) expression. In a separate experiment we applied AP5 or DNQX epidurally in the same cortical location of rats during a binge regimen of mAMPH and assessed mAMPH-induced striatal dopamine transporter (DAT) depletions 1 week later. Our results indicate that both ionotropic glutamate receptor antagonists reduced the mAMPH-induced Fos expression in cerebral cortex regions near the site of epidural application and reduced Fos immunoreactivity in striatal regions innervated by the affected cortical regions. Also, epidural application of the same concentration of either antagonist during a binge mAMPH regimen blunted the mAMPH-induced striatal DAT depletions with a topography similar to its effects on Fos expression. These findings demonstrate that mAMPH-induced dopaminergic injury depends upon cortical NMDA and AMPA receptor activation and suggest the involvement of the

  19. Fronto-Parietal Subnetworks Flexibility Compensates For Cognitive Decline Due To Mental Fatigue.

    PubMed

    Taya, Fumihiko; Dimitriadis, Stavros I; Dragomir, Andrei; Lim, Julian; Sun, Yu; Wong, Kian Foong; Thakor, Nitish V; Bezerianos, Anastasios

    2018-04-24

    Fronto-parietal subnetworks were revealed to compensate for cognitive decline due to mental fatigue by community structure analysis. Here, we investigate changes in topology of subnetworks of resting-state fMRI networks due to mental fatigue induced by prolonged performance of a cognitively demanding task, and their associations with cognitive decline. As it is well established that brain networks have modular organization, community structure analyses can provide valuable information about mesoscale network organization and serve as a bridge between standard fMRI approaches and brain connectomics that quantify the topology of whole brain networks. We developed inter- and intramodule network metrics to quantify topological characteristics of subnetworks, based on our hypothesis that mental fatigue would impact on functional relationships of subnetworks. Functional networks were constructed with wavelet correlation and a data-driven thresholding scheme based on orthogonal minimum spanning trees, which allowed detection of communities with weak connections. A change from pre- to posttask runs was found for the intermodule density between the frontal and the temporal subnetworks. Seven inter- or intramodule network metrics, mostly at the frontal or the parietal subnetworks, showed significant predictive power of individual cognitive decline, while the network metrics for the whole network were less effective in the predictions. Our results suggest that the control-type fronto-parietal networks have a flexible topological architecture to compensate for declining cognitive ability due to mental fatigue. This community structure analysis provides valuable insight into connectivity dynamics under different cognitive states including mental fatigue. © 2018 Wiley Periodicals, Inc.

  20. Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.

    PubMed

    Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong; Reimers, Jeremy M; Liu, Shunan; Powell, Craig M

    2016-03-01

    Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼ 0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

  1. Increased ventral-striatal activity during monetary decision making is a marker of problem poker gambling severity.

    PubMed

    Brevers, Damien; Noël, Xavier; He, Qinghua; Melrose, James A; Bechara, Antoine

    2016-05-01

    The aim of this study was to examine the impact of different neural systems on monetary decision making in frequent poker gamblers, who vary in their degree of problem gambling. Fifteen frequent poker players, ranging from non-problem to high-problem gambling, and 15 non-gambler controls were scanned using functional magnetic resonance imaging (fMRI) while performing the Iowa Gambling Task (IGT). During IGT deck selection, between-group fMRI analyses showed that frequent poker gamblers exhibited higher ventral-striatal but lower dorsolateral prefrontal and orbitofrontal activations as compared with controls. Moreover, using functional connectivity analyses, we observed higher ventral-striatal connectivity in poker players, and in regions involved in attentional/motor control (posterior cingulate), visual (occipital gyrus) and auditory (temporal gyrus) processing. In poker gamblers, scores of problem gambling severity were positively associated with ventral-striatal activations and with the connectivity between the ventral-striatum seed and the occipital fusiform gyrus and the middle temporal gyrus. Present results are consistent with findings from recent brain imaging studies showing that gambling disorder is associated with heightened motivational-reward processes during monetary decision making, which may hamper one's ability to moderate his level of monetary risk taking. © 2015 Society for the Study of Addiction.

  2. The caudate: a key node in the neuronal network imbalance of insomnia?

    PubMed Central

    Altena, Ellemarije; van der Werf, Ysbrand D.; Sanz-Arigita, Ernesto J.; Voorn, Thom A.; Astill, Rebecca G.; Strijers, Rob L. M.; Waterman, Dé; Van Someren, Eus J. W.

    2014-01-01

    Insomnia is prevalent, severe and partially heritable. Unfortunately, its neuronal correlates remain enigmatic, hampering the development of mechanistic models and rational treatments. Consistently reported impairments concern fragmented sleep, hyper-arousal and executive dysfunction. Because fronto-striatal networks could well play a role in sleep, arousal regulation and executive functioning, the present series of studies used an executive task to evaluate fronto-striatal functioning in disturbed sleep. Patients with insomnia showed reduced recruitment of the head of the left caudate nucleus during executive functioning, which was not secondary to altered performance or baseline perfusion. Individual differences in caudate recruitment were associated with hyper-arousal severity. Seed-based functional connectivity analysis suggested that attenuated input from a projecting orbitofrontal area with reduced grey matter density contributes to altered caudate recruitment in patients with insomnia. Attenuated caudate recruitment persisted after successful treatment of insomnia, warranting evaluation as a potential vulnerability trait. A similar selective reduction in caudate recruitment could be elicited in participants without sleep complaints by slow-wave sleep fragmentation, providing a model to facilitate investigation of the causes and consequences of insomnia. PMID:24285642

  3. Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use.

    PubMed

    Ashtari, Manzar; Cervellione, Kelly; Cottone, John; Ardekani, Babak A; Sevy, Serge; Kumra, Sanjiv

    2009-01-01

    There is growing evidence that adolescence is a key period for neuronal maturation. Despite the high prevalence of marijuana use among adolescents and young adults in the United States and internationally, very little is known about its impact on the developing brain. Based on neuroimaging literature on normal brain developmental during adolescence, we hypothesized that individuals with heavy cannabis use (HCU) would have brain structure abnormalities in similar brain regions that undergo development during late adolescence, particularly the fronto-temporal connection. Fourteen young adult males in residential treatment for cannabis dependence and 14 age-matched healthy male control subjects were recruited. Patients had a history of HCU throughout adolescence; 5 had concurrent alcohol abuse. Subjects underwent structural and diffusion tensor magnetic resonance imaging. White matter integrity was compared between subject groups using voxelwise and fiber tractography analysis. Voxelwise and tractography analyses revealed that adolescents with HCU had reduced fractional anisotropy, increased radial diffusivity, and increased trace in the homologous areas known to be involved in ongoing development during late adolescence, particularly in the fronto-temporal connection via arcuate fasciculus. Our results support the hypothesis that heavy cannabis use during adolescence may affect the trajectory of normal brain maturation. Due to concurrent alcohol consumption in five HCU subjects, conclusions from this study should be considered preliminary, as the DTI findings reported here may be reflective of the combination of alcohol and marijuana use. Further research in larger samples, longitudinal in nature, and controlling for alcohol consumption is needed to better understand the pathophysiology of the effect of cannabis on the developing brain.

  4. Dissociation of functional and anatomical brain abnormalities in unaffected siblings of schizophrenia patients.

    PubMed

    Guo, Wenbin; Song, Yan; Liu, Feng; Zhang, Zhikun; Zhang, Jian; Yu, Miaoyu; Liu, Jianrong; Xiao, Changqing; Liu, Guiying; Zhao, Jingping

    2015-05-01

    Schizophrenia patients and their unaffected siblings share similar brain functional and structural abnormalities. However, no study is engaged to investigate whether and how functional abnormalities are related to structural abnormalities in unaffected siblings. This study was undertaken to examine the association between functional and anatomical abnormalities in unaffected siblings. Forty-six unaffected siblings of schizophrenia patients and 46 age-, sex-, and education-matched healthy controls underwent structural and resting-state functional magnetic resonance imaging scanning. Voxel-based morphometry (VBM), amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) were utilized to analyze imaging data. The VBM analysis showed gray matter volume decreases in the fronto-temporal regions (the left middle temporal gyrus and right inferior frontal gyrus, orbital part) and increases in basal ganglia system (the left putamen). Functional abnormalities measured by ALFF and fALFF mainly involved in the fronto-limbic-sensorimotor circuit (decreased ALFF in bilateral middle frontal gyrus and the right middle cingulate gyrus, and decreased fALFF in the right inferior frontal gyrus, orbital part; and increased ALFF in the left fusiform gyrus and left lingual gyrus, and increased fALFF in bilateral calcarine cortex). No significant correlation was found between functional and anatomical abnormalities in the sibling group. A dissociation pattern of brain regions with functional and anatomical abnormalities is observed in unaffected siblings. Our findings suggest that brain functional and anatomical abnormalities might be present independently in unaffected siblings of schizophrenia patients. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  5. Relationship between Duration of Untreated Psychosis and Intrinsic Corticostriatal Connectivity in Patients with Early Phase Schizophrenia.

    PubMed

    Sarpal, Deepak K; Robinson, Delbert G; Fales, Christina; Lencz, Todd; Argyelan, Miklos; Karlsgodt, Katherine H; Gallego, Juan A; John, Majnu; Kane, John M; Szeszko, Philip R; Malhotra, Anil K

    2017-10-01

    Patients with first-episode psychosis experience psychotic symptoms for a mean of up to 2 years prior to initiation of treatment, and long duration of untreated psychosis (DUP) is associated with poor clinical outcomes. Meanwhile, evidence compiled from numerous studies suggests that longer DUP is not associated with structural brain abnormalities. To date, few studies have examined the relationship between DUP and functional neuroimaging measures. In the present study, we used seed-based resting-state functional connectivity to examine the impact of DUP on corticostriatal circuitry. We included 83 patients with early phase schizophrenia and minimal exposure to antipsychotic drugs (<2 years), who underwent resting state scanning while entering 12 weeks of prospective treatment with second-generation antipsychotic drugs. Functional connectivity maps of the striatum were generated and examined in relation to DUP as a covariate. Mediation analyses were performed on a composite measure of corticostriatal connectivity derived from the significant results of our DUP analysis. We found that longer DUP correlated with worse response to treatment as well as overall decreased functional connectivity between striatal nodes and specific regions within frontal and parietal cortices. Moreover, the relationship between DUP and treatment response was significantly mediated by corticostriatal connectivity. Our results indicate that variation in corticostriatal circuitry may play a role in the relationship between longer DUP and worsened response to treatment. Future prospective studies are necessary to further characterize potential causal links between DUP, striatal circuitry and clinical outcomes.

  6. Temporal abnormalities in children with developmental dyscalculia.

    PubMed

    Vicario, Carmelo Mario; Rappo, Gaetano; Pepi, Annamaria; Pavan, Andrea; Martino, Davide

    2012-01-01

    Recent imaging studies have associated Developmental dyscalculia (DD) to structural and functional alterations corresponding Parietal and the Prefrontal cortex (PFC). Since these areas were shown also to be involved in timing abilities, we hypothesized that time processing is abnormal in DD. We compared time processing abilities between 10 children with pure DD (8 years old) and 11 age-matched healthy children. Results show that the DD group underestimated duration of a sub-second scale when asked to perform a time comparison task. The timing abnormality observed in our DD participants is consistent with evidence of a shared fronto-parietal neural network for representing time and quantity.

  7. Abuse of Amphetamines and Structural Abnormalities in Brain

    PubMed Central

    Berman, Steven; O’Neill, Joseph; Fears, Scott; Bartzokis, George; London, Edythe D.

    2009-01-01

    We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse, and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques that include manual tracing, pattern matching, voxel-based, tensor-based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3-4-methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine-rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common, and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross-sectional designs, which cannot infer causality. Potential confounding influences include effects of pre-existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain

  8. Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice.

    PubMed

    Suelves, Nuria; Miguez, Andrés; López-Benito, Saray; Barriga, Gerardo García-Díaz; Giralt, Albert; Alvarez-Periel, Elena; Arévalo, Juan Carlos; Alberch, Jordi; Ginés, Silvia; Brito, Verónica

    2018-05-27

    Deficits in striatal brain-derived neurotrophic factor (BDNF) delivery and/or BDNF/tropomyosin receptor kinase B (TrkB) signaling may contribute to neurotrophic support reduction and selective early degeneration of striatal medium spiny neurons in Huntington's disease (HD). Furthermore, we and others have demonstrated that TrkB/p75 NTR imbalance in vitro increases the vulnerability of striatal neurons to excitotoxic insults and induces corticostriatal synaptic alterations. We have now expanded these studies by analyzing the consequences of BDNF/TrkB/p75 NTR imbalance in the onset of motor behavior and striatal neuropathology in HD mice. Our findings demonstrate for the first time that the onset of motor coordination abnormalities, in a full-length knock-in HD mouse model (KI), correlates with the reduction of BDNF and TrkB levels, along with an increase in p75 NTR expression. Genetic normalization of p75 NTR expression in KI mutant mice delayed the onset of motor deficits and striatal neuropathology, as shown by restored levels of striatal-enriched proteins and dendritic spine density and reduced huntingtin aggregation. We found that the BDNF/TrkB/p75 NTR imbalance led to abnormal BDNF signaling, manifested as a diminished activation of TrkB-phospholipase C-gamma pathway but upregulation of c-Jun kinase pathway. Moreover, we confirmed the contribution of the proper balance of BDNF/TrkB/p75 NTR on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75 NTR levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75 NTR expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75 NTR could be promising to prevent motor deficits in HD.

  9. Professional training in creative writing is associated with enhanced fronto-striatal activity in a literary text continuation task.

    PubMed

    Erhard, K; Kessler, F; Neumann, N; Ortheil, H-J; Lotze, M

    2014-10-15

    The aim of the present study was to explore brain activities associated with creativity and expertise in literary writing. Using functional magnetic resonance imaging (fMRI), we applied a real-life neuroscientific setting that consisted of different writing phases (brainstorming and creative writing; reading and copying as control conditions) to well-selected expert writers and to an inexperienced control group. During creative writing, experts showed cerebral activation in a predominantly left-hemispheric fronto-parieto-temporal network. When compared to inexperienced writers, experts showed increased left caudate nucleus and left dorsolateral and superior medial prefrontal cortex activation. In contrast, less experienced participants recruited increasingly bilateral visual areas. During creative writing activation in the right cuneus showed positive association with the creativity index in expert writers. High experience in creative writing seems to be associated with a network of prefrontal (mPFC and DLPFC) and basal ganglia (caudate) activation. In addition, our findings suggest that high verbal creativity specific to literary writing increases activation in the right cuneus associated with increased resources obtained for reading processes. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Reward-Based Spatial Learning in Teens With Bulimia Nervosa.

    PubMed

    Cyr, Marilyn; Wang, Zhishun; Tau, Gregory Z; Zhao, Guihu; Friedl, Eve; Stefan, Mihaela; Terranova, Kate; Marsh, Rachel

    2016-11-01

    To assess the functioning of mesolimbic and fronto-striatal areas involved in reward-based spatial learning in teenaged girls with bulimia nervosa (BN) that might be involved in the development and maintenance of maladaptive behaviors characteristic of the disorder. We compared functional magnetic resonance imaging blood oxygen level-dependent response in 27 adolescent girls with BN to that of 27 healthy, age-matched control participants during a reward-based learning task that required learning to use extra-maze cues to navigate a virtual 8-arm radial maze to find hidden rewards. We compared groups in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudo-randomly to experimentally prevent learning. Both groups learned to navigate the maze to find hidden rewards, but group differences in brain activity associated with maze navigation and reward processing were detected in the fronto-striatal regions and right anterior hippocampus. Unlike healthy adolescents, those with BN did not engage the right inferior frontal gyrus during maze navigation, activated the right anterior hippocampus during the receipt of unexpected rewards (control condition), and deactivated the left superior frontal gyrus and right anterior hippocampus during expected reward receipt (learning condition). These patterns of hippocampal activation in the control condition were significantly associated with the frequency of binge-eating episodes. Adolescents with BN displayed abnormal functioning of the anterior hippocampus and fronto-striatal regions during reward-based spatial learning. These findings suggest that an imbalance in control and reward circuits may arise early in the course of BN. Clinical trial registration information-An fMRI Study of Self-Regulation in Adolescents With Bulimia Nervosa; https://clinicaltrials.gov/; NCT00345943. Copyright © 2016 American Academy

  11. Reward-Based Spatial Learning in Teens With Bulimia Nervosa

    PubMed Central

    Cyr, Marilyn; Wang, Zhishun; Tau, Gregory Z.; Zhao, Guihu; Friedl, Eve; Stefan, Mihaela; Terranova, Kate; Marsh, Rachel

    2016-01-01

    Objective To assess the functioning of mesolimbic and fronto-striatal areas involved in reward-based spatial learning in teenaged girls with bulimia nervosa (BN) that might be involved in the development and maintenance of maladaptive behaviors characteristic of the disorder. Method We compared functional magnetic resonance imaging blood oxygen level dependent response in 27 adolescent girls with BN to that of 27 healthy, age-matched control participants during a reward-based learning task that required learning to use extra-maze cues to navigate a virtual 8-arm radial maze to find hidden rewards. We compared groups in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudo-randomly to experimentally prevent learning. Results Both groups learned to navigate the maze to find hidden rewards, but group differences in brain activity associated with maze navigation and reward processing were detected in fronto-striatal regions and right anterior hippocampus. Unlike healthy adolescents, those with BN did not engage right inferior frontal gyrus during maze navigation, activated right anterior hippocampus during the receipt of unexpected rewards (control condition), and deactivated left superior frontal gyrus and right anterior hippocampus during expected reward receipt (learning condition). These patterns of hippocampal activation in the control condition were significantly associated with the frequency of binge-eating episodes. Conclusion Adolescents with BN displayed abnormal functioning of anterior hippocampus and fronto-striatal regions during reward-based spatial learning. These findings suggest that an imbalance in control and reward circuits may arise early in the course of BN. Clinical trial registration information An fMRI Study of Self-regulation in Adolescents With Bulimia Nervosa; https://clinicaltrials.gov/ct2/show/NCT00345943; NCT00345943

  12. Optimal balance of the striatal medium spiny neuron network.

    PubMed

    Ponzi, Adam; Wickens, Jeffery R

    2013-04-01

    Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of 10 ~ 20% and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around 15% connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics - it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is

  13. Optimal Balance of the Striatal Medium Spiny Neuron Network

    PubMed Central

    Ponzi, Adam; Wickens, Jeffery R.

    2013-01-01

    Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics – it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to

  14. Abnormal rich club organization and impaired correlation between structural and functional connectivity in migraine sufferers.

    PubMed

    Li, Kang; Liu, Lijun; Yin, Qin; Dun, Wanghuan; Xu, Xiaolin; Liu, Jixin; Zhang, Ming

    2017-04-01

    Because of the unique position of the topologically central role of densely interconnected brain hubs, our study aimed to investigate whether these regions and their related connections would be particularly vulnerable to migraine. In our study, we explored the rich club structure and its role in global functional dynamics in 30 patients with migraine without aura and 30 healthy controls. DTI and resting fMRI were used to construct structural connectivity (SC) and functional connectivity (FC) networks. An independent replication data set of 26 patients and 26 controls was included to replicate and validate significant findings. As compared with the controls, the structural networks of patients exhibited altered rich club organization with higher level of feeder connection density, abnormal small-world organization with increased global efficiency and decreased strength of SC-FC coupling. As these abnormal topological properties and headache attack duration exhibited a significant association with increased density of feeder connections, our results indicated that migraine may be characterized by a selective alteration of the structural connectivity of the rich club regions, tending to have higher 'bridgeness' with non-rich club regions, which may increase the integration among pain-related brain circuits with more excitability but less inhibition for the modulation of migraine.

  15. Frontostriatal connectivity in children during working memory and the effects of prenatal methamphetamine, alcohol, and polydrug exposure.

    PubMed

    Roussotte, Florence F; Rudie, Jeffrey D; Smith, Lynne; O'Connor, Mary J; Bookheimer, Susan Y; Narr, Katherine L; Sowell, Elizabeth R

    2012-01-01

    Various abnormalities in frontal and striatal regions have been reported in children with prenatal alcohol and/or methamphetamine exposure. In a recent fMRI study, we observed a correlation between accuracy on a working-memory task and functional activation in the putamen in children with prenatal methamphetamine and polydrug exposure. Because the putamen is part of the corticostriatal motor loop whereas the caudate is involved in the executive loop, we hypothesized that a loss of segregation between distinct corticostriatal networks may occur in these participants. The current study was designed to test this hypothesis using functional connectivity MRI. We examined 50 children ranging in age from 7 to 15, including 19 with prenatal methamphetamine exposure (15 of whom had concomitant prenatal alcohol exposure), 13 with prenatal exposure to alcohol but not methamphetamine, and 18 unexposed controls. We measured the coupling between blood oxygenation level dependent (BOLD) fluctuations during a working-memory task in four striatal seed regions and those in the rest of the brain. We found that the putamen seeds showed increased connectivity with frontal brain regions involved in executive functions while the caudate seeds showed decreased connectivity with some of these regions in both groups of exposed subjects compared to controls. These findings suggest that localized brain abnormalities resulting from prenatal exposure to alcohol and/or methamphetamine lead to a partial rewiring of corticostriatal networks. These results represent important progress in the field, and could have substantial clinical significance in helping devise more targeted treatments and remediation strategies designed to better serve the needs of this population. Copyright © 2012 S. Karger AG, Basel.

  16. Optogenetic approaches to evaluate striatal function in animal models of Parkinson disease.

    PubMed

    Parker, Krystal L; Kim, Youngcho; Alberico, Stephanie L; Emmons, Eric B; Narayanan, Nandakumar S

    2016-03-01

    Optogenetics refers to the ability to control cells that have been genetically modified to express light-sensitive ion channels. The introduction of optogenetic approaches has facilitated the dissection of neural circuits. Optogenetics allows for the precise stimulation and inhibition of specific sets of neurons and their projections with fine temporal specificity. These techniques are ideally suited to investigating neural circuitry underlying motor and cognitive dysfunction in animal models of human disease. Here, we focus on how optogenetics has been used over the last decade to probe striatal circuits that are involved in Parkinson disease, a neurodegenerative condition involving motor and cognitive abnormalities resulting from degeneration of midbrain dopaminergic neurons. The precise mechanisms underlying the striatal contribution to both cognitive and motor dysfunction in Parkinson disease are unknown. Although optogenetic approaches are somewhat removed from clinical use, insight from these studies can help identify novel therapeutic targets and may inspire new treatments for Parkinson disease. Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.

  17. Abnormal functional network connectivity among resting-state networks in children with frontal lobe epilepsy.

    PubMed

    Widjaja, E; Zamyadi, M; Raybaud, C; Snead, O C; Smith, M L

    2013-12-01

    Epilepsy is considered a disorder of neural networks. The aims of this study were to assess functional connectivity within resting-state networks and functional network connectivity across resting-state networks by use of resting-state fMRI in children with frontal lobe epilepsy and to relate changes in resting-state networks with neuropsychological function. Fifteen patients with frontal lobe epilepsy and normal MR imaging and 14 healthy control subjects were recruited. Spatial independent component analysis was used to identify the resting-state networks, including frontal, attention, default mode network, sensorimotor, visual, and auditory networks. The Z-maps of resting-state networks were compared between patients and control subjects. The relation between abnormal connectivity and neuropsychological function was assessed. Correlations from all pair-wise combinations of independent components were performed for each group and compared between groups. The frontal network was the only network that showed reduced connectivity in patients relative to control subjects. The remaining 5 networks demonstrated both reduced and increased functional connectivity within resting-state networks in patients. There was a weak association between connectivity in frontal network and executive function (P = .029) and a significant association between sensorimotor network and fine motor function (P = .004). Control subjects had 79 pair-wise independent components that showed significant temporal coherence across all resting-state networks except for default mode network-auditory network. Patients had 66 pairs of independent components that showed significant temporal coherence across all resting-state networks. Group comparison showed reduced functional network connectivity between default mode network-attention, frontal-sensorimotor, and frontal-visual networks and increased functional network connectivity between frontal-attention, default mode network-sensorimotor, and frontal

  18. Olfactory identification deficits and associated response inhibition in obsessive-compulsive disorder: on the scent of the orbitofronto-striatal model.

    PubMed

    Bersani, Giuseppe; Quartini, Adele; Ratti, Flavia; Pagliuca, Giulio; Gallo, Andrea

    2013-11-30

    Olfactory identification ability implicates the integrity of the orbitofrontal cortex (OFC). The fronto-striatal circuits including the OFC have been involved in the neuropathology of Obsessive Compulsive Disorder (OCD). However, only a few studies have examined olfactory function in patients with OCD. The Brief Smell Identification Test (B-SIT) and tests from the Cambridge Neuropsychological Automated Battery (CANTAB) were administered to 25 patients with OCD and to 21 healthy matched controls. OCD patients showed a significant impairment in olfactory identification ability as well as widely distributed cognitive deficits in visual memory, executive functions, attention, and response inhibition. The degree of behavioural impairment on motor impulsivity (prolonged response inhibition Stop-Signal Reaction Time) strongly correlated with the B-SIT score. Our study is the first to indicate a shared OFC pathological neural substrate underlying olfactory identification impairment, impulsivity, and OCD. Deficits in visual memory, executive functions and attention further indicate that regions outside of the orbitofronto-striatal loop may be involved in this disorder. Such results may help delineate the clinical complexity of OCD and support more targeted investigations and interventions. In this regard, research on the potential diagnostic utility of olfactory identification deficits in the assessment of OCD would certainly be useful. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

    PubMed Central

    Xenias, Harry S.; Ibáñez-Sandoval, Osvaldo; Koós, Tibor

    2015-01-01

    Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH–Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)–TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP–TH interneurons. Optogenetic activation of striatal EGFP–TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons. PMID:25904808

  20. Diversity in Long-Term Synaptic Plasticity at Inhibitory Synapses of Striatal Spiny Neurons

    ERIC Educational Resources Information Center

    Rueda-Orozco, Pavel E.; Mendoza, Ernesto; Hernandez, Ricardo; Aceves, Jose J.; Ibanez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, Jose

    2009-01-01

    Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term…

  1. Abnormal ventral tegmental area-anterior cingulate cortex connectivity in Parkinson's disease with depression.

    PubMed

    Wei, Luqing; Hu, Xiao; Yuan, Yonggui; Liu, Weiguo; Chen, Hong

    2018-07-16

    Neuropathology suggests that Parkinson's disease (PD) with depression may involve a progressive degeneration of the nigrostriatal and mesocorticolimbic dopaminergic systems. Previous positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies have shown that dopamine changes in individual brain regions constituting the nigrostriatal and mesocorticolimbic circuits are associated with depression in PD. However, few studies have been conducted on the circuit-level alterations in this disease. The present study used resting-state fMRI and seed-based functional connectivity of putative dopaminergic midbrain regions (i.e., substantia nigra (SN) and ventral tegmental area (VTA)) to investigate the circuit-related abnormalities in PD with depression. The results showed that depressed PD (DPD) patients relative to healthy controls (HC) and non-depressed PD (NDPD) patients had increased functional connectivity between VTA and anterior cingulate cortex (ACC), demonstrating that dysfunctional mesocorticolimbic dopaminergic neurotransmission may be associated with depression in PD. Compared with HC, DPD and NDPD patients showed increased functional connectivity from SN to sensorimotor cortex, validating that alterations in the nigrostriatal circuitry could be responsible for cardinal motor features in PD. In addition, aberrant connectivity between VTA and ACC was correlated with the severity of depression in PD patients, further supporting that abnormal mesocorticolimbic system may account for depressive symptoms in PD. These results have provided potential circuit-level biomarkers of depression in PD, and suggested that resting state functional connectivity of midbrain dopaminergic nuclei may be useful for understanding the underlying pathology in PD with depression. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Handwriting analysis indicates spontaneous dyskinesias in neuroleptic naïve adolescents at high risk for psychosis.

    PubMed

    Dean, Derek J; Teulings, Hans-Leo; Caligiuri, Michael; Mittal, Vijay A

    2013-11-21

    Growing evidence suggests that movement abnormalities are a core feature of psychosis. One marker of movement abnormality, dyskinesia, is a result of impaired neuromodulation of dopamine in fronto-striatal pathways. The traditional methods for identifying movement abnormalities include observer-based reports and force stability gauges. The drawbacks of these methods are long training times for raters, experimenter bias, large site differences in instrumental apparatus, and suboptimal reliability. Taking these drawbacks into account has guided the development of better standardized and more efficient procedures to examine movement abnormalities through handwriting analysis software and tablet. Individuals at risk for psychosis showed significantly more dysfluent pen movements (a proximal measure for dyskinesia) in a handwriting task. Handwriting kinematics offers a great advance over previous methods of assessing dyskinesia, which could clearly be beneficial for understanding the etiology of psychosis.

  3. Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic Naïve Adolescents at High Risk for Psychosis

    PubMed Central

    Dean, Derek J.; Teulings, Hans-Leo; Caligiuri, Michael; Mittal, Vijay A.

    2013-01-01

    Growing evidence suggests that movement abnormalities are a core feature of psychosis. One marker of movement abnormality, dyskinesia, is a result of impaired neuromodulation of dopamine in fronto-striatal pathways. The traditional methods for identifying movement abnormalities include observer-based reports and force stability gauges. The drawbacks of these methods are long training times for raters, experimenter bias, large site differences in instrumental apparatus, and suboptimal reliability. Taking these drawbacks into account has guided the development of better standardized and more efficient procedures to examine movement abnormalities through handwriting analysis software and tablet. Individuals at risk for psychosis showed significantly more dysfluent pen movements (a proximal measure for dyskinesia) in a handwriting task. Handwriting kinematics offers a great advance over previous methods of assessing dyskinesia, which could clearly be beneficial for understanding the etiology of psychosis. PMID:24300590

  4. Significance of Input Correlations in Striatal Function

    PubMed Central

    Yim, Man Yi; Aertsen, Ad; Kumar, Arvind

    2011-01-01

    The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia. PMID:22125480

  5. Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

    PubMed Central

    Jaunarajs, K.L. Eskow; Bonsi, P.; Chesselet, M.F.; Standaert, D.G.; Pisani, A.

    2015-01-01

    Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestion of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia. PMID:25697043

  6. Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1.

    PubMed

    Serra, Laura; Silvestri, Gabriella; Petrucci, Antonio; Basile, Barbara; Masciullo, Marcella; Makovac, Elena; Torso, Mario; Spanò, Barbara; Mastropasqua, Chiara; Harrison, Neil A; Bianchi, Maria L E; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2014-05-01

    Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. Resting-state functional magnetic resonance imaging. Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits. Our findings provide novel

  7. Abnormal structural connectivity between the basal ganglia, thalamus, and frontal cortex in patients with disorders of consciousness.

    PubMed

    Weng, Ling; Xie, Qiuyou; Zhao, Ling; Zhang, Ruibin; Ma, Qing; Wang, Junjing; Jiang, Wenjie; He, Yanbin; Chen, Yan; Li, Changhong; Ni, Xiaoxiao; Xu, Qin; Yu, Ronghao; Huang, Ruiwang

    2017-05-01

    Consciousness loss in patients with severe brain injuries is associated with reduced functional connectivity of the default mode network (DMN), fronto-parietal network, and thalamo-cortical network. However, it is still unclear if the brain white matter connectivity between the above mentioned networks is changed in patients with disorders of consciousness (DOC). In this study, we collected diffusion tensor imaging (DTI) data from 13 patients and 17 healthy controls, constructed whole-brain white matter (WM) structural networks with probabilistic tractography. Afterward, we estimated and compared topological properties, and revealed an altered structural organization in the patients. We found a disturbance in the normal balance between segregation and integration in brain structural networks and detected significantly decreased nodal centralities primarily in the basal ganglia and thalamus in the patients. A network-based statistical analysis detected a subnetwork with uniformly significantly decreased structural connections between the basal ganglia, thalamus, and frontal cortex in the patients. Further analysis indicated that along the WM fiber tracts linking the basal ganglia, thalamus, and frontal cortex, the fractional anisotropy was decreased and the radial diffusivity was increased in the patients compared to the controls. Finally, using the receiver operating characteristic method, we found that the structural connections within the NBS-derived component that showed differences between the groups demonstrated high sensitivity and specificity (>90%). Our results suggested that major consciousness deficits in DOC patients may be related to the altered WM connections between the basal ganglia, thalamus, and frontal cortex. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Subthalamic, not striatal, activity correlates with basal ganglia downstream activity in normal and parkinsonian monkeys

    PubMed Central

    Deffains, Marc; Iskhakova, Liliya; Katabi, Shiran; Haber, Suzanne N; Israel, Zvi; Bergman, Hagai

    2016-01-01

    The striatum and the subthalamic nucleus (STN) constitute the input stage of the basal ganglia (BG) network and together innervate BG downstream structures using GABA and glutamate, respectively. Comparison of the neuronal activity in BG input and downstream structures reveals that subthalamic, not striatal, activity fluctuations correlate with modulations in the increase/decrease discharge balance of BG downstream neurons during temporal discounting classical condition task. After induction of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), abnormal low beta (8-15 Hz) spiking and local field potential (LFP) oscillations resonate across the BG network. Nevertheless, LFP beta oscillations entrain spiking activity of STN, striatal cholinergic interneurons and BG downstream structures, but do not entrain spiking activity of striatal projection neurons. Our results highlight the pivotal role of STN divergent projections in BG physiology and pathophysiology and may explain why STN is such an effective site for invasive treatment of advanced Parkinson's disease and other BG-related disorders. DOI: http://dx.doi.org/10.7554/eLife.16443.001 PMID:27552049

  9. A variable number of tandem repeats in the 3'-untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span.

    PubMed

    Sambataro, Fabio; Podell, Jamie E; Murty, Vishnu P; Das, Saumitra; Kolachana, Bhaskar; Goldberg, Terry E; Weinberger, Daniel R; Mattay, Venkata S

    2015-08-01

    Dopamine modulation of striatal function is critical for executive functions such as working memory (WM) updating. The dopamine transporter (DAT) regulates striatal dopamine signaling via synaptic reuptake. A variable number of tandem repeats in the 3'-untranslated region of SLC6A3 (DAT1-3'-UTR-VNTR) is associated with DAT expression, such that 9-repeat allele carriers tend to express lower levels (associated with higher extracellular dopamine concentrations) than 10-repeat homozygotes. Aging is also associated with decline of the dopamine system. The goal of the present study was to investigate the effects of aging and DAT1-3'-UTR-VNTR on the neural activity and functional connectivity of the striatum during WM updating. Our results showed both an age-related decrease in striatal activity and an effect of DAT1-3'-UTR-VNTR. Ten-repeat homozygotes showed reduced striatal activity and increased striatal-hippocampal connectivity during WM updating relative to the 9-repeat carriers. There was no age by DAT1-3'-UTR-VNTR interaction. These results suggest that, whereas striatal function during WM updating is modulated by both age and genetically determined DAT levels, the rate of the age-related decline in striatal function is similar across both DAT1-3'-UTR-VNTR genotype groups. They further suggest that, because of the baseline difference in striatal function based on DAT1-3'-UTR-VNTR polymorphism, 10-repeat homozygotes, who have lower levels of striatal function throughout the adult life span, may reach a threshold of decreased striatal function and manifest impairments in cognitive processes mediated by the striatum earlier in life than the 9-repeat carriers. Our data suggest that age and DAT1-3'-UTR-VNTR polymorphism independently modulate striatal function. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  10. Abnormal white matter integrity in chronic users of codeine-containing cough syrups: a tract-based spatial statistics study.

    PubMed

    Qiu, Y-W; Su, H-H; Lv, X-F; Jiang, G-H

    2015-01-01

    Codeine-containing cough syrups have become one of the most popular drugs of abuse in young people in the world. Chronic codeine-containing cough syrup abuse is related to impairments in a broad range of cognitive functions. However, the potential brain white matter impairment caused by chronic codeine-containing cough syrup abuse has not been reported previously. Our aim was to investigate abnormalities in the microstructure of brain white matter in chronic users of codeine-containing syrups and to determine whether these WM abnormalities are related to the duration of the use these syrups and clinical impulsivity. Thirty chronic codeine-containing syrup users and 30 matched controls were evaluated. Diffusion tensor imaging was performed by using a single-shot spin-echo-planar sequence. Whole-brain voxelwise analysis of fractional anisotropy was performed by using tract-based spatial statistics to localize abnormal WM regions. The Barratt Impulsiveness Scale 11 was surveyed to assess participants' impulsivity. Volume-of-interest analysis was used to detect changes of diffusivity indices in regions with fractional anisotropy abnormalities. Abnormal fractional anisotropy was extracted and correlated with clinical impulsivity and the duration of codeine-containing syrup use. Chronic codeine-containing syrup users had significantly lower fractional anisotropy in the inferior fronto-occipital fasciculus of the bilateral temporo-occipital regions, right frontal region, and the right corona radiata WM than controls. There were significant negative correlations among fractional anisotropy values of the right frontal region of the inferior fronto-occipital fasciculus and the right superior corona radiata WM and Barratt Impulsiveness Scale total scores, and between the right frontal region of the inferior fronto-occipital fasciculus and nonplan impulsivity scores in chronic codeine-containing syrup users. There was also a significant negative correlation between fractional

  11. Striatal abnormalities in trichotillomania: a multi-site MRI analysis.

    PubMed

    Isobe, Masanori; Redden, Sarah A; Keuthen, Nancy J; Stein, Dan J; Lochner, Christine; Grant, Jon E; Chamberlain, Samuel R

    2018-01-01

    Trichotillomania (hair-pulling disorder) is characterized by the repetitive pulling out of one's own hair, and is classified as an Obsessive-Compulsive Related Disorder. Abnormalities of the ventral and dorsal striatum have been implicated in disease models of trichotillomania, based on translational research, but direct evidence is lacking. The aim of this study was to elucidate subcortical morphometric abnormalities, including localized curvature changes, in trichotillomania. De-identified MRI scans were pooled by contacting authors of previous peer-reviewed studies that examined brain structure in adult patients with trichotillomania, following an extensive literature search. Group differences on subcortical volumes of interest were explored (t-tests) and localized differences in subcortical structure morphology were quantified using permutation testing. The pooled sample comprised N=68 individuals with trichotillomania and N=41 healthy controls. Groups were well-matched in terms of age, gender, and educational levels. Significant volumetric reductions were found in trichotillomania patients versus controls in right amygdala and left putamen. Localized shape deformities were found in bilateral nucleus accumbens, bilateral amygdala, right caudate and right putamen. Structural abnormalities of subcortical regions involved in affect regulation, inhibitory control, and habit generation, play a key role in the pathophysiology of trichotillomania. Trichotillomania may constitute a useful model through which to better understand other compulsive symptoms. These findings may account for why certain medications appear effective for trichotillomania, namely those modulating subcortical dopamine and glutamatergic function. Future work should study the state versus trait nature of these changes, and the impact of treatment.

  12. Prefrontal cortical and striatal activity to happy and fear faces in bipolar disorder is associated with comorbid substance abuse and eating disorder.

    PubMed

    Hassel, Stefanie; Almeida, Jorge R; Frank, Ellen; Versace, Amelia; Nau, Sharon A; Klein, Crystal R; Kupfer, David J; Phillips, Mary L

    2009-11-01

    The spectrum approach was used to examine contributions of comorbid symptom dimensions of substance abuse and eating disorder to abnormal prefrontal-cortical and subcortical-striatal activity to happy and fear faces previously demonstrated in bipolar disorder (BD). Fourteen remitted BD-type I and sixteen healthy individuals viewed neutral, mild and intense happy and fear faces in two event-related fMRI experiments. All individuals completed Substance-Use and Eating-Disorder Spectrum measures. Region-of-Interest analyses for bilateral prefrontal and subcortical-striatal regions were performed. BD individuals scored significantly higher on these spectrum measures than healthy individuals (p<0.05), and were distinguished by activity in prefrontal and subcortical-striatal regions. BD relative to healthy individuals showed reduced dorsal prefrontal-cortical activity to all faces. Only BD individuals showed greater subcortical-striatal activity to happy and neutral faces. In BD individuals, negative correlations were shown between substance use severity and right PFC activity to intense happy faces (p<0.04), and between substance use severity and right caudate nucleus activity to neutral faces (p<0.03). Positive correlations were shown between eating disorder and right ventral putamen activity to intense happy (p<0.02) and neutral faces (p<0.03). Exploratory analyses revealed few significant relationships between illness variables and medication upon neural activity in BD individuals. Small sample size of predominantly medicated BD individuals. This study is the first to report relationships between comorbid symptom dimensions of substance abuse and eating disorder and prefrontal-cortical and subcortical-striatal activity to facial expressions in BD. Our findings suggest that these comorbid features may contribute to observed patterns of functional abnormalities in neural systems underlying mood regulation in BD.

  13. Motor complications in Parkinson's disease: Striatal molecular and electrophysiological mechanisms of dyskinesias.

    PubMed

    Picconi, Barbara; Hernández, Ledia F; Obeso, Jose A; Calabresi, Paolo

    2017-12-08

    Long-term levodopa (l-dopa) treatment in patients with Parkinson´s disease (PD) is associated with the development of motor complications (ie, motor fluctuations and dyskinesias). The principal etiopathogenic factors are the degree of nigro-striatal dopaminergic loss and the duration and dose of l-dopa treatment. In this review article we concentrate on analysis of the mechanisms underlying l-dopa-induced dyskinesias, a phenomenon that causes disability in a proportion of patients and that has not benefited from major therapeutic advances. Thus, we discuss the main neurotransmitters, receptors, and pathways that have been thought to play a role in l-dopa-induced dyskinesias from the perspective of basic neuroscience studies. Some important advances in deciphering the molecular pathways involved in these abnormal movements have occurred in recent years to reveal potential targets that could be used for therapeutic purposes. However, it has not been an easy road because there have been a plethora of components involved in the generation of these undesired movements, even bypassing the traditional and well-accepted dopamine receptor activation, as recently revealed by optogenetics. Here, we attempt to unify the available data with the hope of guiding and fostering future research in the field of striatal activation and abnormal movement generation. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  14. Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor.

    PubMed

    Oran, Yael; Bar-Gad, Izhar

    2018-02-14

    Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders. SIGNIFICANCE STATEMENT Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these

  15. Altered default mode, fronto-parietal and salience networks in adolescents with Internet addiction.

    PubMed

    Wang, Lubin; Shen, Hui; Lei, Yu; Zeng, Ling-Li; Cao, Fenglin; Su, Linyan; Yang, Zheng; Yao, Shuqiao; Hu, Dewen

    2017-07-01

    Internet addiction (IA) is a condition characterized by loss of control over Internet use, leading to a variety of negative psychosocial consequences. Recent neuroimaging studies have begun to identify IA-related changes in specific brain regions and connections. However, whether and how the interactions within and between the large-scale brain networks are disrupted in individuals with IA remain largely unexplored. Using group independent component analysis, we extracted five intrinsic connectivity networks (ICNs) from the resting-state fMRI data of 26 adolescents with IA and 43 controls, including the anterior and posterior default mode network (DMN), left and right fronto-parietal network (FPN), and salience network (SN). We then examined the possible group differences in the functional connectivity within each ICN and between the ICNs. We found that, compared with controls, IA subjects showed: (1) reduced inter-hemispheric functional connectivity of the right FPN, whereas increased intra-hemispheric functional connectivity of the left FPN; (2) reduced functional connectivity in the dorsal medial prefrontal cortex (mPFC) of the anterior DMN; (3) reduced functional connectivity between the SN and anterior DMN. Our findings suggest that IA is associated with imbalanced interactions among the DMN, FPN and SN, which may serve as system-level neural underpinnings for the uncontrollable Internet-using behaviors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Neural network alterations across eating disorders: a narrative review of fMRI studies.

    PubMed

    Steward, Trevor; Menchón, José M; Jiménez-Murcia, Susana; Soriano-Mas, Carles; Fernández-Aranda, Fernando

    2017-10-17

    Functional magnetic resonance imaging (fMRI) has provided insight on how neural abnormalities are related to the symptomatology of the eating disorders (EDs): anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). More specifically, an increasingly growing number of brain imaging studies has shed light on how functionally connected brain networks contribute not only to disturbed eating behavior, but also to transdiagnostic alterations in body/interoceptive perception, reward processing and executive functions. This narrative review aims to summarize recent advances in fMRI studies of patients with EDs by highlighting studies investigating network alterations that are shared across EDs. Findings on reward processing in both AN and BN patients point to the presence of altered sensitivity to salient food stimuli in striatal regions and to the possibility of hypothalamic inputs being overridden by top-down cognitive control regions. Additionally, innovative new lines of research suggest that increased activations in fronto-striatal circuits are strongly associated with the maintenance of restrictive eating habits in AN patients. Although significantly fewer studies have been carried out in patients with BN and BED, aberrant neural responses to both food cues and anticipated food receipt appear to occur in these populations. These altered responses, coupled with diminished recruitment of prefrontal cognitive control circuitry, are believed to contribute to the binge eating of palatable foods. Results from functional network connectivity studies are diverse, but findings tend to converge on indicating disrupted resting-state connectivity in executive networks, the default-mode network and the salience network across EDs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Electrical and chemical transmission between striatal GABAergic output neurones in rat brain slices

    PubMed Central

    Venance, Laurent; Glowinski, Jacques; Giaume, Christian

    2004-01-01

    Basal ganglia are interconnected subcortical nuclei, connected to the thalamus and all cortical areas involved in sensory motor control, limbic functions and cognition. The striatal output neurones (SONs), the major striatal population, are believed to act as detectors and integrators of distributed patterns of cerebral cortex inputs. Despite the key role of SONs in cortico-striatal information processing, little is known about their local interactions. Here, we report the existence and characterization of electrical and GABAergic transmission between SONs in rat brain slices. Tracer coupling (biocytin) incidence was high during the first two postnatal weeks and then decreased (postnatal days (P) 5–25, 60%; P25–30, 29%; n = 61). Electrical coupling was observed between 27% of SON pairs (coupling coefficient: 3.1 ± 0.3%, n = 89 at P15) and as shown by single-cell RT-PCR, several connexin (Cx) mRNAs were found to be expressed (Cx31.1, Cx32, Cx36 and Cx47). GABAergic synaptic transmission (abolished by bicuculline, a GABAA receptor antagonist) observed in 19% of SON pairs (n = 62) was reliable (mean failure rate of 6 ± 3%), precise (variation coefficient of latency, 0.06), strong (IPSC amplitudes of 38 ± 12 pA) and unidirectional. Interestingly, electrical and chemical transmission were mutually exclusive. These results suggest that preferential networks of electrically and chemically connected SONs, might be involved in the channelling of cortico-basal ganglia information processing. PMID:15235091

  18. Functional connectivity between prefrontal and parietal cortex drives visuo-spatial attention shifts.

    PubMed

    Heinen, Klaartje; Feredoes, Eva; Ruff, Christian C; Driver, Jon

    2017-05-01

    It is well established that the frontal eye-fields (FEF) in the dorsal attention network (DAN) guide top-down selective attention. In addition, converging evidence implies a causal role for the FEF in attention shifting, which is also known to recruit the ventral attention network (VAN) and fronto-striatal regions. To investigate the causal influence of the FEF as (part of) a central hub between these networks, we applied thetaburst transcranial magnetic stimulation (TBS) off-line, combined with functional magnetic resonance (fMRI) during a cued visuo-spatial attention shifting paradigm. We found that TBS over the right FEF impaired performance on a visual discrimination task in both hemifields following attention shifts, while only left hemifield performance was affected when participants were cued to maintain the focus of attention. These effects recovered ca. 20min post stimulation. Furthermore, particularly following attention shifts, TBS suppressed the neural signal in bilateral FEF, right inferior and superior parietal lobule (IPL/SPL) and bilateral supramarginal gyri (SMG). Immediately post stimulation, functional connectivity was impaired between right FEF and right SMG as well as right putamen. Importantly, the extent of decreased connectivity between right FEF and right SMG correlated with behavioural impairment following attention shifts. The main finding of this study demonstrates that influences from right FEF on SMG in the ventral attention network causally underly attention shifts, presumably by enabling disengagement from the current focus of attention. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Music therapy modulates fronto-temporal activity in rest-EEG in depressed clients.

    PubMed

    Fachner, Jörg; Gold, Christian; Erkkilä, Jaakko

    2013-04-01

    Fronto-temporal areas process shared elements of speech and music. Improvisational psychodynamic music therapy (MT) utilizes verbal and musical reflection on emotions and images arising from clinical improvisation. Music listening is shifting frontal alpha asymmetries (FAA) in depression, and increases frontal midline theta (FMT). In a two-armed randomized controlled trial (RCT) with 79 depressed clients (with comorbid anxiety), we compared standard care (SC) versus MT added to SC at intake and after 3 months. We found that MT significantly reduced depression and anxiety symptoms. The purpose of this study is to test whether or not MT has an impact on anterior fronto-temporal resting state alpha and theta oscillations. Correlations between anterior EEG, Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hospital Anxiety and Depression Scale-Anxiety Subscale (HADS-A), power spectral analysis (topography, means, asymmetry) and normative EEG database comparisons were explored. After 3 month of MT, lasting changes in resting EEG were observed, i.e., significant absolute power increases at left fronto-temporal alpha, but most distinct for theta (also at left fronto-central and right temporoparietal leads). MT differed to SC at F7-F8 (z scored FAA, p < .03) and T3-T4 (theta, p < .005) asymmetry scores, pointing towards decreased relative left-sided brain activity after MT; pre/post increased FMT and decreased HADS-A scores (r = .42, p < .05) indicate reduced anxiety after MT. Verbal reflection and improvising on emotions in MT may induce neural reorganization in fronto-temporal areas. Alpha and theta changes in fronto-temporal and temporoparietal areas indicate MT action and treatment effects on cortical activity in depression, suggesting an impact of MT on anxiety reduction.

  20. Abnormalities in hemispheric specialization of caudate nucleus connectivity in schizophrenia

    PubMed Central

    Mueller, Sophia; Wang, Danhong; Pan, Ruiqi; Holt, Daphne J.; Liu, Hesheng

    2015-01-01

    Importance Hemispheric specialization of the human brain is a marker of successful neurodevelopment. Altered brain asymmetry that has been repeatedly reported in schizophrenia may represent consequences of disrupted neurodevelopment in the disorder. However, a complete picture of functional specialization in the schizophrenic brain and its connectional substrates are yet to be unveiled. Objective We aimed to quantify intrinsic hemispheric specialization at a cortical and subcortical level and to reveal potential disease effects in schizophrenia. Design/Participants Resting-state functional connectivity MRI has been previously used to quantitatively measure hemispheric specialization in healthy subjects, in a reliable manner. Here we quantified the intrinsic hemispheric specialization at the whole brain level in 31 patients with schizophrenia and 37 demographically matched healthy control subjects using resting-state functional connectivity MRI. Results The caudate nucleus, and cortical regions with connections to the caudate nucleus, showed markedly abnormal hemispheric specialization in schizophrenia. Compared to healthy controls, patients exhibited weaker specialization in the left, but the opposite pattern in the right, caudate nucleus. Schizophrenia patients also displayed a disruption of the inter-hemispheric coordination among the cortical regions with connections to the caudate nucleus. A linear classifier based on the specialization of the caudate nucleus distinguished patients from controls with a classification accuracy of 74%. Conclusions and Relevance These data suggested that hemispheric specialization could serve as a potential imaging biomarker of schizophrenia that, compared to task-based fMRI measures, is less prone to the confounding effects of variation in task compliance, cognitive ability, and command of language. PMID:25830688

  1. Abnormal laughter-like vocalisations replacing speech in primary progressive aphasia.

    PubMed

    Rohrer, Jonathan D; Warren, Jason D; Rossor, Martin N

    2009-09-15

    We describe ten patients with a clinical diagnosis of primary progressive aphasia (PPA) (pathologically confirmed in three cases) who developed abnormal laughter-like vocalisations in the context of progressive speech output impairment leading to mutism. Failure of speech output was accompanied by increasing frequency of the abnormal vocalisations until ultimately they constituted the patient's only extended utterance. The laughter-like vocalisations did not show contextual sensitivity but occurred as an automatic vocal output that replaced speech. Acoustic analysis of the vocalisations in two patients revealed abnormal motor features including variable note duration and inter-note interval, loss of temporal symmetry of laugh notes and loss of the normal decrescendo. Abnormal laughter-like vocalisations may be a hallmark of a subgroup in the PPA spectrum with impaired control and production of nonverbal vocal behaviour due to disruption of fronto-temporal networks mediating vocalisation.

  2. A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations

    PubMed Central

    Vinciati, Federica

    2017-01-01

    Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical–basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on “direct pathway” SPNs (dSPNs) and “indirect pathway” SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15–30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits. SIGNIFICANCE STATEMENT Chronic depletion

  3. Dissociation in Response to Methylphenidate on Response Variability in a Group of Medication Naive Children with ADHD

    ERIC Educational Resources Information Center

    Johnson, Katherine A.; Barry, Edwina; Bellgrove, Mark A.; Cox, Marie; Kelly, Simon P.; Daibhis, Aoife; Daly, Michael; Keavey, Michelle; Watchorn, Amy; Fitzgerald, Michael; McNicholas, Fiona; Kirley, Aiveen; Robertson, Ian H.; Gill, Michael

    2008-01-01

    Increased variability in reaction time (RT) has been proposed as a cardinal feature of attention deficit hyperactivity disorder (ADHD). Increased variability during sustained attention tasks may reflect inefficient fronto-striatal and fronto-parietal circuitry; activity within these circuits is modulated by the catecholamines. A disruption to…

  4. Impaired functional connectivity within and between frontostriatal circuits and its association with compulsive drug use and trait impulsivity in cocaine addiction.

    PubMed

    Hu, Yuzheng; Salmeron, Betty Jo; Gu, Hong; Stein, Elliot A; Yang, Yihong

    2015-06-01

    Converging evidence has long identified both impulsivity and compulsivity as key psychological constructs in drug addiction. Although dysregulated striatal-cortical network interactions have been identified in cocaine addiction, the association between these brain networks and addiction is poorly understood. To test the hypothesis that cocaine addiction is associated with disturbances in striatal-cortical communication as captured by resting-state functional connectivity (rsFC), measured from coherent spontaneous fluctuations in the blood oxygenation level-dependent functional magnetic resonance imaging signal, and to explore the relationships between striatal rsFC, trait impulsivity, and uncontrolled drug use in cocaine addiction. A case-control, cross-sectional study was conducted at the National Institute on Drug Abuse Intramural Research Program outpatient magnetic resonance imaging facility. Data used in the present study were collected between December 8, 2005, and September 30, 2011. Participants included 56 non-treatment-seeking cocaine users (CUs) (52 with cocaine dependence and 3 with cocaine abuse) and 56 healthy individuals serving as controls (HCs) matched on age, sex, years of education, race, estimated intelligence, and smoking status. Voxelwise statistical parametric analysis testing the rsFC strength differences between CUs and HCs in brain regions functionally connected to 6 striatal subregions defined a priori. Increased rsFC strength was observed predominantly in striatal-frontal circuits; decreased rsFC was found between the striatum and cingulate, striatal, temporal, hippocampal/amygdalar, and insular regions in the CU group compared with the HCs. Increased striatal-dorsal lateral prefrontal cortex connectivity strength was positively correlated with the amount of recent cocaine use (uncorrected P < .046) and elevated trait impulsivity in the CUs (uncorrected P < .012), and an index reflecting the balance between striatal

  5. T157. FRONTOSTRIATAL CONNECTIVITY IN TREATMENT-RESISTANT SCHIZOPHRENIA: RELATIONSHIP TO POSITIVE SYMPTOMS AND COGNITIVE FLEXIBILITY

    PubMed Central

    Cropley, Vanessa; Ganella, Eleni; Wannan, Cassandra; Zalesky, Andrew; Van Rheenen, Tamsyn; Bousman, Chad; Everall, Ian; Fornito, Alexander; Pantelis, Christos

    2018-01-01

    Abstract Background The frontostriatal circuits linking different parts of the frontal cortex to subregions of the striatum are proposed to regulate different aspects of cognition, executive function, affect and reward processing. Dysregulation of these brain circuits is also known to be important in the etiology of psychotic disorders, with the magnitude of dysfunction correlating with the severity of positive symptoms. These observations suggest that the integrity of brain circuits connected to the striatum is important for antipsychotic treatment response as well as specific cognitive processes. However, not all individuals with schizophrenia benefit from antipsychotic treatment, with up to 20% of individuals considered to be treatment-resistant. These individuals also show pervasive impairments in cognition, including cognitive flexibility. Nevertheless, few studies have examined striatal connectivity in treatment-resistant schizophrenia (TRS), particularly in relation to positive symptomatology and specific cognitive deficits subserved by the striatal circuits. This study therefore aimed to (i) assess for disruptions in frontostriatal connectivity in a sample of TRS and (ii) assess the relationship between the frontostriatal circuits with positive symptoms and attentional set-shifting (cognitive flexibility) given recent associations with the dorsal striatal circuit. Methods Resting-state functional magnetic resonance imaging was used to investigate functional connectivity (FC) in 42 TRS participants prescribed clozapine (30 males, mean age=41.3(10)), and 42 healthy controls (24 males, mean age=38.4(10)). The whole striatum (caudate, putamen and nucleus accumbens) and the left and right dorsal striatum were separately seeded as regions of interest, and Pearson’s correlations between the seeds and all other voxels comprising cortical and subcortical gray matter were investigated. For brain regions that showed significant group differences in FC with the

  6. Differences in functional connectivity between alcohol dependence and internet gaming disorder

    PubMed Central

    Han, Ji Won; Han, Doug Hyun; Bolo, Nicolas; Kim, BoAh; Kim, Boong Nyun; Renshaw, Perry F.

    2017-01-01

    Introduction Internet gaming disorder (IGD) and alcohol dependence (AD) have been reported to share clinical characteristics including craving and over-engagement despite negative consequences. However, there are also clinical factors that differ between individuals with IGD and those with AD in terms of chemical intoxication, prevalence age, and visual and auditory stimulation. Methods We assessed brain functional connectivity within the prefrontal, striatum, and temporal lobe in 15 patients with IGD and in 16 patients with AD. Symptoms of depression, anxiety, and the attention deficit hyperactivity disorder were assessed in patients with IGD and in patients with AD. Results Both AD and IGD subjects have positive functional connectivity between the dorsolateral prefrontal cortex (DLPFC), cingulate, and cerebellum. In addition, both groups have negative functional connectivity between the DLPFC and the orbitofrontal cortex. However, the AD subjects have positive functional connectivity between the DLPFC, temporal lobe and striatal areas while IGD subjects have negative functional connectivity between the DLPFC, temporal lobe and striatal areas. Conclusions AD and IGD subjects may share deficits in executive function, including problems with self-control and adaptive responding. However, the negative connectivity between the DLPFC and the striatal areas in IGD subjects, different from the connectivity observed in AD subjects, may be due to the earlier prevalence age, different comorbid diseases as well as visual and auditory stimulation. PMID:25282597

  7. Differences in functional connectivity between alcohol dependence and internet gaming disorder.

    PubMed

    Han, Ji Won; Han, Doug Hyun; Bolo, Nicolas; Kim, BoAh; Kim, Boong Nyun; Renshaw, Perry F

    2015-02-01

    Internet gaming disorder (IGD) and alcohol dependence (AD) have been reported to share clinical characteristics including craving and over-engagement despite negative consequences. However, there are also clinical factors that differ between individuals with IGD and those with AD in terms of chemical intoxication, prevalence age, and visual and auditory stimulation. We assessed brain functional connectivity within the prefrontal, striatum, and temporal lobe in 15 patients with IGD and in 16 patients with AD. Symptoms of depression, anxiety, and the attention deficit hyperactivity disorder were assessed in patients with IGD and in patients with AD. Both AD and IGD subjects have positive functional connectivity between the dorsolateral prefrontal cortex (DLPFC), cingulate, and cerebellum. In addition, both groups have negative functional connectivity between the DLPFC and the orbitofrontal cortex. However, the AD subjects have positive functional connectivity between the DLPFC, temporal lobe and striatal areas while IGD subjects have negative functional connectivity between the DLPFC, temporal lobe and striatal areas. AD and IGD subjects may share deficits in executive function, including problems with self-control and adaptive responding. However, the negative connectivity between the DLPFC and the striatal areas in IGD subjects, different from the connectivity observed in AD subjects, may be due to the earlier prevalence age, different comorbid diseases as well as visual and auditory stimulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Enhanced prefrontal-amygdala connectivity following childhood adversity as a protective mechanism against internalizing in adolescence.

    PubMed

    Herringa, Ryan J; Burghy, Cory A; Stodola, Diane E; Fox, Michelle E; Davidson, Richard J; Essex, Marilyn J

    2016-07-01

    Much research has focused on the deleterious neurobiological effects of childhood adversity that may underlie internalizing disorders. While most youth show emotional adaptation following adversity, the corresponding neural mechanisms remain poorly understood. In this longitudinal community study, we examined the associations among childhood family adversity, adolescent internalizing symptoms, and their interaction on regional brain activation and amygdala/hippocampus functional connectivity during emotion processing in 132 adolescents. Consistent with prior work, childhood adversity predicted heightened amygdala reactivity to negative, but not positive, images in adolescence. However, amygdala reactivity was not related to internalizing symptoms. Furthermore, childhood adversity predicted increased fronto-amygdala connectivity to negative, but not positive, images, yet only in lower internalizing adolescents. Childhood adversity also predicted increased fronto-hippocampal connectivity to negative images, but was not moderated by internalizing. These findings were unrelated to adolescence adversity or externalizing symptoms, suggesting specificity to childhood adversity and adolescent internalizing. Together, these findings suggest that adaptation to childhood adversity is associated with augmentation of fronto-subcortical circuits specifically for negative emotional stimuli. Conversely, insufficient enhancement of fronto-amygdala connectivity, with increasing amygdala reactivity, may represent a neural signature of vulnerability for internalizing by late adolescence. These findings implicate early childhood as a critical period in determining the brain's adaptation to adversity, and suggest that even normative adverse experiences can have significant impact on neurodevelopment and functioning. These results offer potential neural mechanisms of adaptation and vulnerability which could be used in the prediction of risk for psychopathology following childhood

  9. Abnormal laughter-like vocalisations replacing speech in primary progressive aphasia

    PubMed Central

    Rohrer, Jonathan D.; Warren, Jason D.; Rossor, Martin N.

    2009-01-01

    We describe ten patients with a clinical diagnosis of primary progressive aphasia (PPA) (pathologically confirmed in three cases) who developed abnormal laughter-like vocalisations in the context of progressive speech output impairment leading to mutism. Failure of speech output was accompanied by increasing frequency of the abnormal vocalisations until ultimately they constituted the patient's only extended utterance. The laughter-like vocalisations did not show contextual sensitivity but occurred as an automatic vocal output that replaced speech. Acoustic analysis of the vocalisations in two patients revealed abnormal motor features including variable note duration and inter-note interval, loss of temporal symmetry of laugh notes and loss of the normal decrescendo. Abnormal laughter-like vocalisations may be a hallmark of a subgroup in the PPA spectrum with impaired control and production of nonverbal vocal behaviour due to disruption of fronto-temporal networks mediating vocalisation. PMID:19435636

  10. A prospective study of diffusion weighted magnetic resonance imaging abnormalities in patients with cluster of seizures and status epilepticus.

    PubMed

    Jabeen, S A; Cherukuri, Pavankumar; Mridula, Rukmini; Harshavardhana, K R; Gaddamanugu, Padmaja; Sarva, Sailaja; Meena, A K; Borgohain, Rupam; Jyotsna Rani, Y

    2017-04-01

    To study the frequency, imaging characteristics, and clinical predictors for development of periictal diffusion weighted MRI abnormalities. We prospectively analyzed electro clinical and imaging characteristic of adult patients with cluster of seizures or status epilepticus between November 2013 and November 2015, in whom the diffusion weighted imaging was done within 24h after the end of last seizure (clinical or electrographic). There were thirty patients who fulfilled the inclusion and exclusion criteria. Twenty patients (66%) had periictal MRI abnormalities. Nine patients (34%) did not have any MRI abnormality. All the patients with PMA had abnormalities on diffusion weighted imaging (DWI). Hippocampal abnormalities were seen in nine (53%), perisylvian in two (11.7%), thalamic in five (30%), splenium involvement in two (11.7%) and cortical involvement (temporo-occipital, parieto-occipital, temporo-parietal, fronto-parietal and fronto-temporal) in sixteen (94.1%) patients. Complete reversal of DWI changes was noted in sixteen (80%) patients and four (20%) patients showed partial resolution of MRI abnormalities. Mean duration of seizures was significantly higher among patients with PMA (59.11+20.97h) compared to those without MRI changes (27.33+9.33h) (p<0.001). Diffusion abnormalities on MRI are common in patients with cluster of seizures and status epilepticus and were highly concordant with clinical semiology and EEG activity. Patients with longer duration of seizures/status were more likely to have PMA. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Fronto-orbital feminization technique. A surgical strategy using fronto-orbital burring with or without eggshell technique to optimize the risk/benefit ratio.

    PubMed

    Villepelet, A; Jafari, A; Baujat, B

    2018-05-04

    The demand for facial feminization is increasing in transsexual patients. Masculine foreheads present extensive supraorbital bossing with a more acute glabellar angle, whereas female foreheads show softer features. The aim of this article is to describe our surgical technique for fronto-orbital feminization. The mask-lift technique is an upper face-lift. It provides rejuvenation by correcting collapsed features, and fronto-orbital feminization through burring of orbital rims and lateral canthopexies. Depending on the size of the frontal sinus and the thickness of its anterior wall, frontal remodeling is achieved using simple burring or by means of the eggshell technique. Orbital remodeling comprises a superolateral orbital opening, a reduction of ridges and a trough at the lateral orbital rim to support the lateral canthopexy. Frontal, corrugator and procerus myectomies, plus minimal scalp excision, complete the surgery. Our technique results in significant, natural-looking feminization. No complications were observed in our series of patients. The eggshell technique is an alternative to bone flap on over-pneumatized sinus. Fronto-orbital feminization fits into a wider surgical strategy. It can be associated to rhinoplasty, genioplasty, mandibular angle remodeling, face lift and laryngoplasty. Achieving facial feminization in 2 or 3 stages improves psychological and physiological tolerance. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  12. Functional connectivity abnormalities and associated cognitive deficits in fetal alcohol Spectrum disorders (FASD).

    PubMed

    Wozniak, Jeffrey R; Mueller, Bryon A; Mattson, Sarah N; Coles, Claire D; Kable, Julie A; Jones, Kenneth L; Boys, Christopher J; Lim, Kelvin O; Riley, Edward P; Sowell, Elizabeth R

    2017-10-01

    Consistent with well-documented structural and microstructural abnormalities in prenatal alcohol exposure (PAE), recent studies suggest that functional connectivity (FC) may also be disrupted. We evaluated whole-brain FC in a large multi-site sample, examined its cognitive correlates, and explored its potential to objectively identify neurodevelopmental abnormality in individuals without definitive dysmorphic features. Included were 75 children with PAE and 68 controls from four sites. All participants had documented heavy prenatal alcohol exposure. All underwent a formal evaluation of physical anomalies and dysmorphic facial features. MRI data were collected using modified matched protocols on three platforms (Siemens, GE, and Philips). Resting-state FC was examined using whole-brain graph theory metrics to characterize each individual's connectivity. Although whole-brain FC metrics did not discriminate prenatally-exposed from unexposed overall, atypical FC (> 1 standard deviation from the grand mean) was significantly more common (2.7 times) in the PAE group vs. In a subset of 55 individuals (PAE and controls) whose dysmorphology examination could not definitively characterize them as either Fetal Alcohol Syndrome (FAS) or non-FAS, atypical FC was seen in 27 % of the PAE group, but 0 % of controls. Across participants, a 1 % difference in local network efficiency was associated with a 36 point difference in global cognitive functioning. Whole-brain FC metrics have potential to identify individuals with objective neurodevelopmental abnormalities from prenatal alcohol exposure. When applied to individuals unable to be classified as FAS or non-FAS from dysmorphology alone, these measures separate prenatally-exposed from non-exposed with high specificity.

  13. Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons

    PubMed Central

    Adler, Avital; Katabi, Shiran; Finkes, Inna; Prut, Yifat; Bergman, Hagai

    2013-01-01

    The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs), and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs), which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs), presumably parvalbumin (PV) expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation). TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit. PMID:24027501

  14. Disruptive changes of cerebellar functional connectivity with the default mode network in schizophrenia.

    PubMed

    Wang, Lubin; Zou, Feng; Shao, Yongcong; Ye, Enmao; Jin, Xiao; Tan, Shuwen; Hu, Dewen; Yang, Zheng

    2014-12-01

    The default mode network (DMN) plays an important role in the physiopathology of schizophrenia. Previous studies have suggested that the cerebellum participates in higher-order cognitive networks such as the DMN. However, the specific contribution of the cerebellum to the DMN abnormalities in schizophrenia has yet to be established. In this study, we investigated cerebellar functional connectivity differences between 60 patients with schizophrenia and 60 healthy controls from a public resting-state fMRI database. Seed-based correlation analysis was performed by using seeds from the left Crus I, right Crus I and Lobule IX, which have previously been identified as being involved in the DMN. Our results revealed that, compared with the healthy controls, the patients showed significantly reduced cerebellar functional connectivity with the thalamus and several frontal regions including the middle frontal gyrus, anterior cingulate cortex, and supplementary motor area. Moreover, the positive correlations between the strength of frontocerebellar and thalamocerebellar functional connectivity observed in the healthy subjects were diminished in the patients. Our findings implicate disruptive changes of the fronto-thalamo-cerebellar circuit in schizophrenia, which may provide further evidence for the "cognitive dysmetria" concept of schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1.

    PubMed

    Tomson, Steffie N; Schreiner, Matthew J; Narayan, Manjari; Rosser, Tena; Enrique, Nicole; Silva, Alcino J; Allen, Genevera I; Bookheimer, Susan Y; Bearden, Carrie E

    2015-11-01

    Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. © 2015 Wiley Periodicals, Inc.

  16. Resting state functional MRI reveals abnormal network connectivity in Neurofibromatosis 1

    PubMed Central

    Tomson, S.N.; Schreiner, M.; Narayan, M.; Rosser, Tena; Enrique, Nicole; Silva, Alcino J.; Allen, G.I.; Bookheimer, S.Y.; Bearden, C.E.

    2015-01-01

    Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits and autism spectrum disorders. As a single gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity MRI (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. PMID:26304096

  17. Repetitive behaviors in autism are linked to imbalance of corticostriatal connectivity: a functional connectivity MRI study.

    PubMed

    Abbott, Angela E; Linke, Annika C; Nair, Aarti; Jahedi, Afrooz; Alba, Laura A; Keown, Christopher L; Fishman, Inna; Müller, Ralph-Axel

    2018-01-01

    The neural underpinnings of repetitive behaviors (RBs) in autism spectrum disorders (ASDs), ranging from cognitive to motor characteristics, remain unknown. We assessed RB symptomatology in 50 ASD and 52 typically developing (TD) children and adolescents (ages 8-17 years), examining intrinsic functional connectivity (iFC) of corticostriatal circuitry, which is important for reward-based learning and integration of emotional, cognitive and motor processing, and considered impaired in ASDs. Connectivity analyses were performed for three functionally distinct striatal seeds (limbic, frontoparietal and motor). Functional connectivity with cortical regions of interest was assessed for corticostriatal circuit connectivity indices and ratios, testing the balance of connectivity between circuits. Results showed corticostriatal overconnectivity of limbic and frontoparietal seeds, but underconnectivity of motor seeds. Correlations with RBs were found for connectivity between the striatal motor seeds and cortical motor clusters from the whole-brain analysis, and for frontoparietal/limbic and motor/limbic connectivity ratios. Division of ASD participants into high (n = 17) and low RB subgroups (n = 19) showed reduced frontoparietal/limbic and motor/limbic circuit ratios for high RB compared to low RB and TD groups in the right hemisphere. Results suggest an association between RBs and an imbalance of corticostriatal iFC in ASD, being increased for limbic, but reduced for frontoparietal and motor circuits. © The Author (2017). Published by Oxford University Press.

  18. Repetitive behaviors in autism are linked to imbalance of corticostriatal connectivity: a functional connectivity MRI study

    PubMed Central

    Abbott, Angela E; Linke, Annika C; Nair, Aarti; Jahedi, Afrooz; Alba, Laura A; Keown, Christopher L; Fishman, Inna

    2018-01-01

    Abstract The neural underpinnings of repetitive behaviors (RBs) in autism spectrum disorders (ASDs), ranging from cognitive to motor characteristics, remain unknown. We assessed RB symptomatology in 50 ASD and 52 typically developing (TD) children and adolescents (ages 8–17 years), examining intrinsic functional connectivity (iFC) of corticostriatal circuitry, which is important for reward-based learning and integration of emotional, cognitive and motor processing, and considered impaired in ASDs. Connectivity analyses were performed for three functionally distinct striatal seeds (limbic, frontoparietal and motor). Functional connectivity with cortical regions of interest was assessed for corticostriatal circuit connectivity indices and ratios, testing the balance of connectivity between circuits. Results showed corticostriatal overconnectivity of limbic and frontoparietal seeds, but underconnectivity of motor seeds. Correlations with RBs were found for connectivity between the striatal motor seeds and cortical motor clusters from the whole-brain analysis, and for frontoparietal/limbic and motor/limbic connectivity ratios. Division of ASD participants into high (n = 17) and low RB subgroups (n = 19) showed reduced frontoparietal/limbic and motor/limbic circuit ratios for high RB compared to low RB and TD groups in the right hemisphere. Results suggest an association between RBs and an imbalance of corticostriatal iFC in ASD, being increased for limbic, but reduced for frontoparietal and motor circuits. PMID:29177509

  19. Recruitment of prefrontal-striatal circuit in response to skilled motor challenge.

    PubMed

    Guo, Yumei; Wang, Zhuo; Prathap, Sandhya; Holschneider, Daniel P

    2017-12-13

    A variety of physical fitness regimens have been shown to improve cognition, including executive function, yet our understanding of which parameters of motor training are important in optimizing outcomes remains limited. We used functional brain mapping to compare the ability of two motor challenges to acutely recruit the prefrontal-striatal circuit. The two motor tasks - walking in a complex running wheel with irregularly spaced rungs or walking in a running wheel with a smooth internal surface - differed only in the extent of skill required for their execution. Cerebral perfusion was mapped in rats by intravenous injection of [C]-iodoantipyrine during walking in either a motorized complex wheel or in a simple wheel. Regional cerebral blood flow (rCBF) was quantified by whole-brain autoradiography and analyzed in three-dimensional reconstructed brains by statistical parametric mapping and seed-based functional connectivity. Skilled or simple walking compared with rest, increased rCBF in regions of the motor circuit, somatosensory and visual cortex, as well as the hippocampus. Significantly greater rCBF increases were noted during skilled walking than for simple walking. Skilled walking, unlike simple walking or the resting condition, was associated with a significant positive functional connectivity in the prefrontal-striatal circuit (prelimbic cortex-dorsomedial striatum) and greater negative functional connectivity in the prefrontal-hippocampal circuit. Our findings suggest that the level of skill of a motor training task determines the extent of functional recruitment of the prefrontal-corticostriatal circuit, with implications for a new approach in neurorehabilitation that uses circuit-specific neuroplasticity to improve motor and cognitive functions.

  20. New insights in the homotopic and heterotopic connectivity of the frontal portion of the human corpus callosum revealed by microdissection and diffusion tractography.

    PubMed

    De Benedictis, Alessandro; Petit, Laurent; Descoteaux, Maxime; Marras, Carlo Efisio; Barbareschi, Mattia; Corsini, Francesco; Dallabona, Monica; Chioffi, Franco; Sarubbo, Silvio

    2016-12-01

    Extensive studies revealed that the human corpus callosum (CC) plays a crucial role in providing large-scale bi-hemispheric integration of sensory, motor and cognitive processing, especially within the frontal lobe. However, the literature lacks of conclusive data regarding the structural macroscopic connectivity of the frontal CC. In this study, a novel microdissection approach was adopted, to expose the frontal fibers of CC from the dorsum to the lateral cortex in eight hemispheres and in one entire brain. Post-mortem results were then combined with data from advanced constrained spherical deconvolution in 130 healthy subjects. We demonstrated as the frontal CC provides dense inter-hemispheric connections. In particular, we found three types of fronto-callosal fibers, having a dorso-ventral organization. First, the dorso-medial CC fibers subserve homotopic connections between the homologous medial cortices of the superior frontal gyrus. Second, the ventro-lateral CC fibers subserve homotopic connections between lateral frontal cortices, including both the middle frontal gyrus and the inferior frontal gyrus, as well as heterotopic connections between the medial and lateral frontal cortices. Third, the ventro-striatal CC fibers connect the medial and lateral frontal cortices with the contralateral putamen and caudate nucleus. We also highlighted an intricate crossing of CC fibers with the main association pathways terminating in the lateral regions of the frontal lobes. This combined approach of ex vivo microdissection and in vivo diffusion tractography allowed demonstrating a previously unappreciated three-dimensional architecture of the anterior frontal CC, thus clarifying the functional role of the CC in mediating the inter-hemispheric connectivity. Hum Brain Mapp 37:4718-4735, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Basal Ganglia Disorders Associated with Imbalances in the Striatal Striosome and Matrix Compartments

    PubMed Central

    Crittenden, Jill R.; Graybiel, Ann M.

    2011-01-01

    The striatum is composed principally of GABAergic, medium spiny striatal projection neurons (MSNs) that can be categorized based on their gene expression, electrophysiological profiles, and input–output circuits. Major subdivisions of MSN populations include (1) those in ventromedial and dorsolateral striatal regions, (2) those giving rise to the direct and indirect pathways, and (3) those that lie in the striosome and matrix compartments. The first two classificatory schemes have enabled advances in understanding of how basal ganglia circuits contribute to disease. However, despite the large number of molecules that are differentially expressed in the striosomes or the extra-striosomal matrix, and the evidence that these compartments have different input–output connections, our understanding of how this compartmentalization contributes to striatal function is still not clear. A broad view is that the matrix contains the direct and indirect pathway MSNs that form parts of sensorimotor and associative circuits, whereas striosomes contain MSNs that receive input from parts of limbic cortex and project directly or indirectly to the dopamine-containing neurons of the substantia nigra, pars compacta. Striosomes are widely distributed within the striatum and are thought to exert global, as well as local, influences on striatal processing by exchanging information with the surrounding matrix, including through interneurons that send processes into both compartments. It has been suggested that striosomes exert and maintain limbic control over behaviors driven by surrounding sensorimotor and associative parts of the striatal matrix. Consistent with this possibility, imbalances between striosome and matrix functions have been reported in relation to neurological disorders, including Huntington’s disease, L-DOPA-induced dyskinesias, dystonia, and drug addiction. Here, we consider how signaling imbalances between the striosomes and matrix might relate to symptomatology

  2. A review on functional and structural brain connectivity in numerical cognition

    PubMed Central

    Moeller, Korbinian; Willmes, Klaus; Klein, Elise

    2015-01-01

    Only recently has the complex anatomo-functional system underlying numerical cognition become accessible to evaluation in the living brain. We identified 27 studies investigating brain connectivity in numerical cognition. Despite considerable heterogeneity regarding methodological approaches, populations investigated, and assessment procedures implemented, the results provided largely converging evidence regarding the underlying brain connectivity involved in numerical cognition. Analyses of both functional/effective as well as structural connectivity have consistently corroborated the assumption that numerical cognition is subserved by a fronto-parietal network including (intra)parietal as well as (pre)frontal cortex sites. Evaluation of structural connectivity has indicated the involvement of fronto-parietal association fibers encompassing the superior longitudinal fasciculus dorsally and the external capsule/extreme capsule system ventrally. Additionally, commissural fibers seem to connect the bilateral intraparietal sulci when number magnitude information is processed. Finally, the identification of projection fibers such as the superior corona radiata indicates connections between cortex and basal ganglia as well as the thalamus in numerical cognition. Studies on functional/effective connectivity further indicated a specific role of the hippocampus. These specifications of brain connectivity augment the triple-code model of number processing and calculation with respect to how gray matter areas associated with specific number-related representations may work together. PMID:26029075

  3. Striatal and midbrain connectivity with the hippocampus selectively boosts memory for contextual novelty

    PubMed Central

    Kafkas, Alexandros; Montaldi, Daniela

    2015-01-01

    The role of contextual expectation in processing familiar and novel stimuli was investigated in a series of experiments combining eye tracking, functional magnetic resonance imaging, and behavioral methods. An experimental paradigm emphasizing either familiarity or novelty detection at retrieval was used. The detection of unexpected familiar and novel stimuli, which were characterized by lower probability, engaged activity in midbrain and striatal structures. Specifically, detecting unexpected novel stimuli, relative to expected novel stimuli, produced greater activity in the substantia nigra/ventral tegmental area (SN/VTA), whereas the detection of unexpected familiar, relative to expected, familiar stimuli, elicited activity in the striatum/globus pallidus (GP). An effective connectivity analysis showed greater functional coupling between these two seed areas (GP and SN/VTA) and the hippocampus, for unexpected than for expected stimuli. Within this network of midbrain/striatal–hippocampal interactions two pathways are apparent; the direct SN–hippocampal pathway sensitive to unexpected novelty and the perirhinal–GP–hippocampal pathway sensitive to unexpected familiarity. In addition, increased eye fixations and pupil dilations also accompanied the detection of unexpected relative to expected familiar and novel stimuli, reflecting autonomic activity triggered by the functioning of these two pathways. Finally, subsequent memory for unexpected, relative to expected, familiar, and novel stimuli was characterized by enhanced recollection, but not familiarity, accuracy. Taken together, these findings suggest that a hippocampal–midbrain network, characterized by two distinct pathways, mediates encoding facilitation and most critically, that this facilitation is driven by contextual novelty, rather than by the absolute novelty of a stimulus. This contextually sensitive neural mechanism appears to elicit increased exploratory behavior, leading subsequently to

  4. [18F]fallypride characterization of striatal and extrastriatal D2/3 receptors in Parkinson's disease.

    PubMed

    Stark, Adam J; Smith, Christopher T; Petersen, Kalen J; Trujillo, Paula; van Wouwe, Nelleke C; Donahue, Manus J; Kessler, Robert M; Deutch, Ariel Y; Zald, David H; Claassen, Daniel O

    2018-01-01

    Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D 2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D 2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D 2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [ 18 F]fallypride, a high affinity D 2/3 receptor ligand, to measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BP ND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D 2/3 receptors, where reduced BP ND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D 2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D 2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

  5. Unravelling the Intrinsic Functional Organization of the Human Striatum: A Parcellation and Connectivity Study Based on Resting-State fMRI

    PubMed Central

    Jung, Wi Hoon; Jang, Joon Hwan; Park, Jin Woo; Kim, Euitae; Goo, Eun-Hoe; Im, Oh-Soo; Kwon, Jun Soo

    2014-01-01

    As the main input hub of the basal ganglia, the striatum receives projections from the cerebral cortex. Many studies have provided evidence for multiple parallel corticostriatal loops based on the structural and functional connectivity profiles of the human striatum. A recent resting-state fMRI study revealed the topography of striatum by assigning each voxel in the striatum to its most strongly correlated cortical network among the cognitive, affective, and motor networks. However, it remains unclear what patterns of striatal parcellation would result from performing the clustering without subsequent assignment to cortical networks. Thus, we applied unsupervised clustering algorithms to parcellate the human striatum based on its functional connectivity patterns to other brain regions without any anatomically or functionally defined cortical targets. Functional connectivity maps of striatal subdivisions, identified through clustering analyses, were also computed. Our findings were consistent with recent accounts of the functional distinctions of the striatum as well as with recent studies about its functional and anatomical connectivity. For example, we found functional connections between dorsal and ventral striatal clusters and the areas involved in cognitive and affective processes, respectively, and between rostral and caudal putamen clusters and the areas involved in cognitive and motor processes, respectively. This study confirms prior findings, showing similar striatal parcellation patterns between the present and prior studies. Given such striking similarity, it is suggested that striatal subregions are functionally linked to cortical networks involving specific functions rather than discrete portions of cortical regions. Our findings also demonstrate that the clustering of functional connectivity patterns is a reliable feature in parcellating the striatum into anatomically and functionally meaningful subdivisions. The striatal subdivisions identified here

  6. Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder.

    PubMed

    Ecker, Christine; Ronan, Lisa; Feng, Yue; Daly, Eileen; Murphy, Clodagh; Ginestet, Cedric E; Brammer, Michael; Fletcher, Paul C; Bullmore, Edward T; Suckling, John; Baron-Cohen, Simon; Williams, Steve; Loth, Eva; Murphy, Declan G M

    2013-08-06

    Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of "cortical separation distances" to assess the global and local intrinsic "wiring costs" of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical "connectivity" in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms.

  7. Hydronephrosis in the Wnt5a-ablated kidney is caused by an abnormal ureter-bladder connection.

    PubMed

    Yun, Kangsun; Perantoni, Alan O

    The Wnt5a null mouse is a complex developmental model which, among its several posterior-localized axis defects, exhibits multiple kidney phenotypes, including duplex kidney and loss of the medullary zone. We previously reported that ablation of Wnt5a in nascent mesoderm causes duplex kidney formation as a result of aberrant development of the nephric duct and abnormal extension of intermediate mesoderm. However, these mice also display a loss of the medullary region late in gestation. We have now genetically isolated duplex kidney formation from the medullary defect by specifically targeting the progenitors for both the ureteric bud and metanephric mesenchyme. The conditional mutants fail to form a normal renal medulla but no longer exhibit duplex kidney formation. Approximately 1/3 of the mutants develop hydronephrosis in the kidneys either uni- or bilaterally when using Dll1Cre. The abnormal kidney phenotype becomes prominent at E16.5, which approximates the time when urine production begins in the mouse embryonic kidney, and is associated with a dramatic increase in apoptosis only in mutant kidneys with hydronephrosis. Methylene blue dye injection and histologic examination reveal that aberrant cell death likely results from urine toxicity due to an abnormal ureter-bladder connection. This study shows that Wnt5a is not required for development of the renal medulla and that loss of the renal medullary region in the Wnt5a-deleted kidney is caused by an abnormal ureter-bladder connection. Published by Elsevier B.V.

  8. Abnormal brain connectivity in first-episode psychosis: A diffusion MRI tractography study of the corpus callosum

    PubMed Central

    Price, Gary; Cercignani, Mara; Parker, Geoffrey J.M.; Altmann, Daniel R.; Barnes, Thomas R.E.; Barker, Gareth J.; Joyce, Eileen M.; Ron, Maria A.

    2007-01-01

    A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the clinical manifestations of schizophrenia. Recently, diffusion imaging tractography has made it possible to study white matter pathways in detail and we present here a study of patients with first-episode psychosis using this technique. We selected the corpus callosum for this study because there is evidence that it is abnormal in schizophrenia. In addition, the topographical organization of its fibers makes it possible to relate focal abnormalities to specific cortical regions. Eighteen patients with first-episode psychosis and 21 healthy subjects took part in the study. A probabilistic tractography algorithm (PICo) was used to study fractional anisotropy (FA). Seed regions were placed in the genu and splenium to track fiber tracts traversing these regions, and a multi-threshold approach to study the probability of connection was used. Multiple linear regressions were used to explore group differences. FA, a measure of tract coherence, was reduced in tracts crossing the genu, and to a lesser degree the splenium, in patients compared with controls. FA was also lower in the genu in females across both groups, but there was no gender-by-group interaction. The FA reduction in patients may be due to aberrant myelination or axonal abnormalities, but the similar tract volumes in the two groups suggest that severe axonal loss is unlikely at this stage of the illness. PMID:17275337

  9. Striatal functional connectivity changes following specific balance training in elderly people: MRI results of a randomized controlled pilot study.

    PubMed

    Magon, Stefano; Donath, Lars; Gaetano, Laura; Thoeni, Alain; Radue, Ernst-Wilhelm; Faude, Oliver; Sprenger, Till

    2016-09-01

    Practice-induced effects of specific balance training on brain structure and activity in elderly people are largely unknown. In the present study, we investigated morphological and functional brain changes following slacking training (balancing over nylon ribbons) in a group of elderly people. Twenty-eight healthy volunteers were recruited and randomly assigned to the intervention (mean age: 62.3±5.4years) or control group (mean age: 61.8±5.3years). The intervention group completed six-weeks of slackline training. Brain morphological changes were investigated using voxel-based morphometry and functional connectivity changes were computed via independent component analysis and seed-based analyses. All analyses were applied to the whole sample and to a subgroup of participants who improved in slackline performance. The repeated measures analysis of variance showed a significant interaction effect between groups and sessions. Specifically, the Tukey post-hoc analysis revealed a significantly improved slackline standing performance after training for the left leg stance time (pre: 4.5±3.6s vs. 26.0±30.0s, p<0.038) as well as for tandem stance time (pre: 1.4±0.6s vs. post: 4.5±4.0s, p=0.003) in the intervention group. No significant changes in balance performance were observed in the control group. The MRI analysis did not reveal morphological or functional connectivity differences before or after the training between the intervention and control groups (whole sample). However, subsequent analysis in subjects with improved slackline performance showed a decrease of connectivity between the striatum and other brain areas during the training period. These preliminary results suggest that improved balance performance with slackline training goes along with an increased efficiency of the striatal network. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Abnormalities in hemispheric specialization of caudate nucleus connectivity in schizophrenia.

    PubMed

    Mueller, Sophia; Wang, Danhong; Pan, Ruiqi; Holt, Daphne J; Liu, Hesheng

    2015-06-01

    Hemispheric specialization of the human brain is a marker of successful neurodevelopment. Altered brain asymmetry that has been repeatedly reported in schizophrenia may represent consequences of disrupted neurodevelopment in the disorder. However, a complete picture of functional specialization in the schizophrenic brain and its connectional substrates is yet to be unveiled. To quantify intrinsic hemispheric specialization at cortical and subcortical levels and to reveal potential disease effects in schizophrenia. Resting-state functional connectivity magnetic resonance imaging has been previously used to quantitatively measure hemispheric specialization in healthy individuals in a reliable manner. We quantified the intrinsic hemispheric specialization at the whole brain level in 31 patients with schizophrenia and 37 demographically matched healthy controls from November 28, 2007, through June 29, 2010, using resting-state functional magnetic resonance imaging. The caudate nucleus and cortical regions with connections to the caudate nucleus had markedly abnormal hemispheric specialization in schizophrenia. Compared with healthy controls, patients exhibited weaker specialization in the left, but the opposite pattern in the right, caudate nucleus (P < .001). Patients with schizophrenia also had a disruption of the interhemispheric coordination among the cortical regions with connections to the caudate nucleus. A linear classifier based on the specialization of the caudate nucleus distinguished patients from controls with a classification accuracy of 74% (with a sensitivity of 68% and a specificity of 78%). These data suggest that hemispheric specialization could serve as a potential imaging biomarker of schizophrenia that, compared with task-based functional magnetic resonance imaging measures, is less prone to the confounding effects of variation in task compliance, cognitive ability, and command of language.

  11. Interaction of language, auditory and memory brain networks in auditory verbal hallucinations.

    PubMed

    Ćurčić-Blake, Branislava; Ford, Judith M; Hubl, Daniela; Orlov, Natasza D; Sommer, Iris E; Waters, Flavie; Allen, Paul; Jardri, Renaud; Woodruff, Peter W; David, Olivier; Mulert, Christoph; Woodward, Todd S; Aleman, André

    2017-01-01

    Auditory verbal hallucinations (AVH) occur in psychotic disorders, but also as a symptom of other conditions and even in healthy people. Several current theories on the origin of AVH converge, with neuroimaging studies suggesting that the language, auditory and memory/limbic networks are of particular relevance. However, reconciliation of these theories with experimental evidence is missing. We review 50 studies investigating functional (EEG and fMRI) and anatomic (diffusion tensor imaging) connectivity in these networks, and explore the evidence supporting abnormal connectivity in these networks associated with AVH. We distinguish between functional connectivity during an actual hallucination experience (symptom capture) and functional connectivity during either the resting state or a task comparing individuals who hallucinate with those who do not (symptom association studies). Symptom capture studies clearly reveal a pattern of increased coupling among the auditory, language and striatal regions. Anatomical and symptom association functional studies suggest that the interhemispheric connectivity between posterior auditory regions may depend on the phase of illness, with increases in non-psychotic individuals and first episode patients and decreases in chronic patients. Leading hypotheses involving concepts as unstable memories, source monitoring, top-down attention, and hybrid models of hallucinations are supported in part by the published connectivity data, although several caveats and inconsistencies remain. Specifically, possible changes in fronto-temporal connectivity are still under debate. Precise hypotheses concerning the directionality of connections deduced from current theoretical approaches should be tested using experimental approaches that allow for discrimination of competing hypotheses. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. [The Influence of the Functioning of Brain Regulatory Systems onto the Voluntary Regulation of Cognitive Performance in Children. Report 2. Neuropsychological and Electrophysiological Assessment of Brain Regulatory Functions in Children Aged 10-12 with Learning Difficulties].

    PubMed

    Semenova, O A; Machinskaya, R I

    2015-01-01

    A total number of 172 children aged 10-12 were electrophysiologically and neuropsychologically assessed in order to analyze the influence of the functioning of brain regulatory systems onto the voluntary regulation of cognitive performance during the preteen years. EEG patterns associated with the nonoptimal functioning of brain regulatory systems, particularly fronto-thalamic, limbic and fronto-striatal structures were significantly more often observed in children with learning and behavioral difficulties, as compared to the control group. Neuropsychological assessment showed that the nonoptimal functioning of different brain regulatory systems specifically affect the voluntary regulation of cognitive performance. Children with EEG patterns of fronto-thalamic nonoptimal functioning demonstrated poor voluntary regulation such as impulsiveness and difficulties in continuing the same algorithms. Children with EEG patterns of limbic nonoptimal functioning showed a less pronounced executive dysfunction manifested only in poor switching between program units within a task. Children with EEG patterns of fronto-striatal nonoptimal functioning struggled with such executive dysfunctions as motor and tactile perseverations and emotional-motivational deviations such as poor motivation and communicative skills.

  13. Can understanding the neurobiology of body dysmorphic disorder (BDD) inform treatment?

    PubMed

    Rossell, Susan L; Harrison, Ben J; Castle, David

    2015-08-01

    We aim to provide a clinically focused review of the neurobiological literature in body dysmorphic disorder (BDD), with a focus on structural and functional neuroimaging. There has been a recent influx of studies examining the underlying neurobiology of BDD using structural and functional neuroimaging methods. Despite obvious symptom similarities with obsessive-compulsive disorder (OCD), no study to date has directly compared the two groups using neuroimaging techniques. Studies have established that there are limbic and visual cortex abnormalities in BDD, in contrast to fronto-striatal differences in OCD. Such data suggests affect or visual training maybe useful in BDD. © The Royal Australian and New Zealand College of Psychiatrists 2015.

  14. Differential loss of striatal projection neurons in Huntington disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Reiner, A.; Albin, R.L.; Anderson, K.D.

    1988-08-01

    Huntington disease (HD) is characterized by the loss of striatal projection neurons, which constitute the vast majority of striatal neurons. To determine whether there is differential loss among different populations of striatal projection neurons, the integrity of the axon terminal plexuses arising from the different populations of substance P-containing and enkephalin-containing striatal projection neurons was studied in striatal target areas by immunohistochemistry. Analysis of 17 HD specimens indicated that in early and middle stages of HD, enkephalin-containing neurons projecting to the external segment of the globus pallidus were much more affected than substance P-containing neurons projecting to the internal pallidalmore » segment. Furthermore, substance P-containing neurons projecting to the substantia nigra pars reticulata were more affected than those projecting to the substantia nigra pars compacta. At the most advanced stages of the disease, projections to all striatal target areas were depleted, with the exception of some apparent sparing of the striatal projection to the substantia nigra pars compacta. These finding may explain some of the clinical manifestations and pharmacology of HD. They also may aid in identifying the neural defect underlying HD and provide additional data with which to evaluate current models of HD pathogenesis.« less

  15. Fronto-temporal interactions are functionally relevant for semantic control in language processing.

    PubMed

    Wawrzyniak, Max; Hoffstaedter, Felix; Klingbeil, Julian; Stockert, Anika; Wrede, Katrin; Hartwigsen, Gesa; Eickhoff, Simon B; Classen, Joseph; Saur, Dorothee

    2017-01-01

    Semantic cognition, i.e. processing of meaning is based on semantic representations and their controlled retrieval. Semantic control has been shown to be implemented in a network that consists of left inferior frontal (IFG), and anterior and posterior middle temporal gyri (a/pMTG). We aimed to disrupt semantic control processes with continuous theta burst stimulation (cTBS) over left IFG and pMTG and to study whether behavioral effects are moderated by induced alterations in resting-state functional connectivity. To this end, we applied real cTBS over left IFG and left pMTG as well as sham stimulation on 20 healthy participants in a within-subject design. Stimulation was followed by resting-state functional magnetic resonance imaging and a semantic priming paradigm. Resting-state functional connectivity of regions of interest in left IFG, pMTG and aMTG revealed highly interconnected left-lateralized fronto-temporal networks representing the semantic system. We did not find any significant direct modulation of either task performance or resting-state functional connectivity by effective cTBS. However, after sham cTBS, functional connectivity between IFG and pMTG correlated with task performance under high semantic control demands in the semantic priming paradigm. These findings provide evidence for the functional relevance of interactions between IFG and pMTG for semantic control processes. This interaction was functionally less relevant after cTBS over aIFG which might be interpretable in terms of an indirect disruptive effect of cTBS.

  16. Brain functional network abnormality extends beyond the sensorimotor network in brachial plexus injury patients.

    PubMed

    Feng, Jun-Tao; Liu, Han-Qiu; Hua, Xu-Yun; Gu, Yu-Dong; Xu, Jian-Guang; Xu, Wen-Dong

    2016-12-01

    Brachial plexus injury (BPI) is a type of severe peripheral nerve trauma that leads to central remodeling in the brain, as revealed by functional MRI analysis. However, previously reported remodeling is mostly restricted to sensorimotor areas of the brain. Whether this disturbance in the sensorimotor network leads to larger-scale functional remodeling remains unknown. We sought to explore the higher-level brain functional abnormality pattern of BPI patients from a large-scale network function connectivity dimension in 15 right-handed BPI patients. Resting-state functional MRI data were collected and analyzed using independent component analysis methods. Five components of interest were recognized and compared between patients and healthy subjects. Patients showed significantly altered brain local functional activities in the bilateral fronto-parietal network (FPN), sensorimotor network (SMN), and executive-control network (ECN) compared with healthy subjects. Moreover, functional connectivity between SMN and ECN were significantly less in patients compared with healthy subjects, and connectivity strength between ECN and SMN was negatively correlated with patients' residual function of the affected limb. Functional connectivity between SMN and right FPN were also significantly less than in controls, although connectivity between ECN and default mode network (DMN) was greater than in controls. These data suggested that brain functional disturbance in BPI patients extends beyond the sensorimotor network and cascades serial remodeling in the brain, which significantly correlates with residual hand function of the paralyzed limb. Furthermore, functional remodeling in these higher-level functional networks may lead to cognitive alterations in complex tasks.

  17. Abnormal amygdala connectivity in patients with primary insomnia: evidence from resting state fMRI.

    PubMed

    Huang, Zhaoyang; Liang, Peipeng; Jia, Xiuqin; Zhan, Shuqin; Li, Ning; Ding, Yan; Lu, Jie; Wang, Yuping; Li, Kuncheng

    2012-06-01

    Neurobiological mechanisms underlying insomnia are poorly understood. Previous findings indicated that dysfunction of the emotional circuit might contribute to the neurobiological mechanisms underlying insomnia. The present study will test this hypothesis by examining alterations in functional connectivity of the amygdala in patients with primary insomnia (PI). Resting-state functional connectivity analysis was used to examine the temporal correlation between the amygdala and whole-brain regions in 10 medication-naive PI patients and 10 age- and sex-matched healthy controls. Additionally, the relationship between the abnormal functional connectivity and insomnia severity was investigated. We found decreased functional connectivity mainly between the amygdala and insula, striatum and thalamus, and increased functional connectivity mainly between the amygdala and premotor cortex, sensorimotor cortex in PI patients as compared to healthy controls. The connectivity of the amygdala with the premotor cortex in PI patients showed significant positive correlation with the total score of the Pittsburgh Sleep Quality Index (PSQI). The decreased functional connectivity between the amygdala and insula, striatum, and thalamus suggests that dysfunction in the emotional circuit might contribute to the neurobiological mechanisms underlying PI. The increased functional connectivity of the amygdala with the premotor and sensorimotor cortex demonstrates a compensatory mechanism to overcome the negative effects of sleep deficits and maintain the psychomotor performances in PI patients. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  18. RELATIONSHIP BETWEEN ENTROPY OF SPIKE TIMING AND FIRING RATE IN ENTOPEDUNCULAR NUCLEUS NEURONS IN ANESTHETIZED RATS: FUNCTION OF THE NIGRO-STRIATAL PATHWAY

    PubMed Central

    Darbin, Olivier; Jin, Xingxing; von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K.; Alam, Mesbah

    2016-01-01

    The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus (entopeduncular nucleus, EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD). In both control subjects and subjects with 6-OHDA lesion of the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15Hz and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25Hz. Our data establishes that nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions with movement disorders. PMID:26711712

  19. Age-related differences in striatal, medial temporal, and frontal involvement during value-based decision processing.

    PubMed

    Su, Yu-Shiang; Chen, Jheng-Ting; Tang, Yong-Jheng; Yuan, Shu-Yun; McCarrey, Anna C; Goh, Joshua Oon Soo

    2018-05-21

    Appropriate neural representation of value and application of decision strategies are necessary to make optimal investment choices in real life. Normative human aging alters neural selectivity and control processing in brain regions implicated in value-based decision processing including striatal, medial temporal, and frontal areas. However, the specific neural mechanisms of how these age-related functional brain changes modulate value processing in older adults remain unclear. Here, young and older adults performed a lottery-choice functional magnetic resonance imaging experiment in which probabilities of winning different magnitudes of points constituted expected values of stakes. Increasing probability of winning modulated striatal responses in young adults, but modulated medial temporal and ventromedial prefrontal areas instead in older adults. Older adults additionally engaged higher responses in dorso-medio-lateral prefrontal cortices to more unfavorable stakes. Such extrastriatal involvement mediated age-related increase in risk-taking decisions. Furthermore, lower resting-state functional connectivity between lateral prefrontal and striatal areas also predicted lottery-choice task risk-taking that was mediated by higher functional connectivity between prefrontal and medial temporal areas during the task, with this mediation relationship being stronger in older than younger adults. Overall, we report evidence of a systemic neural mechanistic change in processing of probability in mixed-lottery values with age that increases risk-taking of unfavorable stakes in older adults. Moreover, individual differences in age-related effects on baseline frontostriatal communication may be a central determinant of such subsequent age differences in value-based decision neural processing and resulting behaviors. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Striatal action-value neurons reconsidered.

    PubMed

    Elber-Dorozko, Lotem; Loewenstein, Yonatan

    2018-05-31

    It is generally believed that during economic decisions, striatal neurons represent the values associated with different actions. This hypothesis is based on studies, in which the activity of striatal neurons was measured while the subject was learning to prefer the more rewarding action. Here we show that these publications are subject to at least one of two critical confounds. First, we show that even weak temporal correlations in the neuronal data may result in an erroneous identification of action-value representations. Second, we show that experiments and analyses designed to dissociate action-value representation from the representation of other decision variables cannot do so. We suggest solutions to identifying action-value representation that are not subject to these confounds. Applying one solution to previously identified action-value neurons in the basal ganglia we fail to detect action-value representations. We conclude that the claim that striatal neurons encode action-values must await new experiments and analyses. © 2018, Elber-Dorozko et al.

  1. Differential Hemispheric Predilection of Microstructural White Matter and Functional Connectivity Abnormalities between Respectively Semantic and Behavioral Variant Frontotemporal Dementia.

    PubMed

    Meijboom, Rozanna; Steketee, Rebecca M E; Ham, Leontine S; van der Lugt, Aad; van Swieten, John C; Smits, Marion

    2017-01-01

    Semantic dementia (SD) and behavioral variant frontotemporal dementia (bvFTD), subtypes of frontotemporal dementia, are characterized by distinct clinical symptoms and neuroimaging features, with predominant left temporal grey matter (GM) atrophy in SD and bilateral or right frontal GM atrophy in bvFTD. Such differential hemispheric predilection may also be reflected by other neuroimaging features, such as brain connectivity. This study investigated white matter (WM) microstructure and functional connectivity differences between SD and bvFTD, focusing on the hemispheric predilection of these differences. Eight SD and 12 bvFTD patients, and 17 controls underwent diffusion tensor imaging and resting state functional MRI at 3T. Whole-brain WM microstructure was assessed to determine distinct WM tracts affected in SD and bvFTD. For these tracts, diffusivity measures and lateralization indices were calculated. Functional connectivity was established for GM regions affected in early stage SD or bvFTD. Results of a direct comparison between SD and bvFTD are reported. Whole-brain WM microstructure abnormalities were more pronounced in the left hemisphere in SD and bilaterally- with a slight predilection for the right- in bvFTD. Lateralization of tract-specific abnormalities was seen in SD only, toward the left hemisphere. Functional connectivity of disease-specific regions was mainly decreased bilaterally in SD and in the right hemisphere in bvFTD. SD and bvFTD show WM microstructure and functional connectivity abnormalities in different regions, that are respectively more pronounced in the left hemisphere in SD and in the right hemisphere in bvFTD. This indicates differential hemispheric predilection of brain connectivity abnormalities between SD and bvFTD.

  2. Mapping thalamocortical functional connectivity in chronic and early stages of psychotic disorders

    PubMed Central

    Woodward, Neil D.; Heckers, Stephan

    2015-01-01

    Objective There is considerable evidence that the thalamus is abnormal in psychotic disorders. Resting-state fMRI (RS-fMRI) has revealed an intriguing pattern of thalamic dysconnectivity in psychosis characterized by reduced prefrontal cortex (PFC) connectivity and increased somatomotor-thalamic connectivity. However, critical knowledge gaps remain with respect to the onset, anatomical specificity, and clinical correlates of thalamic dysconnectivity in psychosis. Method RS-fMRI was collected on 105 healthy subjects and 148 individuals with psychosis, including 53 early stage psychosis patients. Using all 253 subjects, the thalamus was parceled into functional regions-of-interest (ROIs) on the basis of connectivity with six a-priori defined cortical ROIs covering most of the cortical mantle. Functional connectivity between each cortical ROI and its corresponding thalamic ROI was quantified and compared across groups. Significant differences in the ROI-to-ROI analysis were followed up with voxel-wise seed-based analyses to further localize thalamic dysconnectivity. Results ROI analysis revealed reduced PFC-thalamic connectivity and increased somatomotor-thalamic connectivity in both chronic and early stages psychosis patients. PFC hypo-connectivity and motor cortex hyper-connectivity correlated in patients suggesting they result from a common pathophysiological mechanism. Seed-based analyses revealed thalamic hypo-connectivity in psychosis localized to dorsolateral PFC, medial PFC, and cerebellar areas of the well-described ‘executive control’ network. Across all subjects, thalamic connectivity with areas of the fronto-parietal network correlated with cognitive functioning, including verbal learning and memory. Conclusions Thalamocortical dysconnectivity is present in both chronic and early stages of psychosis, includes reduced thalamic connectivity with the executive control network, and is related to cognitive impairment. PMID:26248537

  3. Striatal Mechanisms Underlying Movement, Reinforcement, and Punishment

    PubMed Central

    Kravitz, Alexxai V.; Kreitzer, Anatol C.

    2013-01-01

    Direct and indirect pathway striatal neurons are known to exert opposing control over motor output. In this review, we discuss a hypothetical extension of this framework, in which direct pathway striatal neurons also mediate reinforcement and reward, and indirect pathway neurons mediate punishment and aversion. PMID:22689792

  4. Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

    PubMed Central

    Takahashi, Tetsuya; Cho, Raymond Y.; Mizuno, Tomoyuki; Kikuchi, Mitsuru; Murata, Tetsuhito; Takahashi, Koichi; Wada, Yuji

    2010-01-01

    Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics. PMID:20149880

  5. Altered motor network activation and functional connectivity in adult Tourette's syndrome.

    PubMed

    Werner, Cornelius J; Stöcker, Tony; Kellermann, Thilo; Bath, Jessica; Beldoch, Margarete; Schneider, Frank; Wegener, Hans Peter; Shah, Jon N; Neuner, Irene

    2011-11-01

    Tourette's syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics as well as psychiatric comorbidities. Disturbances of the fronto-striatal-thalamic pathways responsible for motor control and impulse inhibition have been previously described in other studies. Although differences in motor performance are well recognized, imaging data elucidating the neuronal correlates are scarce. Here, we examined 19 adult TS patients (13 men, aged 22-52 years, mean = 34.3 years) and 18 age- and sex-matched controls (13 men, aged 24-57 years, mean = 37.6 years) in a functional magnetic resonance imaging study at 1.5 T. We corrected for possible confounds introduced by tics, motion, and brain-structural differences as well as age, sex, comorbidities, and medication. Patients and controls were asked to perform a sequential finger-tapping task using their right, left, and both hands, respectively. Task performance was monitored by simultaneous MR-compatible video recording. Although behavioral data obtained during scanning did not show significant differences across groups, we observed differential neuronal activation patterns depending on both handedness (dominant vs. nondominant) and tapping frequency in frontal, parietal, and subcortical areas. When controlling for open motor performance, a failure of deactivation in easier task conditions was found in the subgenual cingulate cortex in the TS patients. In addition, performance-related functional connectivity of lower- and higher-order motor networks differed between patients and controls. In summary, although open performance was comparable, patients showed different neuronal networks and connectivity patterns when performing increasingly demanding tasks, further illustrating the impact of the disease on the motor system. Copyright © 2011 Wiley-Liss, Inc.

  6. Influence of cortical synaptic input on striatal neuronal dendritic arborization and sensitivity to excitotoxicity in corticostriatal coculture.

    PubMed

    Buren, Caodu; Tu, Gaqi; Parsons, Matthew P; Sepers, Marja D; Raymond, Lynn A

    2016-08-01

    Corticostriatal cocultures are utilized to recapitulate the cortex-striatum connection in vitro as a convenient model to investigate the development, function, and regulation of synapses formed between cortical and striatal neurons. However, optimization of this dissociated neuronal system to more closely reproduce in vivo circuits has not yet been explored. We studied the effect of varying the plating ratio of cortical to striatal neurons on striatal spiny projection neuron (SPN) characteristics in primary neuronal cocultures. Despite the large difference in cortical-striatal neuron ratio (1:1 vs. 1:3) at day of plating, by 18 days in vitro the difference became modest (∼25% lower cortical-striatal neuron ratio in 1:3 cocultures) and the neuronal density was lower in the 1:3 cocultures, indicating enhanced loss of striatal SPNs. Comparing SPNs in cocultures plated at a 1:1 vs. 1:3 ratio, we found that resting membrane potential, input resistance, current injection-induced action potential firing rates, and input-output curves were similar in the two conditions. However, SPNs in the cocultures plated at the lower cortical ratio exhibited reduced membrane capacitance along with significantly shorter total dendritic length, decreased dendritic complexity, and fewer excitatory synapses, consistent with their trend toward reduced miniature excitatory postsynaptic current frequency. Strikingly, the proportion of NMDA receptors found extrasynaptically in recordings from SPNs was significantly higher in the less cortical coculture. Consistently, SPNs in cocultures with reduced cortical input showed decreased basal pro-survival signaling through cAMP response element binding protein and enhanced sensitivity to NMDA-induced apoptosis. Altogether, our study indicates that abundance of cortical input regulates SPN dendritic arborization and survival/death signaling. Copyright © 2016 the American Physiological Society.

  7. Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

    PubMed

    Gross, Noah B; Duncker, Patrick C; Marshall, John F

    2011-11-01

    Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

  8. Morphological and Glucose Metabolism Abnormalities in Alcoholic Korsakoff's Syndrome: Group Comparisons and Individual Analyses

    PubMed Central

    Pitel, Anne-Lise; Aupée, Anne-Marie; Chételat, Gaël; Mézenge, Florence; Beaunieux, Hélène; de la Sayette, Vincent; Viader, Fausto; Baron, Jean-Claude; Eustache, Francis; Desgranges, Béatrice

    2009-01-01

    Background Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS). Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies. Methodology/Principal Findings Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients. Conclusions/Significance These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker. PMID:19936229

  9. Abnormal functional connectivity density in children with anisometropic amblyopia at resting-state.

    PubMed

    Wang, Tianyue; Li, Qian; Guo, Mingxia; Peng, Yanmin; Li, Qingji; Qin, Wen; Yu, Chunshui

    2014-05-14

    Amblyopia is a developmental disorder resulting from anomalous binocular visual input in early life. Task-based neuroimaging studies have widely investigated cortical functional impairments in amblyopia, but changes in spontaneous neuronal functional activities in amblyopia remain largely unknown. In the present study, functional connectivity density (FCD) mapping, an ultrafast data-driven method based on fMRI, was applied for the first time to investigate changes in cortical functional connectivities in amblyopia during the resting-state. We quantified and compared both short- and long-range FCD in both the brains of children with anisometropic amblyopia (AAC) and normal sighted children (NSC). In contrast to the NSC, the AAC showed significantly decreased short-range FCD in the inferior temporal/fusiform gyri, parieto-occipital and rostrolateral prefrontal cortices, as well as decreased long-range FCD in the premotor cortex, dorsal inferior parietal lobule, frontal-insular and dorsal prefrontal cortices. Furthermore, most regions with reduced long-range FCD in the AAC showed decreased functional connectivity with occipital and posterior parietal cortices in the AAC. The results suggest that chronically poor visual input in amblyopia not only impairs the brain's short-range functional connections in visual pathways and in the frontal cortex, which is important for cognitive control, but also affects long-range functional connections among the visual areas, posterior parietal and frontal cortices that subserve visuomotor and visual-guided actions, visuospatial attention modulation and the integration of salient information. This study provides evidence for abnormal spontaneous brain activities in amblyopia. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Response control networks are selectively modulated by attention to rare events and memory load regardless of the need for inhibition.

    PubMed

    Wijeakumar, Sobanawartiny; Magnotta, Vincent A; Buss, Aaron T; Ambrose, Joseph P; Wifall, Timothy A; Hazeltine, Eliot; Spencer, John P

    2015-10-15

    Recent evidence has sparked debate about the neural bases of response selection and inhibition. In the current study, we employed two reactive inhibition tasks, the Go/Nogo (GnG) and Simon tasks, to examine questions central to these debates. First, we investigated whether a fronto-cortical-striatal system was sensitive to the need for inhibition per se or the presentation of infrequent stimuli, by manipulating the proportion of trials that do not require inhibition (Go/Compatible trials) relative to trials that require inhibition (Nogo/Incompatible trials). A cortico-subcortical network composed of insula, putamen, and thalamus showed greater activation on salient and infrequent events, regardless of the need for inhibition. Thus, consistent with recent findings, key parts of the fronto-cortical-striatal system are engaged by salient events and do not appear to play a selective role in response inhibition. Second, we examined how the fronto-cortical-striatal system is modulated by working memory demands by varying the number of stimulus-response (SR) mappings. Right inferior parietal lobule showed decreasing activation as the number of SR mappings increased, suggesting that a form of associative memory - rather than working memory - might underlie performance in these tasks. A broad motor planning and control network showed similar trends that were also modulated by the number of motor responses required in each task. Finally, bilateral lingual gyri were more robustly engaged in the Simon task, consistent with the role of this area in shifts of visuo-spatial attention. The current study sheds light on how the fronto-cortical-striatal network is selectively engaged in reactive control tasks and how control is modulated by manipulations of attention and memory load. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Failing to learn from negative prediction errors: Obesity is associated with alterations in a fundamental neural learning mechanism.

    PubMed

    Mathar, David; Neumann, Jane; Villringer, Arno; Horstmann, Annette

    2017-10-01

    Prediction errors (PEs) encode the difference between expected and actual action outcomes in the brain via dopaminergic modulation. Integration of these learning signals ensures efficient behavioral adaptation. Obesity has recently been linked to altered dopaminergic fronto-striatal circuits, thus implying impairments in cognitive domains that rely on its integrity. 28 obese and 30 lean human participants performed an implicit stimulus-response learning paradigm inside an fMRI scanner. Computational modeling and psycho-physiological interaction (PPI) analysis was utilized for assessing PE-related learning and associated functional connectivity. We show that human obesity is associated with insufficient incorporation of negative PEs into behavioral adaptation even in a non-food context, suggesting differences in a fundamental neural learning mechanism. Obese subjects were less efficient in using negative PEs to improve implicit learning performance, despite proper coding of PEs in striatum. We further observed lower functional coupling between ventral striatum and supplementary motor area in obese subjects subsequent to negative PEs. Importantly, strength of functional coupling predicted task performance and negative PE utilization. These findings show that obesity is linked to insufficient behavioral adaptation specifically in response to negative PEs, and to associated alterations in function and connectivity within the fronto-striatal system. Recognition of neural differences as a central characteristic of obesity hopefully paves the way to rethink established intervention strategies: Differential behavioral sensitivity to negative and positive PEs should be considered when designing intervention programs. Measures relying on penalization of unwanted behavior may prove less effective in obese subjects than alternative approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Unilateral proptosis revealing a fronto-ethmoidal mucocele.

    PubMed

    Lajmi, Houda; Hmaied, Wassim; Ben Jalel, Wady; Ben Romdhane, Khaoula; Chelly, Zied; El Fekih, Lamia

    2017-06-01

    Backgroud: The fronto-ethmoidal mucocele is a benign condition leading commonly to limited eye movement or ocular pain but it could also induce visual acuity impairment by compressing the optic nerve Aim: To discuss, through a case report, different ophthalmologic manifestations of the fronto-ethmoidalmucocele. Reported case: A 46-years-old man with no general history consulted for a bilateral ocular redness and itching. He reported, however, a mild protrusion of his left globe evolving for oneyear. The clinical examination revealed a unilateral proptosis in the left eye with a discrete limitation of theadduction. A brain and orbital computer tomography (CT)and a magnetic resonance imaging(MRI)revealed a grade I exophthalmos caused by an oval formation of fluid density in the left anterior and posterior ethmoidal cells in addition to the frontal sinus,driving theeyeball and internal oculomotor muscles back and out.The patient was referred to otorhinolaryngology department for a precocious surgical management. The ophtalmologic manifestations of the disease depend on the location, the size of the formation and involvement of adjacent structures. The loss of vision and the apex syndrome due to the compressionof the ocular globe are the most serious complications.

  13. Effect of fronto-orbital advancement on astigmatism in patients with anterior plagiocephaly.

    PubMed

    Song, Hyun Beom; Yang, Hee Kyung; Baek, Rong-Min; Hwang, Jeong-Min; Kim, Namju; Wang, Kyu-Chang; Kim, Sukwha

    2016-10-01

    The purpose of this study was to determine the effect of unilateral fronto-orbital advancement (FOA) or bilateral FOA on ocular aspects of plagiocephaly. A retrospective review of ocular findings in 16 patients with plagiocephaly was performed. Patients were divided into 2 groups: 12 patients who underwent bilateral FOA (bFOA) and 4 patients who underwent unilateral FOA (uFOA), and ocular findings were compared. One-half of patients showed strabismus in both groups, and all had exotropia. Hypertropia was found only on the same side of the plagiocephaly in 17% of the bFOA group and 25% of the uFOA group. One-third of the patients in the bFOA group and one-half of patients in the uFOA group had oblique muscle dysfunction. In terms of astigmatism, the degree of with-the-rule astigmatism on the contralateral side was larger in the bFOA group compared to the uFOA group (p = 0.030). The degree of with-the-rule astigmatism was larger on the contralateral side than the ipsilateral side (p = 0.005) in the bFOA group. Patients with abnormalities in ductions/versions had larger astigmatism on the contralateral side than those without abnormalities in ductions/versions. In conclusion, bilateral FOA could induce unwanted outcomes of larger astigmatism on the contralateral side. Astigmatism should be carefully evaluated after bilateral FOA. Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  14. Value-based modulation of memory encoding involves strategic engagement of fronto-temporal semantic processing regions

    PubMed Central

    Cohen, Michael S.; Rissman, Jesse; Suthana, Nanthia A.; Castel, Alan D.; Knowlton, Barbara J.

    2014-01-01

    A number of prior fMRI studies have focused on the ways in which the midbrain dopaminergic reward system co-activates with hippocampus to potentiate memory for valuable items. However, another means by which people could selectively remember more valuable to-be-remembered items is to be selective in their use of effective but effortful encoding strategies. To broadly examine the neural mechanisms of value on subsequent memory, we used fMRI to examine how differences in brain activity at encoding as a function of value relate to subsequent free recall for words. Each word was preceded by an arbitrarily assigned point value, and participants went through multiple study-test cycles with feedback on their point total at the end of each list, allowing for sculpting of cognitive strategies. We examined the correlation between value-related modulation of brain activity and participants’ selectivity index, a measure of how close participants were to their optimal point total given the number of items recalled. Greater selectivity scores were associated with greater differences in activation of semantic processing regions, including left inferior frontal gyrus and left posterior lateral temporal cortex, during encoding of high-value words relative to low-value words. Although we also observed value-related modulation within midbrain and ventral striatal reward regions, our fronto-temporal findings suggest that strategic engagement of deep semantic processing may be an important mechanism for selectively encoding valuable items. PMID:24683066

  15. Value-based modulation of memory encoding involves strategic engagement of fronto-temporal semantic processing regions.

    PubMed

    Cohen, Michael S; Rissman, Jesse; Suthana, Nanthia A; Castel, Alan D; Knowlton, Barbara J

    2014-06-01

    A number of prior fMRI studies have focused on the ways in which the midbrain dopaminergic reward system coactivates with hippocampus to potentiate memory for valuable items. However, another means by which people could selectively remember more valuable to-be-remembered items is to be selective in their use of effective but effortful encoding strategies. To broadly examine the neural mechanisms of value on subsequent memory, we used fMRI to assess how differences in brain activity at encoding as a function of value relate to subsequent free recall for words. Each word was preceded by an arbitrarily assigned point value, and participants went through multiple study-test cycles with feedback on their point total at the end of each list, allowing for sculpting of cognitive strategies. We examined the correlation between value-related modulation of brain activity and participants' selectivity index, which measures how close participants were to their optimal point total, given the number of items recalled. Greater selectivity scores were associated with greater differences in the activation of semantic processing regions, including left inferior frontal gyrus and left posterior lateral temporal cortex, during the encoding of high-value words relative to low-value words. Although we also observed value-related modulation within midbrain and ventral striatal reward regions, our fronto-temporal findings suggest that strategic engagement of deep semantic processing may be an important mechanism for selectively encoding valuable items.

  16. Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder

    PubMed Central

    Ecker, Christine; Ronan, Lisa; Feng, Yue; Daly, Eileen; Murphy, Clodagh; Ginestet, Cedric E.; Brammer, Michael; Fletcher, Paul C.; Bullmore, Edward T.; Suckling, John; Baron-Cohen, Simon; Williams, Steve; Loth, Eva; Murphy, Declan G. M.; Bailey, A. J.; Baron-Cohen, S.; Bolton, P. F.; Bullmore, E. T.; Carrington, S.; Chakrabarti, B.; Daly, E. M.; Deoni, S. C.; Ecker, C.; Happe, F.; Henty, J.; Jezzard, P.; Johnston, P.; Jones, D. K.; Lai, M. C.; Lombardo, M. V.; Madden, A.; Mullins, D.; Murphy, C. M.; Murphy, D. G.; Pasco, G.; Sadek, S.; Spain, D.; Steward, R.; Suckling, J.; Wheelwright, S.; Williams, S. C.

    2013-01-01

    Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of “cortical separation distances” to assess the global and local intrinsic “wiring costs” of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical “connectivity” in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms. PMID:23878213

  17. Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories.

    PubMed

    Zerbi, Valerio; Ielacqua, Giovanna D; Markicevic, Marija; Haberl, Matthias Georg; Ellisman, Mark H; A-Bhaskaran, Arjun; Frick, Andreas; Rudin, Markus; Wenderoth, Nicole

    2018-07-01

    Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.

  18. Volumetric abnormalities in connectivity-based subregions of the thalamus in patients with chronic schizophrenia.

    PubMed

    Kim, Jae-Jin; Kim, Dae-Jin; Kim, Tae-Gyun; Seok, Jeong-Ho; Chun, Ji Won; Oh, Maeng-Keun; Park, Hae-Jeong

    2007-12-01

    The thalamus, which consists of multiple subnuclei, has been of particular interest in the study of schizophrenia. This study aimed to identify abnormalities in the connectivity-based subregions of the thalamus in patients with schizophrenia. Thalamic volume was measured by a manual tracing on superimposed images of T1-weighted and diffusion tensor images in 30 patients with schizophrenia and 22 normal volunteers. Cortical regional volumes automatically measured by a surface-based approach and thalamic subregional volumes measured by a connectivity-based technique were compared between the two groups and their correlations between the connected regions were calculated in each group. Volume reduction was observed in the bilateral orbitofrontal cortices and the left cingulate gyrus on the cortical side, whereas in subregions connected to the right orbitofrontal cortex and bilateral parietal cortices on the thalamic side. Significant volumetric correlations were identified between the right dorsal prefrontal cortex and its related thalamic subregion and between the left parietal cortex and its related thalamic subregion only in the normal group. Our results suggest that patients with schizophrenia have a structural deficit in the corticothalamic systems, especially in the orbitofrontal-thalamic system. Our findings may present evidence of corticothalamic connection problems in schizophrenia.

  19. Uniting functional network topology and oscillations in the fronto-parietal single unit network of behaving primates.

    PubMed

    Dann, Benjamin; Michaels, Jonathan A; Schaffelhofer, Stefan; Scherberger, Hansjörg

    2016-08-15

    The functional communication of neurons in cortical networks underlies higher cognitive processes. Yet, little is known about the organization of the single neuron network or its relationship to the synchronization processes that are essential for its formation. Here, we show that the functional single neuron network of three fronto-parietal areas during active behavior of macaque monkeys is highly complex. The network was closely connected (small-world) and consisted of functional modules spanning these areas. Surprisingly, the importance of different neurons to the network was highly heterogeneous with a small number of neurons contributing strongly to the network function (hubs), which were in turn strongly inter-connected (rich-club). Examination of the network synchronization revealed that the identified rich-club consisted of neurons that were synchronized in the beta or low frequency range, whereas other neurons were mostly non-oscillatory synchronized. Therefore, oscillatory synchrony may be a central communication mechanism for highly organized functional spiking networks.

  20. Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction

    PubMed Central

    Konova, Anna B.; Moeller, Scott J.; Tomasi, Dardo; Volkow, Nora D.; Goldstein, Rita Z.

    2015-01-01

    Importance Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems–level effects of methylphenidate in this population have not yet been described. Objective To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction. Design Randomized, placebo-controlled, before-after, crossover study. Setting Clinical research center. Participants Eighteen nonabstaining individuals with cocaine use disorders. Interventions Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects). Main outcomes and Measures Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems–level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire. Results Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections. Conclusions and Relevance These findings help elucidate the neural systems–level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently

  1. The alcoholic brain: neural bases of impaired reward-based decision-making in alcohol use disorders.

    PubMed

    Galandra, Caterina; Basso, Gianpaolo; Cappa, Stefano; Canessa, Nicola

    2018-03-01

    Neuroeconomics is providing insights into the neural bases of decision-making in normal and pathological conditions. In the neuropsychiatric domain, this discipline investigates how abnormal functioning of neural systems associated with reward processing and cognitive control promotes different disorders, and whether such evidence may inform treatments. This endeavor is crucial when studying different types of addiction, which share a core promoting mechanism in the imbalance between impulsive subcortical neural signals associated with immediate pleasurable outcomes and inhibitory signals mediated by a prefrontal reflective system. The resulting impairment in behavioral control represents a hallmark of alcohol use disorders (AUDs), a chronic relapsing disorder characterized by excessive alcohol consumption despite devastating consequences. This review aims to summarize available magnetic resonance imaging (MRI) evidence on reward-related decision-making alterations in AUDs, and to envision possible future research directions. We review functional MRI (fMRI) studies using tasks involving monetary rewards, as well as MRI studies relating decision-making parameters to neurostructural gray- or white-matter metrics. The available data suggest that excessive alcohol exposure affects neural signaling within brain networks underlying adaptive behavioral learning via the implementation of prediction errors. Namely, weaker ventromedial prefrontal cortex activity and altered connectivity between ventral striatum and dorsolateral prefrontal cortex likely underpin a shift from goal-directed to habitual actions which, in turn, might underpin compulsive alcohol consumption and relapsing episodes despite adverse consequences. Overall, these data highlight abnormal fronto-striatal connectivity as a candidate neurobiological marker of impaired choice in AUDs. Further studies are needed, however, to unveil its implications in the multiple facets of decision-making.

  2. Decreased Functional Brain Connectivity in Adolescents with Internet Addiction

    PubMed Central

    Hong, Soon-Beom; Zalesky, Andrew; Cocchi, Luca; Fornito, Alex; Choi, Eun-Jung; Kim, Ho-Hyun; Suh, Jeong-Eun; Kim, Chang-Dai; Kim, Jae-Won; Yi, Soon-Hyung

    2013-01-01

    Background Internet addiction has become increasingly recognized as a mental disorder, though its neurobiological basis is unknown. This study used functional neuroimaging to investigate whole-brain functional connectivity in adolescents diagnosed with internet addiction. Based on neurobiological changes seen in other addiction related disorders, it was predicted that connectivity disruptions in adolescents with internet addiction would be most prominent in cortico-striatal circuitry. Methods Participants were 12 adolescents diagnosed with internet addiction and 11 healthy comparison subjects. Resting-state functional magnetic resonance images were acquired, and group differences in brain functional connectivity were analyzed using the network-based statistic. We also analyzed network topology, testing for between-group differences in key graph-based network measures. Results Adolescents with internet addiction showed reduced functional connectivity spanning a distributed network. The majority of impaired connections involved cortico-subcortical circuits (∼24% with prefrontal and ∼27% with parietal cortex). Bilateral putamen was the most extensively involved subcortical brain region. No between-group difference was observed in network topological measures, including the clustering coefficient, characteristic path length, or the small-worldness ratio. Conclusions Internet addiction is associated with a widespread and significant decrease of functional connectivity in cortico-striatal circuits, in the absence of global changes in brain functional network topology. PMID:23451272

  3. Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates.

    PubMed

    Quetscher, Clara; Yildiz, Ali; Dharmadhikari, Shalmali; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Dydak, Ulrike; Beste, Christian

    2015-11-01

    Response inhibition processes are important for performance monitoring and are mediated via a network constituted by different cortical areas and basal ganglia nuclei. At the basal ganglia level, striatal GABAergic medium spiny neurons are known to be important for response selection, but the importance of the striatal GABAergic system for response inhibition processes remains elusive. Using a novel combination of behavior al, EEG and magnetic resonance spectroscopy (MRS) data, we examine the relevance of the striatal GABAergic system for response inhibition processes. The study shows that striatal GABA levels modulate the efficacy of response inhibition processes. Higher striatal GABA levels were related to better response inhibition performance. We show that striatal GABA modulate specific subprocesses of response inhibition related to pre-motor inhibitory processes through the modulation of neuronal synchronization processes. To our knowledge, this is the first study providing direct evidence for the relevance of the striatal GABAergic system for response inhibition functions and their cortical electrophysiological correlates in humans.

  4. Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington's disease mice.

    PubMed

    Deng, Y P; Wong, T; Bricker-Anthony, C; Deng, B; Reiner, A

    2013-12-01

    Motor slowing, forebrain white matter loss, and striatal shrinkage have been reported in premanifest Huntington's disease (HD) prior to overt striatal neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticostriatal and thalamostriatal terminals prior to striatal neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticostriatal and thalamostriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to striatal projection neuron pathology. VGLUT1+ axospinous corticostriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2+ axospinous thalamostriatal terminals represented about 35%, with VGLUT1+ and VGLUT2+ axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2+ axodendritic thalamostriatal terminals and a 20% shortfall in axospinous thalamostriatal terminals were already observed at 1 month of age, but VGLUT1+ terminals were normal in abundance. The 20% deficiency in VGLUT2+ thalamostriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1+ corticostriatal terminals was observed at 12 months. The early and persistent deficiency in thalamostriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticostriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticostriatal disconnection early during progression, and can explain both the measurable bradykinesia and striatal white matter loss in late premanifest HD. © 2013.

  5. Functional neural networks underlying response inhibition in adolescents and adults

    PubMed Central

    Stevens, Michael C.; Kiehl, Kent A.; Pearlson, Godfrey D.; Calhoun, Vince D.

    2008-01-01

    This study provides the first description of neural network dynamics associated with response inhibition in healthy adolescents and adults. Functional and effective connectivity analyses of whole brain hemodynamic activity elicited during performance of a Go/No-Go task were used to identify functionally-integrated neural networks and characterize their causal interactions. Three response inhibition circuits formed a hierarchical, inter-dependent system wherein thalamic modulation of input to premotor cortex by frontostriatal regions led to response suppression. Adolescents differed from adults in the degree of network engagement, regional fronto-striatal-thalamic connectivity, and network dynamics. We identify and characterize several age-related differences in the function of neural circuits that are associated with behavioral performance changes across adolescent development. PMID:17467816

  6. Resting-state functional connectivity of neurotransmitter producing sites in female patients with borderline personality disorder.

    PubMed

    Wagner, Gerd; Krause-Utz, Annegret; de la Cruz, Feliberto; Schumann, Andy; Schmahl, Christian; Bär, Karl-Jürgen

    2018-04-20

    Impulsive behavior, difficulties in controlling anger and suicidal behavior are typical patterns of affective/behavioral dysregulation in patients with borderline personality disorder (BPD). Previous functional MRI studies in the resting state condition demonstrated altered functional connectivity (FC) between the anterior cingulate cortex (ACC) and the frontoparietal executive control network (ECN), which was significantly associated with impulsivity in BPD. Impulsivity is often defined as a function of inhibitory control, strongly relying on the proper functioning of the fronto-cingulo-striatal network. Noradrenergic, dopaminergic and serotonergic neurotransmitter systems are assumed to be involved in different forms of impulsive behavior and inhibitory control. In our previous study, we investigated the FC of the main monoamine-producing nuclei within the midbrain and brainstem, which were functionally integrated in specific resting-state networks. In the present study we investigated the resting-state FC of midbrain/brainstem nuclei in 33 unmedicated female patients with BPD and 33 matched healthy controls. We further related altered functional connectivity of these nuclei to the patient's degree of impulsivity. The main finding was that BPD patients showed stronger FC from the noradrenergic locus coeruleus (LC) to the ACC. Functional connectivity between the LC and ACC was positively associated with the degree of motor impulsivity in the total group. Controlling for aggression, a stronger FC was also found between serotonergic nucleus centralis superior (NCS) and the frontopolar cortex (FPC) in patients compared to controls. Furthermore, patients showed a weaker "anti-correlation" from the substantia nigra (SNc) to the left dorsolateral prefrontal cortex (DLPFC). The observed enhanced LC-ACC FC in BPD and its association with the motor impulsivity might be indicative of a noradrenergic dysfunction in the neural inhibitory control network, whereas the

  7. Altered resting state functional connectivity of fear and reward circuitry in comorbid PTSD and major depression.

    PubMed

    Zhu, Xi; Helpman, Liat; Papini, Santiago; Schneier, Franklin; Markowitz, John C; Van Meter, Page E; Lindquist, Martin A; Wager, Tor D; Neria, Yuval

    2017-07-01

    Individuals with comorbid posttraumatic stress disorder and major depressive disorder (PTSD-MDD) often exhibit greater functional impairment and poorer treatment response than individuals with PTSD alone. Research has not determined whether PTSD-MDD is associated with different network connectivity abnormalities than PTSD alone. We used functional magnetic resonance imaging (fMRI) to measure resting state functional connectivity (rs-FC) patterns of brain regions involved in fear and reward processing in three groups: patients with PTSD-alone (n = 27), PTSD-MDD (n = 21), and trauma-exposed healthy controls (TEHCs, n = 34). Based on previous research, seeds included basolateral amygdala (BLA), centromedial amygdala (CMA), and nucleus accumbens (NAcc). Regardless of MDD comorbidity, PTSD was associated with decreased connectivity of BLA-orbitalfrontal cortex (OFC) and CMA-thalamus pathways, key to fear processing, and fear expression, respectively. PTSD-MDD, compared to PTSD-alone and TEHC, was associated with decreased connectivity across multiple amygdala and striatal-subcortical pathways: BLA-OFC, NAcc-thalamus, and NAcc-hippocampus. Further, while both the BLA-OFC and the NAcc-thalamus pathways were correlated with MDD symptoms, PTSD symptoms correlated with the amygdala pathways (BLA-OFC; CMA-thalamus) only. Comorbid PTSD-MDD may be associated with multifaceted functional connectivity alterations in both fear and reward systems. Clinical implications are discussed. © 2016 Wiley Periodicals, Inc.

  8. Successful group psychotherapy of depression in adolescents alters fronto-limbic resting-state connectivity.

    PubMed

    Straub, J; Metzger, C D; Plener, P L; Koelch, M G; Groen, G; Abler, B

    2017-02-01

    Current resting state imaging findings support suggestions that the neural signature of depression and therefore also its therapy should be conceptualized as a network disorder rather than a dysfunction of specific brain regions. In this study, we compared neural connectivity of adolescent patients with depression (PAT) and matched healthy controls (HC) and analysed pre-to-post changes of seed-based network connectivities in PAT after participation in a cognitive behavioral group psychotherapy (CBT). 38 adolescents (30 female; 19 patients; 13-18 years) underwent an eyes-closed resting-state scan. PAT were scanned before (pre) and after (post) five sessions of CBT. Resting-state functional connectivity was analysed in a seed-based approach for right-sided amygdala and subgenual anterior cingulate cortex (sgACC). Symptom severity was assessed using the Beck Depression Inventory Revision (BDI-II). Prior to group CBT, between groups amygdala and sgACC connectivity with regions of the default mode network was stronger in the patients group relative to controls. Within the PAT group, a similar pattern significantly decreased after successful CBT. Conversely, seed-based connectivity with affective regions and regions processing cognition and salient stimuli was stronger in HC relative to PAT before CBT. Within the PAT group, a similar pattern changed with CBT. Changes in connectivity correlated with the significant pre-to-post symptom improvement, and pre-treatment amygdala connectivity predicted treatment response in depressed adolescents. Sample size and missing long-term follow-up limit the interpretability. Successful group psychotherapy of depression in adolescents involved connectivity changes in resting state networks to that of healthy controls. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Abnormalities of hippocampal-cortical connectivity in temporal lobe epilepsy patients with hippocampal sclerosis

    NASA Astrophysics Data System (ADS)

    Li, Wenjing; He, Huiguang; Lu, Jingjing; Wang, Chunheng; Li, Meng; Lv, Bin; Jin, Zhengyu

    2011-03-01

    Hippocampal sclerosis (HS) is the most common damage seen in the patients with temporal lobe epilepsy (TLE). In the present study, the hippocampal-cortical connectivity was defined as the correlation between the hippocampal volume and cortical thickness at each vertex throughout the whole brain. We aimed to investigate the differences of ipsilateral hippocampal-cortical connectivity between the unilateral TLE-HS patients and the normal controls. In our study, the bilateral hippocampal volumes were first measured in each subject, and we found that the ipsilateral hippocampal volume significantly decreased in the left TLE-HS patients. Then, group analysis showed significant thinner average cortical thickness of the whole brain in the left TLE-HS patients compared with the normal controls. We found significantly increased ipsilateral hippocampal-cortical connectivity in the bilateral superior temporal gyrus, the right cingulate gyrus and the left parahippocampal gyrus of the left TLE-HS patients, which indicated structural vulnerability related to the hippocampus atrophy in the patient group. However, for the right TLE-HS patients, no significant differences were found between the patients and the normal controls, regardless of the ipsilateral hippocampal volume, the average cortical thickness or the patterns of hippocampal-cortical connectivity, which might be related to less atrophies observed in the MRI scans. Our study provided more evidence for the structural abnormalities in the unilateral TLE-HS patients.

  10. Lateral and feedforward inhibition suppress asynchronous activity in a large, biophysically-detailed computational model of the striatal network

    PubMed Central

    Moyer, Jason T.; Halterman, Benjamin L.; Finkel, Leif H.; Wolf, John A.

    2014-01-01

    Striatal medium spiny neurons (MSNs) receive lateral inhibitory projections from other MSNs and feedforward inhibitory projections from fast-spiking, parvalbumin-containing striatal interneurons (FSIs). The functional roles of these connections are unknown, and difficult to study in an experimental preparation. We therefore investigated the functionality of both lateral (MSN-MSN) and feedforward (FSI-MSN) inhibition using a large-scale computational model of the striatal network. The model consists of 2744 MSNs comprised of 189 compartments each and 121 FSIs comprised of 148 compartments each, with dendrites explicitly represented and almost all known ionic currents included and strictly constrained by biological data as appropriate. Our analysis of the model indicates that both lateral inhibition and feedforward inhibition function at the population level to limit non-ensemble MSN spiking while preserving ensemble MSN spiking. Specifically, lateral inhibition enables large ensembles of MSNs firing synchronously to strongly suppress non-ensemble MSNs over a short time-scale (10–30 ms). Feedforward inhibition enables FSIs to strongly inhibit weakly activated, non-ensemble MSNs while moderately inhibiting activated ensemble MSNs. Importantly, FSIs appear to more effectively inhibit MSNs when FSIs fire asynchronously. Both types of inhibition would increase the signal-to-noise ratio of responding MSN ensembles and contribute to the formation and dissolution of MSN ensembles in the striatal network. PMID:25505406

  11. Frequency-specific alterations in functional connectivity in treatment-resistant and -sensitive major depressive disorder.

    PubMed

    He, Zongling; Cui, Qian; Zheng, Junjie; Duan, Xujun; Pang, Yajing; Gao, Qing; Han, Shaoqiang; Long, Zhiliang; Wang, Yifeng; Li, Jiao; Wang, Xiao; Zhao, Jingping; Chen, Huafu

    2016-11-01

    Major depressive disorder (MDD) may involve alterations in brain functional connectivity in multiple neural circuits and present large-scale network dysfunction. Patients with treatment-resistant depression (TRD) and treatment-sensitive depression (TSD) show different responses to antidepressants and aberrant brain functions. This study aims to investigate functional connectivity patterns of TRD and TSD at the whole brain resting state. Seventeen patients with TRD, 17 patients with TSD, and 17 healthy controls matched with age, gender, and years of education were recruited in this study. The brain was divided using an automated anatomical labeling atlas into 90 regions of interest, which were used to construct the entire brain functional networks. An analysis method called network-based statistic was used to explore the dysconnected subnetworks of TRD and TSD at different frequency bands. At resting state, TSD and TRD present characteristic patterns of network dysfunction at special frequency bands. The dysconnected subnetwork of TSD mainly lies in the fronto-parietal top-down control network. Moreover, the abnormal neural circuits of TRD are extensive and complex. These circuits not only depend on the abnormal affective network but also involve other networks, including salience network, auditory network, visual network, and language processing cortex. Our findings reflect that the pathological mechanism of TSD may refer to impairment in cognitive control, whereas TRD mainly triggers the dysfunction of emotion processing and affective cognition. This study reveals that differences in brain functional connectivity at resting state reflect distinct pathophysiological mechanisms in TSD and TRD. These findings may be helpful in differentiating two types of MDD and predicting treatment responses. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers.

    PubMed

    Vosberg, Daniel E; Zhang, Yu; Menegaux, Aurore; Chalupa, Amanda; Manitt, Colleen; Zehntner, Simone; Eng, Conrad; DeDuck, Kristina; Allard, Dominique; Durand, France; Dagher, Alain; Benkelfat, Chawki; Srour, Myriam; Joober, Ridha; Lepore, Franco; Rouleau, Guy; Théoret, Hugo; Bedell, Barry J; Flores, Cecilia; Leyton, Marco

    2018-05-16

    The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc -haploinsufficient mice. The human volunteers were 20 DCC +/- mutation carriers, 16 DCC +/+ relatives, and 20 DCC +/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc +/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC +/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [ DCC +/+ : p = 0.0005, r ( effect size ) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex ( DCC +/+ : p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores ( DCC +/+ : p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume ( DCC +/+ : p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc +/- mice, and these were seen during adolescence ( p = 0.0058, d = 1.09) and adulthood ( p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders. SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC

  13. Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans

    PubMed Central

    Haagensen, Brian N.; Christensen, Mark S.; Madsen, Kristoffer H.; Rowe, James B.; Løkkegaard, Annemette; Siebner, Hartwig R.

    2015-01-01

    Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51–84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an

  14. Corticostriatal Connectivity in Antisocial Personality Disorder by MAO-A Genotype and Its Relationship to Aggressive Behavior.

    PubMed

    Kolla, Nathan J; Dunlop, Katharine; Meyer, Jeffrey H; Downar, Jonathan

    2018-05-09

    The influence of genetic variation on resting-state neural networks represents a burgeoning line of inquiry in psychiatric research. Monoamine oxidase A, an X-linked gene, is one example of a molecular target linked to brain activity in psychiatric illness. Monoamine oxidase A genetic variants, including the high and low variable nucleotide tandem repeat polymorphisms, have been shown to differentially affect brain functional connectivity in healthy humans. However, it is currently unknown whether these same polymorphisms influence resting-state brain activity in clinical conditions. Given its high burden on society and strong connection to violent behavior, antisocial personality disorder is a logical condition to study, since in vivo markers of monoamine oxidase A brain enzyme are reduced in key affect-modulating regions, and striatal levels of monoamine oxidase A show a relation with the functional connectivity of this same region. We utilized monoamine oxidase A genotyping and seed-to-voxel-based functional connectivity to investigate the relationship between genotype and corticostriatal connectivity in 21 male participants with severe antisocial personality disorder and 19 male healthy controls. Dorsal striatal connectivity to the frontal pole and anterior cingulate gyrus differentiated antisocial personality disorder subjects and healthy controls by monoamine oxidase A genotype. Furthermore, the linear relationship of proactive aggression to superior ventral striatal-angular gyrus functional connectivity differed by monoamine oxidase A genotype in the antisocial personality disorder groups. These results suggest that monoamine oxidase A genotype may affect corticostriatal connectivity in antisocial personality disorder and that these functional connections may also underlie use of proactive aggression in a genotype-specific manner.

  15. Striatal output markers do not alter in response to circling behaviour in 6-OHDA lesioned rats produced by acute or chronic administration of the monoamine uptake inhibitor BTS 74 398.

    PubMed

    Lane, E L; Cheetham, S; Jenner, P

    2008-01-01

    The monoamine uptake inhibitor BTS 74 398 induces ipsilateral circling in 6-hydroxydopamine (6-OHDA) lesioned rats without induction of abnormal motor behaviours associated with L-dopa administration. We examined whether this was reflected in the expression of peptide mRNA in the direct and indirect striatal output pathways.6-OHDA lesioning of the nigrostriatal pathway increased striatal expression of PPE-A mRNA and decreased levels of PPT mRNA with PPE-B mRNA expression remaining unchanged. Acute L-dopa administration normalised PPE-A mRNA and elevated PPT mRNA while PPE-B mRNA expression remained unchanged. Acute administration of BTS 74 398 did not alter striatal peptide mRNA levels. Following chronic treatment with L-dopa, PPE-A mRNA expression in the lesioned striatum continued to be normalised and PPT mRNA was increased compared to the intact side. PPE-B mRNA expression was also markedly increased relative to the non-lesioned striatum. Chronic BTS 74 398 administration did not alter mRNA expression in the 6-OHDA lesioned striatum although small increases in PPT mRNA expression in the intact and sham lesioned striatum were observed. The failure of BTS 74 398 to induce changes in striatal neuropeptide mRNA correlated with its failure to induce abnormal motor behaviours or behavioural sensitisation but does not explain how it produces a reversal of motor deficits. An action in another area of the brain appears likely and may explain the subsequent failure of BTS 74 398 and related compounds to exert anti-parkinsonian actions in man.

  16. Loss of Corticostriatal and Thalamostriatal Synaptic Terminals Precedes Striatal Projection Neuron Pathology in Heterozygous Q140 Huntington’s Disease Mice

    PubMed Central

    Deng, Y.P.; Wong, T.; Bricker-Anthony, C.; Deng, B.; Reiner, A.

    2013-01-01

    Motor slowing, forebrain white matter loss, and striatal shrinkage have been reported in premanifest Huntington’s disease (HD) prior to overt striatal neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticostriatal and thalamostriatal terminals prior to striatal neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticostriatal and thalamostriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to striatal projection neuron pathology. VGLUT1+ axospinous corticostriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2+ axospinous thalamostriatal terminals represented about 35%, with VGLUT1+ and VGLUT2+ axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2+ axodendritic thalamostriatal terminals and a 20% shortfall in axospinous thalamostriatal terminals was already observed at 1 month of age, but VGLUT1+ terminals were normal in abundance. The 20% deficiency in VGLUT2+ thalamostriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1+ corticostriatal terminals was observed at 12 months. The early and persistent deficiency in thalamostriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticostriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticostriatal disconnection early during progression, and can explain both the measurable bradykinesia and striatal white matter loss in late premanifest HD. PMID:23969239

  17. Abnormalities in Structural Covariance of Cortical Gyrification in Parkinson's Disease.

    PubMed

    Xu, Jinping; Zhang, Jiuquan; Zhang, Jinlei; Wang, Yue; Zhang, Yanling; Wang, Jian; Li, Guanglin; Hu, Qingmao; Zhang, Yuanchao

    2017-01-01

    Although abnormal cortical morphology and connectivity between brain regions (structural covariance) have been reported in Parkinson's disease (PD), the topological organizations of large-scale structural brain networks are still poorly understood. In this study, we investigated large-scale structural brain networks in a sample of 37 PD patients and 34 healthy controls (HC) by assessing the structural covariance of cortical gyrification with local gyrification index (lGI). We demonstrated prominent small-world properties of the structural brain networks for both groups. Compared with the HC group, PD patients showed significantly increased integrated characteristic path length and integrated clustering coefficient, as well as decreased integrated global efficiency in structural brain networks. Distinct distributions of hub regions were identified between the two groups, showing more hub regions in the frontal cortex in PD patients. Moreover, the modular analyses revealed significantly decreased integrated regional efficiency in lateral Fronto-Insula-Temporal module, and increased integrated regional efficiency in Parieto-Temporal module in the PD group as compared to the HC group. In summary, our study demonstrated altered topological properties of structural networks at a global, regional and modular level in PD patients. These findings suggests that the structural networks of PD patients have a suboptimal topological organization, resulting in less effective integration of information between brain regions.

  18. Observing complex action sequences: The role of the fronto-parietal mirror neuron system.

    PubMed

    Molnar-Szakacs, Istvan; Kaplan, Jonas; Greenfield, Patricia M; Iacoboni, Marco

    2006-11-15

    A fronto-parietal mirror neuron network in the human brain supports the ability to represent and understand observed actions allowing us to successfully interact with others and our environment. Using functional magnetic resonance imaging (fMRI), we wanted to investigate the response of this network in adults during observation of hierarchically organized action sequences of varying complexity that emerge at different developmental stages. We hypothesized that fronto-parietal systems may play a role in coding the hierarchical structure of object-directed actions. The observation of all action sequences recruited a common bilateral network including the fronto-parietal mirror neuron system and occipito-temporal visual motion areas. Activity in mirror neuron areas varied according to the motoric complexity of the observed actions, but not according to the developmental sequence of action structures, possibly due to the fact that our subjects were all adults. These results suggest that the mirror neuron system provides a fairly accurate simulation process of observed actions, mimicking internally the level of motoric complexity. We also discuss the results in terms of the links between mirror neurons, language development and evolution.

  19. Receiver-operating-characteristic analysis of an automated program for analyzing striatal uptake of 123I-ioflupane SPECT images: calibration using visual reads.

    PubMed

    Kuo, Phillip Hsin; Avery, Ryan; Krupinski, Elizabeth; Lei, Hong; Bauer, Adam; Sherman, Scott; McMillan, Natalie; Seibyl, John; Zubal, George

    2013-03-01

    A fully automated objective striatal analysis (OSA) program that quantitates dopamine transporter uptake in subjects with suspected Parkinson's disease was applied to images from clinical (123)I-ioflupane studies. The striatal binding ratios or alternatively the specific binding ratio (SBR) of the lowest putamen uptake was computed, and receiver-operating-characteristic (ROC) analysis was applied to 94 subjects to determine the best discriminator using this quantitative method. Ninety-four (123)I-ioflupane SPECT scans were analyzed from patients referred to our clinical imaging department and were reconstructed using the manufacturer-supplied reconstruction and filtering parameters for the radiotracer. Three trained readers conducted independent visual interpretations and reported each case as either normal or showing dopaminergic deficit (abnormal). The same images were analyzed using the OSA software, which locates the striatal and occipital structures and places regions of interest on the caudate and putamen. Additionally, the OSA places a region of interest on the occipital region that is used to calculate the background-subtracted SBR. The lower SBR of the 2 putamen regions was taken as the quantitative report. The 33 normal (bilateral comma-shaped striata) and 61 abnormal (unilateral or bilateral dopaminergic deficit) studies were analyzed to generate ROC curves. Twenty-nine of the scans were interpreted as normal and 59 as abnormal by all 3 readers. For 12 scans, the 3 readers did not unanimously agree in their interpretations (discordant). The ROC analysis, which used the visual-majority-consensus interpretation from the readers as the gold standard, yielded an area under the curve of 0.958 when using 1.08 as the threshold SBR for the lowest putamen. The sensitivity and specificity of the automated quantitative analysis were 95% and 89%, respectively. The OSA program delivers SBR quantitative values that have a high sensitivity and specificity, compared

  20. Alterations in the microstructure of white matter in children and adolescents with Tourette syndrome measured using tract-based spatial statistics and probabilistic tractography.

    PubMed

    Sigurdsson, Hilmar P; Pépés, Sophia E; Jackson, Georgina M; Draper, Amelia; Morgan, Paul S; Jackson, Stephen R

    2018-04-12

    Tourette syndrome (TS) is a neurodevelopmental disorder characterised by repetitive and intermittent motor and vocal tics. TS is thought to reflect fronto-striatal dysfunction and the aetiology of the disorder has been linked to widespread alterations in the functional and structural integrity of the brain. The aim of this study was to assess white matter (WM) abnormalities in a large sample of young patients with TS in comparison to a sample of matched typically developing control individuals (CS) using diffusion MRI. The study included 35 patients with TS (3 females; mean age: 14.0 ± 3.3) and 35 CS (3 females; mean age: 13.9 ± 3.3). Diffusion MRI data was analysed using tract-based spatial statistics (TBSS) and probabilistic tractography. Patients with TS demonstrated both marked and widespread decreases in axial diffusivity (AD) together with altered WM connectivity. Moreover, we showed that tic severity and the frequency of premonitory urges (PU) were associated with increased connectivity between primary motor cortex (M1) and the caudate nuclei, and increased information transfer between M1 and the insula, respectively. This is to our knowledge the first study to employ both TBSS and probabilistic tractography in a sample of young patients with TS. Our results contribute to the limited existing literature demonstrating altered connectivity in TS and confirm previous results suggesting in particular, that altered insular function contributes to increased frequency of PU. Copyright © 2018. Published by Elsevier Ltd.

  1. The pan-Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal Excitability by Direct Action on Striatal Neurons In Vivo.

    PubMed

    Hansen, Henrik H; Weikop, Pia; Mikkelsen, Maria D; Rode, Frederik; Mikkelsen, Jens D

    2017-01-01

    Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener retigabine. The effect of retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c-Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c-Fos-positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  2. Striatal and Hippocampal Involvement in Motor Sequence Chunking Depends on the Learning Strategy

    PubMed Central

    Lungu, Ovidiu; Monchi, Oury; Albouy, Geneviève; Jubault, Thomas; Ballarin, Emanuelle; Burnod, Yves; Doyon, Julien

    2014-01-01

    Motor sequences can be learned using an incremental approach by starting with a few elements and then adding more as training evolves (e.g., learning a piano piece); conversely, one can use a global approach and practice the whole sequence in every training session (e.g., shifting gears in an automobile). Yet, the neural correlates associated with such learning strategies in motor sequence learning remain largely unexplored to date. Here we used functional magnetic resonance imaging to measure the cerebral activity of individuals executing the same 8-element sequence after they completed a 4-days training regimen (2 sessions each day) following either a global or incremental strategy. A network comprised of striatal and fronto-parietal regions was engaged significantly regardless of the learning strategy, whereas the global training regimen led to additional cerebellar and temporal lobe recruitment. Analysis of chunking/grouping of sequence elements revealed a common prefrontal network in both conditions during the chunk initiation phase, whereas execution of chunk cores led to higher mediotemporal activity (involving the hippocampus) after global than incremental training. The novelty of our results relate to the recruitment of mediotemporal regions conditional of the learning strategy. Thus, the present findings may have clinical implications suggesting that the ability of patients with lesions to the medial temporal lobe to learn and consolidate new motor sequences may benefit from using an incremental strategy. PMID:25148078

  3. Striatal and hippocampal involvement in motor sequence chunking depends on the learning strategy.

    PubMed

    Lungu, Ovidiu; Monchi, Oury; Albouy, Geneviève; Jubault, Thomas; Ballarin, Emanuelle; Burnod, Yves; Doyon, Julien

    2014-01-01

    Motor sequences can be learned using an incremental approach by starting with a few elements and then adding more as training evolves (e.g., learning a piano piece); conversely, one can use a global approach and practice the whole sequence in every training session (e.g., shifting gears in an automobile). Yet, the neural correlates associated with such learning strategies in motor sequence learning remain largely unexplored to date. Here we used functional magnetic resonance imaging to measure the cerebral activity of individuals executing the same 8-element sequence after they completed a 4-days training regimen (2 sessions each day) following either a global or incremental strategy. A network comprised of striatal and fronto-parietal regions was engaged significantly regardless of the learning strategy, whereas the global training regimen led to additional cerebellar and temporal lobe recruitment. Analysis of chunking/grouping of sequence elements revealed a common prefrontal network in both conditions during the chunk initiation phase, whereas execution of chunk cores led to higher mediotemporal activity (involving the hippocampus) after global than incremental training. The novelty of our results relate to the recruitment of mediotemporal regions conditional of the learning strategy. Thus, the present findings may have clinical implications suggesting that the ability of patients with lesions to the medial temporal lobe to learn and consolidate new motor sequences may benefit from using an incremental strategy.

  4. Novel in silico multivariate mapping of intrinsic and anticorrelated connectivity to neurocognitive functional maps supports the maturational hypothesis of ADHD.

    PubMed

    de Lacy, Nina; Kodish, Ian; Rachakonda, Srinivas; Calhoun, Vince D

    2018-04-22

    From childhood to adolescence, strengthened coupling in frontal, striatal and parieto-temporal regions associated with cognitive control, and increased anticorrelation between task-positive and task-negative circuits, subserve the reshaping of behavior. ADHD is a common condition peaking in adolescence and regressing in adulthood, with a wide variety of cognitive control deficits. Alternate hypotheses of ADHD emphasize lagging circuitry refinement versus categorical differences in network function. However, quantifying the individual circuit contributions to behavioral findings, and relative roles of maturational versus categorical effects, is challenging in vivo or in meta-analyses using task-based paradigms within the same pipeline, given the multiplicity of neurobehavioral functions implicated. To address this, we analyzed 46 positively-correlated and anticorrelated circuits in a multivariate model in resting-state data from 504 age- and gender-matched youth, and created a novel in silico method to map individual quantified effects to reverse inference maps of 8 neurocognitive functions consistently implicated in ADHD, as well as dopamine and hyperactivity. We identified only age- and gender-related effects in intrinsic connectivity, and found that maturational refinement of circuits in youth with ADHD occupied 3-10x more brain locations than in typical development, with the footprint, effect size and contribution of individual circuits varying substantially. Our analysis supports the maturational hypothesis of ADHD, suggesting lagging connectivity reorganization within specific subnetworks of fronto-parietal control, ventral attention, cingulo-opercular, temporo-limbic and cerebellar sub-networks contribute across neurocognitive findings present in this complex condition. We present the first analysis of anti-correlated connectivity in ADHD and suggest new directions for exploring residual and non-responsive symptoms. © 2018 Wiley Periodicals, Inc.

  5. Cognitive Enhancement Therapy Improves Resting-State Functional Connectivity in Early Course Schizophrenia

    PubMed Central

    Eack, Shaun M.; Newhill, Christina E.; Keshavan, Matcheri S.

    2016-01-01

    Objective Cognitive remediation is emerging as an effective psychosocial intervention for addressing untreated cognitive and functional impairments in persons with schizophrenia, and might achieve its benefits through neuroplastic changes in brain connectivity. This study seeks to examine the effects of cognitive enhancement therapy (CET) on fronto-temporal brain connectivity in a randomized controlled trial with individuals in the early course of schizophrenia. Method Stabilized, early course outpatients with schizophrenia or schizoaffective disorder (N = 41) were randomly assigned to CET (n = 25) or an active enriched supportive therapy (EST) control (n = 16) and treated for 2 years. Functional MRI data were collected annually, and pseudo resting-state functional connectivity analysis was used to examine differential changes in fronto-temporal connectivity between those treated with CET compared with EST. Results Individuals receiving CET evidenced significantly less functional connectivity loss between the resting-state network and the left dorsolateral prefrontal cortex as well as significantly increased connectivity with the right insular cortex compared to EST (all corrected p < .01). These neural networks are involved in emotion processing and problem-solving. Increased connectivity with the right insula significantly mediated CET effects on improved emotion perception (z′ = −1.96, p = .021), and increased connectivity with the left dorsolateral prefrontal cortex mediated CET-related improvements in emotion regulation (z′ = −1.71, p = .052). Conclusions These findings provide preliminary evidence that CET, a psychosocial cognitive remediation intervention, may enhance connectivity between frontal and temporal brain regions implicated in problem-solving and emotion processing in service of cognitive enhancement in schizophrenia. PMID:27713804

  6. Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: A Central Pathway in Psychiatric Disease and Treatment

    PubMed Central

    Peters, Sarah K.; Dunlop, Katharine; Downar, Jonathan

    2016-01-01

    The salience network (SN) plays a central role in cognitive control by integrating sensory input to guide attention, attend to motivationally salient stimuli and recruit appropriate functional brain-behavior networks to modulate behavior. Mounting evidence suggests that disturbances in SN function underlie abnormalities in cognitive control and may be a common etiology underlying many psychiatric disorders. Such functional and anatomical abnormalities have been recently apparent in studies and meta-analyses of psychiatric illness using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM). Of particular importance, abnormal structure and function in major cortical nodes of the SN, the dorsal anterior cingulate cortex (dACC) and anterior insula (AI), have been observed as a common neurobiological substrate across a broad spectrum of psychiatric disorders. In addition to cortical nodes of the SN, the network’s associated subcortical structures, including the dorsal striatum, mediodorsal thalamus and dopaminergic brainstem nuclei, comprise a discrete regulatory loop circuit. The SN’s cortico-striato-thalamo-cortical loop increasingly appears to be central to mechanisms of cognitive control, as well as to a broad spectrum of psychiatric illnesses and their available treatments. Functional imbalances within the SN loop appear to impair cognitive control, and specifically may impair self-regulation of cognition, behavior and emotion, thereby leading to symptoms of psychiatric illness. Furthermore, treating such psychiatric illnesses using invasive or non-invasive brain stimulation techniques appears to modulate SN cortical-subcortical loop integrity, and these effects may be central to the therapeutic mechanisms of brain stimulation treatments in many psychiatric illnesses. Here, we review clinical and experimental evidence for abnormalities in SN cortico-striatal-thalamic loop circuits in major depression, substance use disorders (SUD

  7. Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: A Central Pathway in Psychiatric Disease and Treatment.

    PubMed

    Peters, Sarah K; Dunlop, Katharine; Downar, Jonathan

    2016-01-01

    The salience network (SN) plays a central role in cognitive control by integrating sensory input to guide attention, attend to motivationally salient stimuli and recruit appropriate functional brain-behavior networks to modulate behavior. Mounting evidence suggests that disturbances in SN function underlie abnormalities in cognitive control and may be a common etiology underlying many psychiatric disorders. Such functional and anatomical abnormalities have been recently apparent in studies and meta-analyses of psychiatric illness using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM). Of particular importance, abnormal structure and function in major cortical nodes of the SN, the dorsal anterior cingulate cortex (dACC) and anterior insula (AI), have been observed as a common neurobiological substrate across a broad spectrum of psychiatric disorders. In addition to cortical nodes of the SN, the network's associated subcortical structures, including the dorsal striatum, mediodorsal thalamus and dopaminergic brainstem nuclei, comprise a discrete regulatory loop circuit. The SN's cortico-striato-thalamo-cortical loop increasingly appears to be central to mechanisms of cognitive control, as well as to a broad spectrum of psychiatric illnesses and their available treatments. Functional imbalances within the SN loop appear to impair cognitive control, and specifically may impair self-regulation of cognition, behavior and emotion, thereby leading to symptoms of psychiatric illness. Furthermore, treating such psychiatric illnesses using invasive or non-invasive brain stimulation techniques appears to modulate SN cortical-subcortical loop integrity, and these effects may be central to the therapeutic mechanisms of brain stimulation treatments in many psychiatric illnesses. Here, we review clinical and experimental evidence for abnormalities in SN cortico-striatal-thalamic loop circuits in major depression, substance use disorders (SUD), anxiety

  8. Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia.

    PubMed

    Bernstein, Hans-Gert; Jauch, Esther; Dobrowolny, Henrik; Mawrin, Christian; Steiner, Johann; Bogerts, Bernhard

    2016-09-01

    Profound white matter abnormalities have repeatedly been described in schizophrenia, which involve the altered expression of numerous oligodendrocyte-associated genes. Transcripts of the disrupted-in-schizophrenia 1 (DISC1) gene, a key susceptibility factor in schizophrenia, have recently been shown to be expressed by oligodendroglial cells and to negatively regulate oligodendrocyte differentiation and maturation. To learn more about the putative role(s) of oligodendroglia-associated DISC1 in schizophrenia, we analyzed the density of DISC1-immunoreactive oligodendrocytes in the fronto-parietal white matter in postmortem brains of patients with schizophrenia. Compared with controls (N = 12) and cases with undifferentiated/residual schizophrenia (N = 6), there was a significantly increased density of DISC1-expressing glial cells in paranoid schizophrenia (N = 12), which unlikely resulted from neuroleptic treatment. Pathophysiologically, over-expression of DISC1 protein(s) in white matter oligodendrocytes might add to the reduced levels of two myelin markers, 2',3'-cyclic-nucleotide 3'-phosphodiesterase and myelin basic protein in schizophrenia. Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in schizophrenia.

  9. Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative Review

    PubMed Central

    Fineberg, Naomi A; Potenza, Marc N; Chamberlain, Samuel R; Berlin, Heather A; Menzies, Lara; Bechara, Antoine; Sahakian, Barbara J; Robbins, Trevor W; Bullmore, Edward T; Hollander, Eric

    2010-01-01

    Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive–compulsive disorder (OCD), obsessive–compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field. PMID:19940844

  10. Abnormalities of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study.

    PubMed

    Dobryakova, Ekaterina; Rocca, Maria Assunta; Valsasina, Paola; Ghezzi, Angelo; Colombo, Bruno; Martinelli, Vittorio; Comi, Giancarlo; DeLuca, John; Filippi, Massimo

    2016-06-01

    The Stroop interference task is a cognitively demanding task of executive control, a cognitive ability that is often impaired in patients with multiple sclerosis (MS). The aim of this study was to compare effective connectivity patterns within a network of brain regions involved in the Stroop task performance between MS patients with three disease clinical phenotypes [relapsing-remitting (RRMS), benign (BMS), and secondary progressive (SPMS)] and healthy subjects. Effective connectivity analysis was performed on Stroop task data using a novel method based on causal Bayes networks. Compared with controls, MS phenotypes were slower at performing the task and had reduced performance accuracy during incongruent trials that required increased cognitive control. MS phenotypes also exhibited connectivity abnormalities reflected as weaker shared connections, presence of extra connections (i.e., connections absent in the HC connectivity pattern), connection reversal, and loss. In SPMS and the BMS groups but not in the RRMS group, extra connections were associated with deficits in the Stroop task performance. In the BMS group, the response time associated with correct responses during the congruent condition showed a positive correlation with the left posterior parietal → dorsal anterior cingulate connection. In the SPMS group, performance accuracy during the congruent condition showed a negative correlation with the right insula → left insula connection. No associations between extra connections and behavioral performance measures were observed in the RRMS group. These results suggest that, depending on the phenotype, patients with MS use different strategies when cognitive control demands are high and rely on different network connections. Hum Brain Mapp, 37:2293-2304, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Altered neural reward and loss processing and prediction error signalling in depression

    PubMed Central

    Ubl, Bettina; Kuehner, Christine; Kirsch, Peter; Ruttorf, Michaela

    2015-01-01

    Dysfunctional processing of reward and punishment may play an important role in depression. However, functional magnetic resonance imaging (fMRI) studies have shown heterogeneous results for reward processing in fronto-striatal regions. We examined neural responsivity associated with the processing of reward and loss during anticipation and receipt of incentives and related prediction error (PE) signalling in depressed individuals. Thirty medication-free depressed persons and 28 healthy controls performed an fMRI reward paradigm. Regions of interest analyses focused on neural responses during anticipation and receipt of gains and losses and related PE-signals. Additionally, we assessed the relationship between neural responsivity during gain/loss processing and hedonic capacity. When compared with healthy controls, depressed individuals showed reduced fronto-striatal activity during anticipation of gains and losses. The groups did not significantly differ in response to reward and loss outcomes. In depressed individuals, activity increases in the orbitofrontal cortex and nucleus accumbens during reward anticipation were associated with hedonic capacity. Depressed individuals showed an absence of reward-related PEs but encoded loss-related PEs in the ventral striatum. Depression seems to be linked to blunted responsivity in fronto-striatal regions associated with limited motivational responses for rewards and losses. Alterations in PE encoding might mirror blunted reward- and enhanced loss-related associative learning in depression. PMID:25567763

  12. A selective involvement of putamen functional connectivity in youth with internet gaming disorder.

    PubMed

    Hong, Soon-Beom; Harrison, Ben J; Dandash, Orwa; Choi, Eun-Jung; Kim, Seong-Chan; Kim, Ho-Hyun; Shim, Do-Hyun; Kim, Chang-Dai; Kim, Jae-Won; Yi, Soon-Hyung

    2015-03-30

    Brain cortico-striatal circuits have consistently been implicated in the pathology of addiction related disorders. We applied a reliable seed-based analysis of the resting-state brain activity to comprehensively delineate the subdivisions of striatal functional connectivity implicated in internet gaming disorder. Among twelve right-handed male adolescents with internet gaming disorder and 11 right-handed and gender-matched healthy controls, we examined group differences in the functional connectivity of dorsal and ventral subdivisions of the caudate nucleus and putamen, as well as the association of these connectivity indices with behavioral measures of internet use. Adolescents with internet gaming disorder showed significantly reduced dorsal putamen functional connectivity with the posterior insula-parietal operculum. More time spent playing online games predicted significantly greater functional connectivity between the dorsal putamen and bilateral primary somatosensory cortices in adolescents with internet gaming disorder, and significantly lower functional connectivity between the dorsal putamen and bilateral sensorimotor cortices in healthy controls. The dorsal putamen functional connectivity was significantly and specifically different in adolescents with internet gaming disorder. The findings suggest a possible biomarker of internet gaming disorder. Copyright © 2015. Published by Elsevier B.V.

  13. Obsessive Compulsive Disorder: Beyond Segregated Cortico-striatal Pathways

    PubMed Central

    Milad, Mohammed R.; Rauch, Scott L.

    2016-01-01

    Obsessive-compulsive disorder (OCD) affects ∼2-3% of the population and is characterized by recurrent intrusive thoughts (obsessions) and repetitive behaviors or mental acts (compulsions), typically performed in response to obsessions or related anxiety. In the past few decades, the prevailing models of OCD pathophysiology have focused on cortico-striatal circuitry. More recent neuroimaging evidence, however, points to critical involvement of the lateral and medial orbitofrontal cortices, the dorsal anterior cingulate cortex and amygdalo-cortical circuitry, in addition to cortico-striatal circuitry, in the pathophysiology of the disorder. In this review, we elaborate proposed features of OCD pathophysiology beyond the classic parallel cortico-striatal pathways and argue that this evidence suggests that fear extinction, in addition to behavioral inhibition, may be impaired in OCD. PMID:22138231

  14. Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

    PubMed Central

    Ielacqua, Giovanna D; Markicevic, Marija; Haberl, Matthias Georg; Ellisman, Mark H; A-Bhaskaran, Arjun; Frick, Andreas; Rudin, Markus; Wenderoth, Nicole

    2018-01-01

    Abstract Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1−/y) and contactin-associated (CNTNAP2−/−) knockout mice. Young Fmr1−/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2−/− mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes. PMID:29901787

  15. Marshall-Smith syndrome: natural history and evidence of an osteochondrodysplasia with connective tissue abnormalities.

    PubMed

    Adam, Margaret P; Hennekam, Raoul C M; Keppen, Laura Davis; Bull, Marilyn J; Clericuzio, Carol L; Burke, Leah W; Ormond, Kelly E; Hoyme, Eugene H

    2005-08-30

    The Marshall-Smith syndrome (MSS) is a distinct malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia. At least 33 cases have been reported in the literature, mostly as single case reports or small series. The purpose of the present study is to report on the clinical findings and natural history of MSS in five children and to review the features of three others previously reported, with particular attention to the skeletal and connective tissue findings. Our study demonstrates an increased rate of nontraumatic fractures and other bony and connective tissue abnormalities that support the hypothesis that MSS should be considered an osteochondrodysplasia. In addition, long-term survival beyond infancy is possible if respiratory problems are expectantly and aggressively managed. (c) 2005 Wiley-Liss, Inc.

  16. Emotion-induced loss aversion and striatal-amygdala coupling in low-anxious individuals

    PubMed Central

    Charpentier, Caroline J.; Martino, Benedetto De; Sim, Alena L.; Sharot, Tali; Roiser, Jonathan P.

    2016-01-01

    Adapting behavior to changes in the environment is a crucial ability for survival but such adaptation varies widely across individuals. Here, we asked how humans alter their economic decision-making in response to emotional cues, and whether this is related to trait anxiety. Developing an emotional decision-making task for functional magnetic resonance imaging, in which gambling decisions were preceded by emotional and non-emotional primes, we assessed emotional influences on loss aversion, the tendency to overweigh potential monetary losses relative to gains. Our behavioral results revealed that only low-anxious individuals exhibited increased loss aversion under emotional conditions. This emotional modulation of decision-making was accompanied by a corresponding emotion-elicited increase in amygdala-striatal functional connectivity, which correlated with the behavioral effect across participants. Consistent with prior reports of ‘neural loss aversion’, both amygdala and ventral striatum tracked losses more strongly than gains, and amygdala loss aversion signals were exaggerated by emotion, suggesting a potential role for this structure in integrating value and emotion cues. Increased loss aversion and striatal-amygdala coupling induced by emotional cues may reflect the engagement of adaptive harm-avoidance mechanisms in low-anxious individuals, possibly promoting resilience to psychopathology. PMID:26589451

  17. Trehalose rescues glial cell dysfunction in striatal cultures from HD R6/1 mice at early postnatal development.

    PubMed

    Perucho, Juan; Gómez, Ana; Muñoz, María Paz; de Yébenes, Justo García; Mena, María Ángeles; Casarejos, María José

    2016-07-01

    The pathological hallmark of Huntington disease (HD) is the intracellular aggregation of mutant huntingtin (mHTT) in striatal neurons and glia associated with the selective loss of striatal medium-sized spiny neurons. Up to the present, the role of glia in HD is poorly understood and has been classically considered secondary to neuronal disorder. Trehalose is a disaccharide known to possess many pharmacological properties, acting as an antioxidant, a chemical chaperone, and an inducer of autophagy. In this study, we analyzed at an early postnatal development stage the abnormalities observed in striatal glial cell cultures of postnatal R6/1 mice (HD glia), under baseline and stressing conditions and the protective effects of trehalose. Our data demonstrate that glial HD alterations already occur at early stages of postnatal development. After 20 postnatal days in vitro, striatal HD glia cultures showed more reactive astrocytes with increased expression of glial fibrillary acidic protein (GFAP) but with less replication capacity, less A2B5(+) glial progenitors and more microglia than wild-type (WT) cultures. HD glia had lower levels of intracellular glutathione (GSH) and was more susceptible to H2O2 and epoxomicin insults. The amount of expressed GDNF and secreted mature-BDNF by HD astrocytes were much lower than by WT astrocytes. In addition, HD glial cultures showed a deregulation of the major proteolytic systems, the ubiquitin-proteasomal system (UPS), and the autophagic pathway. This produces a defective protein quality control, indicated by the elevated levels of ubiquitination and p62 protein. Interestingly, we show that trehalose, through its capacity to induce autophagy, inhibited p62/SQSTM1 accumulation and facilitated the degradation of cytoplasmic aggregates from mHTT and α-synuclein proteins. Trehalose also reduced microglia activation and reversed the disrupted cytoskeleton of astrocytes accompanied with an increase in the replication capacity. In

  18. Uniting functional network topology and oscillations in the fronto-parietal single unit network of behaving primates

    PubMed Central

    Dann, Benjamin; Michaels, Jonathan A; Schaffelhofer, Stefan; Scherberger, Hansjörg

    2016-01-01

    The functional communication of neurons in cortical networks underlies higher cognitive processes. Yet, little is known about the organization of the single neuron network or its relationship to the synchronization processes that are essential for its formation. Here, we show that the functional single neuron network of three fronto-parietal areas during active behavior of macaque monkeys is highly complex. The network was closely connected (small-world) and consisted of functional modules spanning these areas. Surprisingly, the importance of different neurons to the network was highly heterogeneous with a small number of neurons contributing strongly to the network function (hubs), which were in turn strongly inter-connected (rich-club). Examination of the network synchronization revealed that the identified rich-club consisted of neurons that were synchronized in the beta or low frequency range, whereas other neurons were mostly non-oscillatory synchronized. Therefore, oscillatory synchrony may be a central communication mechanism for highly organized functional spiking networks. DOI: http://dx.doi.org/10.7554/eLife.15719.001 PMID:27525488

  19. Patterns of Neural Connectivity during an Attention Bias Task Moderate Associations between Early Childhood Temperament and Internalizing Symptoms in Young Adulthood

    PubMed Central

    Hardee, Jillian E.; Benson, Brenda E.; Bar-Haim, Yair; Mogg, Karin; Bradley, Brendan P; Chen, Gang; Britton, Jennifer C.; Ernst, Monique; Fox, Nathan A.; Pine, Daniel S.; Pérez-Edgar, Koraly

    2013-01-01

    Background Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area may clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. Methods Children were assessed for BI at multiple age points from infancy through age seven. Based on a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (N=44). Participants completed an event-related fMRI attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews. Results The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms. Conclusions BI during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology. PMID:23489415

  20. Ophthalmologic Outcomes Following Fronto-Orbital Advancement for Unicoronal Craniosynostosis.

    PubMed

    Gencarelli, John R; Murphy, Amanda; Samargandi, Osama A; Bezuhly, Michael

    2016-10-01

    Unicoronal craniosynostosis predisposes to ophthalmologic abnormalities such as strabismus, astigmatism, and amblyopia. The authors explored the ophthalmologic outcomes following fronto-orbital advancement (FOA). A systematic search of PubMed, Embase, and the Cochrane Library was conducted. Included studies reported postoperative rates of strabismus, astigmatism, and/or amblyopia. Two independent reviewers performed screening and extracted data including preoperative rates, laterality and severity of findings, need for ocular surgery, and timing of FOA. Methodologic quality was assessed using the Methodologic Index for Non-Randomized Studies scale and American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies. A total of 231 abstracts were screened. Sixteen articles were eligible for qualitative synthesis including 13 case series and 3 retrospective comparative studies. Nine studies contained both preoperative and postoperative data, but for strabismus only. Postoperative prevalence of strabismus was 19% to 100%. Rates increased in 4 studies and decreased in 3. Incidences of new and resolved cases of strabismus were 0% to 60% and 0% to 33%, respectively. Twenty-five percent to 100% of patients required strabismus surgery. Postoperative rates of astigmatism were 15% to 92%. Fourteen percent to 41% had clinically significant anisometropia, predisposing to amblyopia. The postoperative prevalence of amblyopia was 3% to 56%. In summary, FOA does not appear to reduce rates of strabismus, astigmatism, or amblyopia. In addition, surgery carries the risk of iatrogenic strabismus. Earlier intervention and endoscopic techniques may reduce prevalence and severity, but additional research is required.

  1. Bayesian network analysis reveals alterations to default mode network connectivity in individuals at risk for Alzheimer's disease.

    PubMed

    Li, Rui; Yu, Jing; Zhang, Shouzi; Bao, Feng; Wang, Pengyun; Huang, Xin; Li, Juan

    2013-01-01

    Alzheimer's disease (AD) is associated with abnormal functioning of the default mode network (DMN). Functional connectivity (FC) changes to the DMN have been found in patients with amnestic mild cognitive impairment (aMCI), which is the prodromal stage of AD. However, whether or not aMCI also alters the effective connectivity (EC) of the DMN remains unknown. We employed a combined group independent component analysis (ICA) and Bayesian network (BN) learning approach to resting-state functional MRI (fMRI) data from 17 aMCI patients and 17 controls, in order to establish the EC pattern of DMN, and to evaluate changes occurring in aMCI. BN analysis demonstrated heterogeneous regional convergence degree across DMN regions, which were organized into two closely interacting subsystems. Compared to controls, the aMCI group showed altered directed connectivity weights between DMN regions in the fronto-parietal, temporo-frontal, and temporo-parietal pathways. The aMCI group also exhibited altered regional convergence degree in the right inferior parietal lobule. Moreover, we found EC changes in DMN regions in aMCI were correlated with regional FC levels, and the connectivity metrics were associated with patients' cognitive performance. This study provides novel sights into our understanding of the functional architecture of the DMN and adds to a growing body of work demonstrating the importance of the DMN as a mechanism of aMCI.

  2. Aberrant function of learning and cognitive control networks underlie inefficient cognitive flexibility in anorexia nervosa: a cross-sectional fMRI study.

    PubMed

    Lao-Kaim, Nick P; Fonville, Leon; Giampietro, Vincent P; Williams, Steven C R; Simmons, Andrew; Tchanturia, Kate

    2015-01-01

    People with Anorexia Nervosa exhibit difficulties flexibly adjusting behaviour in response to environmental changes. This has previously been attributed to problematic behavioural shifting, characterised by a decrease in fronto-striatal activity. Additionally, alterations of instrumental learning, which relies on fronto-striatal networks, may contribute to the observation of inflexible behaviour. The authors sought to investigate the neural correlates of cognitive flexibility and learning in Anorexia Nervosa. Thirty-two adult females with Anorexia Nervosa and thirty-two age-matched female control participants completed the Wisconsin Card Sorting Task whilst undergoing functional magnetic resonance imaging. Event-related analysis permitted the comparison of cognitive shift trials against those requiring maintenance of rule-sets and allowed assessment of trials representing learning. Although both groups performed similarly, we found significant interactions in the left middle frontal gyrus, precuneus and superior parietal lobule whereby blood-oxygenated-level dependent response was higher in Anorexia Nervosa patients during shifting but lower when maintaining rule-sets, as compared to healthy controls. During learning, posterior cingulate cortex activity in healthy controls decreased whilst increasing in the Anorexia Nervosa group, whereas the right precuneus exhibited the opposite pattern. Furthermore, learning was associated with lower blood-oxygenated-level dependent response in the caudate body, as compared to healthy controls. People with Anorexia Nervosa display widespread changes in executive function. Whilst cognitive flexibility appears to be associated with aberrant functioning of the fronto-parietal control network that mediates between internally and externally directed cognition, fronto-striatal alterations, particularly within the caudate body, were associated with instrumental learning. Together, this shows how perseverative tendencies could be a

  3. Differential functional connectivity of rostral anterior cingulate cortex during emotional interference

    PubMed Central

    Szekely, Akos; Silton, Rebecca L.; Heller, Wendy; Miller, Gregory A.

    2017-01-01

    Abstract The rostral-ventral subdivision of the anterior cingulate cortex (rACC) plays a key role in the regulation of emotional processing. Although rACC has strong anatomical connections with anterior insular cortex (AIC), amygdala, prefrontal cortex and striatal brain regions, it is unclear whether the functional connectivity of rACC with these regions changes when regulating emotional processing. Furthermore, it is not known whether this connectivity changes with deficits in emotion regulation seen in different kinds of anxiety and depression. To address these questions regarding rACC functional connectivity, non-patients high in self-reported anxious apprehension (AP), anxious arousal (AR), anhedonic depression (AD) or none (CON) indicated the ink color of pleasant, neutral and unpleasant words during functional magnetic resonance imaging. While ignoring task-irrelevant unpleasant words, AD and CON showed an increase in the functional connectivity of rACC with AIC, putamen, caudate and ventral pallidum. There was a decrease in this connectivity in AP and AR, with AP showing greater reduction than AR. These findings provide support for the role of rACC in integrating interoceptive, emotional and cognitive functions via interactions with insula and striatal regions during effective emotion regulation in healthy individuals and a failure of this integration that may be specific to anxiety, particularly AP. PMID:27998997

  4. Abnormal resting-state connectivity of motor and cognitive networks in early manifest Huntington's disease.

    PubMed

    Wolf, R C; Sambataro, F; Vasic, N; Depping, M S; Thomann, P A; Landwehrmeyer, G B; Süssmuth, S D; Orth, M

    2014-11-01

    Functional magnetic resonance imaging (fMRI) of multiple neural networks during the brain's 'resting state' could facilitate biomarker development in patients with Huntington's disease (HD) and may provide new insights into the relationship between neural dysfunction and clinical symptoms. To date, however, very few studies have examined the functional integrity of multiple resting state networks (RSNs) in manifest HD, and even less is known about whether concomitant brain atrophy affects neural activity in patients. Using MRI, we investigated brain structure and RSN function in patients with early HD (n = 20) and healthy controls (n = 20). For resting-state fMRI data a group-independent component analysis identified spatiotemporally distinct patterns of motor and prefrontal RSNs of interest. We used voxel-based morphometry to assess regional brain atrophy, and 'biological parametric mapping' analyses to investigate the impact of atrophy on neural activity. Compared with controls, patients showed connectivity changes within distinct neural systems including lateral prefrontal, supplementary motor, thalamic, cingulate, temporal and parietal regions. In patients, supplementary motor area and cingulate cortex connectivity indices were associated with measures of motor function, whereas lateral prefrontal connectivity was associated with cognition. This study provides evidence for aberrant connectivity of RSNs associated with motor function and cognition in early manifest HD when controlling for brain atrophy. This suggests clinically relevant changes of RSN activity in the presence of HD-associated cortical and subcortical structural abnormalities.

  5. Does human presynaptic striatal dopamine function predict social conformity?

    PubMed

    Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

    2014-03-01

    Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

  6. Positive reinforcement modulates fronto-limbic systems subserving emotional interference in adolescents.

    PubMed

    Ladouceur, Cecile D; Schlund, Michael W; Segreti, Anna-Maria

    2018-02-15

    Fronto-limbic systems play an important role in supporting resistance to emotional distraction to promote goal-directed behavior. Despite evidence that alterations in the functioning of these systems are implicated in developmental trajectories of psychopathology, most studies have been conducted in adults. This study examined the functioning of fronto-limbic systems subserving emotional interference in adolescents and whether differential reinforcement of correct responding can modulate these neural systems in ways that could promote resistance to emotional distraction. Fourteen healthy adolescents (ages 9-15) completed an emotional delayed working memory task during fMRI with emotional distracters (none, neutral, negative) while positive reinforcement (i.e., monetary reward) was provided for correct responses under some conditions. Adolescents showed slightly reduced behavioral performance and greater activation in amygdala and prefrontal cortical regions (ventrolateral, ventromedial, dorsolateral) on correct trials with negative distracters compared to those with no or neutral distracters. Positive reinforcement yielded an overall improvement in accuracy and reaction times and counteracted the effects of negative distracters as evidenced by significant reductions in activation in key fronto-limbic regions. The present findings extend results on emotional interference from adults to adolescents and suggest that positive reinforcement could be used to potentially promote insulation from emotional distraction. A challenge for the future will be to build upon these findings for constructing reinforcement-based attention training programs that could be used to reduce emotional attention biases in anxious youth. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Abnormalities in lung volumes and airflow in children with newly diagnosed connective tissue disease.

    PubMed

    Peradzyńska, Joanna; Krenke, Katarzyna; Szylling, Anna; Kołodziejczyk, Beata; Gazda, Agnieszka; Rutkowska-Sak, Lidia; Kulus, Marek

    2016-01-01

    Connective tissue diseases (CTDs) of childhood are rare inflammatory disorders, involving various organs and tissues including respiratory system. Pulmonary involvement in patients with CTDs is uncommon but may cause functional impairment. Data on prevalence and type of lung function abnormalities in children with CTDs are scarce. Thus, the aim of this study was to asses pulmonary functional status in children with newly diagnosed CTD and follow the results after two years of the disease course. There were 98 children (mean age: 13 ± 3; 76 girls), treated in Department of Pediatric Rheumatology, Institute of Rheumatology, Warsaw and 80 aged-matched, healthy controls (mean age 12.7 ± 2.4; 50 girls) included into the study. Study procedures included medical history, physical examination, chest radiograph and PFT (spirometry and whole body-plethysmography). Then, the assessment of PFT was performed after 24 months. FEV₁, FEV₁/FVC and MEF50 were significantly lower in CTD as compared to control group, there was no difference in FVC and TLC. The proportion of patients with abnormal lung function was significantly higher in the study group, 41 (42%) vs 9 (11%). 24-months observation didn't reveal progression in lung function impairment. Lung function impairment is relatively common in children with CTDs. Although restrictive ventilatory pattern is considered typical feature of lung involvement in CTDs, airflow limitation could also be an initial abnormality.

  8. Abnormal brain functional connectivity leads to impaired mood and cognition in hyperthyroidism: a resting-state functional MRI study

    PubMed Central

    Li, Ling; Zhi, Mengmeng; Hou, Zhenghua; Zhang, Yuqun; Yue, Yingying; Yuan, Yonggui

    2017-01-01

    Patients with hyperthyroidism frequently have neuropsychiatric complaints such as lack of concentration, poor memory, depression, anxiety, nervousness, and irritability, suggesting brain dysfunction. However, the underlying process of these symptoms remains unclear. Using resting-state functional magnetic resonance imaging (rs-fMRI), we depicted the altered graph theoretical metric degree centrality (DC) and seed-based resting-state functional connectivity (FC) in 33 hyperthyroid patients relative to 33 healthy controls. The peak points of significantly altered DC between the two groups were defined as the seed regions to calculate FC to the whole brain. Then, partial correlation analyses were performed between abnormal DC, FC and neuropsychological performances, as well as some clinical indexes. The decreased intrinsic functional connectivity in the posterior lobe of cerebellum (PLC) and medial frontal gyrus (MeFG), as well as the abnormal seed-based FC anchored in default mode network (DMN), attention network, visual network and cognitive network in this study, possibly constitutes the latent mechanism for emotional and cognitive changes in hyperthyroidism, including anxiety and impaired processing speed. PMID:28009983

  9. Abnormal brain functional connectivity leads to impaired mood and cognition in hyperthyroidism: a resting-state functional MRI study.

    PubMed

    Li, Ling; Zhi, Mengmeng; Hou, Zhenghua; Zhang, Yuqun; Yue, Yingying; Yuan, Yonggui

    2017-01-24

    Patients with hyperthyroidism frequently have neuropsychiatric complaints such as lack of concentration, poor memory, depression, anxiety, nervousness, and irritability, suggesting brain dysfunction. However, the underlying process of these symptoms remains unclear. Using resting-state functional magnetic resonance imaging (rs-fMRI), we depicted the altered graph theoretical metric degree centrality (DC) and seed-based resting-state functional connectivity (FC) in 33 hyperthyroid patients relative to 33 healthy controls. The peak points of significantly altered DC between the two groups were defined as the seed regions to calculate FC to the whole brain. Then, partial correlation analyses were performed between abnormal DC, FC and neuropsychological performances, as well as some clinical indexes. The decreased intrinsic functional connectivity in the posterior lobe of cerebellum (PLC) and medial frontal gyrus (MeFG), as well as the abnormal seed-based FC anchored in default mode network (DMN), attention network, visual network and cognitive network in this study, possibly constitutes the latent mechanism for emotional and cognitive changes in hyperthyroidism, including anxiety and impaired processing speed.

  10. Clozapine and olanzapine but not risperidone impair the pre-frontal striatal system in relation to egocentric spatial orientation in a Y-maze.

    PubMed

    Castro, Cibele Canal; Dos Reis-Lunardelli, Eleonora Araujo; Schmidt, Werner J; Coitinho, Adriana Simon; Izquierdo, Iván

    2007-11-01

    Many studies indicate a dissociation between two forms of orientation: allocentric orientation, in which an organism orients on the basis of cues external to the organism, and egocentric spatial orientation (ESO) by which an organism orients on the basis of proprioceptive information. While allocentric orientation is mediated primarily by the hippocampus and its afferent and efferent connections, ESO is mediated by the prefronto-striatal system. Striatal lesions as well as classical neuroleptics, which block dopamine receptors, act through the prefronto-striatal system and impair ESO. The purpose of the present study was to determine the effects of the atypical antipsychotics clozapine, olanzapine and risperidone which are believed to exert its antipsychotic effects mainly by dopaminergic, cholinergic and serotonergic mechanisms. A delayed-two-alternative-choice-task, under conditions that required ESO and at the same time excluded allocentric spatial orientation was used. Clozapine and olanzapine treated rats made more errors than risperidone treated rats in the delayed alternation in comparison with the controls. Motor abilities were not impaired by any of the drugs. Thus, with regard to the delayed alternation requiring ESO, clozapine and olanzapine but not risperidone affects the prefronto-striatal system in a similar way as classical neuroleptics does.

  11. The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics.

    PubMed

    Sonuga-Barke, Edmund J S

    2003-11-01

    The currently dominant neuro-cognitive model of Attention Deficit Hyperactivity Disorder (AD/HD) presents the condition as executive dysfunction (EDF) underpinned by disturbances in the fronto-dorsal striatal circuit and associated dopaminergic branches (e.g. meso-cortical). In contrast, motivationally-based accounts focus on altered reward processes and implicate fronto-ventral striatal reward circuits and those meso-limbic branches that terminate in the ventral striatum especially the nucleus accumbens. One such account, delay aversion (DEL), presents AD/HD as a motivational style-characterised by attempts to escape or avoid delay-arising from fundamental disturbances in these reward centres. While traditionally regarded as competing, EDF and DEL models have recently been presented as complimentary accounts of two psycho-patho-physiological subtypes of AD/HD with different developmental pathways, underpinned by different cortico-striatal circuits and modulated by different branches of the dopamine system. In the current paper we describe the development of this model in more detail. We elaborate on the neuro-circuitry possibly underpinning these two pathways and explore their developmental significance within a neuro-ecological framework.

  12. QEEG and LORETA in Teenagers With Conduct Disorder and Psychopathic Traits.

    PubMed

    Calzada-Reyes, Ana; Alvarez-Amador, Alfredo; Galán-García, Lídice; Valdés-Sosa, Mitchell

    2017-05-01

    Few studies have investigated the impact of the psychopathic traits on the EEG of teenagers with conduct disorder (CD). To date, there is no other research studying low-resolution brain electromagnetic tomography (LORETA) technique using quantitative EEG (QEEG) analysis in adolescents with CD and psychopathic traits. To find electrophysiological differences specifically related to the psychopathic traits. The current investigation compares the QEEG and the current source density measures between adolescents with CD and psychopathic traits and adolescents with CD without psychopathic traits. The resting EEG activity and LORETA for the EEG fast spectral bands were evaluated in 42 teenagers with CD, 25 with and 17 without psychopathic traits according to the Antisocial Process Screening Device. All adolescents were assessed using the DSM-IV-TR criteria. The EEG visual inspection characteristics and the use of frequency domain quantitative analysis techniques (narrow band spectral parameters) are described. QEEG analysis showed a pattern of beta activity excess on the bilateral frontal-temporal regions and decreases of alpha band power on the left central-temporal and right frontal-central-temporal regions in the psychopathic traits group. Current source density calculated at 17.18 Hz showed an increase within fronto-temporo-striatal regions in the psychopathic relative to the nonpsychopathic traits group. These findings indicate that QEEG analysis and techniques of source localization may reveal differences in brain electrical activity among teenagers with CD and psychopathic traits, which was not obvious to visual inspection. Taken together, these results suggest that abnormalities in a fronto-temporo-striatal network play a relevant role in the neurobiological basis of psychopathic behavior.

  13. Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders.

    PubMed

    Kos, Claire; van Tol, Marie-José; Marsman, Jan-Bernard C; Knegtering, Henderikus; Aleman, André

    2016-10-01

    Apathy can be described as a loss of goal-directed purposeful behavior and is common in a variety of neurological and psychiatric disorders. Although previous studies investigated associations between abnormal brain functioning and apathy, it is unclear whether the neural basis of apathy is similar across different pathological conditions. The purpose of this systematic review was to provide an extensive overview of the neuroimaging literature on apathy including studies of various patient populations, and evaluate whether the current state of affairs suggest disorder specific or shared neural correlates of apathy. Results suggest that abnormalities within fronto-striatal circuits are most consistently associated with apathy across the different pathological conditions. Of note, abnormalities within the inferior parietal cortex were also linked to apathy, a region previously not included in neuroanatomical models of apathy. The variance in brain regions implicated in apathy may suggest that different routes towards apathy are possible. Future research should investigate possible alterations in different processes underlying goal-directed behavior, ranging from intention and goal-selection to action planning and execution. Copyright © 2016. Published by Elsevier Ltd.

  14. Double-dissociation between the mechanism leading to impulsivity and inattention in Attention Deficit Hyperactivity Disorder: A resting-state functional connectivity study.

    PubMed

    Sanefuji, Masafumi; Craig, Michael; Parlatini, Valeria; Mehta, Mitul A; Murphy, Declan G; Catani, Marco; Cerliani, Leonardo; Thiebaut de Schotten, Michel

    2017-01-01

    Two core symptoms characterize Attention Deficit Hyperactivity Disorder (ADHD) subtypes: inattentiveness and hyperactivity-impulsivity. While previous brain imaging research investigated ADHD as if it was a homogenous condition, its two core symptoms may originate from different brain mechanisms. We, therefore, hypothesized that the functional connectivity of cortico-striatal and attentional networks would be different between ADHD subtypes. We studied 165 children (mean age 10.93 years; age range, 7-17 year old) diagnosed as having ADHD based on their revised Conner's rating scale score and 170 typical developing individuals (mean age 11.46 years; age range, 7-17 year old) using resting state functional fMRI. Groups were matched for age, IQ and head motion during the MRI acquisition. We fractionated the ADHD group into predominantly inattentive, hyperactive-impulsive and combined subtypes based on their revised Conner's rating scale score. We then analyzed differences in resting state functional connectivity of the cortico-striatal and attentional networks between these subtypes. We found a double dissociation of functional connectivity in the cortico-striatal and ventral attentional networks, reflecting the subtypes of the ADHD participants. Particularly, the hyperactive-impulsive subtype was associated with increased connectivity in cortico-striatal network, whereas the inattentive subtype was associated with increased connectivity in the right ventral attention network. Our study demonstrated for the first time a right lateralized, double dissociation between specific networks associated with hyperactivity-impulsivity and inattentiveness in ADHD children, providing a biological basis for exploring symptom dimensions and revealing potential targets for more personalized treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Altered structural connectivity of cortico-striato-pallido-thalamic networks in Gilles de la Tourette syndrome.

    PubMed

    Worbe, Yulia; Marrakchi-Kacem, Linda; Lecomte, Sophie; Valabregue, Romain; Poupon, Fabrice; Guevara, Pamela; Tucholka, Alan; Mangin, Jean-François; Vidailhet, Marie; Lehericy, Stephane; Hartmann, Andreas; Poupon, Cyril

    2015-02-01

    -frontal cortex, inferior frontal, temporo-parietal junction, medial temporal and frontal pole also had enhanced structural connectivity with the striatum and thalamus in patients with Gilles de la Tourette syndrome. In addition, the cortico-striatal pathways were characterized by elevated fractional anisotropy and diminished radial diffusivity, suggesting microstructural axonal abnormalities of white matter in Gilles de la Tourette syndrome. These changes were more prominent in females with Gilles de la Tourette syndrome compared to males and were not related to the current medication status. Taken together, our data showed widespread structural abnormalities in cortico-striato-pallido-thalamic white matter pathways in patients with Gilles de la Tourette, which likely result from abnormal brain development in this syndrome. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

  16. Functional connectivity during phonemic and semantic verbal fluency test: a multi-channel near infrared spectroscopy study (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Huang, Chun-Jung; Sun, Chia-Wei; Chou, Po-Han; Chuang, Ching-Cheng

    2016-03-01

    Verbal fluency tests (VFT) are widely used neuropsychological tests of frontal lobe and have been frequently used in various functional brain mapping studies. There are two versions of VFT based on the type of cue: the letter fluency task (LFT) and the category fluency task (CFT). However, the fundamental aspect of the brain connectivity across spatial regions of the fronto-temporal regions during the VFTs has not been elucidated to date. In this study we hypothesized that different cortical functional connectivity over bilateral fronto-temporal regions can be observed by means of multi-channel fNIRS in the LFT and the CFT respectively. Our results from fNIRS (ETG-4000) showed different patterns of brain functional connectivity consistent with these different cognitive requirements. We demonstrate more brain functional connectivity over frontal and temporal regions during LFT than CFT, and this was in line with previous brain activity studies using fNIRS demonstrating increased frontal and temporal region activation during LFT and CFT and more pronounced frontal activation by the LFT.

  17. Conflicting Demands of Abstract and Specific Visual Object Processing Resolved by Fronto-Parietal Networks

    PubMed Central

    McMenamin, Brenton W.; Marsolek, Chad J.; Morseth, Brianna K.; Speer, MacKenzie F.; Burton, Philip C.; Burgund, E. Darcy

    2016-01-01

    Object categorization and exemplar identification place conflicting demands on the visual system, yet humans easily perform these fundamentally contradictory tasks. Previous studies suggest the existence of dissociable visual processing subsystems to accomplish the two abilities – an abstract category (AC) subsystem that operates effectively in the left hemisphere, and a specific exemplar (SE) subsystem that operates effectively in the right hemisphere. This multiple subsystems theory explains a range of visual abilities, but previous studies have not explored what mechanisms exist for coordinating the function of multiple subsystems and/or resolving the conflicts that would arise between them. We collected functional MRI data while participants performed two variants of a cue-probe working memory task that required AC or SE processing. During the maintenance phase of the task, the bilateral intraparietal sulcus (IPS) exhibited hemispheric asymmetries in functional connectivity consistent with exerting proactive control over the two visual subsystems: greater connectivity to the left hemisphere during the AC task, and greater connectivity to the right hemisphere during the SE task. Moreover, probe-evoked activation revealed activity in a broad fronto-parietal network (containing IPS) associated with reactive control when the two visual subsystems were in conflict, and variations in this conflict signal across trials was related to the visual similarity of the cue/probe stimulus pairs. Although many studies have confirmed the existence of multiple visual processing subsystems, this study is the first to identify the mechanisms responsible for coordinating their operations. PMID:26883940

  18. GABA content within medial prefrontal cortex predicts the variability of fronto-limbic effective connectivity

    PubMed Central

    Pizzi, Stefano Delli; Chiacchieretta, Piero; Mantini, Dante; Bubbico, Giovanna; Edden, Richard A.; Onofrj, Marco; Ferretti, Antonio

    2017-01-01

    The amygdala-medial prefrontal cortex (mPFC) circuit plays a key role in social behavior. The amygdala and mPFC are bidirectionally connected, functionally and anatomically, via the uncinate fasciculus. Recent evidence suggests that GABA-ergic neurotransmission within the mPFC could be central to the regulation of amygdala activity related to emotions and anxiety processing. However, the functional and neurochemical interactions within amygdala-mPFC circuits are unclear. In the current study, multimodal magnetic resonance imaging techniques were combined to investigate effective connectivity within the amygdala-mPFC network and its relationship with mPFC neurotransmission in 22 healthy subjects aged between 41 and 88 years. Effective connectivity in the amygdala-mPFC circuit was assessed on resting-state functional magnetic resonance imaging data using spectral dynamic causal modelling. State and trait anxiety were also assessed. The mPFC was shown to be the target of incoming outputs from the amygdalae and the source of exciting inputs to the limbic system. The amygdalae were reciprocally connected by excitatory projections. About half of the variance relating to the strength of top–down endogenous connection between right amygdala and mPFC was explained by mPFC GABA levels. State anxiety was correlated with the strength of the endogenous connections between right amygdala and mPFC. We suggest that mPFC GABA content predicts variability in the effective connectivity within the mPFC-amygdala circuit, providing new insights on emotional physiology and the underlying functional and neurochemical interactions. PMID:28386778

  19. Dopamine-dependent periadolescent maturation of corticostriatal functional connectivity in mouse.

    PubMed

    Galiñanes, Gregorio L; Taravini, Irene R E; Murer, M Gustavo

    2009-02-25

    Altered corticostriatal information processing associated with early dopamine systems dysfunction may contribute to attention deficit/hyperactivity disorder (ADHD). Mice with neonatal dopamine-depleting lesions exhibit hyperactivity that wanes after puberty and is reduced by psychostimulants, reminiscent of some aspects of ADHD. To assess whether the maturation of corticostriatal functional connectivity is altered by early dopamine depletion, we examined preadolescent and postadolescent urethane-anesthetized mice with or without dopamine-depleting lesions. Specifically, we assessed (1) synchronization between striatal neuron discharges and oscillations in frontal cortex field potentials and (2) striatal neuron responses to frontal cortex stimulation. In adult control mice striatal neurons were less spontaneously active, less responsive to cortical stimulation, and more temporally tuned to cortical rhythms than in infants. Striatal neurons from hyperlocomotor mice required more current to respond to cortical input and were less phase locked to ongoing oscillations, resulting in fewer neurons responding to refined cortical commands. By adulthood some electrophysiological deficits waned together with hyperlocomotion, but striatal spontaneous activity remained substantially elevated. Moreover, dopamine-depleted animals showing normal locomotor scores exhibited normal corticostriatal synchronization, suggesting that the lesion allows, but is not sufficient, for the emergence of corticostriatal changes and hyperactivity. Although amphetamine normalized corticostriatal tuning in hyperlocomotor mice, it reduced horizontal activity in dopamine-depleted animals regardless of their locomotor phenotype, suggesting that amphetamine modified locomotion through a parallel mechanism, rather than that modified by dopamine depletion. In summary, functional maturation of striatal activity continues after infancy, and early dopamine depletion delays the maturation of core functional

  20. Dopamine-dependent periadolescent maturation of corticostriatal functional connectivity in mouse

    PubMed Central

    Galiñanes, Gregorio L.; Taravini, Irene R.E.; Murer, M. Gustavo

    2009-01-01

    Altered corticostriatal information processing associated with early dopamine systems dysfunction may contribute to attention deficit/hyperactivity disorder (ADHD). Mice with neonatal dopamine-depleting lesions exhibit hyperactivity that wanes after puberty and is reduced by psychostimulants, reminiscent of some aspects of ADHD. To assess whether the maturation of corticostriatal functional connectivity is altered by early dopamine depletion, we examined pre- and post-adolescent urethane-anesthetized mice with or without dopamine-depleting lesions. Specifically, we assessed (1) synchronization between striatal neuron discharges and oscillations in frontal cortex field potentials and (2) striatal neuron responses to frontal cortex stimulation. In adult control mice striatal neurons were less spontaneously active, less responsive to cortical stimulation and more temporally tuned to cortical rhythms than in infants. Striatal neurons from hyperlocomotor mice required more current to respond to cortical input and were less phase-locked to ongoing oscillations, resulting in fewer neurons responding to refined cortical commands. By adulthood some electrophysiological deficits waned together with hyperlocomotion, but striatal spontaneous activity remained substantially elevated. Moreover, dopamine-depleted animals showing normal locomotor scores exhibited normal corticostriatal synchronization, suggesting that the lesion allows, but is not sufficient, for the emergence of corticostriatal changes and hyperactivity. Although amphetamine normalized corticostriatal tuning in hyperlocomotor mice, it reduced horizontal activity in dopamine-depleted animals irrespective of their locomotor phenotype, suggesting that amphetamine modified locomotion through a parallel mechanism, rather than that modified by dopamine depletion. In summary, functional maturation of striatal activity continues after infancy, and early dopamine depletion delays the maturation of core functional

  1. 3D PATTERN OF BRAIN ABNORMALITIES IN FRAGILE X SYNDROME VISUALIZED USING TENSOR-BASED MORPHOMETRY

    PubMed Central

    Lee, Agatha D.; Leow, Alex D.; Lu, Allen; Reiss, Allan L.; Hall, Scott; Chiang, Ming-Chang; Toga, Arthur W.; Thompson, Paul M.

    2007-01-01

    Fragile X syndrome (FraX), a genetic neurodevelopmental disorder, results in impaired cognition with particular deficits in executive function and visuo-spatial skills. Here we report the first detailed 3D maps of the effects of the Fragile X mutation on brain structure, using tensor-based morphometry. TBM visualizes structural brain deficits automatically, without time-consuming specification of regions-of-interest. We compared 36 subjects with FraX (age: 14.66+/−1.58SD, 18 females/18 males), and 33 age-matched healthy controls (age: 14.67+/−2.2SD, 17 females/16 males), using high-dimensional elastic image registration. All 69 subjects' 3D T1-weighted brain MRIs were spatially deformed to match a high-resolution single-subject average MRI scan in ICBM space, whose geometry was optimized to produce a minimal deformation target. Maps of the local Jacobian determinant (expansion factor) were computed from the deformation fields. Statistical maps showed increased caudate (10% higher; p=0.001) and lateral ventricle volumes (19% higher; p=0.003), and trend-level parietal and temporal white matter excesses (10% higher locally; p=0.04). In affected females, volume abnormalities correlated with reduction in systemically measured levels of the fragile X mental retardation protein (FMRP; Spearman's r<−0.5 locally). Decreased FMRP correlated with ventricular expansion (p=0.042; permutation test), and anterior cingulate tissue reductions (p=0.0026; permutation test) supporting theories that FMRP is required for normal dendritic pruning in fronto-striatal-limbic pathways. No sex differences were found; findings were confirmed using traditional volumetric measures in regions of interest. Deficit patterns were replicated using Lie group statistics optimized for tensor-valued data. Investigation of how these anomalies emerge over time will accelerate our understanding of FraX and its treatment. PMID:17161622

  2. Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: A combined PET, fMRI and DTI study

    PubMed Central

    Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

    2013-01-01

    Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D2/D3 receptor radioligand [11C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in its both associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

  3. Patterns of neural connectivity during an attention bias task moderate associations between early childhood temperament and internalizing symptoms in young adulthood.

    PubMed

    Hardee, Jillian E; Benson, Brenda E; Bar-Haim, Yair; Mogg, Karin; Bradley, Brendan P; Chen, Gang; Britton, Jennifer C; Ernst, Monique; Fox, Nathan A; Pine, Daniel S; Pérez-Edgar, Koraly

    2013-08-15

    Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area might clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. Children were assessed for BI at multiple age points from infancy through age seven. On the basis of a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (n = 44). Participants completed an event-related functional magnetic resonance imaging attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews. The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms. Behavioral inhibition during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology. Copyright © 2013 Society of Biological Psychiatry. All rights reserved.

  4. Fronto-parietal coding of goal-directed actions performed by artificial agents.

    PubMed

    Kupferberg, Aleksandra; Iacoboni, Marco; Flanagin, Virginia; Huber, Markus; Kasparbauer, Anna; Baumgartner, Thomas; Hasler, Gregor; Schmidt, Florian; Borst, Christoph; Glasauer, Stefan

    2018-03-01

    With advances in technology, artificial agents such as humanoid robots will soon become a part of our daily lives. For safe and intuitive collaboration, it is important to understand the goals behind their motor actions. In humans, this process is mediated by changes in activity in fronto-parietal brain areas. The extent to which these areas are activated when observing artificial agents indicates the naturalness and easiness of interaction. Previous studies indicated that fronto-parietal activity does not depend on whether the agent is human or artificial. However, it is unknown whether this activity is modulated by observing grasping (self-related action) and pointing actions (other-related action) performed by an artificial agent depending on the action goal. Therefore, we designed an experiment in which subjects observed human and artificial agents perform pointing and grasping actions aimed at two different object categories suggesting different goals. We found a signal increase in the bilateral inferior parietal lobule and the premotor cortex when tool versus food items were pointed to or grasped by both agents, probably reflecting the association of hand actions with the functional use of tools. Our results show that goal attribution engages the fronto-parietal network not only for observing a human but also a robotic agent for both self-related and social actions. The debriefing after the experiment has shown that actions of human-like artificial agents can be perceived as being goal-directed. Therefore, humans will be able to interact with service robots intuitively in various domains such as education, healthcare, public service, and entertainment. © 2017 Wiley Periodicals, Inc.

  5. Ventral Fronto-Temporal Pathway Supporting Cognitive Control of Episodic Memory Retrieval

    PubMed Central

    Barredo, Jennifer; Öztekin, Ilke; Badre, David

    2015-01-01

    Achieving our goals often requires guiding access to relevant information from memory. Such goal-directed retrieval requires interactions between systems supporting cognitive control, including ventrolateral prefrontal cortex (VLPFC), and those supporting declarative memory, such as the medial temporal lobes (MTL). However, the pathways by which VLPFC interacts with MTL during retrieval are underspecified. Prior neuroanatomical evidence suggests that a polysynaptic ventral fronto-temporal pathway may support VLPFC–MTL interactions. To test this hypothesis, human participants were scanned using fMRI during performance of a source-monitoring task. The strength of source information was varied via repetition during encoding. Single encoding events should produce a weaker memory trace, thus recovering source information about these items should demand greater cognitive control. Results demonstrated that cortical targets along the ventral path—anterior VLPFC, temporal pole, anterior parahippocampus, and hippocampus—exhibited increases in univariate BOLD response correlated with increases in controlled retrieval demand, independent of factors related to response selection. Further, a functional connectivity analysis indicated that these regions functionally couple and are distinguishable from a dorsal pathway related to response selection demands. These data support a ventral retrieval pathway linking PFC and MTL. PMID:24177990

  6. Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses.

    PubMed

    Gay, Charles W; Robinson, Michael E; Lai, Song; O'Shea, Andrew; Craggs, Jason G; Price, Donald D; Staud, Roland

    2016-02-01

    Although altered resting-state functional connectivity (FC) is a characteristic of many chronic pain conditions, it has not yet been evaluated in patients with chronic fatigue. Our objective was to investigate the association between fatigue and altered resting-state FC in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Thirty-six female subjects, 19 ME/CFS and 17 healthy controls, completed a fatigue inventory before undergoing functional magnetic resonance imaging. Two methods, (1) data driven and (2) model based, were used to estimate and compare the intraregional FC between both groups during the resting state (RS). The first approach using independent component analysis was applied to investigate five RS networks: the default mode network, salience network (SN), left frontoparietal networks (LFPN) and right frontoparietal networks, and the sensory motor network (SMN). The second approach used a priori selected seed regions demonstrating abnormal regional cerebral blood flow (rCBF) in ME/CFS patients at rest. In ME/CFS patients, Method-1 identified decreased intrinsic connectivity among regions within the LFPN. Furthermore, the FC of the left anterior midcingulate with the SMN and the connectivity of the left posterior cingulate cortex with the SN were significantly decreased. For Method-2, five distinct clusters within the right parahippocampus and occipital lobes, demonstrating significant rCBF reductions in ME/CFS patients, were used as seeds. The parahippocampal seed and three occipital lobe seeds showed altered FC with other brain regions. The degree of abnormal connectivity correlated with the level of self-reported fatigue. Our results confirm altered RS FC in patients with ME/CFS, which was significantly correlated with the severity of their chronic fatigue.

  7. Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses

    PubMed Central

    Gay, Charles W.; Robinson, Michael E.; Lai, Song; O'Shea, Andrew; Craggs, Jason G.; Price, Donald D.

    2016-01-01

    Abstract Although altered resting-state functional connectivity (FC) is a characteristic of many chronic pain conditions, it has not yet been evaluated in patients with chronic fatigue. Our objective was to investigate the association between fatigue and altered resting-state FC in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Thirty-six female subjects, 19 ME/CFS and 17 healthy controls, completed a fatigue inventory before undergoing functional magnetic resonance imaging. Two methods, (1) data driven and (2) model based, were used to estimate and compare the intraregional FC between both groups during the resting state (RS). The first approach using independent component analysis was applied to investigate five RS networks: the default mode network, salience network (SN), left frontoparietal networks (LFPN) and right frontoparietal networks, and the sensory motor network (SMN). The second approach used a priori selected seed regions demonstrating abnormal regional cerebral blood flow (rCBF) in ME/CFS patients at rest. In ME/CFS patients, Method-1 identified decreased intrinsic connectivity among regions within the LFPN. Furthermore, the FC of the left anterior midcingulate with the SMN and the connectivity of the left posterior cingulate cortex with the SN were significantly decreased. For Method-2, five distinct clusters within the right parahippocampus and occipital lobes, demonstrating significant rCBF reductions in ME/CFS patients, were used as seeds. The parahippocampal seed and three occipital lobe seeds showed altered FC with other brain regions. The degree of abnormal connectivity correlated with the level of self-reported fatigue. Our results confirm altered RS FC in patients with ME/CFS, which was significantly correlated with the severity of their chronic fatigue. PMID:26449441

  8. Differential functional connectivity of rostral anterior cingulate cortex during emotional interference.

    PubMed

    Szekely, Akos; Silton, Rebecca L; Heller, Wendy; Miller, Gregory A; Mohanty, Aprajita

    2017-03-01

    The rostral-ventral subdivision of the anterior cingulate cortex (rACC) plays a key role in the regulation of emotional processing. Although rACC has strong anatomical connections with anterior insular cortex (AIC), amygdala, prefrontal cortex and striatal brain regions, it is unclear whether the functional connectivity of rACC with these regions changes when regulating emotional processing. Furthermore, it is not known whether this connectivity changes with deficits in emotion regulation seen in different kinds of anxiety and depression. To address these questions regarding rACC functional connectivity, non-patients high in self-reported anxious apprehension (AP), anxious arousal (AR), anhedonic depression (AD) or none (CON) indicated the ink color of pleasant, neutral and unpleasant words during functional magnetic resonance imaging. While ignoring task-irrelevant unpleasant words, AD and CON showed an increase in the functional connectivity of rACC with AIC, putamen, caudate and ventral pallidum. There was a decrease in this connectivity in AP and AR, with AP showing greater reduction than AR. These findings provide support for the role of rACC in integrating interoceptive, emotional and cognitive functions via interactions with insula and striatal regions during effective emotion regulation in healthy individuals and a failure of this integration that may be specific to anxiety, particularly AP. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  9. Striatal volume predicts level of video game skill acquisition.

    PubMed

    Erickson, Kirk I; Boot, Walter R; Basak, Chandramallika; Neider, Mark B; Prakash, Ruchika S; Voss, Michelle W; Graybiel, Ann M; Simons, Daniel J; Fabiani, Monica; Gratton, Gabriele; Kramer, Arthur F

    2010-11-01

    Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.

  10. Emotion-induced loss aversion and striatal-amygdala coupling in low-anxious individuals.

    PubMed

    Charpentier, Caroline J; De Martino, Benedetto; Sim, Alena L; Sharot, Tali; Roiser, Jonathan P

    2016-04-01

    Adapting behavior to changes in the environment is a crucial ability for survival but such adaptation varies widely across individuals. Here, we asked how humans alter their economic decision-making in response to emotional cues, and whether this is related to trait anxiety. Developing an emotional decision-making task for functional magnetic resonance imaging, in which gambling decisions were preceded by emotional and non-emotional primes, we assessed emotional influences on loss aversion, the tendency to overweigh potential monetary losses relative to gains. Our behavioral results revealed that only low-anxious individuals exhibited increased loss aversion under emotional conditions. This emotional modulation of decision-making was accompanied by a corresponding emotion-elicited increase in amygdala-striatal functional connectivity, which correlated with the behavioral effect across participants. Consistent with prior reports of 'neural loss aversion', both amygdala and ventral striatum tracked losses more strongly than gains, and amygdala loss aversion signals were exaggerated by emotion, suggesting a potential role for this structure in integrating value and emotion cues. Increased loss aversion and striatal-amygdala coupling induced by emotional cues may reflect the engagement of adaptive harm-avoidance mechanisms in low-anxious individuals, possibly promoting resilience to psychopathology. © The Author (2015). Published by Oxford University Press.

  11. Cerebro-fronto-facial syndrome type 3 with polymicrogyria: a clinical presentation of Baraitser-Winter syndrome.

    PubMed

    Eker, Hatice Koçak; Derinkuyu, Betül Emine; Ünal, Sevim; Masliah-Planchon, Julien; Drunat, Séverine; Verloes, Alain

    2014-01-01

    Baraitser-Winter syndrome (BRWS) is a rare condition affecting the development of the brain and the face. The most common characteristics are unusual facial appearance including hypertelorism and ptosis, ocular colobomas, hearing loss, impaired neuronal migration and intellectual disability. BRWS is caused by mutations in the ACTB and ACTG1 genes. Cerebro-fronto-facial syndrome (CFFS) is a clinically heterogeneous condition with distinct facial dysmorphism, and brain abnormalities. Three subtypes are identified. We report a female infant with striking facial features and brain anomalies (included polymicrogyria) that fit into the spectrum of the CFFS type 3 (CFFS3). She also had minor anomalies on her hands and feet, heart and kidney malformations, and recurrent infections. DNA investigations revealed c.586C>T mutation (p.Arg196Cys) in ACTB. This mutation places this patient in the spectrum of BRWS. The same mutation has been detected in a polymicrogyric patient reported previously in literature. We expand the malformation spectrum of BRWS/CFFS3, and present preliminary findings for phenotype-genotype correlation in this spectrum. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  12. Fronto-limbic dysfunction in borderline personality disorder: a 18F-FDG positron emission tomography study.

    PubMed

    Salavert, José; Gasol, Miquel; Vieta, Eduard; Cervantes, Ana; Trampal, Carlos; Gispert, Juan Domingo

    2011-06-01

    Several functional neuroimaging studies have demonstrated abnormalities in fronto-limbic pathways when comparing borderline personality disorder (BPD) patients with controls. The present study aimed to evaluate regional cerebral metabolism in euthymic BPD patients with similar measured impulsivity levels by means of 18F-FDG PET during resting state and to compare them against a control group. The present study evaluates regional cerebral metabolism in 8 euthymic BPD patients with 18F-FDG PET during resting state as compared to 8 controls with similar socio-geographic characteristics. BPD patients presented a marked hypo-metabolism in frontal lobe and showed hyper-metabolism in motor cortex (paracentral lobules and post-central cortex), medial and anterior cingulus, occipital lobe, temporal pole, left superior parietal gyrus and right superior frontal gyrus. No significant differences appeared in basal ganglia or thalamus. Results reveal a dysfunction in patients' frontolimbic network during rest and provide further evidence for the importance of these regions in relation to BPD symptomatology. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

    PubMed Central

    Pappas, Samuel S.; Leventhal, Daniel K.; Albin, Roger L.; Dauer, William T.

    2014-01-01

    This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role—Tourette syndrome and obsessive-compulsive disorder, Rett's syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function. PMID:24947237

  14. Tinnitus alters resting state functional connectivity (RSFC) in human auditory and non-auditory brain regions as measured by functional near-infrared spectroscopy (fNIRS)

    PubMed Central

    Hu, Xiao-Su; Issa, Mohamad; Bisconti, Silvia; Kovelman, Ioulia; Kileny, Paul; Basura, Gregory

    2017-01-01

    Tinnitus, or phantom sound perception, leads to increased spontaneous neural firing rates and enhanced synchrony in central auditory circuits in animal models. These putative physiologic correlates of tinnitus to date have not been well translated in the brain of the human tinnitus sufferer. Using functional near-infrared spectroscopy (fNIRS) we recently showed that tinnitus in humans leads to maintained hemodynamic activity in auditory and adjacent, non-auditory cortices. Here we used fNIRS technology to investigate changes in resting state functional connectivity between human auditory and non-auditory brain regions in normal-hearing, bilateral subjective tinnitus and controls before and after auditory stimulation. Hemodynamic activity was monitored over the region of interest (primary auditory cortex) and non-region of interest (adjacent non-auditory cortices) and functional brain connectivity was measured during a 60-second baseline/period of silence before and after a passive auditory challenge consisting of alternating pure tones (750 and 8000Hz), broadband noise and silence. Functional connectivity was measured between all channel-pairs. Prior to stimulation, connectivity of the region of interest to the temporal and fronto-temporal region was decreased in tinnitus participants compared to controls. Overall, connectivity in tinnitus was differentially altered as compared to controls following sound stimulation. Enhanced connectivity was seen in both auditory and non-auditory regions in the tinnitus brain, while controls showed a decrease in connectivity following sound stimulation. In tinnitus, the strength of connectivity was increased between auditory cortex and fronto-temporal, fronto-parietal, temporal, occipito-temporal and occipital cortices. Together these data suggest that central auditory and non-auditory brain regions are modified in tinnitus and that resting functional connectivity measured by fNIRS technology may contribute to conscious phantom

  15. Local functional connectivity suggests functional immaturity in children with attention-deficit/hyperactivity disorder.

    PubMed

    Marcos-Vidal, Luis; Martínez-García, Magdalena; Pretus, Clara; Garcia-Garcia, David; Martínez, Kenia; Janssen, Joost; Vilarroya, Oscar; Castellanos, Francisco X; Desco, Manuel; Sepulcre, Jorge; Carmona, Susanna

    2018-06-01

    Previous studies have associated Attention-Deficit/Hyperactivity Disorder (ADHD) with a maturational lag of brain functional networks. Functional connectivity of the human brain changes from primarily local to more distant connectivity patterns during typical development. Under the maturational lag hypothesis, we expect children with ADHD to exhibit increased local connectivity and decreased distant connectivity compared with neurotypically developing (ND) children. We applied a graph-theory method to compute local and distant connectivity levels and cross-sectionally compared them in a sample of 120 children with ADHD and 120 age-matched ND children (age range = 7-17 years). In addition, we measured if potential group differences in local and distant connectivity were stable across the age range considered. Finally, we assessed the clinical relevance of observed group differences by correlating the connectivity levels and ADHD symptoms severity separately for each group. Children with ADHD exhibited more local connectivity than age-matched ND children in multiple brain regions, mainly overlapping with default mode, fronto-parietal and ventral attentional functional networks (p < .05- threshold free-cluster enhancement-family-wise error). We detected an atypical developmental pattern of local connectivity in somatomotor regions, that is, decreases with age in ND children, and increases with age in children with ADHD. Furthermore, local connectivity within somatomotor areas correlated positively with clinical severity of ADHD symptoms, both in ADHD and ND children. Results suggest an immature functional state of multiple brain networks in children with ADHD. Whereas the ADHD diagnosis is associated with the integrity of the system comprising the fronto-parietal, default mode and ventral attentional networks, the severity of clinical symptoms is related to atypical functional connectivity within somatomotor areas. Additionally, our findings are in line with

  16. Impaired pitch perception and memory in congenital amusia: the deficit starts in the auditory cortex.

    PubMed

    Albouy, Philippe; Mattout, Jérémie; Bouet, Romain; Maby, Emmanuel; Sanchez, Gaëtan; Aguera, Pierre-Emmanuel; Daligault, Sébastien; Delpuech, Claude; Bertrand, Olivier; Caclin, Anne; Tillmann, Barbara

    2013-05-01

    Congenital amusia is a lifelong disorder of music perception and production. The present study investigated the cerebral bases of impaired pitch perception and memory in congenital amusia using behavioural measures, magnetoencephalography and voxel-based morphometry. Congenital amusics and matched control subjects performed two melodic tasks (a melodic contour task and an easier transposition task); they had to indicate whether sequences of six tones (presented in pairs) were the same or different. Behavioural data indicated that in comparison with control participants, amusics' short-term memory was impaired for the melodic contour task, but not for the transposition task. The major finding was that pitch processing and short-term memory deficits can be traced down to amusics' early brain responses during encoding of the melodic information. Temporal and frontal generators of the N100m evoked by each note of the melody were abnormally recruited in the amusic brain. Dynamic causal modelling of the N100m further revealed decreased intrinsic connectivity in both auditory cortices, increased lateral connectivity between auditory cortices as well as a decreased right fronto-temporal backward connectivity in amusics relative to control subjects. Abnormal functioning of this fronto-temporal network was also shown during the retention interval and the retrieval of melodic information. In particular, induced gamma oscillations in right frontal areas were decreased in amusics during the retention interval. Using voxel-based morphometry, we confirmed morphological brain anomalies in terms of white and grey matter concentration in the right inferior frontal gyrus and the right superior temporal gyrus in the amusic brain. The convergence between functional and structural brain differences strengthens the hypothesis of abnormalities in the fronto-temporal pathway of the amusic brain. Our data provide first evidence of altered functioning of the auditory cortices during pitch

  17. Glutaric Acid-Mediated Apoptosis in Primary Striatal Neurons

    PubMed Central

    Tian, Fengyan; Fu, Xi; Gao, Jinzhi; Ying, Yanqin; Hou, Ling; Liang, Yan; Ning, Qin; Luo, Xiaoping

    2014-01-01

    Glutaric acid (GA) has been implicated in the mechanism of neurodegeneration in glutaric aciduria type I. In the present study, the potential cytotoxic effects of GA (0.1~50 mM for 24~96 h) were examined in cultured primary rat striatal neurons. Results showed increase in the number of cells labeled by annexin-V or with apoptotic features shown by Hoechst/PI staining and transmission electron microscopy (TEM) and upregulation of the expression of mRNA as well as the active protein fragments caspase 3, suggesting involvement of the caspase 3-dependent apoptotic pathway in GA-induced striatal neuronal death. This effect was in part suppressed by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 but not the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist 6-cyano-7-nitroquinoxalone-2,3-dione (CNQX). Thus, GA may trigger neuronal damage partially through apoptotic pathway and via activation of NMDA receptors in cultured primary striatal neurons. PMID:24900967

  18. Striatal Pleiotrophin Overexpression Provides Functional and Morphological Neuroprotection in the 6-Hydroxydopamine Model

    PubMed Central

    Gombash, Sara E; Lipton, Jack W; Collier, Timothy J; Madhavan, Lalitha; Steece-Collier, Kathy; Cole-Strauss, Allyson; Terpstra, Brian T; Spieles-Engemann, Anne L; Daley, Brian F; Wohlgenant, Susan L; Thompson, Valerie B; Manfredsson, Fredric P; Mandel, Ronald J; Sortwell, Caryl E

    2012-01-01

    Neurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for Parkinson's disease (PD). Pleiotrophin (PTN) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (DA) system. The present study examined the ability of striatal PTN overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (rAAV2/1), to provide neuroprotection and functional restoration from 6-hydroxydopamine (6-OHDA). Striatal PTN overexpression led to significant neuroprotection of tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and THir neurite density in the striatum, with long-term PTN overexpression producing recovery from 6-OHDA-induced deficits in contralateral forelimb use. Transduced striatal PTN levels were increased threefold compared to adult striatal PTN expression and approximated peak endogenous developmental levels (P1). rAAV2/1 vector exclusively transduced neurons within the striatum and SNpc with approximately half the total striatal volume routinely transduced using our injection parameters. Our results indicate that striatal PTN overexpression can provide neuroprotection for the 6-OHDA lesioned nigrostriatal system based upon morphological and functional measures and that striatal PTN levels similar in magnitude to those expressed in the striatum during development are sufficient to provide neuroprotection from Parkinsonian insult. PMID:22008908

  19. Abnormal connection of the inferior vena cava to the left atrium with double outlet right ventricle and heterotaxia: a case report.

    PubMed

    Günal, N; Bilgiç, A; Lenk, M K; Yurdakul, Y; Sarigül, A; Ispir, S

    1996-03-01

    A 4-year-old boy with abnormal connection of the inferior vena cava to the left atrium and double outlet right ventricle and right atrial isomerism is presented. The anomalies were detected by echocardiography and angiography, and later verified through surgical intervention.

  20. Aberrant Spontaneous and Task-Dependent Functional Connections in the Anxious Brain

    PubMed Central

    MacNamara, Annmarie; DiGangi, Julia; Phan, K. Luan

    2016-01-01

    A number of brain regions have been implicated in the anxiety disorders, yet none of these regions in isolation has been distinguished as the sole or discrete site responsible for anxiety disorder pathology. Therefore, the identification of dysfunctional neural networks as represented by alterations in the temporal correlation of blood-oxygen level dependent (BOLD) signal across several brain regions in anxiety disorders has been increasingly pursued in the past decade. Here, we review task-independent (e.g., resting state) and task-induced functional connectivity magnetic resonance imaging (fcMRI) studies in the adult anxiety disorders (including trauma- and stressor-related and obsessive compulsive disorders). The results of this review suggest that anxiety disorder pathophysiology involves aberrant connectivity between amygdala-frontal and frontal-striatal regions, as well as within and between canonical “intrinsic” brain networks - the default mode and salience networks, and that evidence of these aberrations may help inform findings of regional activation abnormalities observed in the anxiety disorders. Nonetheless, significant challenges remain, including the need to better understand mixed findings observed using different methods (e.g., resting state and task-based approaches); the need for more developmental work; the need to delineate disorder-specific and transdiagnostic fcMRI aberrations in the anxiety disorders; and the need to better understand the clinical significance of fcMRI abnormalities. In meeting these challenges, future work has the potential to elucidate aberrant neural networks as intermediate, brain-based phenotypes to predict disease onset and progression, refine diagnostic nosology, and ascertain treatment mechanisms and predictors of treatment response across anxiety, trauma-related and obsessive compulsive disorders. PMID:27141532

  1. Microstructure of frontoparietal connections predicts individual resistance to sleep deprivation.

    PubMed

    Cui, Jiaolong; Tkachenko, Olga; Gogel, Hannah; Kipman, Maia; Preer, Lily A; Weber, Mareen; Divatia, Shreya C; Demers, Lauren A; Olson, Elizabeth A; Buchholz, Jennifer L; Bark, John S; Rosso, Isabelle M; Rauch, Scott L; Killgore, William D S

    2015-02-01

    Sleep deprivation (SD) can degrade cognitive functioning, but growing evidence suggests that there are large individual differences in the vulnerability to this effect. Some evidence suggests that baseline differences in the responsiveness of a fronto-parietal attention system that is activated during working memory (WM) tasks may be associated with the ability to sustain vigilance during sleep deprivation. However, the neurocircuitry underlying this network remains virtually unexplored. In this study, we employed diffusion tensor imaging (DTI) to investigate the association between the microstructure of the axonal pathway connecting the frontal and parietal regions--i.e., the superior longitudinal fasciculus (SLF)--and individual resistance to SD. Thirty healthy participants (15 males) aged 20-43 years underwent functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) at rested wakefulness prior to a 28-hour period of SD. Task-related fronto-parietal fMRI activation clusters during a Sternberg WM Task were localized and used as seed regions for probabilistic fiber tractography. DTI metrics, including fractional anisotropy, mean diffusivity, axial and radial diffusivity were measured in the SLF. The psychomotor vigilance test (PVT) was used to evaluate resistance to SD. We found that activation in the left inferior parietal lobule (IPL) and dorsolateral prefrontal cortex (DLPFC) positively correlated with resistance. Higher fractional anisotropy of the left SLF comprising the primary axons connecting IPL and DLPFC was also associated with better resistance. These findings suggest that individual differences in resistance to SD are associated with the functional responsiveness of a fronto-parietal attention system and the microstructural properties of the axonal interconnections. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Altered striatal circuits underlie characteristic personality traits in Parkinson's disease.

    PubMed

    Ishii, Toru; Sawamoto, Nobukatsu; Tabu, Hayato; Kawashima, Hidekazu; Okada, Tomohisa; Togashi, Kaori; Takahashi, Ryosuke; Fukuyama, Hidenao

    2016-09-01

    Patients with Parkinson's disease (PD) have been suggested to share personality traits characterised by low novelty-seeking and high harm-avoidance. Although a link between novelty-seeking and dopamine is hypothesised, the link is not fully supported by 6-[(18)F]fluoro-L-dopa positron emission tomography (PET) studies. Meanwhile, tractography studies with magnetic resonance imaging (MRI) link personality to the connectivity of the striatum in healthy subjects. Here, we investigated neurochemical and anatomical correlates of characteristic personality traits in PD. Sixteen PD patients and 28 healthy controls were assessed using the Temperament and Character Inventory. All patients and 17 randomly selected controls were scanned with 2β-carbomethoxy-3β-(4-fluorophenyl)-[N-(11)C-methyl]tropane ([(11)C]CFT) PET to measure striatal dopamine transporter availability. All subjects were scanned with MRI to evaluate the connectivity of the striatum using probabilistic tractography. PET findings revealed no correlation of novelty-seeking and harm-avoidance with [(11)C]CFT uptake in patients or controls. Novelty-seeking correlated positively with the connectivity strength of the striatum with the hippocampus and amygdala in both patients and controls. Harm-avoidance and the fibre connectivity strength of the striatum including ventral area with the amygdala correlated negatively in patients and positively in controls, which differed significantly between the groups. Our data support the notion that the fibre connectivity of the striatum with limbic and frontal areas underlies the personality profile. Furthermore, our findings suggest that higher harm-avoidance in PD is linked to alterations of the network, including the nucleus accumbens and amygdala.

  3. Exogenous vs. endogenous attention: Shifting the balance of fronto-parietal activity.

    PubMed

    Meyer, Kristin N; Du, Feng; Parks, Emily; Hopfinger, Joseph B

    2018-03-01

    Despite behavioral and electrophysiological evidence for dissociations between endogenous (voluntary) and exogenous (reflexive) attention, fMRI results have yet to consistently and clearly differentiate neural activation patterns between these two types of attention. This study specifically aimed to determine whether activity in the dorsal fronto-parietal network differed between endogenous and exogenous conditions. Participants performed a visual discrimination task in endogenous and exogenous attention conditions while undergoing fMRI scanning. Analyses revealed robust and bilateral activation throughout the dorsal fronto-parietal network for each condition, in line with many previous results. In order to investigate possible differences in the balance of neural activity within this network with greater sensitivity, a priori regions of interest (ROIs) were selected for analysis, centered on the frontal eye fields (FEF) and intraparietal sulcus (IPS) regions identified in previous studies. The results revealed a significant interaction between region, condition, and hemisphere. Specifically, in the left hemisphere, frontal areas were more active than parietal areas, but only during endogenous attention. Activity in the right hemisphere, in contrast, remained relatively consistent for these regions across conditions. Analysis of this activity over time indicates that this left-hemispheric regional imbalance is present within the FEF early, at 3-6.5 s post-stimulus presentation, whereas a regional imbalance in the exogenous condition is not evident until 6.5-8 s post-stimulus presentation. Overall, our results provide new evidence that although the dorsal fronto-parietal network is indeed associated with both types of attentional orienting, regions of the network are differentially engaged over time and across hemispheres depending on the type of attention. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. MK-801 protection against methamphetamine-induced striatal dopamine terminal injury is associated with attenuated dopamine overflow.

    PubMed

    Weihmuller, F B; O'Dell, S J; Marshall, J F

    1992-06-01

    Repeated administrations of methamphetamine (m-AMPH) produce high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors has been shown previously to prevent m-AMPH-induced striatal DA terminal injury, but the mechanism for this protection is unclear. In the present study, in vivo microdialysis was used to determine the effects of blockade of NMDA receptors with the noncompetitive antagonist MK-801 on m-AMPH-induced striatal DA overflow. Four injections of MK-801 (0.5 mg/kg, ip) alone did not significantly change extracellular striatal DA concentrations from pretreatment values. Four treatments with m-AMPH (4.0 mg/kg, sc at 2-hr intervals) increased striatal DA overflow, and the overflow was particularly extensive following the fourth injection. This m-AMPH regimen produced a 40% reduction in striatal DA tissue content 1 week later. Treatment with MK-801 15 min before each of the four m-AMPH injections or prior to only the last two m-AMPH administrations attenuated the m-AMPH-induced increase in striatal DA overflow and protected completely against striatal DA depletions. Other MK-801 treatment regimens less effectively reduced the m-AMPH-induced striatal DA efflux and were ineffective in protecting against striatal DA depletions. Linear regression analysis indicated that cumulative DA overflow was strongly predictive (r = -.68) of striatal DA tissue levels measured one week later. These findings suggest that the extensive DA overflow seen during a neurotoxic regimen of m-AMPH is a crucial component of the subsequent neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Preserved Fronto-Striatal Plasticity and Enhanced Procedural Learning in a Transgenic Mouse Model of Alzheimer's Disease Overexpressing Mutant "hAPPswe"

    ERIC Educational Resources Information Center

    Middei, Silvia; Geracitano, Raffaella; Caprioli, Antonio; Mercuri, Nicola; Ammassari-Teule, Martine

    2004-01-01

    Mutations in the amyloid precursor protein (APP) gene inducing abnormal processing and deposition of [beta]-amyloid protein in the brain have been implicated in the pathogenesis of Alzheimer's disease (AD). Although Tg2576 mice with the Swedish mutation ("hAPPswe") exhibit age-related [Alpha][beta]-plaque formation in brain regions like the…

  6. β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

    PubMed Central

    Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

    2010-01-01

    Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

  7. Reduced striatal D2 receptor binding in myoclonus-dystonia.

    PubMed

    Beukers, R J; Booij, J; Weisscher, N; Zijlstra, F; van Amelsvoort, T A M J; Tijssen, M A J

    2009-02-01

    To study striatal dopamine D(2) receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus-dystonia (M-D). Fifteen DYT11 mutation carriers (11 clinically affected) and 15 age- and sex-matched controls were studied using (123)I-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas. Multivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects. Our findings are consistent with the theory of reduced dopamine D(2) receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.

  8. Large-Scale Brain Systems in ADHD: Beyond the Prefrontal-Striatal Model

    PubMed Central

    Castellanos, F. Xavier; Proal, Erika

    2012-01-01

    Attention-deficit/hyperactivity disorder (ADHD) has long been thought to reflect dysfunction of prefrontal-striatal circuitry, with involvement of other circuits largely ignored. Recent advances in systems neuroscience-based approaches to brain dysfunction enable the development of models of ADHD pathophysiology that encompass a number of different large-scale “resting state” networks. Here we review progress in delineating large-scale neural systems and illustrate their relevance to ADHD. We relate frontoparietal, dorsal attentional, motor, visual, and default networks to the ADHD functional and structural literature. Insights emerging from mapping intrinsic brain connectivity networks provide a potentially mechanistic framework for understanding aspects of ADHD, such as neuropsychological and behavioral inconsistency, and the possible role of primary visual cortex in attentional dysfunction in the disorder. PMID:22169776

  9. Early white matter abnormalities, progressive brain pathology and motor deficits in a novel knock-in mouse model of Huntington's disease

    PubMed Central

    Jin, Jing; Peng, Qi; Hou, Zhipeng; Jiang, Mali; Wang, Xin; Langseth, Abraham J.; Tao, Michael; Barker, Peter B.; Mori, Susumu; Bergles, Dwight E.; Ross, Christopher A.; Detloff, Peter J.; Zhang, Jiangyang; Duan, Wenzhen

    2015-01-01

    White matter abnormalities have been reported in premanifest Huntington's disease (HD) subjects before overt striatal neuronal loss, but whether the white matter changes represent a necessary step towards further pathology and the underlying mechanism of these changes remains unknown. Here, we characterized a novel knock-in mouse model that expresses mouse HD gene homolog (Hdh) with extended CAG repeat- HdhQ250, which was derived from the selective breeding of HdhQ150 mice. HdhQ250 mice manifest an accelerated and robust phenotype compared with its parent line. HdhQ250 mice exhibit progressive motor deficits, reduction in striatal and cortical volume, accumulation of mutant huntingtin aggregation, decreased levels of DARPP32 and BDNF and altered striatal metabolites. The abnormalities detected in this mouse model are reminiscent of several aspects of human HD. In addition, disturbed myelination was evident in postnatal Day 14 HdhQ250 mouse brain, including reduced levels of myelin regulatory factor and myelin basic protein, and decreased numbers of myelinated axons in the corpus callosum. Thinner myelin sheaths, indicated by increased G-ratio of myelin, were also detected in the corpus callosum of adult HdhQ250 mice. Moreover, proliferation of oligodendrocyte precursor cells is altered by mutant huntingtin both in vitro and in vivo. Our data indicate that this model is suitable for understanding comprehensive pathogenesis of HD in white matter and gray matter as well as developing therapeutics for HD. PMID:25609071

  10. Activation of the right fronto-temporal cortex during maternal facial recognition in young infants.

    PubMed

    Carlsson, Jakob; Lagercrantz, Hugo; Olson, Linus; Printz, Gordana; Bartocci, Marco

    2008-09-01

    Within the first days of life infants can already recognize their mother. This ability is based on several sensory mechanisms and increases during the first year of life, having its most crucial phase between 6 and 9 months when cortical circuits develop. The underlying cortical structures that are involved in this process are still unknown. Herein we report how the prefrontal cortices of healthy 6- to 9-month-old infants react to the sight of their mother's faces compared to that of an unknown female face. Concentrations of oxygenated haemoglobin [HbO2] and deoxygenated haemoglobin [HHb] were measured using near infrared spectroscopy (NIRS) in both fronto-temporal and occipital areas on the right side during the exposure to maternal and unfamiliar faces. The infants exhibited a distinct and significantly higher activation-related haemodynamic response in the right fronto-temporal cortex following exposure to the image of their mother's face, [HbO2] (0.75 micromol/L, p < 0.001), as compared to that of an unknown face (0.25 micromol/L, p < 0.001). Event-related haemodynamic changes, suggesting cortical activation, in response to the sight of human faces were detected in 6- to 9-month old children. The right fronto-temporal cortex appears to be involved in face recognition processes at this age.

  11. Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value

    PubMed Central

    Tai, Lung-Hao; Lee, A. Moses; Benavidez, Nora; Bonci, Antonello; Wilbrecht, Linda

    2012-01-01

    In changing environments animals must adaptively select actions to achieve their goals. In tasks involving goal-directed action selection, striatal neural activity has been shown to represent the value of competing actions. Striatal representations of action value could potentially bias responses toward actions of higher value. However, no study to date has demonstrated the direct impact of distinct striatal pathways in goal-directed action selection. Here we show in mice that transient optogenetic stimulation of dorsal striatal dopamine D1 and D2 receptor-expressing neurons during decision-making introduces opposing biases in the distribution of choices. The effect of stimulation on choice is dependent on recent reward history and mimics an additive change in the action value. While stimulation prior to and during movement initiation produces a robust bias in choice behavior, this bias is significantly diminished when stimulation is delayed after response initiation. Together, our data demonstrate the role of striatal activity in goal-directed action selection. PMID:22902719

  12. Probabilistic classification learning with corrective feedback is associated with in vivo striatal dopamine release in the ventral striatum, while learning without feedback is not

    PubMed Central

    Wilkinson, Leonora; Tai, Yen Foung; Lin, Chia Shu; Lagnado, David Albert; Brooks, David James; Piccini, Paola; Jahanshahi, Marjan

    2014-01-01

    The basal ganglia (BG) mediate certain types of procedural learning, such as probabilistic classification learning on the ‘weather prediction task’ (WPT). Patients with Parkinson's disease (PD), who have BG dysfunction, are impaired at WPT-learning, but it remains unclear what component of the WPT is important for learning to occur. We tested the hypothesis that learning through processing of corrective feedback is the essential component and is associated with release of striatal dopamine. We employed two WPT paradigms, either involving learning via processing of corrective feedback (FB) or in a paired associate manner (PA). To test the prediction that learning on the FB but not PA paradigm would be associated with dopamine release in the striatum, we used serial 11C-raclopride (RAC) positron emission tomography (PET), to investigate striatal dopamine release during FB and PA WPT-learning in healthy individuals. Two groups, FB, (n = 7) and PA (n = 8), underwent RAC PET twice, once while performing the WPT and once during a control task. Based on a region-of-interest approach, striatal RAC-binding potentials reduced by 13–17% in the right ventral striatum when performing the FB compared to control task, indicating release of synaptic dopamine. In contrast, right ventral striatal RAC binding non-significantly increased by 9% during the PA task. While differences between the FB and PA versions of the WPT in effort and decision-making is also relevant, we conclude striatal dopamine is released during FB-based WPT-learning, implicating the striatum and its dopamine connections in mediating learning with FB. PMID:24777947

  13. Activity in the fronto-parietal network indicates numerical inductive reasoning beyond calculation: An fMRI study combined with a cognitive model

    PubMed Central

    Liang, Peipeng; Jia, Xiuqin; Taatgen, Niels A.; Borst, Jelmer P.; Li, Kuncheng

    2016-01-01

    Numerical inductive reasoning refers to the process of identifying and extrapolating the rule involved in numeric materials. It is associated with calculation, and shares the common activation of the fronto-parietal regions with calculation, which suggests that numerical inductive reasoning may correspond to a general calculation process. However, compared with calculation, rule identification is critical and unique to reasoning. Previous studies have established the central role of the fronto-parietal network for relational integration during rule identification in numerical inductive reasoning. The current question of interest is whether numerical inductive reasoning exclusively corresponds to calculation or operates beyond calculation, and whether it is possible to distinguish between them based on the activity pattern in the fronto-parietal network. To directly address this issue, three types of problems were created: numerical inductive reasoning, calculation, and perceptual judgment. Our results showed that the fronto-parietal network was more active in numerical inductive reasoning which requires more exchanges between intermediate representations and long-term declarative knowledge during rule identification. These results survived even after controlling for the covariates of response time and error rate. A computational cognitive model was developed using the cognitive architecture ACT-R to account for the behavioral results and brain activity in the fronto-parietal network. PMID:27193284

  14. Activity in the fronto-parietal network indicates numerical inductive reasoning beyond calculation: An fMRI study combined with a cognitive model.

    PubMed

    Liang, Peipeng; Jia, Xiuqin; Taatgen, Niels A; Borst, Jelmer P; Li, Kuncheng

    2016-05-19

    Numerical inductive reasoning refers to the process of identifying and extrapolating the rule involved in numeric materials. It is associated with calculation, and shares the common activation of the fronto-parietal regions with calculation, which suggests that numerical inductive reasoning may correspond to a general calculation process. However, compared with calculation, rule identification is critical and unique to reasoning. Previous studies have established the central role of the fronto-parietal network for relational integration during rule identification in numerical inductive reasoning. The current question of interest is whether numerical inductive reasoning exclusively corresponds to calculation or operates beyond calculation, and whether it is possible to distinguish between them based on the activity pattern in the fronto-parietal network. To directly address this issue, three types of problems were created: numerical inductive reasoning, calculation, and perceptual judgment. Our results showed that the fronto-parietal network was more active in numerical inductive reasoning which requires more exchanges between intermediate representations and long-term declarative knowledge during rule identification. These results survived even after controlling for the covariates of response time and error rate. A computational cognitive model was developed using the cognitive architecture ACT-R to account for the behavioral results and brain activity in the fronto-parietal network.

  15. Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing.

    PubMed

    Drew, Michael R; Simpson, Eleanor H; Kellendonk, Christoph; Herzberg, William G; Lipatova, Olga; Fairhurst, Stephen; Kandel, Eric R; Malapani, Chara; Balsam, Peter D

    2007-07-18

    The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D2 overexpression is reversed in the adult. Here we report that overexpression of striatal D2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D2 overexpression with doxycycline. These results suggest that early D2 overexpression alters the organization of interval timing circuits and confirms that striatal D2 signaling in the adult regulates motivational process. Moreover, overexpression of D2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.

  16. Early Environmental Enrichment Enhances Abnormal Brain Connectivity in a Rabbit Model of Intrauterine Growth Restriction.

    PubMed

    Illa, Miriam; Brito, Verónica; Pla, Laura; Eixarch, Elisenda; Arbat-Plana, Ariadna; Batallé, Dafnis; Muñoz-Moreno, Emma; Crispi, Fatima; Udina, Esther; Figueras, Francesc; Ginés, Silvia; Gratacós, Eduard

    2017-10-12

    The structural correspondence of neurodevelopmental impairments related to intrauterine growth restriction (IUGR) that persists later in life remains elusive. Moreover, early postnatal stimulation strategies have been proposed to mitigate these effects. Long-term brain connectivity abnormalities in an IUGR rabbit model and the effects of early postnatal environmental enrichment (EE) were explored. IUGR was surgically induced in one horn, whereas the contralateral one produced the controls. Postnatally, a subgroup of IUGR animals was housed in an enriched environment. Functional assessment was performed at the neonatal and long-term periods. At the long-term period, structural brain connectivity was evaluated by means of diffusion-weighted brain magnetic resonance imaging and by histological assessment focused on the hippocampus. IUGR animals displayed poorer functional results and presented altered whole-brain networks and decreased median fractional anisotropy in the hippocampus. Reduced density of dendritic spines and perineuronal nets from hippocampal neurons were also observed. Of note, IUGR animals exposed to enriched environment presented an improvement in terms of both function and structure. IUGR is associated with altered brain connectivity at the global and cellular level. A strategy based on early EE has the potential to restore the neurodevelopmental consequences of IUGR. © 2017 S. Karger AG, Basel.

  17. Structural and functional connectivity underlying grey matter covariance: impact of developmental insult.

    PubMed

    Paquola, Casey; Bennett, Maxwell; Lagopoulos, Jim

    2018-05-15

    Structural covariance networks (SCNs) may offer unique insights into the developmental impact of childhood maltreatment because they are thought to reflect coordinated maturation of distinct grey matter regions. T1-weighted magnetic resonance images were acquired from 121 young people with emerging mental illness. Diffusion weighted and resting state functional imaging was also acquired from a random subset of the participants (n=62). Ten study-specific SCNs were identified using a whole brain grey matter independent component analysis. The effects of childhood maltreatment and age on average grey matter density and the expression of each SCN were calculated. Childhood maltreatment was linked to age-related decreases in grey matter density across a SCN that overlapped with the default mode and fronto-parietal networks. Resting state functional connectivity and structural connectivity were calculated in the study-specific SCN and across the whole brain. Grey matter covariance was significantly correlated with rsFC across the SCN, and rsFC fully mediated the relationship between grey matter covariance and structural connectivity in the non-maltreated group. A unique association of grey matter covariance with structural connectivity was detected amongst individuals with a history of childhood maltreatment. Perturbation of grey matter development across the default mode and fronto-parietal networks following childhood maltreatment may have significant implications for mental well-being, given the networks' roles in self-referential activity. Cross-modal comparisons suggest reduced grey matter following childhood maltreatment could arise from deficient functional activity earlier in life.

  18. The von Economo neurons in fronto-insular and anterior cingulate cortex

    PubMed Central

    Allman, John M.; Tetreault, Nicole A.; Hakeem, Atiya Y.; Manaye, Kebreten F.; Semendeferi, Katerina; Erwin, Joseph M.; Park, Soyoung; Goubert, Virginie; Hof, Patrick R.

    2011-01-01

    The von Economo neurons (VENs) are large bipolar neurons located in fronto-insular cortex (FI) and anterior limbic area (LA) in great apes and humans but not in other primates. Our stereological counts of VENs in FI and LA show them to be more numerous in humans than in apes. In humans, small numbers of VENs appear the 36th week post conception, with numbers increasing during the first eight months after birth. There are significantly more VENs in the right hemisphere in postnatal brains; this may be related to asymmetries in the autonomic nervous system. VENs are also present in elephants and whales and may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI and LA to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of fronto-temporal dementia implies that they are involved in empathy, social awareness, and self-control, consistent with evidence from functional imaging. PMID:21534993

  19. Intrastriatal administration of botulinum neurotoxin A normalizes striatal D2 R binding and reduces striatal D1 R binding in male hemiparkinsonian rats.

    PubMed

    Wedekind, Franziska; Oskamp, Angela; Lang, Markus; Hawlitschka, Alexander; Zilles, Karl; Wree, Andreas; Bauer, Andreas

    2018-01-01

    Cerebral administration of botulinum neurotoxin A (BoNT-A) has been shown to improve disease-specific motor behavior in a rat model of Parkinson disease (PD). Since the dopaminergic system of the basal ganglia fundamentally contributes to motor function, we investigated the impact of BoNT-A on striatal dopamine receptor expression using in vitro and in vivo imaging techniques (positron emission tomography and quantitative autoradiography, respectively). Seventeen male Wistar rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and assigned to two treatment groups 7 weeks later: 10 rats were treated ipsilaterally with an intrastriatal injection of 1 ng BoNT-A, while the others received vehicle (n = 7). All animals were tested for asymmetric motor behavior (apomorphine-induced rotations and forelimb usage) and for striatal expression of dopamine receptors and transporters (D 1 R, D 2 R, and DAT). The striatal D 2 R availability was also quantified longitudinally (1.5, 3, and 5 months after intervention) in 5 animals per treatment group. The 6-OHDA lesion alone induced a unilateral PD-like phenotype and a 13% increase of striatal D 2 R. BoNT-A treatment reduced the asymmetry in both apomorphine-induced rotational behavior and D 2 R expression, with the latter returning to normal values 5 months after intervention. D 1 R expression was significantly reduced, while DAT concentrations showed no alteration. Independent of the treatment, higher interhemispheric symmetry in raclopride binding to D 2 R was generally associated with reduced forelimb akinesia. Our findings indicate that striatal BoNT-A treatment diminishes motor impairment and induces changes in D 1 and D 2 binding site density in the 6-OHDA rat model of PD. © 2017 Wiley Periodicals, Inc.

  20. A small number of abnormal brain connections predicts adult autism spectrum disorder

    PubMed Central

    Yahata, Noriaki; Morimoto, Jun; Hashimoto, Ryuichiro; Lisi, Giuseppe; Shibata, Kazuhisa; Kawakubo, Yuki; Kuwabara, Hitoshi; Kuroda, Miho; Yamada, Takashi; Megumi, Fukuda; Imamizu, Hiroshi; Náñez Sr, José E.; Takahashi, Hidehiko; Okamoto, Yasumasa; Kasai, Kiyoto; Kato, Nobumasa; Sasaki, Yuka; Watanabe, Takeo; Kawato, Mitsuo

    2016-01-01

    Although autism spectrum disorder (ASD) is a serious lifelong condition, its underlying neural mechanism remains unclear. Recently, neuroimaging-based classifiers for ASD and typically developed (TD) individuals were developed to identify the abnormality of functional connections (FCs). Due to over-fitting and interferential effects of varying measurement conditions and demographic distributions, no classifiers have been strictly validated for independent cohorts. Here we overcome these difficulties by developing a novel machine-learning algorithm that identifies a small number of FCs that separates ASD versus TD. The classifier achieves high accuracy for a Japanese discovery cohort and demonstrates a remarkable degree of generalization for two independent validation cohorts in the USA and Japan. The developed ASD classifier does not distinguish individuals with major depressive disorder and attention-deficit hyperactivity disorder from their controls but moderately distinguishes patients with schizophrenia from their controls. The results leave open the viable possibility of exploring neuroimaging-based dimensions quantifying the multiple-disorder spectrum. PMID:27075704

  1. Altered Cortico-Striatal–Thalamic Connectivity in Relation to Spatial Working Memory Capacity in Children with ADHD

    PubMed Central

    Mills, Kathryn L.; Bathula, Deepti; Dias, Taciana G. Costa; Iyer, Swathi P.; Fenesy, Michelle C.; Musser, Erica D.; Stevens, Corinne A.; Thurlow, Bria L.; Carpenter, Samuel D.; Nagel, Bonnie J.; Nigg, Joel T.; Fair, Damien A.

    2012-01-01

    Introduction: Attention deficit hyperactivity disorder (ADHD) captures a heterogeneous group of children, who are characterized by a range of cognitive and behavioral symptoms. Previous resting-state functional connectivity MRI (rs-fcMRI) studies have sought to understand the neural correlates of ADHD by comparing connectivity measurements between those with and without the disorder, focusing primarily on cortical–striatal circuits mediated by the thalamus. To integrate the multiple phenotypic features associated with ADHD and help resolve its heterogeneity, it is helpful to determine how specific circuits relate to unique cognitive domains of the ADHD syndrome. Spatial working memory has been proposed as a key mechanism in the pathophysiology of ADHD. Methods: We correlated the rs-fcMRI of five thalamic regions of interest (ROIs) with spatial span working memory scores in a sample of 67 children aged 7–11 years [ADHD and typically developing children (TDC)]. In an independent dataset, we then examined group differences in thalamo-striatal functional connectivity between 70 ADHD and 89 TDC (7–11 years) from the ADHD-200 dataset. Thalamic ROIs were created based on previous methods that utilize known thalamo-cortical loops and rs-fcMRI to identify functional boundaries in the thalamus. Results/Conclusion: Using these thalamic regions, we found atypical rs-fcMRI between specific thalamic groupings with the basal ganglia. To identify the thalamic connections that relate to spatial working memory in ADHD, only connections identified in both the correlational and comparative analyses were considered. Multiple connections between the thalamus and basal ganglia, particularly between medial and anterior dorsal thalamus and the putamen, were related to spatial working memory and also altered in ADHD. These thalamo-striatal disruptions may be one of multiple atypical neural and cognitive mechanisms that relate to the ADHD clinical phenotype. PMID:22291667

  2. Disrupted resting-state brain network properties in obesity: decreased global and putaminal cortico-striatal network efficiency.

    PubMed

    Baek, K; Morris, L S; Kundu, P; Voon, V

    2017-03-01

    The efficient organization and communication of brain networks underlie cognitive processing and their disruption can lead to pathological behaviours. Few studies have focused on whole-brain networks in obesity and binge eating disorder (BED). Here we used multi-echo resting-state functional magnetic resonance imaging (rsfMRI) along with a data-driven graph theory approach to assess brain network characteristics in obesity and BED. Multi-echo rsfMRI scans were collected from 40 obese subjects (including 20 BED patients) and 40 healthy controls and denoised using multi-echo independent component analysis (ME-ICA). We constructed a whole-brain functional connectivity matrix with normalized correlation coefficients between regional mean blood oxygenation level-dependent (BOLD) signals from 90 brain regions in the Automated Anatomical Labeling atlas. We computed global and regional network properties in the binarized connectivity matrices with an edge density of 5%-25%. We also verified our findings using a separate parcellation, the Harvard-Oxford atlas parcellated into 470 regions. Obese subjects exhibited significantly reduced global and local network efficiency as well as decreased modularity compared with healthy controls, showing disruption in small-world and modular network structures. In regional metrics, the putamen, pallidum and thalamus exhibited significantly decreased nodal degree and efficiency in obese subjects. Obese subjects also showed decreased connectivity of cortico-striatal/cortico-thalamic networks associated with putaminal and cortical motor regions. These findings were significant with ME-ICA with limited group differences observed with conventional denoising or single-echo analysis. Using this data-driven analysis of multi-echo rsfMRI data, we found disruption in global network properties and motor cortico-striatal networks in obesity consistent with habit formation theories. Our findings highlight the role of network properties in

  3. Effects of exercise on depressive behavior and striatal levels of norepinephrine, serotonin and their metabolites in sleep-deprived mice.

    PubMed

    Daniele, Thiago Medeiros da Costa; de Bruin, Pedro Felipe Carvalhedo; Rios, Emiliano Ricardo Vasconcelos; de Bruin, Veralice Meireles Sales

    2017-08-14

    Exercise is a promising adjunctive therapy for depressive behavior, sleep/wake abnormalities, cognition and motor dysfunction. Conversely, sleep deprivation impairs mood, cognition and functional performance. The objective of this study is to evaluate the effects of exercise on anxiety and depressive behavior and striatal levels of norepinephrine (NE), serotonin and its metabolites in mice submitted to 6h of total sleep deprivation (6h-TSD) and 72h of Rapid Eye Movement (REM) sleep deprivation (72h-REMSD). Experimental groups were: (1) mice submitted to 6h-TSD by gentle handling; (2) mice submitted to 72h-REMSD by the flower pot method; (3) exercise (treadmill for 8 weeks); (4) exercise followed by 6h-TSD; (5) exercise followed by 72h-REMSD; (6) control (home cage). Behavioral tests included the Elevated Plus Maze and tail-suspension. NE, serotonin and its metabolites were determined in the striatum using high-performance liquid chromatography (HPLC). Sleep deprivation increased depressive behavior (time of immobilization in the tail-suspension test) and previous exercise hindered it. Sleep deprivation increased striatal NE and previous exercise reduced it. Exercise only was associated with higher levels of serotonin. Furthermore, exercise reduced serotonin turnover associated with sleep deprivation. In brief, previous exercise prevented depressive behavior and reduced striatal high NE levels and serotonin turnover. The present findings confirm the effects of exercise on behavior and neurochemical alterations associated with sleep deprivation. These findings provide new avenues for understanding the mechanisms of exercise. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Integrating Genetic, Psychopharmacological and Neuroimaging Studies: A Converging Methods Approach to Understanding the Neurobiology of ADHD

    ERIC Educational Resources Information Center

    Durston, Sarah; Konrad, Kerstin

    2007-01-01

    This paper aims to illustrate how combining multiple approaches can inform us about the neurobiology of ADHD. Converging evidence from genetic, psychopharmacological and functional neuroimaging studies has implicated dopaminergic fronto-striatal circuitry in ADHD. However, while the observation of converging evidence from multiple vantage points…

  5. Carbachol inhibits basal and forskolin-evoked adult rat striatal acetylcholine release.

    PubMed

    Login, I S

    1997-05-27

    Acutely dissociated adult rat striatal cholinergic neurons labeled with [3H]choline were used in a perifusion system to study muscarinic regulation of basal and forskolin-stimulated fractional [3H]acetylcholine ([3H]-ACh) efflux in the absence of synaptic modulation. Carbachol inhibited basal (40% maximal inhibition; IC50 approximately 0.7 microM) and forskolin-evoked release (75% inhibition; IC50 approximately 0.05 microM) in a concentration-dependent manner, and both carbachol actions were abolished with atropine. Thus, activation of striatal muscarinic cholinergic autoreceptors potently inhibits basal and adenylate cyclase-stimulated ACh release. Tonic inhibitory control of cholinergic activity by functional striatal circuitry apparently prevents detection of these important physiological interactions in slices or in situ.

  6. Abnormal functional global and local brain connectivity in female patients with anorexia nervosa

    PubMed Central

    Geisler, Daniel; Borchardt, Viola; Lord, Anton R.; Boehm, Ilka; Ritschel, Franziska; Zwipp, Johannes; Clas, Sabine; King, Joseph A.; Wolff-Stephan, Silvia; Roessner, Veit; Walter, Martin; Ehrlich, Stefan

    2016-01-01

    Background Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. Methods To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well-established global and local graph metrics across a range of network densities. Results Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. Limitations The present results may be limited to the methods applied during preprocessing and network construction. Conclusion We demonstrated anorexia nervosa–related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger. PMID:26252451

  7. Abnormal functional global and local brain connectivity in female patients with anorexia nervosa.

    PubMed

    Geisler, Daniel; Borchardt, Viola; Lord, Anton R; Boehm, Ilka; Ritschel, Franziska; Zwipp, Johannes; Clas, Sabine; King, Joseph A; Wolff-Stephan, Silvia; Roessner, Veit; Walter, Martin; Ehrlich, Stefan

    2016-01-01

    Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well-established global and local graph metrics across a range of network densities. Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. The present results may be limited to the methods applied during preprocessing and network construction. We demonstrated anorexia nervosa-related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger.

  8. Fronto-orbital reconstruction using polymethyl methacrylate implant

    PubMed Central

    Ghosh, Samiran; Pramanick, Debolina; Ray, Amit; Burman, Richi; Saha, Ashistaru

    2017-01-01

    The objective of this article is to show a case of fronto-orbital reconstruction with prefabricated polymethyl methacrylate prosthesis. A 35-year-old male with alleged history of trauma following road traffic accident 3 months back reported with unaesthetic scar and deformity in right supraorbital region to us. As there was no functional deformity, the management was aimed at correcting the contour and esthetic only. The correction was achieved by overlaying the defect with a polymethyl methacrylate implant fabricated over a three-dimensional stereolithographically printed rapidly prototyped model. Postoperative phase was uneventful and esthetic outcome was satisfactory. The patient after 4-year follow-up reported with no discomfort and definite improvement in facial contour. PMID:29386820

  9. Fronto-orbital reconstruction using polymethyl methacrylate implant.

    PubMed

    Ghosh, Samiran; Pramanick, Debolina; Ray, Amit; Burman, Richi; Saha, Ashistaru

    2017-01-01

    The objective of this article is to show a case of fronto-orbital reconstruction with prefabricated polymethyl methacrylate prosthesis. A 35-year-old male with alleged history of trauma following road traffic accident 3 months back reported with unaesthetic scar and deformity in right supraorbital region to us. As there was no functional deformity, the management was aimed at correcting the contour and esthetic only. The correction was achieved by overlaying the defect with a polymethyl methacrylate implant fabricated over a three-dimensional stereolithographically printed rapidly prototyped model. Postoperative phase was uneventful and esthetic outcome was satisfactory. The patient after 4-year follow-up reported with no discomfort and definite improvement in facial contour.

  10. Melatonin Ameliorates Injury and Specific Responses of Ischemic Striatal Neurons in Rats

    PubMed Central

    Ma, Yuxin; Feng, Qiqi; Ma, Jing; Feng, Zhibo; Zhan, Mali; OuYang, Lisi; Mu, Shuhua; Liu, Bingbing; Jiang, Zhuyi; Jia, Yu; Li, Youlan

    2013-01-01

    Studies have confirmed that middle cerebral artery occlusion (MCAO) causes striatal injury in which oxidative stress is involved in the pathological mechanism. Increasing evidence suggests that melatonin may have a neuroprotective effect on cerebral ischemic damage. This study aimed to examine the morphological changes of different striatal neuron types and the effect of melatonin on striatal injury by MCAO. The results showed that MCAO induced striatum-related dysfunctions of locomotion, coordination, and cognition, which were remarkably relieved with melatonin treatment. MCAO induced severe striatal neuronal apoptosis and loss, which was significantly decreased with melatonin treatment. Within the outer zone of the infarct, the number of Darpp-32+ projection neurons and the densities of dopamine-receptor-1 (D1)+ and dopamine-receptor-2 (D2)+ fibers were reduced; however, both parvalbumin (Parv)+ and choline acetyltransferase (ChAT)+ interneurons were not significantly decreased in number, and neuropeptide Y (NPY)+ and calretinin (Cr)+ interneurons were even increased. With melatonin treatment, the loss of projection neurons and characteristic responses of interneurons were notably attenuated. The present study demonstrates that the projection neurons are rather vulnerable to ischemic damage, whereas the interneurons display resistance and even hyperplasia against injury. In addition, melatonin alleviates striatal dysfunction, neuronal loss, and morphological transformation of interneurons resulting from cerebral ischemia. PMID:23686363

  11. Functional alterations of fronto-limbic circuit and default mode network systems in first-episode, drug-naïve patients with major depressive disorder: A meta-analysis of resting-state fMRI data.

    PubMed

    Zhong, Xue; Pu, Weidan; Yao, Shuqiao

    2016-12-01

    The neurobiological mechanisms of depression are increasingly being explored through resting-state brain imaging studies. However, resting-state fMRI findings have varied, perhaps because of differences between study populations, which included the disorder course and medication use. The aim of our study was to integrate studies of resting-state fMRI and explore the alterations of abnormal brain activity in first-episode, drug-naïve patients with major depressive disorder. Relevant imaging reports in English were searched, retrieved, selected and subjected to analysis by activation likelihood estimation, a coordinate-based meta-analysis technique (final sample, 31 studies). Coordinates extracted from the original reports were assigned to two categories based on effect directionality. Compared with healthy controls, the first-episode, medication-naïve major depressive disorder patients showed decreased brain activity in the dorsolateral prefrontal cortex, superior temporal gyrus, posterior precuneus, and posterior cingulate, as well as in visual areas within the occipital lobe, lingual gyrus, and fusiform gyrus, and increased activity in the putamen and anterior precuneus. Not every study that has reported relevant data met the inclusion criteria. Resting-state functional alterations were located mainly in the fronto-limbic system, including the dorsolateral prefrontal cortex and putamen, and in the default mode network, namely the precuneus and superior/middle temporal gyrus. Abnormal functional alterations of the fronto-limbic circuit and default mode network may be characteristic of first-episode, drug-naïve major depressive disorder patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Age-associated striatal dopaminergic denervation and falls in community-dwelling subjects

    PubMed Central

    Bohnen, Nicolaas I.; Muller, Martijn L. T. M.; Kuwabara, Hiroto; Cham, Rakié; Constantine, Gregory M.; Studenski, Stephanie A.

    2016-01-01

    Older adults have a high prevalence of gait and balance disturbances and falls. Normal aging is associated with significant striatal dopaminergic denervation, which might be a previously unrecognized additional contributor to geriatric falls. This study investigated the relationship between the severity of age-associated striatal dopaminergic denervation (AASDD) and falls in community-dwelling subjects. Community-dwelling subjects who did not have a clinical diagnosis to explain falls (n = 77: 43 female, 34 male; mean age 61.4 +/− 16.4; range 20–85) completed clinical assessment and brain dopamine transporter (DAT) [11C]beta-CFT (2-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane) positron emission tomography imaging followed by 6 months of prospective fall monitoring using diaries. Results showed a significant inverse relationship between striatal DAT activity and age (r = −0.82, p < 0.001). A total of 26 subjects (33.8%) reported at least one fall, with 5 subjects (6.5%) reporting two or more falls. While no significant difference was noted in striatal DAT activity between nonfallers (n = 51) and fallers (n = 26; f = 0.02, not significant), striatal DAT activity was modestly reduced in the small subgroup of recurrent fallers compared with the other subjects (f = 5.07, p < 0.05). Findings indicate that AASDD does not explain isolated self-reported falls in community-dwelling subjects. However, it may be a contributing factor in the small subgroup of subjects with recurrent falls. PMID:20157861

  13. Neuroticism is linked to microstructural left-right asymmetry of fronto-limbic fibre tracts in adolescents with opposite effects in boys and girls.

    PubMed

    Madsen, Kathrine Skak; Jernigan, Terry L; Vestergaard, Martin; Mortensen, Erik Lykke; Baaré, William F C

    2018-06-01

    Neuroticism is a fundamental personality trait that reflects a tendency to experience heightened negative affect and susceptibility to stress. Negative emotionality has been associated with fronto-limbic brain structures and connecting fibre tracts. The major fibre tracts connecting the frontal and limbic brain regions are the cingulum bundle and uncinate fasciculus. We previously found that healthy adults with higher neuroticism scores had decreased left relative to right fractional anisotropy (FA) of the cingulum. Both cingulum and uncinate fasciculus FA increases throughout childhood and into early adulthood. Since adolescence is associated with an increased incidence of anxiety and mood disorders, for which neuroticism is a known risk factor, the question arises whether the association between neuroticism and fronto-limbic white matter microstructure asymmetry is already present in children and adolescents or whether such relationship emerges during this age period. To address this question, we assessed 72 typically-developing 10-to-15 year-olds with diffusion-weighted imaging on a 3 T magnetic resonance scanner. Neuroticism was assessed with the Junior Eysenck Personality Questionnaire. FA and parallel and perpendicular diffusivity measures were extracted for cingulum, uncinate fasciculus as well as the white matter underlying the ventromedial prefrontal cortex. Higher neuroticism scores were associated with decreased left relative to right cingulum FA in boys, while in girls, higher neuroticism scores were associated with increased left relative to right cingulum and ventromedial prefrontal white matter FA, indicating that there are sex differences in the neural correlates of neuroticism. Our findings suggest that the link between neuroticism and frontal-limbic white matter microstructure asymmetry likely predates early adolescence. Future studies need to elucidate the significance of the observed sex differences in the neural correlates of neuroticism

  14. Abnormalities of Intrinsic Functional Connectivity in Autism Spectrum Disorders

    PubMed Central

    Monk, Christopher S.; Peltier, Scott J.; Wiggins, Jillian Lee; Weng, Shih-Jen; Carrasco, Melisa; Risi, Susan; Lord, Catherine

    2009-01-01

    Autism spectrum disorders (ASD) impact social functioning and communication, and individuals with these disorders often have restrictive and repetitive behaviors. Accumulating data indicate that ASD is associated with alterations of neural circuitry. Functional MRI (FMRI) studies have focused on connectivity in the context of psychological tasks. However, even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic or resting connectivity. Notably, the default network, which includes the posterior cingulate cortex, retro-splenial, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus, is strongly active when there is no task. Altered intrinsic connectivity within the default network may underlie offline processing that may actuate ASD impairments. Using FMRI, we sought to evaluate intrinsic connectivity within the default network in ASD. Relative to controls, the ASD group showed weaker connectivity between the posterior cingulate cortex and superior frontal gyrus and stronger connectivity between the posterior cingulate cortex and both the right temporal lobe and right parahippocampal gyrus. Moreover, poorer social functioning in the ASD group was correlated with weaker connectivity between the posterior cingulate cortex and the superior frontal gyrus. In addition, more severe restricted and repetitive behaviors in ASD were correlated with stronger connectivity between the posterior cingulate cortex and right parahippocampal gyrus. These findings indicate that ASD subjects show altered intrinsic connectivity within the default network, and connectivity between these structures is associated with specific ASD symptoms. PMID:19409498

  15. Brief Report: Alterations in Cerebral Blood Flow as Assessed by PET/CT in Adults with Autism Spectrum Disorder with Normal IQ

    ERIC Educational Resources Information Center

    Pagani, Marco; Manouilenko, Irina; Stone-Elander, Sharon; Odh, Richard; Salmaso, Dario; Hatherly, Robert; Brolin, Fredrik; Jacobsson, Hans; Larsson, Stig A.; Bejerot, Susanne

    2012-01-01

    Specific biological markers for Autism Spectrum Disorder (ASD) have not yet been established. Functional studies have shown abnormalities in the anatomo-functional connectivity of the limbic-striatal "social" brain. This study aimed to investigate regional cerebral blood flow (rCBF) at rest. Thirteen patients with ASD of normal intelligence and…

  16. Frontostriatal anatomical connections predict age- and difficulty-related differences in reinforcement learning.

    PubMed

    van de Vijver, Irene; Ridderinkhof, K Richard; Harsay, Helga; Reneman, Liesbeth; Cavanagh, James F; Buitenweg, Jessika I V; Cohen, Michael X

    2016-10-01

    Reinforcement learning (RL) is supported by a network of striatal and frontal cortical structures that are connected through white-matter fiber bundles. With age, the integrity of these white-matter connections declines. The role of structural frontostriatal connectivity in individual and age-related differences in RL is unclear, although local white-matter density and diffusivity have been linked to individual differences in RL. Here we show that frontostriatal tract counts in young human adults (aged 18-28), as assessed noninvasively with diffusion-weighted magnetic resonance imaging and probabilistic tractography, positively predicted individual differences in RL when learning was difficult (70% valid feedback). In older adults (aged 63-87), in contrast, learning under both easy (90% valid feedback) and difficult conditions was predicted by tract counts in the same frontostriatal network. Furthermore, network-level analyses showed a double dissociation between the task-relevant networks in young and older adults, suggesting that older adults relied on different frontostriatal networks than young adults to obtain the same task performance. These results highlight the importance of successful information integration across striatal and frontal regions during RL, especially with variable outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Fronto-temporal white matter connectivity predicts reversal learning errors

    PubMed Central

    Alm, Kylie H.; Rolheiser, Tyler; Mohamed, Feroze B.; Olson, Ingrid R.

    2015-01-01

    Each day, we make hundreds of decisions. In some instances, these decisions are guided by our innate needs; in other instances they are guided by memory. Probabilistic reversal learning tasks exemplify the close relationship between decision making and memory, as subjects are exposed to repeated pairings of a stimulus choice with a reward or punishment outcome. After stimulus–outcome associations have been learned, the associated reward contingencies are reversed, and participants are not immediately aware of this reversal. Individual differences in the tendency to choose the previously rewarded stimulus reveal differences in the tendency to make poorly considered, inflexible choices. Lesion studies have strongly linked reversal learning performance to the functioning of the orbitofrontal cortex, the hippocampus, and in some instances, the amygdala. Here, we asked whether individual differences in the microstructure of the uncinate fasciculus, a white matter tract that connects anterior and medial temporal lobe regions to the orbitofrontal cortex, predict reversal learning performance. Diffusion tensor imaging and behavioral paradigms were used to examine this relationship in 33 healthy young adults. The results of tractography revealed a significant negative relationship between reversal learning performance and uncinate axial diffusivity, but no such relationship was demonstrated in a control tract, the inferior longitudinal fasciculus. Our findings suggest that the uncinate might serve to integrate associations stored in the anterior and medial temporal lobes with expectations about expected value based on feedback history, computed in the orbitofrontal cortex. PMID:26150776

  18. Diminished fronto-limbic functional connectivity in child sexual offenders.

    PubMed

    Kneer, Jonas; Borchardt, Viola; Kärgel, Christian; Sinke, Christopher; Massau, Claudia; Tenbergen, Gilian; Ponseti, Jorge; Walter, Henrik; Beier, Klaus M; Schiffer, Boris; Schiltz, Kolja; Walter, Martin; Kruger, Tillmann H C

    2018-02-22

    Child sexual abuse and neglect have been related to an increased risk for the development of a wide range of behavioral, psychological, and sexual problems and increased rates of suicidal behavior. Contrary to the large amount of research focusing on the negative mental health consequences of child sexual abuse, very little is known about the characteristics of child sexual offenders and the neuronal underpinnings contributing to child sexual offending. This study investigates differences in resting state functional connectivity (rs-FC) between non-pedophilic child sexual offenders (N = 20; CSO-P) and matched healthy controls (N = 20; HC) using a seed-based approach. The focus of this investigation of rs-FC in CSO-P was put on prefrontal and limbic regions highly relevant for emotional and behavioral processing. Results revealed a significant reduction of rs-FC between the right centromedial amygdala and the left dorsolateral prefrontal cortex in child sexual offenders compared to controls. Given that, in the healthy brain, there is a strong top-down inhibitory control of prefrontal over limbic structures, these results suggest that diminished rs-FC between the amygdala and the dorsolateral prefrontal cortex and may foster sexual deviance and sexual offending. A profound understanding of these concepts should contribute to a better understanding of the occurrence of child sexual offending, as well as further development of more differentiated and effective interventions. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Dopamine Is Differentially Encoded by D2 Receptors in Striatal Subregions.

    PubMed

    Engeln, Michel; Fox, Megan E; Lobo, Mary Kay

    2018-05-02

    Striatal dopamine signaling is differentially regulated along the dorso-ventral axis, but how these differences are encoded by dopamine receptors is unknown. In this issue of Neuron, Marcott et al. (2018) show that dopamine activates D2 receptors in regionally distinct ways and dissect the underlying mechanisms behind striatal D2 heterogeneity. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Control networks in paediatric Tourette syndrome show immature and anomalous patterns of functional connectivity

    PubMed Central

    Fair, Damien A.; Dosenbach, Nico U. F.; Cohen, Alexander L.; Miezin, Francis M.; Petersen, Steven E.; Schlaggar, Bradley L.

    2009-01-01

    Tourette syndrome (TS) is a developmental disorder characterized by unwanted, repetitive behaviours that manifest as stereotyped movements and vocalizations called ‘tics’. Operating under the hypothesis that the brain's control systems may be impaired in TS, we measured resting-state functional connectivity MRI (rs-fcMRI) between 39 previously defined putative control regions in 33 adolescents with TS. We were particularly interested in the effect of TS on two of the brain's task control networks—a fronto-parietal network likely involved in more rapid, adaptive online control, and a cingulo-opercular network apparently important for set-maintenance. To examine the relative maturity of connections in the Tourette subjects, functional connections that changed significantly over typical development were examined. Age curves were created for each functional connection charting correlation coefficients over age for 210 healthy people aged 7–31 years, and the TS group correlation coefficients were compared to these curves. Many of these connections were significantly less ‘mature’ than expected in the TS group. This immaturity was true not only for functional connections that grow stronger with age, but also for those that diminish in strength with age. To explore other differences between Tourette and typically developing subjects further, we performed a second analysis in which the TS group was directly compared to an age-matched, movement-matched group of typically developing, unaffected adolescents. A number of functional connections were found to differ between the two groups. For these identified connections, a large number of connectional differences were found where the TS group value was out of range compared to typical developmental age curves. These anomalous connections were primarily found in the fronto-parietal network, thought to be important for online adaptive control. These results suggest that in adolescents with TS, immature functional

  1. Left hemisphere structural connectivity abnormality in pediatric hydrocephalus patients following surgery.

    PubMed

    Yuan, Weihong; Meller, Artur; Shimony, Joshua S; Nash, Tiffany; Jones, Blaise V; Holland, Scott K; Altaye, Mekibib; Barnard, Holly; Phillips, Jannel; Powell, Stephanie; McKinstry, Robert C; Limbrick, David D; Rajagopal, Akila; Mangano, Francesco T

    2016-01-01

    -II)]. However, one global network measure (global efficiency) and two regional network measures in the insula (local efficiency and between centrality) tested at 3-month post-surgery were found to correlate with GAC score tested at 12-month post-surgery with statistical significance (all p  < 0.05, corrected). Our data showed that the structural connectivity analysis based on DTI and graph theory was sensitive in detecting both global and regional network abnormality when the analysis was conducted in the left hemisphere only. This approach provides a new avenue enabling the application of advanced neuroimaging analysis methods in quantifying brain damage in children with hydrocephalus surgically treated with programmable shunts.

  2. Dynamic Amygdala Influences on the Fronto-Striatal Brain Mechanisms Involved in Self-Control of Impulsive Desires.

    PubMed

    Krämer, Bernd; Gruber, Oliver

    2015-01-01

    Human decisions are guided by a variety of motivational factors, such as immediate rewards, long-term goals, and emotions. We used functional magnetic resonance imaging to investigate the dynamic functional interactions between the amygdala, the nucleus accumbens, and the prefrontal cortex that underlie the influences of emotions, desires, and rationality on human decisions. We found that increased functional connectivity between the amygdala and the nucleus accumbens facilitated the approach of an immediate reward in the presence of emotional information. Further, increased functional interactions of the anteroventral prefrontal cortex with the amygdala and the nucleus accumbens were associated with rational decisions in dilemma situations. These findings support previous animal studies by demonstrating that emotional signals from the amygdala and goal-oriented information from prefrontal cortices interface in the nucleus accumbens to guide human decisions and reward-directed actions. © 2015 S. Karger AG, Basel.

  3. Abnormal cerebral functional connectivity in esophageal cancer patients with theory of mind deficits in resting state.

    PubMed

    Cao, Yin; Xiang, JianBo; Qian, Nong; Sun, SuPing; Hu, LiJun; Yuan, YongGui

    2015-01-01

    To explore the function of the default mode network (DMN) in the psychopathological mechanisms of theory of mind deficits in patients with an esophageal cancer concomitant with depression in resting the state. Twenty-five cases of esophageal cancer with theory of mind deficits (test group) that meet the diagnostic criteria of esophageal cancer and neuropsychological tests, including Beck depression inventory, reading the mind in the eyes, and Faux pas, were included, Another 25 cases of esophageal cancer patients but without theory of mind deficits (control group) were enrolled. Each patient completed a resting-state functional magnetic resonance imaging. The functional connectivity intensities within the cerebral regions in the DMN of all the enrolled patients were analyzed. The results of each group were compared. The functional connectivity of the bilateral prefrontal central region with the precuneus, bilateral posterior cingulate gyrus and bilateral ventral anterior cingulate gyrus in the patients of the test group were all reduced significantly (P < 0.05). In the resting state, the functional connectivity is abnormal in the cerebral regions in the DMN of esophageal cancer patients with theory of mind deficits. The theory of mind deficits might have an important function in the pathogenesis of esophageal cancer.

  4. Estimates of projection overlap and zones of convergence within frontal-striatal circuits.

    PubMed

    Averbeck, Bruno B; Lehman, Julia; Jacobson, Moriah; Haber, Suzanne N

    2014-07-16

    Frontal-striatal circuits underlie important decision processes, and pathology in these circuits is implicated in many psychiatric disorders. Studies have shown a topographic organization of cortical projections into the striatum. However, work has also shown that there is considerable overlap in the striatal projection zones of nearby cortical regions. To characterize this in detail, we quantified the complete striatal projection zones from 34 cortical injection locations in rhesus monkeys. We first fit a statistical model that showed that the projection zone of a cortical injection site could be predicted with considerable accuracy using a cross-validated model estimated on only the other injection sites. We then examined the fraction of overlap in striatal projection zones as a function of distance between cortical injection sites, and found that there was a highly regular relationship. Specifically, nearby cortical locations had as much as 80% overlap, and the amount of overlap decayed exponentially as a function of distance between the cortical injection sites. Finally, we found that some portions of the striatum received inputs from all the prefrontal regions, making these striatal zones candidates as information-processing hubs. Thus, the striatum is a site of convergence that allows integration of information spread across diverse prefrontal cortical areas. Copyright © 2014 the authors 0270-6474/14/339497-09$15.00/0.

  5. Elevated striatal γ-aminobutyric acid in youth with major depressive disorder.

    PubMed

    Bradley, Kailyn A; Alonso, Carmen M; Mehra, Lushna M; Xu, Junqian; Gabbay, Vilma

    2018-06-08

    Alterations in γ-aminobutyric acid (GABA) have been hypothesized to play a role in the pathogenesis of psychiatric illness. Our previous work has specifically linked anterior cingulate cortex (ACC) GABA deficits with anhedonia in youth with major depressive disorder (MDD). As anhedonia reflects alterations within the reward circuitry, we sought to extend this investigation and examine GABA levels in another key reward-related region, the striatum, in the same adolescent population. Thirty-six youth [20 with MDD and 16 healthy controls; (HC)], ages 12 to 21 years old, underwent J-edited proton magnetic resonance spectroscopy ( 1 H MRS) whereby GABA levels were measured in striatal and ACC voxels. GABA levels were compared between groups and between voxel positions and were examined in relation to clinical symptomatology, such as depression severity, anhedonia, anxiety, and suicidality. Depressed youth had unexpectedly higher GABA levels in the striatum compared to HC. In both depressed and healthy youth, GABA levels were higher in the striatum than in the ACC, while the differences in depressed youth were greater. Moreover, in depressed youth, higher striatal GABA above the mean of HCs was correlated with lower ACC GABA below the mean of HCs. Striatal GABA was not correlated with clinical symptomatology in this small sample. Together, these findings suggest that higher striatal GABA levels may serve some compensatory function as a result of lower ACC GABA in depressed adolescents. It is also possible that, like lower ACC GABA, higher striatal GABA might simply be another pathological feature of adolescent depression. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Episodic Memory Encoding Interferes with Reward Learning and Decreases Striatal Prediction Errors

    PubMed Central

    Braun, Erin Kendall; Daw, Nathaniel D.

    2014-01-01

    Learning is essential for adaptive decision making. The striatum and its dopaminergic inputs are known to support incremental reward-based learning, while the hippocampus is known to support encoding of single events (episodic memory). Although traditionally studied separately, in even simple experiences, these two types of learning are likely to co-occur and may interact. Here we sought to understand the nature of this interaction by examining how incremental reward learning is related to concurrent episodic memory encoding. During the experiment, human participants made choices between two options (colored squares), each associated with a drifting probability of reward, with the goal of earning as much money as possible. Incidental, trial-unique object pictures, unrelated to the choice, were overlaid on each option. The next day, participants were given a surprise memory test for these pictures. We found that better episodic memory was related to a decreased influence of recent reward experience on choice, both within and across participants. fMRI analyses further revealed that during learning the canonical striatal reward prediction error signal was significantly weaker when episodic memory was stronger. This decrease in reward prediction error signals in the striatum was associated with enhanced functional connectivity between the hippocampus and striatum at the time of choice. Our results suggest a mechanism by which memory encoding may compete for striatal processing and provide insight into how interactions between different forms of learning guide reward-based decision making. PMID:25378157

  7. Dopamine D4 Receptor Gene Associated with the Frontal-Striatal-Cerebellar Loop in Children with ADHD: A Resting-State fMRI Study.

    PubMed

    Qian, Andan; Wang, Xin; Liu, Huiru; Tao, Jiejie; Zhou, Jiejie; Ye, Qiong; Li, Jiance; Yang, Chuang; Cheng, Jingliang; Zhao, Ke; Wang, Meihao

    2018-06-01

    Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.

  8. Reward-Related Dorsal Striatal Activity Differences between Former and Current Cocaine Dependent Individuals during an Interactive Competitive Game

    PubMed Central

    Hyatt, Christopher J.; Assaf, Michal; Muska, Christine E.; Rosen, Rivkah I.; Thomas, Andre D.; Johnson, Matthew R.; Hylton, Jennifer L.; Andrews, Melissa M.; Reynolds, Brady A.; Krystal, John H.; Potenza, Marc N.; Pearlson, Godfrey D.

    2012-01-01

    Cocaine addiction is characterized by impulsivity, impaired social relationships, and abnormal mesocorticolimbic reward processing, but their interrelationships relative to stages of cocaine addiction are unclear. We assessed blood-oxygenation-level dependent (BOLD) signal in ventral and dorsal striatum during functional magnetic resonance imaging (fMRI) in current (CCD; n = 30) and former (FCD; n = 28) cocaine dependent subjects as well as healthy control (HC; n = 31) subjects while playing an interactive competitive Domino game involving risk-taking and reward/punishment processing. Out-of-scanner impulsivity-related measures were also collected. Although both FCD and CCD subjects scored significantly higher on impulsivity-related measures than did HC subjects, only FCD subjects had differences in striatal activation, specifically showing hypoactivation during their response to gains versus losses in right dorsal caudate, a brain region linked to habituation, cocaine craving and addiction maintenance. Right caudate activity in FCD subjects also correlated negatively with impulsivity-related measures of self-reported compulsivity and sensitivity to reward. These findings suggest that remitted cocaine dependence is associated with striatal dysfunction during social reward processing in a manner linked to compulsivity and reward sensitivity measures. Future research should investigate the extent to which such differences might reflect underlying vulnerabilities linked to cocaine-using propensities (e.g., relapses). PMID:22606228

  9. Abnormal early dynamic individual patterns of functional networks in low gamma band for depression recognition.

    PubMed

    Bi, Kun; Chattun, Mahammad Ridwan; Liu, Xiaoxue; Wang, Qiang; Tian, Shui; Zhang, Siqi; Lu, Qing; Yao, Zhijian

    2018-06-13

    The functional networks are associated with emotional processing in depression. The mapping of dynamic spatio-temporal brain networks is used to explore individual performance during early negative emotional processing. However, the dysfunctions of functional networks in low gamma band and their discriminative potentialities during early period of emotional face processing remain to be explored. Functional brain networks were constructed from the MEG recordings of 54 depressed patients and 54 controls in low gamma band (30-48 Hz). Dynamic connectivity regression (DCR) algorithm analyzed the individual change points of time series in response to emotional stimuli and constructed individualized spatio-temporal patterns. The nodal characteristics of patterns were calculated and fed into support vector machine (SVM). Performance of the classification algorithm in low gamma band was validated by dynamic topological characteristics of individual patterns in comparison to alpha and beta band. The best discrimination accuracy of individual spatio-temporal patterns was 91.01% in low gamma band. Individual temporal patterns had better results compared to group-averaged temporal patterns in all bands. The most important discriminative networks included affective network (AN) and fronto-parietal network (FPN) in low gamma band. The sample size is relatively small. High gamma band was not considered. The abnormal dynamic functional networks in low gamma band during early emotion processing enabled depression recognition. The individual information processing is crucial in the discovery of abnormal spatio-temporal patterns in depression during early negative emotional processing. Individual spatio-temporal patterns may reflect the real dynamic function of subjects while group-averaged data may neglect some individual information. Copyright © 2018. Published by Elsevier B.V.

  10. Fronto-Parietal gray matter and white matter efficiency differentially predict intelligence in males and females.

    PubMed

    Ryman, Sephira G; Yeo, Ronald A; Witkiewitz, Katie; Vakhtin, Andrei A; van den Heuvel, Martijn; de Reus, Marcel; Flores, Ranee A; Wertz, Christopher R; Jung, Rex E

    2016-11-01

    While there are minimal sex differences in overall intelligence, males, on average, have larger total brain volume and corresponding regional brain volumes compared to females, measures that are consistently related to intelligence. Limited research has examined which other brain characteristics may differentially contribute to intelligence in females to facilitate equal performance on intelligence measures. Recent reports of sex differences in the neural characteristics of the brain further highlight the need to differentiate how the structural neural characteristics relate to intellectual ability in males and females. The current study utilized a graph network approach in conjunction with structural equation modeling to examine potential sex differences in the relationship between white matter efficiency, fronto-parietal gray matter volume, and general cognitive ability (GCA). Participants were healthy adults (n = 244) who completed a battery of cognitive testing and underwent structural neuroimaging. Results indicated that in males, a latent factor of fronto-parietal gray matter was significantly related to GCA when controlling for total gray matter volume. In females, white matter efficiency and total gray matter volume were significantly related to GCA, with no specificity of the fronto-parietal gray matter factor over and above total gray matter volume. This work highlights that different neural characteristics across males and females may contribute to performance on intelligence measures. Hum Brain Mapp 37:4006-4016, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

    PubMed

    Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

    2010-02-22

    Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

  12. Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

    PubMed Central

    Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Bianco, Luciana Lo; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

    2010-01-01

    Background Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway. PMID:20179754

  13. Geldanamycin attenuates 3-nitropropionic acid-induced apoptosis and JNK activation through the expression of HSP 70 in striatal cells

    PubMed Central

    CHOI, YONG-JOON; KIM, NAM HO; LIM, MAN SUP; LEE, HEE JAE; KIM, SUNG SOO; CHUN, WANJOO

    2014-01-01

    Although selective striatal cell death is a characteristic hallmark in the pathogenesis of Huntington’s disease (HD), the underlying mechanism of striatal susceptibility remains to be clarified. Heat shock proteins (HSPs) have been reported to suppress the aggregate formation of mutant huntingtin and concurrent striatal cell death. In a previous study, we observed that heat shock transcription factor 1 (HSF1), a major transcription factor of HSPs, significantly attenuated 3-nitropropionic acid (3NP)-induced reactive oxygen species (ROS) production and apoptosis through the expression of HSP 70 in striatal cells. To investigate the differential roles of HSPs in 3NP-induced striatal cell death, the effect of geldanamycin (GA), an HSP 90 inhibitor, was examined in 3NP-stimulated striatal cells. GA significantly attenuated 3NP-induced striatal apoptosis and ROS production with an increased expression of HSP 70. Triptolide (TL), an HSP 70 inhibitor, abolished GA-mediated protective effects in 3NP-stimulated striatal cells. To understand the underlying mechanism by which GA-mediated HSP 70 protects striatal cells against 3NP stimulation, the involvement of various signaling pathways was examined. GA significantly attenuated 3NP-induced c-Jun N-terminal kinase (JNK) phosphorylation and subsequent c-Jun phosphorylation in striatal cells. Taken together, the present study demonstrated that GA exhibits protective properties against 3NP-induced apoptosis and JNK activation via the induction of HSP 70 in striatal cells, suggesting that expression of HSP 70 may be a valuable therapeutic target in the treatment of HD. PMID:24756698

  14. Recognition Memory Span in Autopsy-Confirmed Dementia with Lewy Bodies and Alzheimer’s Disease

    PubMed Central

    Salmon, David P.; Heindel, William C.; Hamilton, Joanne M.; Filoteo, J. Vincent; Cidambi, Varun; Hansen, Lawrence A.; Masliah, Eliezer; Galasko, Douglas

    2016-01-01

    Evidence from patients with amnesia suggests that recognition memory span tasks engage both long-term memory (i.e., secondary memory) processes mediated by the diencephalic-medial temporal lobe memory system and working memory processes mediated by fronto-striatal systems. Thus, the recognition memory span task may be particularly effective for detecting memory deficits in disorders that disrupt both memory systems. The presence of unique pathology in fronto-striatal circuits in Dementia with Lewy Bodies (DLB) compared to AD suggests that performance on the recognition memory span task might be differentially affected in the two disorders even though they have quantitatively similar deficits in secondary memory. In the present study, patients with autopsy-confirmed DLB or AD, and normal control (NC) participants, were tested on separate recognition memory span tasks that required them to retain increasing amounts of verbal, spatial, or visual object (i.e., faces) information across trials. Results showed that recognition memory spans for verbal and spatial stimuli, but not face stimuli, were lower in patients with DLB than in those with AD, and more impaired relative to NC performance. This was despite similar deficits in the two patient groups on independent measures of secondary memory such as the total number of words recalled from Long-Term Storage on the Buschke Selective Reminding Test. The disproportionate vulnerability of recognition memory span task performance in DLB compared to AD may be due to greater fronto-striatal involvement in DLB and a corresponding decrement in cooperative interaction between working memory and secondary memory processes. Assessment of recognition memory span may contribute to the ability to distinguish between DLB and AD relatively early in the course of disease. PMID:26184443

  15. Increasing cyanosis early after cavopulmonary connection caused by abnormal systemic venous channels.

    PubMed

    Gatzoulis, M A; Shinebourne, E A; Redington, A N; Rigby, M L; Ho, S Y; Shore, D F

    1995-02-01

    To show that abnormal systemic venous channels in patients who undergo cavopulmonary anastomoses can become manifest and haemodynamically important only after surgery despite detailed preoperative investigation. Descriptive study of patients fulfilling the above criteria selected from hospital records over the past three years. A tertiary referral centre. Of the three cases identified, two were isomeric, one with left atrial isomerism and hemiazygos continuation of the inferior vena cava who underwent bilateral bidirectional Glenn anastomoses and one with right isomerism who underwent total cavopulmonary anastomosis. Case 3 had absent left atrioventricular connection with a hypoplastic left lung and underwent a classic right Glenn procedure. All three cases presented with progressive cyanosis in the early postoperative period. Postoperative angiography in case 1 showed a remnant of a left inferior vena cava draining to the atrium to have become grossly dilated causing cyanosis, which resolved after redirection of this vessel and of the hepatic veins into the right pulmonary artery with an intra-atrial baffle. Cyanosis in case 2 was caused by intra-hepatic shunting to a hepatic vein draining to the left of the intra-atrial baffle. The diagnosis was made at necropsy, being overlooked on postoperative angiography. Repeat angiography in case 3 showed progressive dilatation of a small left superior vena cava to coronary sinus. Test occlusion with a view to embolisation revealed hitherto an undemonstrated hemiazygos continuation of inferior caval to brachiocephalic vein. The patient underwent surgical ligation of these two venous channels. Despite appropriate investigation some "abnormal" venous pathways manifest themselves, dilate, and become haemodynamically important only after surgical cavopulmonary anastomoses. In the presence of early postoperative cyanosis "new" systemic venous collateral channels should be considered as a possible cause, which may require

  16. Exercise training reinstates cortico-cortical sensorimotor functional connectivity following striatal lesioning: Development and application of a subregional-level analytic toolbox for perfusion autoradiographs of the rat brain

    NASA Astrophysics Data System (ADS)

    Peng, Yu-Hao; Heintz, Ryan; Wang, Zhuo; Guo, Yumei; Myers, Kalisa; Scremin, Oscar; Maarek, Jean-Michel; Holschneider, Daniel

    2014-12-01

    Current rodent connectome projects are revealing brain structural connectivity with unprecedented resolution and completeness. How subregional structural connectivity relates to subregional functional interactions is an emerging research topic. We describe a method for standardized, mesoscopic-level data sampling from autoradiographic coronal sections of the rat brain, and for correlation-based analysis and intuitive display of cortico-cortical functional connectivity (FC) on a flattened cortical map. A graphic user interface “Cx-2D” allows for the display of significant correlations of individual regions-of-interest, as well as graph theoretical metrics across the cortex. Cx-2D was tested on an autoradiographic data set of cerebral blood flow (CBF) of rats that had undergone bilateral striatal lesions, followed by 4 weeks of aerobic exercise training or no exercise. Effects of lesioning and exercise on cortico-cortical FC were examined during a locomotor challenge in this rat model of Parkinsonism. Subregional FC analysis revealed a rich functional reorganization of the brain in response to lesioning and exercise that was not apparent in a standard analysis focused on CBF of isolated brain regions. Lesioned rats showed diminished degree centrality of lateral primary motor cortex, as well as neighboring somatosensory cortex--changes that were substantially reversed in lesioned rats following exercise training. Seed analysis revealed that exercise increased positive correlations in motor and somatosensory cortex, with little effect in non-sensorimotor regions such as visual, auditory, and piriform cortex. The current analysis revealed that exercise partially reinstated sensorimotor FC lost following dopaminergic deafferentation. Cx-2D allows for standardized data sampling from images of brain slices, as well as analysis and display of cortico-cortical FC in the rat cerebral cortex with potential applications in a variety of autoradiographic and histologic

  17. Right hemisphere dominance during spatial selective attention and target detection occurs outside the dorsal fronto-parietal network

    PubMed Central

    Shulman, Gordon L.; Pope, Daniel L. W.; Astafiev, Serguei V.; McAvoy, Mark P.; Snyder, Abraham Z.; Corbetta, Maurizio

    2010-01-01

    Spatial selective attention is widely considered to be right hemisphere dominant. Previous functional magnetic resonance imaging (fMRI) studies, however, have reported bilateral blood-oxygenation-level-dependent (BOLD) responses in dorsal fronto-parietal regions during anticipatory shifts of attention to a location (Kastner et al., 1999; Corbetta et al., 2000; Hopfinger et al., 2000). Right-lateralized activity has mainly been reported in ventral fronto-parietal regions for shifts of attention to an unattended target stimulus (Arrington et al., 2000; Corbetta et al., 2000). However, clear conclusions cannot be drawn from these studies because hemispheric asymmetries were not assessed using direct voxel-wise comparisons of activity in left and right hemispheres. Here, we used this technique to measure hemispheric asymmetries during shifts of spatial attention evoked by a peripheral cue stimulus and during target detection at the cued location. Stimulus-driven shifts of spatial attention in both visual fields evoked right-hemisphere dominant activity in temporo-parietal junction (TPJ). Target detection at the attended location produced a more widespread right hemisphere dominance in frontal, parietal, and temporal cortex, including the TPJ region asymmetrically activated during shifts of spatial attention. However, hemispheric asymmetries were not observed during either shifts of attention or target detection in the dorsal fronto-parietal regions (anterior precuneus, medial intraparietal sulcus, frontal eye fields) that showed the most robust activations for shifts of attention. Therefore, right hemisphere dominance during stimulus-driven shifts of spatial attention and target detection reflects asymmetries in cortical regions that are largely distinct from the dorsal fronto-parietal network involved in the control of selective attention. PMID:20219998

  18. Atomoxetine restores the response inhibition network in Parkinson’s disease

    PubMed Central

    Rae, Charlotte L.; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E.; Jones, P. Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

    2016-01-01

    stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson’s disease. PMID:27343257

  19. Sex-related differences in striatal dopaminergic system after traumatic brain injury.

    PubMed

    Xu, Xiupeng; Cao, Shengwu; Chao, Honglu; Liu, Yinlong; Ji, Jing

    2016-06-01

    Several studies have demonstrated alterations in the dopamine (DA) system after traumatic brain injury (TBI). Additionally, the existence of significant sex-related differences in the dopaminergic system has long been recognized. Accordingly, the purpose of the present study was to investigate whether TBI would differentially alter, in female and male mice, the expression and the function of the striatal vesicular monoamine transporter-2 (VMAT-2), an important DA transporter. After controlled cortical impact (CCI) injury, female mice showed significantly lower striatal DA concentrations and K(+)-evoked DA output. By contrast, no significant sex-related differences were observed in the mRNA and protein levels of striatal dopamine transporter (DAT) and VMAT-2 and the methamphetamine (MA)-evoked DA output. These results demonstrated clear sex-related differences in striatal VMAT-2 function in response to TBI and suggested that female mice may be more sensitive to the TBI-induced inhibition of the VMAT-2 function, as indicated by the greater degree of deficits observed when the VMAT-2 DA-storage function was inhibited by TBI. Moreover, the TBI-induced suppression of locomotion was more pronounced than female mice. Such findings highlight the need for sex-specific considerations when examining differences among brain injury conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. The Influence of Dopaminergic Striatal Innervation on Upper Limb Locomotor Synergies

    PubMed Central

    Isaias, Ioannis U.; Volkmann, Jens; Marzegan, Alberto; Marotta, Giorgio; Cavallari, Paolo; Pezzoli, Gianni

    2012-01-01

    To determine the role of striatal dopaminergic innervation on upper limb synergies during walking, we measured arm kinematics in 13 subjects with Parkinson disease. Patients were recruited according to several inclusion criteria to represent the best possible in vivo model of dopaminergic denervation. Of relevance, we included only subjects with normal spatio-temporal parameters of the stride and gait speed to avoid an impairment of upper limbs locomotor synergies as a consequence of gait impairment per se. Dopaminergic innervation of the striatum was measured by FP-CIT and SPECT. All patients showed a reduction of gait-associated arms movement. No linear correlation was found between arm ROM reduction and contralateral dopaminergic putaminal innervation loss. Still, a partition analysis revealed a 80% chance of reduced arm ROM when putaminal dopamine content loss was >47%. A significant correlation was described between the asymmetry indices of the swinging of the two arms and dopaminergic striatal innervation. When arm ROM was reduced, we found a positive correlation between upper-lower limb phase shift modulation (at different gait velocities) and striatal dopaminergic innervation. These findings are preliminary evidence that dopaminergic striatal tone plays a modulatory role in upper-limb locomotor synergies and upper-lower limb coupling while walking at different velocities. PMID:23236504

  1. Biochemical markers of striatal desensitization in cortical-limbic hyperglutamatergic TS- & OCD-like transgenic mice.

    PubMed

    O'Brien, Kylie B; Sharrief, Anjail Z; Nordstrom, Eric J; Travanty, Anthony J; Huynh, Mailee; Romero, Megan P; Bittner, Katie C; Bowser, Michael T; Burton, Frank H

    2018-04-01

    Tics and compulsions in comorbid Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) are associated with chronic hyperactivity of parallel cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Comorbid TS- & OCD-like behaviors have likewise been observed in D1CT-7 mice, in which an artificial neuropotentiating transgene encoding the cAMP-elevating intracellular subunit of cholera toxin (CT) is chronically expressed selectively in somatosensory cortical & amygdalar dopamine (DA) D1 receptor-expressing neurons that activate cortico/amygdalo-striatal glutamate (GLU) output. We've now examined in D1CT-7 mice whether the chronic GLU output from their potentiated cortical/limbic CSTC subcircuit afferents associated with TS- & OCD-like behaviors elicits desensitizing neurochemical changes in the striatum (STR). Microdialysis-capillary electrophoresis and in situ hybridization reveal that the mice's chronic GLU-excited STR exhibits pharmacodynamic changes in three independently GLU-regulated measures of output neuron activation, co-excitation, and desensitization, signifying hyperactive striatal CSTC output and compensatory striatal glial and neuronal desensitization: 1) Striatal GABA, an output neurotransmitter induced by afferent GLU, is increased. 2) Striatal d-serine, a glial excitatory co-transmitter inhibited by afferent GLU, is decreased. 3) Striatal Period1 (Per1), which plays a non-circadian role in the STR as a GLU + DA D1- (cAMP-) dependent repressor thought to feedback-inhibit GLU + DA- triggered ultradian urges and motions, is transcriptionally abolished. These data imply that chronic cortical/limbic GLU excitation of the STR desensitizes its co-excitatory d-serine & DA inputs while freezing its GABA output in an active state to mediate chronic tics and compulsions - possibly in part by abolishing striatal Per1-dependent ultradian extinction of urges and motions. Copyright © 2018 The Authors. Published by Elsevier B.V. All

  2. Modelling dynamic fronto-parietal behaviour during minimally invasive surgery--a Markovian trip distribution approach.

    PubMed

    Leff, Daniel Richard; Orihuela-Espina, Felipe; Leong, Julian; Darzi, Ara; Yang, Guang-Zhong

    2008-01-01

    Learning to perform Minimally Invasive Surgery (MIS) requires considerable attention, concentration and spatial ability. Theoretically, this leads to activation in executive control (prefrontal) and visuospatial (parietal) centres of the brain. A novel approach is presented in this paper for analysing the flow of fronto-parietal haemodynamic behaviour and the associated variability between subjects. Serially acquired functional Near Infrared Spectroscopy (fNIRS) data from fourteen laparoscopic novices at different stages of learning is projected into a low-dimensional 'geospace', where sequentially acquired data is mapped to different locations. A trip distribution matrix based on consecutive directed trips between locations in the geospace reveals confluent fronto-parietal haemodynamic changes and a gravity model is applied to populate this matrix. To model global convergence in haemodynamic behaviour, a Markov chain is constructed and by comparing sequential haemodynamic distributions to the Markov's stationary distribution, inter-subject variability in learning an MIS task can be identified.

  3. Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers

    PubMed Central

    Wiers, C E; Shumay, E; Cabrera, E; Shokri-Kojori, E; Gladwin, T E; Skarda, E; Cunningham, S I; Kim, S W; Wong, T C; Tomasi, D; Wang, G-J; Volkow, N D

    2016-01-01

    Neuroimaging studies have documented reduced striatal dopamine D2/D3 receptor (D2/D3R) availability in cocaine abusers, which has been associated with impaired prefrontal activity and vulnerability for relapse. However, the mechanism(s) underlying the decreases in D2/D3R remain poorly understood. Recent studies have shown that sleep deprivation is associated with a downregulation of striatal D2/D3R in healthy volunteers. As cocaine abusers have disrupted sleep patterns, here we investigated whether reduced sleep duration mediates the relationship between cocaine abuse and low striatal D2/D3R availability. We used positron emission tomography with [11C]raclopride to measure striatal D2/D3R availability in 24 active cocaine abusers and 21 matched healthy controls, and interviewed them about their daily sleep patterns. Compared with controls, cocaine abusers had shorter sleep duration, went to bed later and reported longer periods of sleep disturbances. In addition, cocaine abusers had reduced striatal D2/D3R availability. Sleep duration predicted striatal D2/D3R availability and statistically mediated the relationship between cocaine abuse and striatal D2/D3R availability. These findings suggest that impaired sleep patterns contribute to the low striatal D2/D3R availability in cocaine abusers. As sleep impairments are similarly observed in other types of substance abusers (for example, alcohol and methamphetamine), this mechanism may also underlie reductions in D2/D3R availability in these groups. The current findings have clinical implications suggesting that interventions to improve sleep patterns in cocaine abusers undergoing detoxification might be beneficial in improving their clinical outcomes. PMID:26954979

  4. Molecular substrates of action control in cortico-striatal circuits.

    PubMed

    Shiflett, Michael W; Balleine, Bernard W

    2011-09-15

    The purpose of this review is to describe the molecular mechanisms in the striatum that mediate reward-based learning and action control during instrumental conditioning. Experiments assessing the neural bases of instrumental conditioning have uncovered functional circuits in the striatum, including dorsal and ventral striatal sub-regions, involved in action-outcome learning, stimulus-response learning, and the motivational control of action by reward-associated cues. Integration of dopamine (DA) and glutamate neurotransmission within these striatal sub-regions is hypothesized to enable learning and action control through its role in shaping synaptic plasticity and cellular excitability. The extracellular signal regulated kinase (ERK) appears to be particularly important for reward-based learning and action control due to its sensitivity to combined DA and glutamate receptor activation and its involvement in a range of cellular functions. ERK activation in striatal neurons is proposed to have a dual role in both the learning and performance factors that contribute to instrumental conditioning through its regulation of plasticity-related transcription factors and its modulation of intrinsic cellular excitability. Furthermore, perturbation of ERK activation by drugs of abuse may give rise to behavioral disorders such as addiction. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. The role of striatal NMDA receptors in drug addiction.

    PubMed

    Ma, Yao-Ying; Cepeda, Carlos; Cui, Cai-Lian

    2009-01-01

    The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.

  6. Altered retrieval of melodic information in congenital amusia: insights from dynamic causal modeling of MEG data.

    PubMed

    Albouy, Philippe; Mattout, Jérémie; Sanchez, Gaëtan; Tillmann, Barbara; Caclin, Anne

    2015-01-01

    Congenital amusia is a neuro-developmental disorder that primarily manifests as a difficulty in the perception and memory of pitch-based materials, including music. Recent findings have shown that the amusic brain exhibits altered functioning of a fronto-temporal network during pitch perception and short-term memory. Within this network, during the encoding of melodies, a decreased right backward frontal-to-temporal connectivity was reported in amusia, along with an abnormal connectivity within and between auditory cortices. The present study investigated whether connectivity patterns between these regions were affected during the short-term memory retrieval of melodies. Amusics and controls had to indicate whether sequences of six tones that were presented in pairs were the same or different. When melodies were different only one tone changed in the second melody. Brain responses to the changed tone in "Different" trials and to its equivalent (original) tone in "Same" trials were compared between groups using Dynamic Causal Modeling (DCM). DCM results confirmed that congenital amusia is characterized by an altered effective connectivity within and between the two auditory cortices during sound processing. Furthermore, right temporal-to-frontal message passing was altered in comparison to controls, with notably an increase in "Same" trials. An additional analysis in control participants emphasized that the detection of an unexpected event in the typically functioning brain is supported by right fronto-temporal connections. The results can be interpreted in a predictive coding framework as reflecting an abnormal prediction error sent by temporal auditory regions towards frontal areas in the amusic brain.

  7. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation.

    PubMed

    Robbins, T W; Arnsten, A F T

    2009-01-01

    We review the modulatory effects of the catecholamine neurotransmitters noradrenaline and dopamine on prefrontal cortical function. The effects of pharmacologic manipulations of these systems, sometimes in comparison with the indoleamine serotonin (5-HT), on performance on a variety of tasks that tap working memory, attentional-set formation and shifting, reversal learning, and response inhibition are compared in rodents, nonhuman primates, and humans using, in a behavioral context, several techniques ranging from microiontophoresis and single-cell electrophysiological recording to pharmacologic functional magnetic resonance imaging. Dissociable effects of drugs and neurotoxins affecting these monoamine systems suggest new ways of conceptualizing state-dependent fronto-executive functions, with implications for understanding the molecular genetic basis of mental illness and its treatment.

  8. Striatal dopamine release codes uncertainty in pathological gambling.

    PubMed

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka; Møller, Arne; Doudet, Doris Jeanne; Gjedde, Albert

    2012-10-30

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. Beer flavor provokes striatal dopamine release in male drinkers: mediation by family history of alcoholism.

    PubMed

    Oberlin, Brandon G; Dzemidzic, Mario; Tran, Stella M; Soeurt, Christina M; Albrecht, Daniel S; Yoder, Karmen K; Kareken, David A

    2013-08-01

    Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol's classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer's flavor alone can reduce the binding potential (BP) of [(11)C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [(11)C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [(11)C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.

  10. Geldanamycin attenuates 3‑nitropropionic acid‑induced apoptosis and JNK activation through the expression of HSP 70 in striatal cells.

    PubMed

    Choi, Yong-Joon; Kim, Nam Ho; Lim, Man Sup; Lee, Hee Jae; Kim, Sung Soo; Chun, Wanjoo

    2014-07-01

    Although selective striatal cell death is a characteristic hallmark in the pathogenesis of Huntington's disease (HD), the underlying mechanism of striatal susceptibility remains to be clarified. Heat shock proteins (HSPs) have been reported to suppress the aggregate formation of mutant huntingtin and concurrent striatal cell death. In a previous study, we observed that heat shock transcription factor 1 (HSF1), a major transcription factor of HSPs, significantly attenuated 3‑nitropropionic acid (3NP)‑induced reactive oxygen species (ROS) production and apoptosis through the expression of HSP 70 in striatal cells. To investigate the differential roles of HSPs in 3NP‑induced striatal cell death, the effect of geldanamycin (GA), an HSP 90 inhibitor, was examined in 3NP‑stimulated striatal cells. GA significantly attenuated 3NP‑induced striatal apoptosis and ROS production with an increased expression of HSP 70. Triptolide (TL), an HSP 70 inhibitor, abolished GA‑mediated protective effects in 3NP‑stimulated striatal cells. To understand the underlying mechanism by which GA‑mediated HSP 70 protects striatal cells against 3NP stimulation, the involvement of various signaling pathways was examined. GA significantly attenuated 3NP‑induced c‑Jun N‑terminal kinase (JNK) phosphorylation and subsequent c‑Jun phosphorylation in striatal cells. Taken together, the present study demonstrated that GA exhibits protective properties against 3NP‑induced apoptosis and JNK activation via the induction of HSP 70 in striatal cells, suggesting that expression of HSP 70 may be a valuable therapeutic target in the treatment of HD.

  11. A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment

    PubMed Central

    Fryer, Tim D.; Hong, Young T.; Smith, Rob; Brichard, Laurent; Acosta-Cabronero, Julio; Chamberlain, Samuel R.; Tait, Roger; Izquierdo, David; Regenthal, Ralf; Dowson, Jonathan; Suckling, John; Baron, Jean-Claude; Aigbirhio, Franklin I.; Robbins, Trevor W.; Sahakian, Barbara J.; Müller, Ulrich

    2013-01-01

    Through the combined use of 18F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto

  12. Altered striatal function in a mutant mouse lacking D1A dopamine receptors.

    PubMed Central

    Drago, J; Gerfen, C R; Lachowicz, J E; Steiner, H; Hollon, T R; Love, P E; Ooi, G T; Grinberg, A; Lee, E J; Huang, S P

    1994-01-01

    Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway. Images Fig. 2 Fig. 4 PMID:7809078

  13. Dissociation of long-term verbal memory and fronto-executive impairment in first-episode psychosis

    PubMed Central

    Leeson, V. C.; Robbins, T. W.; Franklin, C.; Harrison, M.; Harrison, I.; Ron, M. A.; Barnes, T. R. E.; Joyce, E. M.

    2009-01-01

    Background Verbal memory is frequently and severely affected in schizophrenia and has been implicated as a mediator of poor clinical outcome. Whereas encoding deficits are well demonstrated, it is unclear whether retention is impaired. This distinction is important because accelerated forgetting implies impaired consolidation attributable to medial temporal lobe (MTL) dysfunction whereas impaired encoding and retrieval implicates involvement of prefrontal cortex. Method We assessed a group of healthy volunteers (n=97) and pre-morbid IQ- and sex-matched first-episode psychosis patients (n=97), the majority of whom developed schizophrenia. We compared performance of verbal learning and recall with measures of visuospatial working memory, planning and attentional set-shifting, and also current IQ. Results All measures of performance, including verbal memory retention, a memory savings score that accounted for learning impairments, were significantly impaired in the schizophrenia group. The difference between groups for delayed recall remained even after the influence of learning and recall was accounted for. Factor analyses showed that, in patients, all variables except verbal memory retention loaded on a single factor, whereas in controls verbal memory and fronto-executive measures were separable. Conclusions The results suggest that IQ, executive function and verbal learning deficits in schizophrenia may reflect a common abnormality of information processing in prefrontal cortex rather than specific impairments in different cognitive domains. Verbal memory retention impairments, however, may have a different aetiology. PMID:19419594

  14. Fronto-limbic novelty processing in acute psychosis: disrupted relationship with memory performance and potential implications for delusions

    PubMed Central

    Schott, Björn H.; Voss, Martin; Wagner, Benjamin; Wüstenberg, Torsten; Düzel, Emrah; Behr, Joachim

    2015-01-01

    Recent concepts have highlighted the role of the hippocampus and adjacent medial temporal lobe (MTL) in positive symptoms like delusions in schizophrenia. In healthy individuals, the MTL is critically involved in the detection and encoding of novel information. Here, we aimed to investigate whether dysfunctional novelty processing by the MTL might constitute a potential neural mechanism contributing to the pathophysiology of delusions, using functional magnetic resonance imaging (fMRI) in 16 unmedicated patients with paranoid schizophrenia and 20 age-matched healthy controls. All patients experienced positive symptoms at time of participation. Participants performed a visual target detection task with complex scene stimuli in which novel and familiar rare stimuli were presented randomly intermixed with a standard and a target picture. Presentation of novel relative to familiar images was associated with hippocampal activation in both patients and healthy controls, but only healthy controls showed a positive relationship between novelty-related hippocampal activation and recognition memory performance after 24 h. Patients, but not controls, showed a robust neural response in the orbitofrontal cortex (OFC) during presentation of novel stimuli. Functional connectivity analysis in the patients further revealed a novelty-related increase of functional connectivity of both the hippocampus and the OFC with the rostral anterior cingulate cortex (rACC) and the ventral striatum (VS). Notably, delusions correlated positively with the difference of the functional connectivity of the hippocampus vs. the OFC with the rACC. Taken together, our results suggest that alterations of fronto-limbic novelty processing may contribute to the pathophysiology of delusions in patients with acute psychosis. PMID:26082697

  15. Adversity in childhood linked to elevated striatal dopamine function in adulthood.

    PubMed

    Egerton, Alice; Valmaggia, Lucia R; Howes, Oliver D; Day, Fern; Chaddock, Christopher A; Allen, Paul; Winton-Brown, Toby T; Bloomfield, Michael A P; Bhattacharyya, Sagnik; Chilcott, Jack; Lappin, Julia M; Murray, Robin M; McGuire, Philip

    2016-10-01

    Childhood adversity increases the risk of psychosis in adulthood. Theoretical and animal models suggest that this effect may be mediated by increased striatal dopamine neurotransmission. The primary objective of this study was to examine the relationship between adversity in childhood and striatal dopamine function in early adulthood. Secondary objectives were to compare exposure to childhood adversity and striatal dopamine function in young people at ultra high risk (UHR) of psychosis and healthy volunteers. Sixty-seven young adults, comprising 47 individuals at UHR for psychosis and 20 healthy volunteers were recruited from the same geographic area and were matched for age, gender and substance use. Presynaptic dopamine function in the associative striatum was assessed using 18F-DOPA positron emission tomography. Childhood adversity was assessed using the Childhood Experience of Care and Abuse questionnaire. Within the sample as a whole, both severe physical or sexual abuse (T63=2.92; P=0.005), and unstable family arrangements (T57=2.80; P=0.007) in childhood were associated with elevated dopamine function in the associative striatum in adulthood. Comparison of the UHR and volunteer subgroups revealed similar incidence of childhood adverse experiences, and there was no significant group difference in dopamine function. This study provides evidence that childhood adversity is linked to elevated striatal dopamine function in adulthood. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Reduced Implicit and Explicit Sequence Learning in First-Episode Schizophrenia

    ERIC Educational Resources Information Center

    Pedersen, Anya; Siegmund, Ansgar; Ohrmann, Patricia; Rist, Fred; Rothermundt, Matthias; Suslow, Thomas; Arolt, Volker

    2008-01-01

    A high prevalence of deficits in explicit learning has been reported for schizophrenic patients, but it is less clear whether these patients are impaired in implicit learning. Deficits in implicit learning indicative of a fronto-striatal dysfunction have been reported using a serial reaction-time task (SRT), but the impact of typical neuroleptic…

  17. Reduced striatal dopamine transporters in people with internet addiction disorder.

    PubMed

    Hou, Haifeng; Jia, Shaowe; Hu, Shu; Fan, Rong; Sun, Wen; Sun, Taotao; Zhang, Hong

    2012-01-01

    In recent years, internet addiction disorder (IAD) has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased. However, the neurobiological mechanism of IAD has not bee fully expressed. The present study was designed to determine if the striatal dopamine transporter (DAT) levels measured by (99m)Tc-TRODAT-1 single photon emission computed tomography (SPECT) brain scans were altered in individuals with IAD. SPECT brain scans were acquired on 5 male IAD subjects and 9 healthy age-matched controls. The volume (V) and weight (W) of bilateral corpus striatum as well as the (99m)Tc-TRODAT-1 uptake ratio of corpus striatum/the whole brain (Ra) were calculated using mathematical models. It was displayed that DAT expression level of striatum was significantly decreased and the V, W, and Ra were greatly reduced in the individuals with IAD compared to controls. Taken together, these results suggest that IAD may cause serious damages to the brain and the neuroimaging findings further illustrate IAD is associated with dysfunctions in the dopaminergic brain systems. Our findings also support the claim that IAD may share similar neurobiological abnormalities with other addictive disorders.

  18. Cortical Regulation of Dopamine Depletion-Induced Dendritic Spine Loss in Striatal Medium Spiny Neurons

    PubMed Central

    Neely, M. Diana; Schmidt, Dennis E.; Deutch, Ariel Y.

    2007-01-01

    The proximate cause of Parkinson’s Disease is striatal dopamine depletion. Although no overt toxicity to striatal neurons has been reported in Parkinson’s Disease, one of the consequences of striatal dopamine loss is a decrease in the number of dendritic spines on striatal medium spiny neurons (MSNs). Dendrites of these neurons receive cortical glutamatergic inputs onto the dendritic spine head and dopaminergic inputs from the substantia nigra onto the spine neck. This synaptic arrangement suggests that dopamine gates corticostriatal glutamatergic drive onto spines. Using triple organotypic slice cultures comprised of ventral mesencephalon, striatum, and cortex, we examined the role of the cortex in dopamine depletion-induced dendritic spine loss in MSNs. The striatal dopamine innervation was lesioned by treatment of the cultures with the dopaminergic neurotoxin MPP+ or by removing the mesencephalon. Both MPP+ and mesencephalic ablation decreased MSN dendritic spine density. Analysis of spine morphology revealed that thin spines were preferentially lost after dopamine depletion. Removal of the cortex completely prevented dopamine depletion-induced spine loss. These data indicate that the dendritic remodeling of MSNs seen in parkinsonism occurs secondary to increases in corticostriatal glutamatergic drive, and suggest that modulation of cortical activity may be a useful therapeutic strategy in Parkinson’s Disease. PMID:17888581

  19. [Endoscopically assisted fronto-orbitary correction in trigonocephaly].

    PubMed

    Hinojosa, J; Esparza, J; García-Recuero, I; Romance, A

    2007-01-01

    The development of multidisciplinar Units for Craneofacial Surgery has led to a considerable decrease in morbidity even in the cases of more complex craniofacial syndromes. The use of minimally invasive techniques for the correction of some of these malformations allows the surgeon to minimize the incidence of complications by means of a decrease in the surgical time, blood salvage and shortening of postoperative hospitalization in comparison to conventional craniofacial techniques. Simple and milder craniosynostosis are best approached by these techniques and render the best results. Different osteotomies resembling standard fronto-orbital remodelling besides simple suturectomies and the use of postoperative cranial orthesis may improve the final aesthetic appearence. In endoscopic treatment of trigonocephaly the use of preauricular incisions achieves complete pterional resection, lower lateral orbital osteotomies and successful precoronal frontal osteotomies to obtain long lasting and satisfactory outcomes.

  20. Multimodal Magnetic Resonance Imaging Study of Treatment-Naïve Adults with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Chaim, Tiffany M.; Zhang, Tianhao; Zanetti, Marcus V.; da Silva, Maria Aparecida; Louzã, Mário R.; Doshi, Jimit; Serpa, Mauricio H.; Duran, Fabio L. S.; Caetano, Sheila C.; Davatzikos, Christos; Busatto, Geraldo F.

    2014-01-01

    Background Attention-Deficit/Hiperactivity Disorder (ADHD) is a prevalent disorder, but its neuroanatomical circuitry is still relatively understudied, especially in the adult population. The few morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies available to date have found heterogeneous results. This may be at least partly attributable to some well-known technical limitations of the conventional voxel-based methods usually employed to analyze such neuroimaging data. Moreover, there is a great paucity of imaging studies of adult ADHD to date that have excluded patients with history of use of stimulant medication. Methods A newly validated method named optimally-discriminative voxel-based analysis (ODVBA) was applied to multimodal (structural and DTI) MRI data acquired from 22 treatment-naïve ADHD adults and 19 age- and gender-matched healthy controls (HC). Results Regarding DTI data, we found higher fractional anisotropy in ADHD relative to HC encompassing the white matter (WM) of the bilateral superior frontal gyrus, right middle frontal left gyrus, left postcentral gyrus, bilateral cingulate gyrus, bilateral middle temporal gyrus and right superior temporal gyrus; reductions in trace (a measure of diffusivity) in ADHD relative to HC were also found in fronto-striatal-parieto-occipital circuits, including the right superior frontal gyrus and bilateral middle frontal gyrus, right precentral gyrus, left middle occipital gyrus and bilateral cingulate gyrus, as well as the left body and right splenium of the corpus callosum, right superior corona radiata, and right superior longitudinal and fronto-occipital fasciculi. Volumetric abnormalities in ADHD subjects were found only at a trend level of significance, including reduced gray matter (GM) in the right angular gyrus, and increased GM in the right supplementary motor area and superior frontal gyrus. Conclusions Our results suggest that adult ADHD is associated with

  1. Dynamic Changes in Phase-Amplitude Coupling Facilitate Spatial Attention Control in Fronto-Parietal Cortex

    PubMed Central

    Szczepanski, Sara M.; Crone, Nathan E.; Kuperman, Rachel A.; Auguste, Kurtis I.; Parvizi, Josef; Knight, Robert T.

    2014-01-01

    Attention is a core cognitive mechanism that allows the brain to allocate limited resources depending on current task demands. A number of frontal and posterior parietal cortical areas, referred to collectively as the fronto-parietal attentional control network, are engaged during attentional allocation in both humans and non-human primates. Numerous studies have examined this network in the human brain using various neuroimaging and scalp electrophysiological techniques. However, little is known about how these frontal and parietal areas interact dynamically to produce behavior on a fine temporal (sub-second) and spatial (sub-centimeter) scale. We addressed how human fronto-parietal regions control visuospatial attention on a fine spatiotemporal scale by recording electrocorticography (ECoG) signals measured directly from subdural electrode arrays that were implanted in patients undergoing intracranial monitoring for localization of epileptic foci. Subjects (n = 8) performed a spatial-cuing task, in which they allocated visuospatial attention to either the right or left visual field and detected the appearance of a target. We found increases in high gamma (HG) power (70–250 Hz) time-locked to trial onset that remained elevated throughout the attentional allocation period over frontal, parietal, and visual areas. These HG power increases were modulated by the phase of the ongoing delta/theta (2–5 Hz) oscillation during attentional allocation. Critically, we found that the strength of this delta/theta phase-HG amplitude coupling predicted reaction times to detected targets on a trial-by-trial basis. These results highlight the role of delta/theta phase-HG amplitude coupling as a mechanism for sub-second facilitation and coordination within human fronto-parietal cortex that is guided by momentary attentional demands. PMID:25157678

  2. Buspirone anti-dyskinetic effect is correlated with temporal normalization of dysregulated striatal DRD1 signalling in L-DOPA-treated rats.

    PubMed

    Azkona, Garikoitz; Sagarduy, Ainhoa; Aristieta, Asier; Vazquez, Nerea; Zubillaga, Verónica; Ruíz-Ortega, José Angel; Pérez-Navarro, Esther; Ugedo, Luisa; Sánchez-Pernaute, Rosario

    2014-04-01

    Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood. In this study, we used a well-characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias. We then investigated the molecular substrates implicated in the anti-dyskinetic effect of buspirone, a 5HT1A partial agonist. Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor (DR)D3, ΔFosB and phospho (p)CREB, as well as an over-activation of the DRD1 signalling pathway, reflected by elevated ratios of phosphorylated DARPP32 and ERK2. Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose-dependent fashion. Buspirone (4 mg/kg) dramatically reduced the presence and severity of dyskinesias (by 83%) and normalized DARPP32 and ERK2 phosphorylation ratios, while the increases in DRD3, ΔFosB and pCREB observed in dyskinetic rats were not modified. Pharmacological experiments combining buspirone with 5HT1A and DRD3 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required, but not sufficient, for blocking dyskinesias. The correlation between pDARPP32 ratio and dyskinesias was significant but not strong, pointing to the involvement of convergent factors and signalling pathways. Our results suggest that in dyskinetic rats DRD3 striatal over-expression could be instrumental in the activation of DRD1-downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with DRD1 pathway normalization. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Postnatal functional inactivation of the entorhinal cortex or ventral subiculum has different consequences for latent inhibition-related striatal dopaminergic responses in adult rats.

    PubMed

    Meyer, F; Peterschmitt, Y; Louilot, A

    2009-05-01

    Latent inhibition has been found to be disrupted in patients with acute schizophrenia. Striatal dopaminergic dysregulation is commonly acknowledged in schizophrenia. This disease may be consecutive to a functional disconnection between integrative regions, stemming from neurodevelopmental failures. Various anomalies suggesting early abnormal brain development have been described in the entorhinal cortex (ENT) and ventral subiculum (SUB) of patients. This study examines the consequences of a neonatal transitory blockade of the left ENT or left SUB for latent inhibition-related dopamine responses in the anterior part of the dorsal striatum using in-vivo voltammetry in freely moving adult rats. Reversible inactivation of both structures in different animals was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8. Results obtained during the retention session of a three-stage latent inhibition protocol showed that the functional neonatal disconnection of the ENT or SUB caused the behavioural latent inhibition expression in pre-exposed (PE)-TTX-conditioned adult rats to disappear. After postnatal inactivation of the SUB, PE-TTX-conditioned rats displayed a reversal of the latent inhibition-related striatal dopamine responses, whereas after neonatal blockade of the ENT, dopamine changes in PE-TTX-conditioned rats monitored in the anterior striatum were between those observed in PE-phosphate-buffered-saline-conditioned and non-PE-TTX-conditioned animals. These data suggest that neonatal functional inactivation of the SUB disrupts latent inhibition-related striatal dopamine responses in adult animals more than that of the ENT. They may help improve understanding of the pathophysiology of schizophrenia.

  4. Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models.

    PubMed

    Yokoi, Fumiaki; Dang, Mai T; Zhou, Tong; Li, Yuqing

    2012-02-15

    DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ε-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ε-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ε-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ε-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients.

  5. Resting-State Connectivity of the Left Frontal Cortex to the Default Mode and Dorsal Attention Network Supports Reserve in Mild Cognitive Impairment.

    PubMed

    Franzmeier, Nicolai; Göttler, Jens; Grimmer, Timo; Drzezga, Alexander; Áraque-Caballero, Miguel A; Simon-Vermot, Lee; Taylor, Alexander N W; Bürger, Katharina; Catak, Cihan; Janowitz, Daniel; Müller, Claudia; Duering, Marco; Sorg, Christian; Ewers, Michael

    2017-01-01

    Reserve refers to the phenomenon of relatively preserved cognition in disproportion to the extent of neuropathology, e.g., in Alzheimer's disease. A putative functional neural substrate underlying reserve is global functional connectivity of the left lateral frontal cortex (LFC, Brodmann Area 6/44). Resting-state fMRI-assessed global LFC-connectivity is associated with protective factors (education) and better maintenance of memory in mild cognitive impairment (MCI). Since the LFC is a hub of the fronto-parietal control network that regulates the activity of other networks, the question arises whether LFC-connectivity to specific networks rather than the whole-brain may underlie reserve. We assessed resting-state fMRI in 24 MCI and 16 healthy controls (HC) and in an independent validation sample (23 MCI/32 HC). Seed-based LFC-connectivity to seven major resting-state networks (i.e., fronto-parietal, limbic, dorsal-attention, somatomotor, default-mode, ventral-attention, visual) was computed, reserve was quantified as residualized memory performance after accounting for age and hippocampal atrophy. In both samples of MCI, LFC-activity was anti-correlated with the default-mode network (DMN), but positively correlated with the dorsal-attention network (DAN). Greater education predicted stronger LFC-DMN-connectivity (anti-correlation) and LFC-DAN-connectivity. Stronger LFC-DMN and LFC-DAN-connectivity each predicted higher reserve, consistently in both MCI samples. No associations were detected for LFC-connectivity to other networks. These novel results extend our previous findings on global functional connectivity of the LFC, showing that LFC-connectivity specifically to the DAN and DMN, two core memory networks, enhances reserve in the memory domain in MCI.

  6. Analyzing the association between functional connectivity of the brain and intellectual performance

    PubMed Central

    Pamplona, Gustavo S. P.; Santos Neto, Gérson S.; Rosset, Sara R. E.; Rogers, Baxter P.; Salmon, Carlos E. G.

    2015-01-01

    Measurements of functional connectivity support the hypothesis that the brain is composed of distinct networks with anatomically separated nodes but common functionality. A few studies have suggested that intellectual performance may be associated with greater functional connectivity in the fronto-parietal network and enhanced global efficiency. In this fMRI study, we performed an exploratory analysis of the relationship between the brain's functional connectivity and intelligence scores derived from the Portuguese language version of the Wechsler Adult Intelligence Scale (WAIS-III) in a sample of 29 people, born and raised in Brazil. We examined functional connectivity between 82 regions, including graph theoretic properties of the overall network. Some previous findings were extended to the Portuguese-speaking population, specifically the presence of small-world organization of the brain and relationships of intelligence with connectivity of frontal, pre-central, parietal, occipital, fusiform and supramarginal gyrus, and caudate nucleus. Verbal comprehension was associated with global network efficiency, a new finding. PMID:25713528

  7. Recognition memory span in autopsy-confirmed Dementia with Lewy Bodies and Alzheimer's Disease.

    PubMed

    Salmon, David P; Heindel, William C; Hamilton, Joanne M; Vincent Filoteo, J; Cidambi, Varun; Hansen, Lawrence A; Masliah, Eliezer; Galasko, Douglas

    2015-08-01

    Evidence from patients with amnesia suggests that recognition memory span tasks engage both long-term memory (i.e., secondary memory) processes mediated by the diencephalic-medial temporal lobe memory system and working memory processes mediated by fronto-striatal systems. Thus, the recognition memory span task may be particularly effective for detecting memory deficits in disorders that disrupt both memory systems. The presence of unique pathology in fronto-striatal circuits in Dementia with Lewy Bodies (DLB) compared to AD suggests that performance on the recognition memory span task might be differentially affected in the two disorders even though they have quantitatively similar deficits in secondary memory. In the present study, patients with autopsy-confirmed DLB or AD, and Normal Control (NC) participants, were tested on separate recognition memory span tasks that required them to retain increasing amounts of verbal, spatial, or visual object (i.e., faces) information across trials. Results showed that recognition memory spans for verbal and spatial stimuli, but not face stimuli, were lower in patients with DLB than in those with AD, and more impaired relative to NC performance. This was despite similar deficits in the two patient groups on independent measures of secondary memory such as the total number of words recalled from long-term storage on the Buschke Selective Reminding Test. The disproportionate vulnerability of recognition memory span task performance in DLB compared to AD may be due to greater fronto-striatal involvement in DLB and a corresponding decrement in cooperative interaction between working memory and secondary memory processes. Assessment of recognition memory span may contribute to the ability to distinguish between DLB and AD relatively early in the course of disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Adrenergic receptor-mediated modulation of striatal firing patterns.

    PubMed

    Ohta, Hiroyuki; Kohno, Yu; Arake, Masashi; Tamura, Risa; Yukawa, Suguru; Sato, Yoshiaki; Morimoto, Yuji; Nishida, Yasuhiro; Yawo, Hiromu

    2016-11-01

    Although noradrenaline and adrenaline are some of the most important neurotransmitters in the central nervous system, the effects of noradrenergic/adrenergic modulation on the striatum have not been determined. In order to explore the effects of adrenergic receptor (AR) agonists on the striatal firing patterns, we used optogenetic methods which can induce continuous firings. We employed transgenic rats expressing channelrhodopsin-2 (ChR2) in neurons. The medium spiny neuron showed a slow rising depolarization during the 1-s long optogenetic striatal photostimulation and a residual potential with 8.6-s half-life decay after the photostimulation. As a result of the residual potential, five repetitive 1-sec long photostimulations with 20-s onset intervals cumulatively increased the number of spikes. This 'firing increment', possibly relating to the timing control function of the striatum, was used to evaluate the AR modulation. The β-AR agonist isoproterenol decreased the firing increment between the 1st and 5th stimulation cycles, while the α 1 -AR agonist phenylephrine enhanced the firing increment. Isoproterenol and adrenaline increased the early phase (0-0.5s of the photostimulation) firing response. This adrenergic modulation was inhibited by the β-antagonist propranolol. Conversely, phenylephrine and noradrenaline reduced the early phase response. β-ARs and α 1 -ARs work in opposition controlling the striatal firing initiation and the firing increment. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  9. Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis.

    PubMed

    Rossi, Silvia; Muzio, Luca; De Chiara, Valentina; Grasselli, Giorgio; Musella, Alessandra; Musumeci, Gabriele; Mandolesi, Georgia; De Ceglia, Roberta; Maida, Simona; Biffi, Emilia; Pedrocchi, Alessandra; Menegon, Andrea; Bernardi, Giorgio; Furlan, Roberto; Martino, Gianvito; Centonze, Diego

    2011-07-01

    Synaptic dysfunction triggers neuronal damage in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). While excessive glutamate signaling has been reported in the striatum of EAE, it is still uncertain whether GABA synapses are altered. Electrophysiological recordings showed a reduction of spontaneous GABAergic synaptic currents (sIPSCs) recorded from striatal projection neurons of mice with MOG((35-55))-induced EAE. GABAergic sIPSC deficits started in the acute phase of the disease (20-25days post immunization, dpi), and were exacerbated at later time-points (35, 50, 70 and 90dpi). Of note, in slices they were independent of microglial activation and of release of TNF-α. Indeed, sIPSC inhibition likely involved synaptic inputs arising from GABAergic interneurons, because EAE preferentially reduced sIPSCs of high amplitude, and was associated with a selective loss of striatal parvalbumin (PV)-positive GABAergic interneurons, which contact striatal projection neurons in their somatic region, giving rise to more efficient synaptic inhibition. Furthermore, we found also that the chronic persistence of pro-inflammatory cytokines were able, per se, to produce profound alterations of electrophysiological network properties, that were reverted by GABA administration. The results of the present investigation indicate defective GABA transmission in MS models depending from alteration of PV cells number and, in part, deriving from the effects of a chronic inflammation, and suggest that pharmacological agents potentiating GABA signaling might be considered to limit neuronal damage in MS patients. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia.

    PubMed

    Grimm, Oliver; Heinz, Andreas; Walter, Henrik; Kirsch, Peter; Erk, Susanne; Haddad, Leila; Plichta, Michael M; Romanczuk-Seiferth, Nina; Pöhland, Lydia; Mohnke, Sebastian; Mühleisen, Thomas W; Mattheisen, Manuel; Witt, Stephanie H; Schäfer, Axel; Cichon, Sven; Nöthen, Markus; Rietschel, Marcella; Tost, Heike; Meyer-Lindenberg, Andreas

    2014-05-01

    Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. Schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder. To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929). Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied. Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype. Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P < .03 for multiple comparisons across the whole brain). Supplemental analyses confirmed that the identified systems-level functional phenotype is reliable (with intraclass correlation coefficients of 0.59-0.73), independent of local gray matter volume (with no

  11. Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac.

    PubMed

    Paz, Rodrigo Manuel; Tubert, Cecilia; Stahl, Agostina; Díaz, Analía López; Etchenique, Roberto; Murer, Mario Gustavo; Rela, Lorena

    2018-05-11

    Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs. We found that autonomous firing of striatal cholinergic interneurons is not regulated by Kv7 channels. In contrast, Kv7 channels limit the summation of excitatory postsynaptic potentials in cholinergic interneurons through a postsynaptic mechanism. Striatal cholinergic interneurons have a high reserve of Kv7 channels, as their opening using pharmacological tools completely silenced the tonic firing and markedly reduced their intrinsic excitability. A strong inhibition of striatal cholinergic interneurons was also observed in response to the anti-inflammatory drugs diclofenac and meclofenamic acid, however, this effect was independent of Kv7 channels. These data bring attention to new potential molecular targets and pharmacological tools to control striatal cholinergic interneuron activity in pathological conditions where they are believed to be hyperactive, including Parkinson's disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. DRD2 Schizophrenia-Risk Allele Is Associated With Impaired Striatal Functioning in Unaffected Siblings of Schizophrenia Patients

    PubMed Central

    Vink, Matthijs; de Leeuw, Max; Luykx, Jurjen J.; van Eijk, Kristel R.; van den Munkhof, Hanna E.; van Buuren, Mariët; Kahn, René S.

    2016-01-01

    A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n = 21) and noncarriers (n = 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location. PMID:26598739

  13. "Default mode functional connectivity is associated with social functioning in schizophrenia": Correction to Fox et al. (2017).

    PubMed

    2017-07-01

    Reports an error in "Default mode functional connectivity is associated with social functioning in schizophrenia" by Jaclyn M. Fox, Samantha V. Abram, James L. Reilly, Shaun Eack, Morris B. Goldman, John G. Csernansky, Lei Wang and Matthew J. Smith ( Journal of Abnormal Psychology , 2017[May], Vol 126[4], 392-405). In the article, the email address of corresponding author Matthew J. Smith was set as matthewsmith@northwestern.edu. It should have been mattjsmi@umich.edu. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-14073-001.) Individuals with schizophrenia display notable deficits in social functioning. Research indicates that neural connectivity within the default mode network (DMN) is related to social cognition and social functioning in healthy and clinical populations. However, the association between DMN connectivity, social cognition, and social functioning has not been studied in schizophrenia. For the present study, the authors used resting-state neuroimaging data to evaluate connectivity between the main DMN hubs (i.e., the medial prefrontal cortex [mPFC] and the posterior cingulate cortex-anterior precuneus [PPC]) in individuals with schizophrenia (n = 28) and controls (n = 32). The authors also examined whether DMN connectivity was associated with social functioning via social attainment (measured by the Specific Levels of Functioning Scale) and social competence (measured by the Social Skills Performance Assessment), and if social cognition mediates the association between DMN connectivity and these measures of social functioning. Results revealed that DMN connectivity did not differ between individuals with schizophrenia and controls. However, connectivity between the mPFC and PCC hubs was significantly associated with social competence and social attainment in individuals with schizophrenia but not in controls as reflected by a significant group-by-connectivity

  14. Selective functional integration between anterior temporal and distinct fronto-mesolimbic regions during guilt and indignation

    PubMed Central

    Green, Sophie; Lambon Ralph, Matthew A.; Moll, Jorge; Stamatakis, Emmanuel A.; Grafman, Jordan; Zahn, Roland

    2010-01-01

    It has been hypothesized that the experience of different moral sentiments such as guilt and indignation is underpinned by activation in temporal and fronto-mesolimbic regions and that functional integration between these regions is necessary for the differentiated experience of these moral sentiments. A recent fMRI study revealed that the right superior anterior temporal lobe (ATL) was activated irrespective of the context of moral feelings (guilt or indignation). This region has been associated with context-independent conceptual social knowledge which allows us to make fine-grained differentiations between qualities of social behaviours (e.g. “critical” and “faultfinding”). This knowledge is required to make emotional evaluations of social behaviour. In contrast to the context-independent activation of the ATL, there were context-dependent activations within different fronto-mesolimbic regions for guilt and indignation. However, it is unknown whether functional integration occurs between these regions and whether regional patterns of integration are distinctive for the experience of different moral sentiments. Here, we used fMRI and psychophysiological interaction analysis, an established measure of functional integration to investigate this issue. We found selective functional integration between the right superior ATL and a subgenual cingulate region during the experience of guilt and between the right superior ATL and the lateral orbitofrontal cortex for indignation. Our data provide the first evidence for functional integration of conceptual social knowledge representations in the right superior ATL with representations of different feeling contexts in fronto-mesolimbic regions. We speculate that this functional architecture allows for the conceptually differentiated experience of moral sentiments in healthy individuals. PMID:20493953

  15. Changes in Striatal Dopamine Release Associated with Human Motor-Skill Acquisition

    PubMed Central

    Kawashima, Shoji; Ueki, Yoshino; Kato, Takashi; Matsukawa, Noriyuki; Mima, Tatsuya; Hallett, Mark; Ito, Kengo; Ojika, Kosei

    2012-01-01

    The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using 11C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The 11C-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that 11C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition. PMID:22355391

  16. Striatal Cholinergic Interneurons Modulate Spike-Timing in Striosomes and Matrix by an Amphetamine-Sensitive Mechanism

    PubMed Central

    Crittenden, Jill R.; Lacey, Carolyn J.; Weng, Feng-Ju; Garrison, Catherine E.; Gibson, Daniel J.; Lin, Yingxi; Graybiel, Ann M.

    2017-01-01

    The striatum is key for action-selection and the motivation to move. Dopamine and acetylcholine release sites are enriched in the striatum and are cross-regulated, possibly to achieve optimal behavior. Drugs of abuse, which promote abnormally high dopamine release, disrupt normal action-selection and drive restricted, repetitive behaviors (stereotypies). Stereotypies occur in a variety of disorders including obsessive-compulsive disorder, autism, schizophrenia and Huntington's disease, as well as in addictive states. The severity of drug-induced stereotypy is correlated with induction of c-Fos expression in striosomes, a striatal compartment that is related to the limbic system and that directly projects to dopamine-producing neurons of the substantia nigra. These characteristics of striosomes contrast with the properties of the extra-striosomal matrix, which has strong sensorimotor and associative circuit inputs and outputs. Disruption of acetylcholine signaling in the striatum blocks the striosome-predominant c-Fos expression pattern induced by drugs of abuse and alters drug-induced stereotypy. The activity of striatal cholinergic interneurons is associated with behaviors related to sensory cues, and cortical inputs to striosomes can bias action-selection in the face of conflicting cues. The neurons and neuropil of striosomes and matrix neurons have observably separate distributions, both at the input level in the striatum and at the output level in the substantia nigra. Notably, cholinergic axons readily cross compartment borders, providing a potential route for local cross-compartment communication to maintain a balance between striosomal and matrix activity. We show here, by slice electrophysiology in transgenic mice, that repetitive evoked firing patterns in striosomal and matrix striatal projection neurons (SPNs) are interrupted by optogenetic activation of cholinergic interneurons either by the addition or the deletion of spikes. We demonstrate that this

  17. Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder.

    PubMed

    Manning, Joshua; Reynolds, Gretchen; Saygin, Zeynep M; Hofmann, Stefan G; Pollack, Mark; Gabrieli, John D E; Whitfield-Gabrieli, Susan

    2015-01-01

    We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.

  18. Altered auditory processing and effective connectivity in 22q11.2 deletion syndrome.

    PubMed

    Larsen, Kit Melissa; Mørup, Morten; Birknow, Michelle Rosgaard; Fischer, Elvira; Hulme, Oliver; Vangkilde, Anders; Schmock, Henriette; Baaré, William Frans Christiaan; Didriksen, Michael; Olsen, Line; Werge, Thomas; Siebner, Hartwig R; Garrido, Marta I

    2018-01-30

    22q11.2 deletion syndrome (22q11.2DS) is one of the most common copy number variants and confers a markedly increased risk for schizophrenia. As such, 22q11.2DS is a homogeneous genetic liability model which enables studies to delineate functional abnormalities that may precede disease onset. Mismatch negativity (MMN), a brain marker of change detection, is reduced in people with schizophrenia compared to healthy controls. Using dynamic causal modelling (DCM), previous studies showed that top-down effective connectivity linking the frontal and temporal cortex is reduced in schizophrenia relative to healthy controls in MMN tasks. In the search for early risk-markers for schizophrenia we investigated the neural basis of change detection in a group with 22q11.2DS. We recorded high-density EEG from 19 young non-psychotic 22q11.2 deletion carriers, as well as from 27 healthy non-carriers with comparable age distribution and sex ratio, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Despite finding no significant reduction in the MMN responses, whole-scalp spatiotemporal analysis of responses to the tones revealed a greater fronto-temporal N1 component in the 22q11.2 deletion carriers. DCM showed reduced intrinsic connection within right primary auditory cortex as well as in the top-down, connection from the right inferior frontal gyrus to right superior temporal gyrus for 22q11.2 deletion carriers although not surviving correction for multiple comparison. We discuss these findings in terms of reduced adaptation and a general increased sensitivity to tones in 22q11.2DS. Copyright © 2018. Published by Elsevier B.V.

  19. Regulation of striatal nitric oxide synthesis by local dopamine and glutamate interactions

    PubMed Central

    Park, Diana J.; West, Anthony R.

    2009-01-01

    Nitric oxide (NO) is a key neuromodulator of corticostriatal synaptic transmission. We have shown previously that dopamine (DA) D1/5 receptor stimulation facilitates neuronal NO synthase (nNOS) activity in the intact striatum. To study the impact of local manipulations of D1/5 and glutamatergic NMDA receptors on striatal nNOS activity, we combined the techniques of in vivo amperometry and reverse microdialysis. Striatal NO efflux was monitored proximal to the microdialysis probe in urethane anesthetized rats during local infusion of vehicle or drug. NO efflux elicited by systemic administration of SKF-81297 was blocked following intrastriatal infusion of: 1) the D1/5 receptor antagonist SCH-23390, 2) the nNOS inhibitor 7-nitroindazole, 3) the nonspecific ionotropic glutamate receptor antagonist kynurenic acid, and 4) the selective NMDA receptor antagonist 3-phosphonopropyl-piperazine-2-carboxylic acid. Glycine coperfusion did not affect SKF-81297-induced NO efflux. Furthermore, intrastriatal infusion of SKF-81297 potentiated NO efflux evoked during electrical stimulation of the motor cortex. The facilitatory effects of cortical stimulation and SKF-81297 were both blocked by intrastriatal infusion of SCH-23390, indicating that striatal D1/5 receptor activation is necessary for the activation of nNOS by corticostriatal afferents. These studies demonstrate for the first time that reciprocal DA-glutamate interactions play a critical role in stimulating striatal nNOS activity. PMID:19799710

  20. Patterns, evolution, and severity of striatal injury in insidious- versus acute-onset glutaric aciduria type 1.

    PubMed

    Boy, Nikolas; Garbade, Sven F; Heringer, Jana; Seitz, Angelika; Kölker, Stefan; Harting, Inga

    2018-05-02

    Striatal injury in patients with glutaric aciduria type 1 (GA1) results in a complex, predominantly dystonic, movement disorder. Onset may be acute following acute encephalopathic crisis (AEC) or insidious without apparent acute event. We analyzed clinical and striatal magnetic resonance imaging (MRI) findings in 21 symptomatic GA1 patients to investigate if insidious- and acute-onset patients differed in timing, pattern of striatal injury, and outcome. Eleven patients had acute and ten had insidious onset, two with later AEC (acute-on-insidious). The median onset of dystonia was 10 months in both groups, and severity was greater in patients after AEC (n = 8 severe, n = 5 moderate) than in insidious onset (n = 4 mild, n = 3 moderate, n = 1 severe). Deviations from guideline-recommended basic metabolic treatment were identified in six insidious-onset patients. Striatal lesions were extensive in all acute-onset patients and restricted to the dorsolateral putamen in eight of ten insidious-onset patients. After AEC, the two acute-on-insidious patients had extensive striatal changes superimposed on pre-existing dorsolateral putaminal lesions. Two insidious-onset patients with progressive dystonia without overt AEC also had extensive striatal changes, one with sequential striatal injury revealed by diffusion-weighted imaging. Insidious-onset patients had a latency phase of 3.5 months to 6.5 years between detection and clinical manifestation of dorsolateral putaminal lesions. Insidious-onset type GA1 is characterized by dorsolateral putaminal lesions, less severe dystonia, and an asymptomatic latency phase, despite already existing lesions. Initially normal MRI during the first months and deviations from guideline-recommended treatment in a large proportion of insidious-onset patients substantiate the protective effect of neonatally initiated treatment.

  1. Common limbic and frontal-striatal disturbances in patients with obsessive compulsive disorder, panic disorder and hypochondriasis.

    PubMed

    van den Heuvel, O A; Mataix-Cols, D; Zwitser, G; Cath, D C; van der Werf, Y D; Groenewegen, H J; van Balkom, A J L M; Veltman, D J

    2011-11-01

    Direct comparisons of brain function between obsessive compulsive disorder (OCD) and other anxiety or OCD spectrum disorders are rare. This study aimed to investigate the specificity of altered frontal-striatal and limbic activations during planning in OCD, a prototypical anxiety disorder (panic disorder) and a putative OCD spectrum disorder (hypochondriasis). The Tower of London task, a 'frontal-striatal' task, was used during functional magnetic resonance imaging measurements in 50 unmedicated patients, diagnosed with OCD (n=22), panic disorder (n=14) or hypochondriasis (n=14), and in 22 healthy subjects. Blood oxygen level-dependent (BOLD) signal changes were calculated for contrasts of interest (planning versus baseline and task load effects). Moreover, correlations between BOLD responses and both task performance and state anxiety were analysed. Overall, patients showed a decreased recruitment of the precuneus, caudate nucleus, globus pallidus and thalamus, compared with healthy controls. There were no statistically significant differences in brain activation between the three patient groups. State anxiety was negatively correlated with dorsal frontal-striatal activation. Task performance was positively correlated with dorsal frontal-striatal recruitment and negatively correlated with limbic and ventral frontal-striatal recruitment. Multiple regression models showed that adequate task performance was best explained by independent contributions from dorsolateral prefrontal cortex (positive correlation) and amygdala (negative correlation), even after controlling for state anxiety. Patients with OCD, panic disorder and hypochondriasis share similar alterations in frontal-striatal brain regions during a planning task, presumably partly related to increased limbic activation.

  2. Effort-Based Reinforcement Processing and Functional Connectivity Underlying Amotivation in Medicated Patients with Depression and Schizophrenia.

    PubMed

    Park, Il Ho; Lee, Boung Chul; Kim, Jae-Jin; Kim, Joong Il; Koo, Min-Seung

    2017-04-19

    Amotivation is a common phenotype of major depressive disorder and schizophrenia, which are clinically distinct disorders. Effective treatment targets and strategies can be discovered by examining the dopaminergic reward network function underlying amotivation between these disorders. We conducted an fMRI study in healthy human participants and medicated patients with depression and schizophrenia using an effort-based reinforcement task. We examined regional activations related to reward type (positive and negative reinforcement), effort level, and their composite value, as well as resting-state functional connectivities within the meso-striatal-prefrontal pathway. We found that integrated reward and effort values of low effort-positive reinforcement and high effort-negative reinforcement were behaviorally anticipated and represented in the putamen and medial orbitofrontal cortex activities. Patients with schizophrenia and depression did not show anticipation-related and work-related reaction time reductions, respectively. Greater amotivation severity correlated with smaller work-related putamen activity changes according to reward type in schizophrenia and effort level in depression. Patients with schizophrenia showed feedback-related putamen hyperactivity of low effort compared with healthy controls and depressed patients. The strength of medial orbitofrontal-striatal functional connectivity predicted work-related reaction time reduction of high effort negative reinforcement in healthy controls and amotivation severity in both patients with schizophrenia and those with depression. Patients with depression showed deficient medial orbitofrontal-striatal functional connectivity compared with healthy controls and patients with schizophrenia. These results indicate that amotivation in depression and schizophrenia involves different pathophysiology in the prefrontal-striatal circuitry. SIGNIFICANCE STATEMENT Amotivation is present in both depression and schizophrenia

  3. Impaired thalamocortical connectivity in autism spectrum disorder: a study of functional and anatomical connectivity.

    PubMed

    Nair, Aarti; Treiber, Jeffrey M; Shukla, Dinesh K; Shih, Patricia; Müller, Ralph-Axel

    2013-06-01

    The thalamus plays crucial roles in the development and mature functioning of numerous sensorimotor, cognitive and attentional circuits. Currently limited evidence suggests that autism spectrum disorder may be associated with thalamic abnormalities, potentially related to sociocommunicative and other impairments in this disorder. We used functional connectivity magnetic resonance imaging and diffusion tensor imaging probabilistic tractography to study the functional and anatomical integrity of thalamo-cortical connectivity in children and adolescents with autism spectrum disorder and matched typically developing children. For connectivity with five cortical seeds (prefontal, parieto-occipital, motor, somatosensory and temporal), we found evidence of both anatomical and functional underconnectivity. The only exception was functional connectivity with the temporal lobe, which was increased in the autism spectrum disorders group, especially in the right hemisphere. However, this effect was robust only in partial correlation analyses (partialling out time series from other cortical seeds), whereas findings from total correlation analyses suggest that temporo-thalamic overconnectivity in the autism group was only relative to the underconnectivity found for other cortical seeds. We also found evidence of microstructural compromise within the thalamic motor parcel, associated with compromise in tracts between thalamus and motor cortex, suggesting that the thalamus may play a role in motor abnormalities reported in previous autism studies. More generally, a number of correlations of diffusion tensor imaging and functional connectivity magnetic resonance imaging measures with diagnostic and neuropsychological scores indicate involvement of abnormal thalamocortical connectivity in sociocommunicative and cognitive impairments in autism spectrum disorder.

  4. Cerebellar Influence on Motor Cortex Plasticity: Behavioral Implications for Parkinson’s Disease

    PubMed Central

    Kishore, Asha; Meunier, Sabine; Popa, Traian

    2014-01-01

    Normal motor behavior involves the creation of appropriate activity patterns across motor networks, enabling firing synchrony, synaptic integration, and normal functioning of these networks. Strong topography-specific connections among the basal ganglia, cerebellum, and their projections to overlapping areas in the motor cortices suggest that these networks could influence each other’s plastic responses and functions. The defective striatal signaling in Parkinson’s disease (PD) could therefore lead to abnormal oscillatory activity and aberrant plasticity at multiple levels within the interlinked motor networks. Normal striatal dopaminergic signaling and cerebellar sensory processing functions influence the scaling and topographic specificity of M1 plasticity. Both these functions are abnormal in PD and appear to contribute to the abnormal M1 plasticity. Defective motor map plasticity and topographic specificity within M1 could lead to incorrect muscle synergies, which could manifest as abnormal or undesired movements, and as abnormal motor learning in PD. We propose that the loss of M1 plasticity in PD reflects a loss of co-ordination among the basal ganglia, cerebellar, and cortical inputs which translates to an abnormal plasticity of motor maps within M1 and eventually to some of the motor signs of PD. The initial benefits of dopamine replacement therapy on M1 plasticity and motor signs are lost during the progressive course of disease. Levodopa-induced dyskinesias in patients with advanced PD is linked to a loss of M1 sensorimotor plasticity and the attenuation of dyskinesias by cerebellar inhibitory stimulation is associated with restoration of M1 plasticity. Complimentary interventions should target reestablishing physiological communication between the striatal and cerebellar circuits, and within striato-cerebellar loop. This may facilitate correct motor synergies and reduce abnormal movements in PD. PMID:24834063

  5. Elevated Striatal Reactivity Across Monetary and Social Rewards in Bipolar I Disorder

    PubMed Central

    Dutra, Sunny J.; Cunningham, William A.; Kober, Hedy; Gruber, June

    2016-01-01

    Bipolar disorder (BD) is associated with increased reactivity to rewards and heightened positive affectivity. It is less clear to what extent this heightened reward sensitivity is evident across contexts and what the associated neural mechanisms might be. The present investigation employed both a monetary and social incentive delay task among adults with remitted BD type I (N=24) and a healthy non-psychiatric control group (HC; N=25) using fMRI. Both whole-brain and region-of-interest analyses revealed elevated ventral and dorsal striatal reactivity across monetary and social reward receipt, but not anticipation, in the BD group. Post-hoc analyses further suggested that greater striatal reactivity to reward receipt across monetary and social reward tasks predicted decreased self-reported positive affect when anticipating subsequent rewards in the HC, but not BD, group. Results point toward elevated striatal reactivity to reward receipt as a potential neural mechanism of reward reactivity. PMID:26390194

  6. Distinctive striatal dopamine signaling after dieting and gastric bypass.

    PubMed

    Hankir, Mohammed K; Ashrafian, Hutan; Hesse, Swen; Horstmann, Annette; Fenske, Wiebke K

    2015-05-01

    Highly palatable and/or calorically dense foods, such as those rich in fat, engage the striatum to govern and set complex behaviors. Striatal dopamine signaling has been implicated in hedonic feeding and the development of obesity. Dieting and bariatric surgery have markedly different outcomes on weight loss, yet how these interventions affect central homeostatic and food reward processing remains poorly understood. Here, we propose that dieting and gastric bypass produce distinct changes in peripheral factors with known roles in regulating energy homeostasis, resulting in differential modulation of nigrostriatal and mesolimbic dopaminergic reward circuits. Enhancement of intestinal fat metabolism after gastric bypass may also modify striatal dopamine signaling contributing to its unique long-term effects on feeding behavior and body weight in obese individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Selective functional integration between anterior temporal and distinct fronto-mesolimbic regions during guilt and indignation.

    PubMed

    Green, Sophie; Ralph, Matthew A Lambon; Moll, Jorge; Stamatakis, Emmanuel A; Grafman, Jordan; Zahn, Roland

    2010-10-01

    It has been hypothesized that the experience of different moral sentiments such as guilt and indignation is underpinned by activation in temporal and fronto-mesolimbic regions and that functional integration between these regions is necessary for the differentiated experience of these moral sentiments. A recent fMRI study revealed that the right superior anterior temporal lobe (ATL) was activated irrespective of the context of moral feelings (guilt or indignation). This region has been associated with context-independent conceptual social knowledge which allows us to make fine-grained differentiations between qualities of social behaviours (e.g. "critical" and "faultfinding"). This knowledge is required to make emotional evaluations of social behaviour. In contrast to the context-independent activation of the ATL, there were context-dependent activations within different fronto-mesolimbic regions for guilt and indignation. However, it is unknown whether functional integration occurs between these regions and whether regional patterns of integration are distinctive for the experience of different moral sentiments. Here, we used fMRI and psychophysiological interaction analysis, an established measure of functional integration to investigate this issue. We found selective functional integration between the right superior ATL and a subgenual cingulate region during the experience of guilt and between the right superior ATL and the lateral orbitofrontal cortex for indignation. Our data provide the first evidence for functional integration of conceptual social knowledge representations in the right superior ATL with representations of different feeling contexts in fronto-mesolimbic regions. We speculate that this functional architecture allows for the conceptually differentiated experience of moral sentiments in healthy individuals. Copyright 2010 Elsevier Inc. All rights reserved.

  8. Beta-phenylethylamine stimulates striatal acetylcholine release through activation of the AMPA glutamatergic pathway.

    PubMed

    Ishida, Kota; Murata, Mikio; Kato, Masatoshi; Utsunomiya, Iku; Hoshi, Keiko; Taguchi, Kyoji

    2005-09-01

    Using an in vivo intra-striatal microdialysis technique, we examined the effects of systemically administered beta-phenylethylamine (beta-PEA), a psychomotor stimulating trace amine, on striatal acetylcholine release in freely moving rats. Infusion of N-methyl-D-aspartic acid (NMDA; 10(-5) M) significantly increased acetylcholine release. In addition, locally applied amino-3-hydroxy-5-methylisozasole-4-propionic acid (AMPA; 10(-5) M) significantly increased acetylcholine release in the striatum. Intra-striatal application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10(-5) M), an AMPA-type glutamatergic receptor antagonist, had little effect on acetylcholine release, while application of MK-801 (10(-5) M, 10(-6) M), an NMDA-type glutamatergic receptor antagonist, significantly reduced acetylcholine release. Acetylcholine within striatal perfusate was significantly increased by intraperitoneal administration of beta-PEA in a dose-dependent manner. This increase in acetylcholine release was completely blocked by application of CNQX (10(-5) M) through the microdialysis probe into the striatum. However, increased acetylcholine response to systemic beta-PEA was unaltered by addition of MK-801 to the perfusion medium. These results suggest a regulatory function of beta-PEA, mediated by AMPA-type glutamatergic receptors, on the release of acetylcholine in the rat striatum.

  9. Fronto-parietal regulation of media violence exposure in adolescents: a multi-method study

    PubMed Central

    Strenziok, Maren; Krueger, Frank; Deshpande, Gopikrishna; Lenroot, Rhoshel K.; van der Meer, Elke

    2011-01-01

    Adolescents spend a significant part of their leisure time watching TV programs and movies that portray violence. It is unknown, however, how the extent of violent media use and the severity of aggression displayed affect adolescents’ brain function. We investigated skin conductance responses, brain activation and functional brain connectivity to media violence in healthy adolescents. In an event-related functional magnetic resonance imaging experiment, subjects repeatedly viewed normed videos that displayed different degrees of aggressive behavior. We found a downward linear adaptation in skin conductance responses with increasing aggression and desensitization towards more aggressive videos. Our results further revealed adaptation in a fronto-parietal network including the left lateral orbitofrontal cortex (lOFC), right precuneus and bilateral inferior parietal lobules, again showing downward linear adaptations and desensitization towards more aggressive videos. Granger causality mapping analyses revealed attenuation in the left lOFC, indicating that activation during viewing aggressive media is driven by input from parietal regions that decreased over time, for more aggressive videos. We conclude that aggressive media activates an emotion–attention network that has the capability to blunt emotional responses through reduced attention with repeated viewing of aggressive media contents, which may restrict the linking of the consequences of aggression with an emotional response, and therefore potentially promotes aggressive attitudes and behavior. PMID:20934985

  10. Striatal necrosis in type 1 glutaric aciduria: Different stages in two siblings.

    PubMed

    Sen, Anitha; Pillay, Rajesh Subramonia

    2011-07-01

    Two siblings born of a consanguineous marriage with history of neurologic deterioration were imaged. Imaging features are classical of glutaric aciduria type 1 (GA-1), acute (striatal necrosis) stage in younger sibling, and chronic stage in older sibling. GA-1 is an autosomal recessive disease with typical imaging features. Greater awareness about this condition among clinicians and radiologists is essential for early diagnosis and prevention of its catastrophic consequences. Striatal necrosis with stroke-like signal intensity on imaging correlates with clinical stage of patients.

  11. Striatal necrosis in type 1 glutaric aciduria: Different stages in two siblings

    PubMed Central

    Sen, Anitha; Pillay, Rajesh Subramonia

    2011-01-01

    Two siblings born of a consanguineous marriage with history of neurologic deterioration were imaged. Imaging features are classical of glutaric aciduria type 1 (GA-1), acute (striatal necrosis) stage in younger sibling, and chronic stage in older sibling. GA-1 is an autosomal recessive disease with typical imaging features. Greater awareness about this condition among clinicians and radiologists is essential for early diagnosis and prevention of its catastrophic consequences. Striatal necrosis with stroke-like signal intensity on imaging correlates with clinical stage of patients. PMID:22408669

  12. Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models

    PubMed Central

    Yokoi, Fumiaki; Dang, Mai T.; Zhou, Tong; Li, Yuqing

    2012-01-01

    DYT11 myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonic symptoms and caused by mutations in paternally expressed SGCE, which codes for ɛ-sarcoglycan. Paternally inherited Sgce heterozygous knock-out (KO) mice exhibit motor deficits and spontaneous myoclonus. Abnormal nuclear envelopes have been reported in cellular and mouse models of early-onset DYT1 generalized torsion dystonia; however, the relationship between the abnormal nuclear envelopes and motor symptoms are not clear. Furthermore, it is not known whether abnormal nuclear envelope exists in non-DYT1 dystonia. In the present study, abnormal nuclear envelopes in the striatal medium spiny neurons (MSNs) were found in Sgce KO mice. To analyze whether the loss of ɛ-sarcoglycan in the striatum alone causes abnormal nuclear envelopes, motor deficits or myoclonus, we produced paternally inherited striatum-specific Sgce conditional KO (Sgce sKO) mice and analyzed their phenotypes. Sgce sKO mice exhibited motor deficits in both beam-walking and accelerated rotarod tests, while they did not exhibit abnormal nuclear envelopes, alteration in locomotion, or myoclonus. The results suggest that the loss of ɛ-sarcoglycan in the striatum contributes to motor deficits, while it alone does not produce abnormal nuclear envelopes or myoclonus. Development of therapies targeting the striatum to compensate for the loss of ɛ-sarcoglycan function may rescue the motor deficits in DYT11 M-D patients. PMID:22080833

  13. Changes in corticostriatal connectivity during reinforcement learning in humans.

    PubMed

    Horga, Guillermo; Maia, Tiago V; Marsh, Rachel; Hao, Xuejun; Xu, Dongrong; Duan, Yunsuo; Tau, Gregory Z; Graniello, Barbara; Wang, Zhishun; Kangarlu, Alayar; Martinez, Diana; Packard, Mark G; Peterson, Bradley S

    2015-02-01

    Many computational models assume that reinforcement learning relies on changes in synaptic efficacy between cortical regions representing stimuli and striatal regions involved in response selection, but this assumption has thus far lacked empirical support in humans. We recorded hemodynamic signals with fMRI while participants navigated a virtual maze to find hidden rewards. We fitted a reinforcement-learning algorithm to participants' choice behavior and evaluated the neural activity and the changes in functional connectivity related to trial-by-trial learning variables. Activity in the posterior putamen during choice periods increased progressively during learning. Furthermore, the functional connections between the sensorimotor cortex and the posterior putamen strengthened progressively as participants learned the task. These changes in corticostriatal connectivity differentiated participants who learned the task from those who did not. These findings provide a direct link between changes in corticostriatal connectivity and learning, thereby supporting a central assumption common to several computational models of reinforcement learning. © 2014 Wiley Periodicals, Inc.

  14. Atomoxetine restores the response inhibition network in Parkinson's disease.

    PubMed

    Rae, Charlotte L; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E; Jones, P Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

    2016-08-01

    time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

  15. Electrophysiological signatures of atypical intrinsic brain connectivity networks in autism

    NASA Astrophysics Data System (ADS)

    Shou, Guofa; Mosconi, Matthew W.; Wang, Jun; Ethridge, Lauren E.; Sweeney, John A.; Ding, Lei

    2017-08-01

    Objective. Abnormal local and long-range brain connectivity have been widely reported in autism spectrum disorder (ASD), yet the nature of these abnormalities and their functional relevance at distinct cortical rhythms remains unknown. Investigations of intrinsic connectivity networks (ICNs) and their coherence across whole brain networks hold promise for determining whether patterns of functional connectivity abnormalities vary across frequencies and networks in ASD. In the present study, we aimed to probe atypical intrinsic brain connectivity networks in ASD from resting-state electroencephalography (EEG) data via characterizing the whole brain network. Approach. Connectivity within individual ICNs (measured by spectral power) and between ICNs (measured by coherence) were examined at four canonical frequency bands via a time-frequency independent component analysis on high-density EEG, which were recorded from 20 ASD and 20 typical developing (TD) subjects during an eyes-closed resting state. Main results. Among twelve identified electrophysiological ICNs, individuals with ASD showed hyper-connectivity in individual ICNs and hypo-connectivity between ICNs. Functional connectivity alterations in ASD were more severe in the frontal lobe and the default mode network (DMN) and at low frequency bands. These functional connectivity measures also showed abnormal age-related associations in ICNs related to frontal, temporal and motor regions in ASD. Significance. Our findings suggest that ASD is characterized by the opposite directions of abnormalities (i.e. hypo- and hyper-connectivity) in the hierarchical structure of the whole brain network, with more impairments in the frontal lobe and the DMN at low frequency bands, which are critical for top-down control of sensory systems, as well as for both cognition and social skills.

  16. Neonatal status epilepticus alters prefrontal-striatal circuitry and enhances methamphetamine-induced behavioral sensitization in adolescence.

    PubMed

    Lin, Tzu-Chao; Huang, Li-Tung; Huang, Ya-Ni; Chen, Gunng-Shinng; Wang, Jia-Yi

    2009-02-01

    Neonatal seizures may alter the developing neurocircuitry and cause behavioral abnormalities in adulthood. We found that rats previously subjected to lithium-pilocarpine (LiPC)-induced neonatal status epilepticus (NeoSE) exhibited enhanced behavioral sensitization to methamphetamine (MA) in adolescence. Neurochemically, dopamine (DA) and metabolites were markedly decreased in prefrontal cortex (PFC) and insignificantly changed in striatum by NeoSE, but were increased in both PFC and striatum by NeoSE+MA. Glutamate levels were increased in both PFC and striatum in the NeoSE+MA group. DA turnover, an index of utilization and activity, was increased by NeoSE but reversed by MA in PFC. Gene expression of the regulator of G-protein signaling 4 (RGS4) was downregulated in PFC and striatum by NeoSE and further suppressed by MA. These findings suggest NeoSE affects both dopaminergic and glutamatergic systems in the prefrontal-striatal circuitry that manifests as enhanced behavioral sensitization to MA in adolescence.

  17. Identifying Dynamic Functional Connectivity Changes in Dementia with Lewy Bodies Based on Product Hidden Markov Models.

    PubMed

    Sourty, Marion; Thoraval, Laurent; Roquet, Daniel; Armspach, Jean-Paul; Foucher, Jack; Blanc, Frédéric

    2016-01-01

    Exploring time-varying connectivity networks in neurodegenerative disorders is a recent field of research in functional MRI. Dementia with Lewy bodies (DLB) represents 20% of the neurodegenerative forms of dementia. Fluctuations of cognition and vigilance are the key symptoms of DLB. To date, no dynamic functional connectivity (DFC) investigations of this disorder have been performed. In this paper, we refer to the concept of connectivity state as a piecewise stationary configuration of functional connectivity between brain networks. From this concept, we propose a new method for group-level as well as for subject-level studies to compare and characterize connectivity state changes between a set of resting-state networks (RSNs). Dynamic Bayesian networks, statistical and graph theory-based models, enable one to learn dependencies between interacting state-based processes. Product hidden Markov models (PHMM), an instance of dynamic Bayesian networks, are introduced here to capture both statistical and temporal aspects of DFC of a set of RSNs. This analysis was based on sliding-window cross-correlations between seven RSNs extracted from a group independent component analysis performed on 20 healthy elderly subjects and 16 patients with DLB. Statistical models of DFC differed in patients compared to healthy subjects for the occipito-parieto-frontal network, the medial occipital network and the right fronto-parietal network. In addition, pairwise comparisons of DFC of RSNs revealed a decrease of dependency between these two visual networks (occipito-parieto-frontal and medial occipital networks) and the right fronto-parietal control network. The analysis of DFC state changes thus pointed out networks related to the cognitive functions that are known to be impaired in DLB: visual processing as well as attentional and executive functions. Besides this context, product HMM applied to RSNs cross-correlations offers a promising new approach to investigate structural and

  18. The Functional Organisation of the Fronto-Temporal Language System: Evidence from Syntactic and Semantic Ambiguity

    ERIC Educational Resources Information Center

    Rodd, Jennifer M.; Longe, Olivia A.; Randall, Billi; Tyler, Lorraine K.

    2010-01-01

    Spoken language comprehension is known to involve a large left-dominant network of fronto-temporal brain regions, but there is still little consensus about how the syntactic and semantic aspects of language are processed within this network. In an fMRI study, volunteers heard spoken sentences that contained either syntactic or semantic ambiguities…

  19. Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

    PubMed

    Kaasinen, Valtteri; Vahlberg, Tero

    2017-12-01

    A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. © 2017 American Neurological Association.

  20. Right Fronto-Temporal EEG can Differentiate the Affective Responses to Award-Winning Advertisements.

    PubMed

    Wang, Regina W Y; Huarng, Shy-Peih; Chuang, Shang-Wen

    2018-04-01

    Affective engineering aims to improve service/product design by translating the customer's psychological feelings. Award-winning advertisements (AAs) were selected on the basis of the professional standards that consider creativity as a prerequisite. However, it is unknown if AA is related to satisfactory advertising performance among customers or only to the experts' viewpoints towards the advertisements. This issue in the field of affective engineering and design merits in-depth evaluation. We recruited 30 subjects and performed an electroencephalography (EEG) experiment while watching AAs and non-AAs (NAAs). The event-related potential (ERP) data showed that AAs evoked larger positive potentials 250-1400 [Formula: see text]ms after stimulus onset, particularly in the right fronto-temporal regions. The behavioral results were consistent with the professional recognition given to AAs by experts. The perceived levels of creativity and "product-like" quality were higher for the AAs than for the NAAs. Event-related spectral perturbation (ERSP) analysis further revealed statistically significant differences in the theta, alpha, beta, and gamma band activity in the right fronto-temporal regions between the AAs and NAAs. Our results confirm that EEG features from the time/frequency domains can differentiate affective responses to AAs at a neural circuit level, and provide scientific evidence to support the identification of AAs.

  1. D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans.

    PubMed

    Fazio, Leonardo; Blasi, Giuseppe; Taurisano, Paolo; Papazacharias, Apostolos; Romano, Raffaella; Gelao, Barbara; Ursini, Gianluca; Quarto, Tiziana; Lo Bianco, Luciana; Di Giorgio, Annabella; Mancini, Marina; Popolizio, Teresa; Rubini, Giuseppe; Bertolino, Alessandro

    2011-02-14

    Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. Gain in Body Fat Is Associated with Increased Striatal Response to Palatable Food Cues, whereas Body Fat Stability Is Associated with Decreased Striatal Response

    PubMed Central

    Yokum, Sonja

    2016-01-01

    Cross-sectional brain-imaging studies reveal that obese versus lean humans show greater responsivity of reward and attention regions to palatable food cues, but lower responsivity of reward regions to palatable food receipt. However, these individual differences in responsivity may result from a period of overeating. We conducted a repeated-measures fMRI study to test whether healthy weight adolescent humans who gained body fat over a 2 or 3 year follow-up period show an increase in responsivity of reward and attention regions to a cue signaling impending milkshake receipt and a simultaneous decrease in responsivity of reward regions to milkshake receipt versus adolescents who showed stability of or loss of body fat. Adolescents who gained body fat, who largely remained in a healthy weight range, showed increases in activation in the putamen, mid-insula, Rolandic operculum, and precuneus to a cue signaling impending milkshake receipt versus those who showed stability of or loss of body fat, though these effects were partially driven by reductions in responsivity among the latter groups. Adolescents who gained body fat reported significantly greater milkshake wanting and milkshake pleasantness ratings at follow-up compared to those who lost body fat. Adolescents who gained body fat did not show a reduction in responsivity of reward regions to milkshake receipt or changes in responsivity to receipt and anticipated receipt of monetary reward. Data suggest that initiating a prolonged period of overeating may increase striatal responsivity to food cues, and that maintaining a balance between caloric intake and expenditure may reduce striatal, insular, and Rolandic operculum responsivity. SIGNIFICANCE STATEMENT This novel, repeated-measures brain-imaging study suggests that adolescents who gained body fat over our follow-up period experienced an increase in striatal responsivity to cues for palatable foods compared to those who showed stability of or loss of body fat

  3. Abnormal regional activity and functional connectivity in resting-state brain networks associated with etiology confirmed unilateral pulsatile tinnitus in the early stage of disease.

    PubMed

    Lv, Han; Zhao, Pengfei; Liu, Zhaohui; Li, Rui; Zhang, Ling; Wang, Peng; Yan, Fei; Liu, Liheng; Wang, Guopeng; Zeng, Rong; Li, Ting; Dong, Cheng; Gong, Shusheng; Wang, Zhenchang

    2017-03-01

    Abnormal neural activities can be revealed by resting-state functional magnetic resonance imaging (rs-fMRI) using analyses of the regional activity and functional connectivity (FC) of the networks in the brain. This study was designed to demonstrate the functional network alterations in the patients with pulsatile tinnitus (PT). In this study, we recruited 45 patients with unilateral PT in the early stage of disease (less than 48 months of disease duration) and 45 normal controls. We used regional homogeneity (ReHo) and seed-based FC computational methods to reveal resting-state brain activity features associated with pulsatile tinnitus. Compared with healthy controls, PT patients showed regional abnormalities mainly in the left middle occipital gyrus (MOG), posterior cingulate gyrus (PCC), precuneus and right anterior insula (AI). When these regions were defined as seeds, we demonstrated widespread modification of interaction between the auditory and non-auditory networks. The auditory network was positively connected with the cognitive control network (CCN), which may associate with tinnitus related distress. Both altered regional activity and changed FC were found in the visual network. The modification of interactions of higher order networks were mainly found in the DMN, CCN and limbic networks. Functional connectivity between the left MOG and left parahippocampal gyrus could also be an index to reflect the disease duration. This study helped us gain a better understanding of the characteristics of neural network modifications in patients with pulsatile tinnitus. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Distributed abnormalities of brain white matter architecture in patients with dominant optic atrophy and OPA1 mutations.

    PubMed

    Rocca, Maria A; Bianchi-Marzoli, Stefania; Messina, Roberta; Cascavilla, Maria Lucia; Zeviani, Massimo; Lamperti, Costanza; Milesi, Jacopo; Carta, Arturo; Cammarata, Gabriella; Leocani, Letizia; Lamantea, Eleonora; Bandello, Francesco; Comi, Giancarlo; Falini, Andrea; Filippi, Massimo

    2015-05-01

    Using advanced MRI techniques, we investigated the presence and topographical distribution of brain grey matter (GM) and white matter (WM) alterations in dominant optic atrophy (DOA) patients with genetically proven OPA1 mutation as well as their correlation with clinical and neuro-ophthalmologic findings. Nineteen DOA patients underwent neurological, neuro-ophthalmologic and brainstem auditory evoked potentials (BAEP) evaluations. Voxel-wise methods were applied to assess regional GM and WM abnormalities in patients compared to 20 healthy controls. Visual acuity was reduced in 16 patients. Six DOA patients (4 with missense mutations) had an abnormal I peripheral component (auditory nerve) at BAEP. Compared to controls, DOA patients had significant atrophy of the optic nerves (p < 0.0001). Voxel-based morphometry (VBM) analysis showed that, compared to controls, DOA patients had significant WM atrophy of the chiasm and optic tracts; whereas no areas of GM atrophy were found. Tract-based spatial statistics (TBSS) analysis showed that compared to controls, DOA patients had significantly lower mean diffusivity, axial and radial diffusivity in the WM of the cerebellum, brainstem, thalamus, fronto-occipital-temporal lobes, including the cingulum, corpus callosum, corticospinal tract and optic radiation bilaterally. No abnormalities of fractional anisotropy were detected. No correlations were found between volumetric and diffusivity abnormalities quantified with MRI and clinical and neuro-ophthalmologic measures of disease severity. Consistently with pathological studies, tissue loss in DOA patients is limited to anterior optic pathways reflecting retinal ganglion cell degeneration. Distributed abnormalities of diffusivity indexes might reflect abnormal intracellular mitochondrial morphology as well as alteration of protein levels due to OPA1 mutations.

  5. Effective connectivity within the frontoparietal control network differentiates cognitive control and working memory.

    PubMed

    Harding, Ian H; Yücel, Murat; Harrison, Ben J; Pantelis, Christos; Breakspear, Michael

    2015-02-01

    Cognitive control and working memory rely upon a common fronto-parietal network that includes the inferior frontal junction (IFJ), dorsolateral prefrontal cortex (dlPFC), pre-supplementary motor area/dorsal anterior cingulate cortex (pSMA/dACC), and intraparietal sulcus (IPS). This network is able to flexibly adapt its function in response to changing behavioral goals, mediating a wide range of cognitive demands. Here we apply dynamic causal modeling to functional magnetic resonance imaging data to characterize task-related alterations in the strength of network interactions across distinct cognitive processes. Evidence in favor of task-related connectivity dynamics was accrued across a very large space of possible network structures. Cognitive control and working memory demands were manipulated using a factorial combination of the multi-source interference task and a verbal 2-back working memory task, respectively. Both were found to alter the sensitivity of the IFJ to perceptual information, and to increase IFJ-to-pSMA/dACC connectivity. In contrast, increased connectivity from the pSMA/dACC to the IPS, as well as from the dlPFC to the IFJ, was uniquely driven by cognitive control demands; a task-induced negative influence of the dlPFC on the pSMA/dACC was specific to working memory demands. These results reflect a system of both shared and unique context-dependent dynamics within the fronto-parietal network. Mechanisms supporting cognitive engagement, response selection, and action evaluation may be shared across cognitive domains, while dynamic updating of task and context representations within this network are potentially specific to changing demands on cognitive control. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Dynamic Reorganization of Functional Connectivity Reveals Abnormal Temporal Efficiency in Schizophrenia.

    PubMed

    Sun, Yu; Collinson, Simon L; Suckling, John; Sim, Kang

    2018-06-07

    Emerging evidence suggests that schizophrenia is associated with brain dysconnectivity. Nonetheless, the implicit assumption of stationary functional connectivity (FC) adopted in most previous resting-state functional magnetic resonance imaging (fMRI) studies raises an open question of schizophrenia-related aberrations in dynamic properties of resting-state FC. This study introduces an empirical method to examine the dynamic functional dysconnectivity in patients with schizophrenia. Temporal brain networks were estimated from resting-state fMRI of 2 independent datasets (patients/controls = 18/19 and 53/57 for self-recorded dataset and a publicly available replication dataset, respectively) by the correlation of sliding time-windowed time courses among regions of a predefined atlas. Through the newly introduced temporal efficiency approach and temporal random network models, we examined, for the first time, the 3D spatiotemporal architecture of the temporal brain network. We found that although prominent temporal small-world properties were revealed in both groups, temporal brain networks of patients with schizophrenia in both datasets showed a significantly higher temporal global efficiency, which cannot be simply attributable to head motion and sampling error. Specifically, we found localized changes of temporal nodal properties in the left frontal, right medial parietal, and subcortical areas that were associated with clinical features of schizophrenia. Our findings demonstrate that altered dynamic FC may underlie abnormal brain function and clinical symptoms observed in schizophrenia. Moreover, we provide new evidence to extend the dysconnectivity hypothesis in schizophrenia from static to dynamic brain network and highlight the potential of aberrant brain dynamic FC in unraveling the pathophysiologic mechanisms of the disease.

  7. Context-specific differences in fronto-parieto-occipital effective connectivity during short-term memory maintenance.

    PubMed

    Kundu, Bornali; Chang, Jui-Yang; Postle, Bradley R; Van Veen, Barry D

    2015-07-01

    Although visual short-term memory (VSTM) performance has been hypothesized to rely on two distinct mechanisms, capacity and filtering, the two have not been dissociated using network-level causality measures. Here, we hypothesized that behavioral tasks challenging capacity or distraction filtering would both engage a common network of areas, namely dorsolateral prefrontal cortex (dlPFC), superior parietal lobule (SPL), and occipital cortex, but would do so according to dissociable patterns of effective connectivity. We tested this by estimating directed connectivity between areas using conditional Granger causality (cGC). Consistent with our prediction, the results indicated that increasing mnemonic load (capacity) increased the top-down drive from dlPFC to SPL, and cGC in the alpha (8-14Hz) frequency range was a predominant component of this effect. The presence of distraction during encoding (filtering), in contrast, was associated with increased top-down drive from dlPFC to occipital cortices directly and from SPL to occipital cortices directly, in both cases in the beta (15-25Hz) range. Thus, although a common anatomical network may serve VSTM in different contexts, it does so via specific functions that are carried out within distinct, dynamically configured frequency channels. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Cognitive neuroscience of social emotions and implications for psychopathology: examining embarrassment, guilt, envy, and schadenfreude.

    PubMed

    Jankowski, Kathryn F; Takahashi, Hidehiko

    2014-05-01

    Social emotions are affective states elicited during social interactions and integral for promoting socially appropriate behaviors and discouraging socially inappropriate ones. Social emotion-processing deficits significantly impair interpersonal relationships, and play distinct roles in the manifestation and maintenance of clinical symptomatology. Elucidating the neural correlates of discrete social emotions can serve as a window to better understanding and treating neuropsychiatric disorders. Moral cognition and social emotion-processing broadly recruit a fronto-temporo-subcortical network, supporting empathy, perspective-taking, self-processing, and reward-processing. The present review specifically examines the neural correlates of embarrassment, guilt, envy, and schadenfreude. Embarrassment and guilt are self-conscious emotions, evoked during negative evaluation following norm violations and supported by a fronto-temporo-posterior network. Embarrassment is evoked by social transgressions and recruits greater anterior temporal regions, representing conceptual social knowledge. Guilt is evoked by moral transgressions and recruits greater prefrontal regions, representing perspective-taking and behavioral change demands. Envy and schadenfreude are fortune-of-other emotions, evoked during social comparison and supported by a prefronto-striatal network. Envy represents displeasure in others' fortunes, and recruits increased dorsal anterior cingulate cortex, representing cognitive dissonance, and decreased reward-related striatal regions. Schadenfreude represents pleasure in others' misfortunes, and recruits reduced empathy-related insular regions and increased reward-related striatal regions. Implications for psychopathology and treatment design are discussed. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

  9. Cortico-striatal synaptic defects and OCD-like behaviors in SAPAP3 mutant mice

    PubMed Central

    Welch, Jeffrey M.; Lu, Jing; Rodriguiz, Ramona M.; Trotta, Nicholas C.; Peca, Joao; Ding, Jin-Dong; Feliciano, Catia; Chen, Meng; Adams, J. Paige; Luo, Jianhong; Dudek, Serena M.; Weinberg, Richard J.; Calakos, Nicole; Wetsel, William C.; Feng, Guoping

    2008-01-01

    Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, though the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of SAPAP3 exhibit increased anxiety and compulsive grooming behavior leading to facial hair loss and skin lesions; both behaviors are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural, and biochemical studies of SAPAP3 mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of SAPAP3 in the striatum rescues the synaptic and behavioral defects of SAPAP3 mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviors. PMID:17713528

  10. Functional hierarchy underlies preferential connectivity disturbances in schizophrenia.

    PubMed

    Yang, Genevieve J; Murray, John D; Wang, Xiao-Jing; Glahn, David C; Pearlson, Godfrey D; Repovs, Grega; Krystal, John H; Anticevic, Alan

    2016-01-12

    Schizophrenia may involve an elevated excitation/inhibition (E/I) ratio in cortical microcircuits. It remains unknown how this regulatory disturbance maps onto neuroimaging findings. To address this issue, we implemented E/I perturbations within a neural model of large-scale functional connectivity, which predicted hyperconnectivity following E/I elevation. To test predictions, we examined resting-state functional MRI in 161 schizophrenia patients and 164 healthy subjects. As predicted, patients exhibited elevated functional connectivity that correlated with symptom levels, and was most prominent in association cortices, such as the fronto-parietal control network. This pattern was absent in patients with bipolar disorder (n = 73). To account for the pattern observed in schizophrenia, we integrated neurobiologically plausible, hierarchical differences in association vs. sensory recurrent neuronal dynamics into our model. This in silico architecture revealed preferential vulnerability of association networks to E/I imbalance, which we verified empirically. Reported effects implicate widespread microcircuit E/I imbalance as a parsimonious mechanism for emergent inhomogeneous dysconnectivity in schizophrenia.

  11. Functional hierarchy underlies preferential connectivity disturbances in schizophrenia

    PubMed Central

    Yang, Genevieve J.; Murray, John D.; Wang, Xiao-Jing; Glahn, David C.; Pearlson, Godfrey D.; Repovs, Grega; Krystal, John H.; Anticevic, Alan

    2016-01-01

    Schizophrenia may involve an elevated excitation/inhibition (E/I) ratio in cortical microcircuits. It remains unknown how this regulatory disturbance maps onto neuroimaging findings. To address this issue, we implemented E/I perturbations within a neural model of large-scale functional connectivity, which predicted hyperconnectivity following E/I elevation. To test predictions, we examined resting-state functional MRI in 161 schizophrenia patients and 164 healthy subjects. As predicted, patients exhibited elevated functional connectivity that correlated with symptom levels, and was most prominent in association cortices, such as the fronto-parietal control network. This pattern was absent in patients with bipolar disorder (n = 73). To account for the pattern observed in schizophrenia, we integrated neurobiologically plausible, hierarchical differences in association vs. sensory recurrent neuronal dynamics into our model. This in silico architecture revealed preferential vulnerability of association networks to E/I imbalance, which we verified empirically. Reported effects implicate widespread microcircuit E/I imbalance as a parsimonious mechanism for emergent inhomogeneous dysconnectivity in schizophrenia. PMID:26699491

  12. Chronic nicotine administration differentially affects neurotransmitter release from rat striatal slices.

    PubMed

    Yu, Z J; Wecker, L

    1994-07-01

    The objective of these experiments was to determine whether the chronic administration of nicotine, at a dose regimen that increases the density of nicotine binding sites, alters the nicotine-induced release of [3H]-dopamine ([3H]DA), [3H]norepinephrine ([3H]NE), [3H]-serotonin ([3H]5-HT), or [3H]acetylcholine ([3H]ACh) from rat striatal slices. For these experiments, rats received subcutaneous injections of either saline or nicotine bitartrate [1.76 mg (3.6 mumol)/kg, dissolved in saline] twice daily for 10 days, and neurotransmitter release was measured following preloading of the tissues with [3H]DA, [3H]NE, [3H]5-HT, or [3H]choline. Chronic nicotine administration did not affect the accumulation of tritium by striatal slices, the basal release of radioactivity, or the 25 mM KCl-evoked release of neurotransmitter. Superfusion of striatal slices with 1, 10, and 100 microM nicotine increased [3H]DA release in a concentration-dependent manner, and release from slices from nicotine-injected animals was significantly (p < 0.05) greater than release from saline-injected controls; release from the former increased to 132, 191, and 172% of release from the controls following superfusion with 1, 10, and 100 microM nicotine, respectively. Similarly, [3H]5-HT release increased in a concentration-related manner following superfusion with nicotine, and release from slices from nicotine-injected rats was significantly (p < 0.05) greater than that from controls. [3H]5-HT release from slices from nicotine-injected rats evoked by superfusion with 1 and 10 microM nicotine increased to 453 and 217%, respectively, of release from slices from saline-injected animals. The nicotine-induced release of [3H]NE from striatal slices was also concentration dependent but was unaffected by chronic nicotine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Resting state functional MRI in Parkinson's disease: the impact of deep brain stimulation on 'effective' connectivity.

    PubMed

    Kahan, Joshua; Urner, Maren; Moran, Rosalyn; Flandin, Guillaume; Marreiros, Andre; Mancini, Laura; White, Mark; Thornton, John; Yousry, Tarek; Zrinzo, Ludvic; Hariz, Marwan; Limousin, Patricia; Friston, Karl; Foltynie, Tom

    2014-04-01

    Depleted of dopamine, the dynamics of the parkinsonian brain impact on both 'action' and 'resting' motor behaviour. Deep brain stimulation has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Non-invasive characterizations of induced brain responses, and the effective connectivity underlying them, generally appeals to dynamic causal modelling of neuroimaging data. When the brain is at rest, however, this sort of characterization has been limited to correlations (functional connectivity). In this work, we model the 'effective' connectivity underlying low frequency blood oxygen level-dependent fluctuations in the resting Parkinsonian motor network-disclosing the distributed effects of deep brain stimulation on cortico-subcortical connections. Specifically, we show that subthalamic nucleus deep brain stimulation modulates all the major components of the motor cortico-striato-thalamo-cortical loop, including the cortico-striatal, thalamo-cortical, direct and indirect basal ganglia pathways, and the hyperdirect subthalamic nucleus projections. The strength of effective subthalamic nucleus afferents and efferents were reduced by stimulation, whereas cortico-striatal, thalamo-cortical and direct pathways were strengthened. Remarkably, regression analysis revealed that the hyperdirect, direct, and basal ganglia afferents to the subthalamic nucleus predicted clinical status and therapeutic response to deep brain stimulation; however, suppression of the sensitivity of the subthalamic nucleus to its hyperdirect afferents by deep brain stimulation may subvert the clinical efficacy of deep brain stimulation. Our findings highlight the distributed effects of stimulation on the resting motor network and provide a framework for analysing effective connectivity in resting state functional MRI with strong a priori hypotheses.

  14. Fronto-ethmoidal Osteoma with Secondary Intradural Mucocele Extension causing Frontal Lobe Syndrome and Pneumocephalus: Case Report and Review of the Literature.

    PubMed

    Maria, Licci; Christian, Zweifel; Jürgen, Hench; Raphael, Guzman; Jehuda, Soleman

    2018-04-18

    Paranasal sinus osteoma is a common, asymptomatic, histologically benign, and slow-growing tumor. However, it can give rise to secondary pathologies such as a mucocele in about 50% of the cases. Rarely, intracranial and orbital extension is present leading to rhinoliquorrhea, pneumocephalus, or neurological and visual impairment, which might be potentially life-threatening. A 49-year old man presented with an acute frontal lobe syndrome and rhinoliquorrhea. Cranial magnetic resonance tomography showed a suspected fronto-ethmoidal osteoma with a mucocele expanding intradurally, into the left frontal lobe. It was accompanied by pneumocephalus and showed communication with the left lateral ventricle. Through a bifrontal craniotomy in toto resection of the fronto-ethmoidal bony tumor and the intradural mucocele was performed, while thereafter the frontal sinus was cranialized using a pedunculated periosteal flap. Postoperative recovery was uneventful with complete resolvement of the tension pneumocephalus and the rhinoliquorrhea, and led to an improvement of the frontal lobe syndrome. We present a rare case of pneumocephalus caused by a fronto-ethmoidal osteoma associated with an intradural mucocele. A review of the literature, focusing on the surgical strategies in such cases, is provided. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Spatio-temporal source cluster analysis reveals fronto-temporal auditory change processing differences within a shared autistic and schizotypal trait phenotype.

    PubMed

    Ford, Talitha C; Woods, Will; Crewther, David P

    2017-01-01

    Social Disorganisation (SD) is a shared autistic and schizotypal phenotype that is present in the subclinical population. Auditory processing deficits, particularly in mismatch negativity/field (MMN/F) have been reported across both spectrum disorders. This study investigates differences in MMN/F cortical spatio-temporal source activity between higher and lower quintiles of the SD spectrum. Sixteen low (9 female) and 19 high (9 female) SD subclinical adults (18-40years) underwent magnetoencephalography (MEG) during an MMF paradigm where standard tones (50ms) were interrupted by infrequent duration deviants (100ms). Spatio-temporal source cluster analysis with permutation testing revealed no difference between the groups in source activation to the standard tone. To the deviant tone however, there was significantly reduced right hemisphere fronto-temporal and insular cortex activation for the high SD group ( p = 0.038). The MMF, as a product of the cortical response to the deviant minus that to the standard, did not differ significantly between the high and low Social Disorganisation groups. These data demonstrate a deficit in right fronto-temporal processing of an auditory change for those with more of the shared SD phenotype, indicating that right fronto-temporal auditory processing may be associated with psychosocial functioning.

  16. Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

    PubMed

    Robertson, Chelsea L; Ishibashi, Kenji; Chudzynski, Joy; Mooney, Larissa J; Rawson, Richard A; Dolezal, Brett A; Cooper, Christopher B; Brown, Amira K; Mandelkern, Mark A; London, Edythe D

    2016-05-01

    Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

  17. Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment

    PubMed Central

    Robertson, Chelsea L; Ishibashi, Kenji; Chudzynski, Joy; Mooney, Larissa J; Rawson, Richard A; Dolezal, Brett A; Cooper, Christopher B; Brown, Amira K; Mandelkern, Mark A; London, Edythe D

    2016-01-01

    Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [18F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence. PMID:26503310

  18. Reduced prefrontal connectivity in psychopathy.

    PubMed

    Motzkin, Julian C; Newman, Joseph P; Kiehl, Kent A; Koenigs, Michael

    2011-11-30

    Linking psychopathy to a specific brain abnormality could have significant clinical, legal, and scientific implications. Theories on the neurobiological basis of the disorder typically propose dysfunction in a circuit involving ventromedial prefrontal cortex (vmPFC). However, to date there is limited brain imaging data to directly test whether psychopathy may indeed be associated with any structural or functional abnormality within this brain area. In this study, we employ two complementary imaging techniques to assess the structural and functional connectivity of vmPFC in psychopathic and non-psychopathic criminals. Using diffusion tensor imaging, we show that psychopathy is associated with reduced structural integrity in the right uncinate fasciculus, the primary white matter connection between vmPFC and anterior temporal lobe. Using functional magnetic resonance imaging, we show that psychopathy is associated with reduced functional connectivity between vmPFC and amygdala as well as between vmPFC and medial parietal cortex. Together, these data converge to implicate diminished vmPFC connectivity as a characteristic neurobiological feature of psychopathy.

  19. Shared and Disorder-Specific Neurocomputational Mechanisms of Decision-Making in Autism Spectrum Disorder and Obsessive-Compulsive Disorder.

    PubMed

    Carlisi, Christina O; Norman, Luke; Murphy, Clodagh M; Christakou, Anastasia; Chantiluke, Kaylita; Giampietro, Vincent; Simmons, Andrew; Brammer, Michael; Murphy, Declan G; Mataix-Cols, David; Rubia, Katya

    2017-12-01

    Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) often share phenotypes of repetitive behaviors, possibly underpinned by abnormal decision-making. To compare neural correlates underlying decision-making between these disorders, brain activation of boys with ASD (N = 24), OCD (N = 20) and typically developing controls (N = 20) during gambling was compared, and computational modeling compared performance. Patients were unimpaired on number of risky decisions, but modeling showed that both patient groups had lower choice consistency and relied less on reinforcement learning compared to controls. ASD individuals had disorder-specific choice perseverance abnormalities compared to OCD individuals. Neurofunctionally, ASD and OCD boys shared dorsolateral/inferior frontal underactivation compared to controls during decision-making. During outcome anticipation, patients shared underactivation compared to controls in lateral inferior/orbitofrontal cortex and ventral striatum. During reward receipt, ASD boys had disorder-specific enhanced activation in inferior frontal/insular regions relative to OCD boys and controls. Results showed that ASD and OCD individuals shared decision-making strategies that differed from controls to achieve comparable performance to controls. Patients showed shared abnormalities in lateral-(orbito)fronto-striatal reward circuitry, but ASD boys had disorder-specific lateral inferior frontal/insular overactivation, suggesting that shared and disorder-specific mechanisms underpin decision-making in these disorders. Findings provide evidence for shared neurobiological substrates that could serve as possible future biomarkers. © The Author 2017. Published by Oxford University Press.

  20. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

    PubMed

    Bossong, Matthijs G; Mehta, Mitul A; van Berckel, Bart N M; Howes, Oliver D; Kahn, René S; Stokes, Paul R A

    2015-08-01

    Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.