Effect of D-cycloserine in conjunction with fear extinction training on extracellular signal-regulated kinase activation in the medial prefrontal cortex and amygdala in rat.

PubMed

Gupta, Subhash C; Hillman, Brandon G; Prakash, Anand; Ugale, Rajesh R; Stairs, Dustin J; Dravid, Shashank M

2013-06-01

D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity [phospho-extracellular signal-regulated kinase (pERK)] markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24-28 days old) increased c-fos- and pERK-stained neurons in both the prelimbic and infralimbic division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus of the central amygdala. Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in the mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in the infralimbic prefrontal cortex, prelimbic prefrontal cortex intercalated cells and lateral nucleus of the central amygdala, compared with saline control. In the synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared with context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS, the conjunction with extinction training led to an increase in iGluR subunit expression, compared with the extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Emotion recognition and theory of mind are related to gray matter volume of the prefrontal cortex in schizophrenia.

PubMed

Maat, Arija; van Haren, Neeltje E M; Bartholomeusz, Cali F; Kahn, René S; Cahn, Wiepke

2016-02-01

Investigations of social cognition in schizophrenia have demonstrated consistent impairments compared to healthy controls. Functional imaging studies in schizophrenia patients and healthy controls have revealed that social cognitive processing depends critically on the amygdala and the prefrontal cortex (PFC). However, the relationship between social cognition and structural brain abnormalities in these regions in schizophrenia patients is less well understood. Measures of facial emotion recognition and theory of mind (ToM), two key social cognitive abilities, as well as face perception and IQ, were assessed in 166 patients with schizophrenia and 134 healthy controls. MRI brain scans were acquired. Automated parcellation of the brain to determine gray matter volume of the amygdala and the superior, middle, inferior and orbital PFC was performed. Between-group analyses showed poorer recognition of angry faces and ToM performance, and decreased amygdala and PFC gray matter volumes in schizophrenia patients as compared to healthy controls. Moreover, in schizophrenia patients, recognition of angry faces was associated with inferior PFC gray matter volume, particularly the pars triangularis (p=0.006), with poor performance being related to reduced pars triangularis gray matter volume. In addition, ToM ability was related to PFC gray matter volume, particularly middle PFC (p=0.001), in that poor ToM skills in schizophrenia patients were associated with reduced middle PFC gray matter volume. In conclusion, reduced PFC, but not amygdala, gray matter volume is associated with social cognitive deficits in schizophrenia. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Dysregulation of prefrontal cortex-mediated slow evolving limbic dynamics drives stress-induced emotional pathology

PubMed Central

Hultman, Rainbo; Mague, Stephen D.; Li, Qiang; Katz, Brittany M.; Michel, Nadine; Lin, Lizhen; Wang, Joyce; David, Lisa K.; Blount, Cameron; Chandy, Rithi; Carlson, David; Ulrich, Kyle; Carin, Lawrence; Dunson, David; Kumar, Sunil; Deisseroth, Karl; Moore, Scott D.; Dzirasa, Kafui

2016-01-01

Summary Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social-defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions. PMID:27346529

Regulating prefrontal cortex activation: an emerging role for the 5-HT₂A serotonin receptor in the modulation of emotion-based actions?

PubMed

Aznar, Susana; Klein, Anders B

2013-12-01

The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.

Altered amygdala-prefrontal connectivity during emotion perception in schizophrenia.

PubMed

Bjorkquist, Olivia A; Olsen, Emily K; Nelson, Brady D; Herbener, Ellen S

2016-08-01

Individuals with schizophrenia evidence impaired emotional functioning. Abnormal amygdala activity has been identified as an etiological factor underlying affective impairment in this population, but the exact nature remains unclear. The current study utilized psychophysiological interaction analyses to examine functional connectivity between the amygdala and medial prefrontal cortex (mPFC) during an emotion perception task. Participants with schizophrenia (SZ) and healthy controls (HC) viewed and rated positive, negative, and neutral images while undergoing functional neuroimaging. Results revealed a significant group difference in right amygdala-mPFC connectivity during perception of negative versus neutral images. Specifically, HC participants demonstrated positive functional coupling between the amygdala and mPFC, consistent with co-active processing of salient information. In contrast, SZ participants evidenced negative functional coupling, consistent with top-down inhibition of the amygdala by the mPFC. A significant positive correlation between connectivity strength during negative image perception and clinician-rated social functioning was also observed in SZ participants, such that weaker right amygdala-mPFC coupling during negative compared to neutral image perception was associated with poorer social functioning. Overall, results suggest that emotional dysfunction and associated deficits in functional outcome in schizophrenia may relate to abnormal interactions between the amygdala and mPFC during perception of emotional stimuli. This study adds to the growing literature on abnormal functional connections in schizophrenia and supports the functional disconnection hypothesis of schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

Amygdala habituation and prefrontal functional connectivity in youth with autism spectrum disorders.

PubMed

Swartz, Johnna R; Wiggins, Jillian Lee; Carrasco, Melisa; Lord, Catherine; Monk, Christopher S

2013-01-01

Amygdala habituation, the rapid decrease in amygdala responsiveness to the repeated presentation of stimuli, is fundamental to the nervous system. Habituation is important for maintaining adaptive levels of arousal to predictable social stimuli and decreased habituation is associated with heightened anxiety. Input from the ventromedial prefrontal cortex (vmPFC) regulates amygdala activity. Although previous research has shown abnormal amygdala function in youth with autism spectrum disorders (ASD), no study has examined amygdala habituation in a young sample or whether habituation is related to amygdala connectivity with the vmPFC. Data were analyzed from 32 children and adolescents with ASD and 56 typically developing controls who underwent functional magnetic resonance imaging while performing a gender identification task for faces that were fearful, happy, sad, or neutral. Habituation was tested by comparing amygdala activation to faces during the first half versus the second half of the session. VmPFC-amygdala connectivity was examined through psychophysiologic interaction analysis. Youth with ASD had decreased amygdala habituation to sad and neutral faces compared with controls. Moreover, decreased amygdala habituation correlated with autism severity as measured by the Social Responsiveness Scale. There was a group difference in vmPFC-amygdala connectivity while viewing sad faces, and connectivity predicted amygdala habituation to sad faces in controls. Sustained amygdala activation to faces suggests that repeated face presentations are processed differently in individuals with ASD, which could contribute to social impairments. Abnormal modulation of the amygdala by the vmPFC may play a role in decreased habituation. Copyright © 2013 American Academy of Child & Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Putting race in context: social class modulates processing of race in the ventromedial prefrontal cortex and amygdala

PubMed Central

Hitlin, Steven; Magnotta, Vincent; Tranel, Daniel

2017-01-01

Abstract A growing body of literature demonstrates that racial group membership can influence neural responses, e.g. when individuals perceive or interact with persons of another race. However, little attention has been paid to social class, a factor that interacts with racial inequalities in American society. We extend previous literature on race-related neural activity by focusing on how the human brain responds to racial out-groups cast in positively valued social class positions vs less valued ones. We predicted that the ventromedial prefrontal cortex (vmPFC) and the amygdala would have functionally dissociable roles, with the vmPFC playing a more significant role within socially valued in-groups (i.e. the middle-class) and the amygdala having a more crucial role for socially ambivalent and threatening categories (i.e. upper and lower class). We tested these predictions with two complementary studies: (i) a neuropsychological experiment with patients with the vmPFC or amygdala lesions, contrasted with brain damaged and normal comparison participants, and (ii) a functional magnetic resonance imaging experiment with 15 healthy adults. Our findings suggest that two distinct mechanisms underlie class-based racial evaluations, one engaging the vmPFC for positively identified in-group class and another recruiting the amygdala for the class groups that are marginalized or perceived as potential threats. PMID:28398590

Putting race in context: social class modulates processing of race in the ventromedial prefrontal cortex and amygdala.

PubMed

Firat, Rengin B; Hitlin, Steven; Magnotta, Vincent; Tranel, Daniel

2017-08-01

A growing body of literature demonstrates that racial group membership can influence neural responses, e.g. when individuals perceive or interact with persons of another race. However, little attention has been paid to social class, a factor that interacts with racial inequalities in American society. We extend previous literature on race-related neural activity by focusing on how the human brain responds to racial out-groups cast in positively valued social class positions vs less valued ones. We predicted that the ventromedial prefrontal cortex (vmPFC) and the amygdala would have functionally dissociable roles, with the vmPFC playing a more significant role within socially valued in-groups (i.e. the middle-class) and the amygdala having a more crucial role for socially ambivalent and threatening categories (i.e. upper and lower class). We tested these predictions with two complementary studies: (i) a neuropsychological experiment with patients with the vmPFC or amygdala lesions, contrasted with brain damaged and normal comparison participants, and (ii) a functional magnetic resonance imaging experiment with 15 healthy adults. Our findings suggest that two distinct mechanisms underlie class-based racial evaluations, one engaging the vmPFC for positively identified in-group class and another recruiting the amygdala for the class groups that are marginalized or perceived as potential threats. © The Author (2017). Published by Oxford University Press.

Progesterone modifies the responsivity of the amygdala-mPFC connection in male but not female Wistar rats.

PubMed

Contreras, Carlos M; Gutiérrez-García, Ana G

2017-05-10

Amygdala-medial prefrontal cortex (mPFC) connections partially regulate fear, anxiety, and the acquisition of conditioned fear. Progesterone exerts some effects on anxiety and fear. Currently unknown, however, are the actions of progesterone on the responsivity of amygdala-mPFC connections and possible sex differences. We performed single-unit extracellular recordings from the prelimbic (PL) and infralimbic (IL) cortices of the mPFC during stimulation of the basal amygdala (BA) in anesthetized male and diestrus female rats. Basal amygdala stimulation produced an initial excitatory paucisynaptic response that was similar between sexes and unaffected by progesterone. A long-lasting inhibitory response followed the initial brief excitatory response, which was more pronounced in the PL region in males. The unit activity ratio analysis indicated that progesterone negated the sex difference in the PL region response to BA stimulation. The results suggest that progesterone decreases the responsivity to amygdala stimulation, particularly in males compared with diestrus females, which may be related to sex differences in the strategies to cope with threatening situations. Copyright © 2017 Elsevier B.V. All rights reserved.

Amygdala activity and prefrontal cortex-amygdala effective connectivity to emerging emotional faces distinguish remitted and depressed mood states in bipolar disorder.

PubMed

Perlman, Susan B; Almeida, Jorge R C; Kronhaus, Dina M; Versace, Amelia; Labarbara, Edmund J; Klein, Crystal R; Phillips, Mary L

2012-03-01

Few studies have employed effective connectivity (EC) to examine the functional integrity of neural circuitry supporting abnormal emotion processing in bipolar disorder (BD), a key feature of the illness. We used Granger Causality Mapping (GCM) to map EC between the prefrontal cortex (PFC) and bilateral amygdala and a novel paradigm to assess emotion processing in adults with BD. Thirty-one remitted adults with BD [(remitted BD), mean age = 32 years], 21 adults with BD in a depressed episode [(depressed BD), mean age = 33 years], and 25 healthy control participants [(HC), mean age = 31 years] performed a block-design emotion processing task requiring color-labeling of a color flash superimposed on a task-irrelevant face morphing from neutral to emotional (happy, sad, angry, or fearful). GCM measured EC preceding (top-down) and following (bottom-up) activity between the PFC and the left and right amygdalae. Our findings indicated patterns of abnormally elevated bilateral amygdala activity in response to emerging fearful, sad, and angry facial expressions in remitted-BD subjects versus HC, and abnormally elevated right amygdala activity to emerging fearful faces in depressed-BD subjects versus HC. We also showed distinguishable patterns of abnormal EC between the amygdala and dorsomedial and ventrolateral PFC, especially to emerging happy and sad facial expressions in remitted-BD and depressed-BD subjects. EC measures of neural system level functioning can further understanding of neural mechanisms associated with abnormal emotion processing and regulation in BD. Our findings suggest major differences in recruitment of amygdala-PFC circuitry, supporting implicit emotion processing between remitted-BD and depressed-BD subjects, which may underlie changes from remission to depression in BD. © 2012 John Wiley and Sons A/S.

Neural Correlates of Hostile Jokes: Cognitive and Motivational Processes in Humor Appreciation.

PubMed

Chan, Yu-Chen; Liao, Yi-Jun; Tu, Cheng-Hao; Chen, Hsueh-Chih

2016-01-01

Hostile jokes (HJs) provide aggressive catharsis and a feeling of superiority. Behavioral research has found that HJs are perceived as funnier than non-hostile jokes (NJs). The purpose of the present study was to identify the neural correlates of the interaction between type and humor by comparing HJs, NJs, and their corresponding hostile sentences (HSs) and non-hostile sentences (NSs). HJs primarily showed activation in the dorsomedial prefrontal cortex (dmPFC) and midbrain compared with the corresponding hostile baseline. Conversely, NJs primarily revealed activation in the ventromedial PFC (vmPFC), amygdala, midbrain, ventral anterior cingulate cortex, and nucleus accumbens (NAcc) compared with the corresponding non-hostile baseline. These results support the critical role of the medial PFC (mPFC) for the neural correlates of social cognition and socio-emotional processing in response to different types of jokes. Moreover, the processing of HJs showed increased activation in the dmPFC, which suggested cognitive operations of social motivation, whereas the processing of NJs displayed increased activation in the vmPFC, which suggested social-affective engagement. HJs versus NJs primarily showed increased activation in the dmPFC and midbrain, whereas NJs versus HJs primarily displayed greater activation in the amygdala and midbrain. The psychophysiological interaction (PPI) analysis demonstrated functional coupling of the dmPFC-dlPFC and midbrain-dmPFC for HJs and functional coupling of the vmPFC-midbrain and amygdala-midbrain-NAcc for NJs. Surprisingly, HJs were not perceived as funnier than NJs. Future studies could further investigate the neural correlates of potentially important traits of high-hostility tendencies in humor appreciation based on the psychoanalytic and superiority theories of humor.

Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology.

PubMed

Hultman, Rainbo; Mague, Stephen D; Li, Qiang; Katz, Brittany M; Michel, Nadine; Lin, Lizhen; Wang, Joyce; David, Lisa K; Blount, Cameron; Chandy, Rithi; Carlson, David; Ulrich, Kyle; Carin, Lawrence; Dunson, David; Kumar, Sunil; Deisseroth, Karl; Moore, Scott D; Dzirasa, Kafui

2016-07-20

Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1 Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

Distinct Contributions of the Basolateral Amygdala and the Medial Prefrontal Cortex to Learning and Relearning Extinction of Context Conditioned Fear

ERIC Educational Resources Information Center

Laurent, Vincent; Westbrook, R. Frederick

2008-01-01

We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but…

The neurobiology of emotion regulation in posttraumatic stress disorder: Amygdala downregulation via real-time fMRI neurofeedback.

PubMed

Nicholson, Andrew A; Rabellino, Daniela; Densmore, Maria; Frewen, Paul A; Paret, Christian; Kluetsch, Rosemarie; Schmahl, Christian; Théberge, Jean; Neufeld, Richard W J; McKinnon, Margaret C; Reiss, Jim; Jetly, Rakesh; Lanius, Ruth A

2017-01-01

Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real-time fMRI neurofeedback (rt-fMRI-nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt-fMRI-nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task-based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala- and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top-down and bottom-up information flow with regard to observed PFC-amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt-fMRI-nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541-560, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A model of amygdala-hippocampal-prefrontal interaction in fear conditioning and extinction in animals

PubMed Central

Moustafa, Ahmed A.; Gilbertson, Mark W.; Orr, Scott P.; Herzallah, Mohammad M.; Servatius, Richard. J.; Myers, Catherine E.

2012-01-01

Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning. PMID:23164732

Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress.

PubMed

Abelaira, Helena M; Réus, Gislaine Z; Ignácio, Zuleide M; Dos Santos, Maria Augusta B; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Danielski, Lucineia G; Petronilho, Fabricia; Carvalho, André F; Quevedo, João

2017-09-01

Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine's antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against oxidative stress, without affecting inflammation parameters.

Resting-state functional connectivity between amygdala and the ventromedial prefrontal cortex following fear reminder predicts fear extinction

PubMed Central

Feng, Pan; Zheng, Yong

2016-01-01

Investigations of fear conditioning have elucidated the neural mechanisms of fear acquisition, consolidation and extinction, but it is not clear how the neural activation following fear reminder influence the following extinction. To address this question, we measured human brain activity following fear reminder using resting-state functional magnetic resonance imaging, and investigated whether the extinction effect can be predicted by resting-state functional connectivity (RSFC). Behaviorally, we found no significant differences of fear ratings between the reminder group and the no reminder group at the fear acquisition and extinction stages, but spontaneous recovery during re-extinction stage appeared only in the no reminder group. Imaging data showed that functional connectivity between ventromedial prefrontal cortex (vmPFC) and amygdala in the reminder group was greater than that in the no reminder group after fear memory reactivation. More importantly, the functional connectivity between amygdala and vmPFC of the reminder group after fear memory reactivation was positively correlated with extinction effect. These results suggest RSFC between amygdala and the vmPFC following fear reminder can predict fear extinction, which provide important insight into the neural mechanisms of fear memory after fear memory reactivation. PMID:27013104

Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome.

PubMed

Huang, Wen-Chin; Chen, Youjun; Page, Damon T

2016-11-15

Multiple autism risk genes converge on the regulation of mTOR signalling, which is a key effector of neuronal growth and connectivity. We show that mTOR signalling is dysregulated during early postnatal development in the cerebral cortex of germ-line heterozygous Pten mutant mice (Pten +/- ), which model macrocephaly/autism syndrome. The basolateral amygdala (BLA) receives input from subcortical-projecting neurons in the medial prefrontal cortex (mPFC). Analysis of mPFC to BLA axonal projections reveals that Pten +/- mice exhibit increased axonal branching and connectivity, which is accompanied by increased activity in the BLA in response to social stimuli and social behavioural deficits. The latter two phenotypes can be suppressed by pharmacological inhibition of S6K1 during early postnatal life or by reducing the activity of mPFC-BLA circuitry in adulthood. These findings identify a mechanism of altered connectivity that has potential relevance to the pathophysiology of macrocephaly/autism syndrome and autism spectrum disorders featuring dysregulated mTOR signalling.

The Central Amygdala Nucleus is Critical for Incubation of Methamphetamine Craving

PubMed Central

Li, Xuan; Zeric, Tamara; Kambhampati, Sarita; Bossert, Jennifer M; Shaham, Yavin

2015-01-01

Cue-induced methamphetamine seeking progressively increases after withdrawal but mechanisms underlying this ‘incubation of methamphetamine craving' are unknown. Here we studied the role of central amygdala (CeA), ventral medial prefrontal cortex (vmPFC), and orbitofrontal cortex (OFC), brain regions implicated in incubation of cocaine and heroin craving, in incubation of methamphetamine craving. We also assessed the role of basolateral amygdala (BLA) and dorsal medial prefrontal cortex (dmPFC). We trained rats to self-administer methamphetamine (10 days; 9 h/day, 0.1 mg/kg/infusion) and tested them for cue-induced methamphetamine seeking under extinction conditions during early (2 days) or late (4–5 weeks) withdrawal. We first confirmed that ‘incubation of methamphetamine craving' occurs under our experimental conditions. Next, we assessed the effect of reversible inactivation of CeA or BLA by GABAA+GABAB receptor agonists (muscimol+baclofen, 0.03+0.3 nmol) on cue-induced methamphetamine seeking during early and late withdrawal. We also assessed the effect of muscimol+baclofen reversible inactivation of vmPFC, dmPFC, and OFC on ‘incubated' cue-induced methamphetamine seeking during late withdrawal. Lever presses in the cue-induced methamphetamine extinction tests were higher during late withdrawal than during early withdrawal (incubation of methamphetamine craving). Muscimol+baclofen injections into CeA but not BLA decreased cue-induced methamphetamine seeking during late but not early withdrawal. Muscimol+baclofen injections into dmPFC, vmPFC, or OFC during late withdrawal had no effect on incubated cue-induced methamphetamine seeking. Together with previous studies, results indicate that the CeA has a critical role in incubation of both drug and non-drug reward craving and demonstrate an unexpected dissociation in mechanisms of incubation of methamphetamine vs cocaine craving. PMID:25475163

Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure.

PubMed

Hervig, Mona El-Sayed; Jensen, Nadja Cecilie Hvid; Rasmussen, Nadja Bredo; Rydbirk, Rasmus; Olesen, Mikkel Vestergaard; Hay-Schmidt, Anders; Pakkenberg, Bente; Aznar, Susana

2017-05-30

The medial prefrontal cortex (PFC) plays a major role in executive function by exerting a top-down control onto subcortical areas. Novelty-induced frontal cortex activation is 5-HT 2A receptor (5-HT 2A R) dependent. Here, we further investigated how blockade of 5-HT 2A Rs in mice exposed to a novel open-field arena affects medial PFC activation and basolateral amygdala (BLA) reactivity. We used c-Fos immunoreactivity (IR) as a marker of neuronal activation and stereological quantification for obtaining the total number of c-Fos-IR neurons as a measure of regional activation. We further examined the impact of 5-HT 2A R blockade on the striatal-projecting BLA neurons. Systemic administration of ketanserin (0.5mg/kg) prior to novel open-field exposure resulted in reduced total numbers of c-Fos-IR cells in dorsomedial PFC areas and the BLA. Moreover, there was a positive correlation between the relative time spent in the centre of the open-field and BLA c-Fos-IR in the ketanserin-treated animals. Unilateral medial PFC lesions blocked this effect, ascertaining an involvement of this frontal cortex area. On the other hand, medial PFC lesioning exacerbated the more anxiogenic-like behaviour of the ketanserin-treated animals, upholding its involvement in modulating averseness. Ketanserin did not affect the number of activated striatal-projecting BLA neurons (measured by number of Cholera Toxin b (CTb) retrograde labelled neurons also being c-Fos-IR) following CTb injection in the ventral striatum. These results support a role of 5-HT 2A R activation in modulating mPFC and BLA activation during exposure to a novel environment, which may be interrelated. Conversely, 5-HT 2A R blockade does not seem to affect the amygdala-striatal projection. Copyright © 2017 Elsevier B.V. All rights reserved.

Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory

PubMed Central

Hübner, Cora; Bosch, Daniel; Gall, Andrea; Lüthi, Andreas; Ehrlich, Ingrid

2014-01-01

Many lines of evidence suggest that a reciprocally interconnected network comprising the amygdala, ventral hippocampus (vHC), and medial prefrontal cortex (mPFC) participates in different aspects of the acquisition and extinction of conditioned fear responses and fear behavior. This could at least in part be mediated by direct connections from mPFC or vHC to amygdala to control amygdala activity and output. However, currently the interactions between mPFC and vHC afferents and their specific targets in the amygdala are still poorly understood. Here, we use an ex-vivo optogenetic approach to dissect synaptic properties of inputs from mPFC and vHC to defined neuronal populations in the basal amygdala (BA), the area that we identify as a major target of these projections. We find that BA principal neurons (PNs) and local BA interneurons (INs) receive monosynaptic excitatory inputs from mPFC and vHC. In addition, both these inputs also recruit GABAergic feedforward inhibition in a substantial fraction of PNs, in some neurons this also comprises a slow GABAB-component. Amongst the innervated PNs we identify neurons that project back to subregions of the mPFC, indicating a loop between neurons in mPFC and BA, and a pathway from vHC to mPFC via BA. Interestingly, mPFC inputs also recruit feedforward inhibition in a fraction of INs, suggesting that these inputs can activate dis-inhibitory circuits in the BA. A general feature of both mPFC and vHC inputs to local INs is that excitatory inputs display faster rise and decay kinetics than in PNs, which would enable temporally precise signaling. However, mPFC and vHC inputs to both PNs and INs differ in their presynaptic release properties, in that vHC inputs are more depressing. In summary, our data describe novel wiring, and features of synaptic connections from mPFC and vHC to amygdala that could help to interpret functions of these interconnected brain areas at the network level. PMID:24634648

Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder.

PubMed

Morey, Rajendra A; Haswell, Courtney C; Hooper, Stephen R; De Bellis, Michael D

2016-02-01

Posttraumatic stress disorder (PTSD) is considered a disorder of recovery where individuals fail to learn and retain extinction of the traumatic fear response. In maltreated youth, PTSD is common, chronic, and associated with comorbidity. Studies of extinction-related structural volumes (amygdala, hippocampus, anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC)) and this stress diathesis, in maltreated youth were not previously investigated. In this cross-sectional study, neuroanatomical volumes associated with extinction in maltreated youth with PTSD (N=31), without PTSD (N=32), and in non-maltreated healthy volunteers (n=57) were examined using magnetic resonance imaging. Groups were sociodemographically similar. Participants underwent extensive assessments for strict inclusion/exclusion criteria and DSM-IV disorders. Maltreated youth with PTSD demonstrated decreased right vmPFC volumes compared with both maltreated youth without PTSD and non-maltreated controls. Maltreated youth without PTSD demonstrated larger left amygdala and right hippocampal volumes compared with maltreated youth with PTSD and non-maltreated control youth. PTSD symptoms inversely correlated with right and left hippocampal and left amygdala volumes. Confirmatory masked voxel base morphometry analyses demonstrated greater medial orbitofrontal cortex gray matter intensity in controls than maltreated youth with PTSD. Volumetric results were not influenced by psychopathology or maltreatment variables. We identified volumetric differences in extinction-related structures between maltreated youth with PTSD from those without PTSD. Alterations of the vmPFC may be one mechanism that mediates the pathway from PTSD to comorbidity. Further longitudinal work is needed to determine neurobiological factors related to chronic and persistent PTSD, and to PTSD resilience despite maltreatment.

Integrative moral judgment: dissociating the roles of the amygdala and ventromedial prefrontal cortex.

PubMed

Shenhav, Amitai; Greene, Joshua D

2014-03-26

A decade's research highlights a critical dissociation between automatic and controlled influences on moral judgment, which is subserved by distinct neural structures. Specifically, negative automatic emotional responses to prototypically harmful actions (e.g., pushing someone off of a footbridge) compete with controlled responses favoring the best consequences (e.g., saving five lives instead of one). It is unknown how such competitions are resolved to yield "all things considered" judgments. Here, we examine such integrative moral judgments. Drawing on insights from research on self-interested, value-based decision-making in humans and animals, we test a theory concerning the respective contributions of the amygdala and ventromedial prefrontal cortex (vmPFC) to moral judgment. Participants undergoing fMRI responded to moral dilemmas, separately evaluating options for their utility (Which does the most good?), emotional aversiveness (Which feels worse?), and overall moral acceptability. Behavioral data indicate that emotional aversiveness and utility jointly predict "all things considered" integrative judgments. Amygdala response tracks the emotional aversiveness of harmful utilitarian actions and overall disapproval of such actions. During such integrative moral judgments, the vmPFC is preferentially engaged relative to utilitarian and emotional assessments. Amygdala-vmPFC connectivity varies with the role played by emotional input in the task, being the lowest for pure utilitarian assessments and the highest for pure emotional assessments. These findings, which parallel those of research on self-interested economic decision-making, support the hypothesis that the amygdala provides an affective assessment of the action in question, whereas the vmPFC integrates that signal with a utilitarian assessment of expected outcomes to yield "all things considered" moral judgments.

The medial prefrontal cortex differentially regulates stress-induced c-fos expression in the forebrain depending on type of stressor.

PubMed

Figueiredo, Helmer F; Bruestle, Amy; Bodie, Bryan; Dolgas, Charles M; Herman, James P

2003-10-01

The medial prefrontal cortex (mPFC) plays an important inhibitory role in the hypothalamic-pituitary-adrenal (HPA) axis response. The involvement of the mPFC appears to depend on the type of stressor, preferentially affecting 'psychogenic' stimuli. In this study, we mapped expression of c-fos mRNA to assess the neural circuitry underlying stressor-specific actions of the mPFC on HPA reactivity. Thus, groups of mPFC-lesioned and sham-operated rats were restrained for 20 min or exposed to ether fumes for 2 min. In both cases, the animals were killed at 40 min from the onset of stress. Interestingly, bilateral lesions of the mPFC significantly enhanced c-fos mRNA expression in the hypothalamic paraventricular nucleus of restrained animals, an effect that was paralleled by potentiation of circulating ACTH concentrations in these animals. On the other hand, lesions of the mPFC did not affect neither PVN c-fos mRNA expression nor plasma ACTH concentrations in animals exposed to ether. Lesions of the mPFC also enhanced c-fos activation in the medial amygdala following restraint, but not following ether exposure. Additional regions whose activity was affected by mPFC lesions or stressor differences included the ventrolateral division of the bed nucleus of the stria terminalis, CA3 hippocampus, piriform cortex, and dorsal endopiriform nucleus. Expression of c-fos mRNA was nearly absent in the central amygdala of all stressed animals, regardless of lesion. Furthermore, prefrontal cortex lesions did not change stress-induction levels of c-fos in the CA1 hippocampus, dentate gyrus, anteromedial division of the bed nucleus of the stria terminalis, lateral septum, and claustrum. Taken together, this study indicates that the medial prefrontal cortex differentially regulates cellular activation of specific stress-related brain regions, thus exerting stressor-dependent inhibition of the HPA axis.

Resting-state functional connectivity between amygdala and the ventromedial prefrontal cortex following fear reminder predicts fear extinction.

PubMed

Feng, Pan; Zheng, Yong; Feng, Tingyong

2016-06-01

Investigations of fear conditioning have elucidated the neural mechanisms of fear acquisition, consolidation and extinction, but it is not clear how the neural activation following fear reminder influence the following extinction. To address this question, we measured human brain activity following fear reminder using resting-state functional magnetic resonance imaging, and investigated whether the extinction effect can be predicted by resting-state functional connectivity (RSFC). Behaviorally, we found no significant differences of fear ratings between the reminder group and the no reminder group at the fear acquisition and extinction stages, but spontaneous recovery during re-extinction stage appeared only in the no reminder group. Imaging data showed that functional connectivity between ventromedial prefrontal cortex (vmPFC) and amygdala in the reminder group was greater than that in the no reminder group after fear memory reactivation. More importantly, the functional connectivity between amygdala and vmPFC of the reminder group after fear memory reactivation was positively correlated with extinction effect. These results suggest RSFC between amygdala and the vmPFC following fear reminder can predict fear extinction, which provide important insight into the neural mechanisms of fear memory after fear memory reactivation. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Optogenetic Examination of Prefrontal-Amygdala Synaptic Development.

PubMed

Arruda-Carvalho, Maithe; Wu, Wan-Chen; Cummings, Kirstie A; Clem, Roger L

2017-03-15

A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network. SIGNIFICANCE STATEMENT Human mPFC-amygdala functional connectivity is developmentally regulated and figures prominently in numerous psychiatric disorders with a high incidence of adolescent onset. However, it remains unclear when synaptic connections between these structures emerge or how their properties change with age. Our work establishes developmental windows and cellular substrates for synapse maturation in this pathway involving both excitatory and inhibitory circuits. The engagement of these substrates by early life experience may support the ontogeny of fundamental behaviors but could also lead to inappropriate circuit refinement and psychopathology in adverse situations. Copyright © 2017 the authors 0270-6474/17/372976-10$15.00/0.

Effect of D-cycloserine in conjunction with fear extinction training on extracellular signal-regulated kinase activation in medial prefrontal cortex and amygdala in rat

PubMed Central

Gupta, Subhash C.; Hillman, Brandon G.; Prakash, Anand; Ugale, Rajesh R; Stairs, Dustin J.; Dravid, Shashank M.

2013-01-01

D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity (phospho-extracellular signal-regulated kinase, pERK) markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24–28 days old) increased c-fos and pERK-stained neurons in both the prelimbic (PL) and infralimbic (IL) division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus (CeL) of the central amygdala (CeA). Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in IL, PL, intercalated cells and CeL, compared to saline control. In synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared to context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS in conjunction with extinction training led to an increase in iGluR subunit expression, compared to extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei. PMID:23551217

Monitoring and control of amygdala neurofeedback involves distributed information processing in the human brain.

PubMed

Paret, Christian; Zähringer, Jenny; Ruf, Matthias; Gerchen, Martin Fungisai; Mall, Stephanie; Hendler, Talma; Schmahl, Christian; Ende, Gabriele

2018-03-30

Brain-computer interfaces provide conscious access to neural activity by means of brain-derived feedback ("neurofeedback"). An individual's abilities to monitor and control feedback are two necessary processes for effective neurofeedback therapy, yet their underlying functional neuroanatomy is still being debated. In this study, healthy subjects received visual feedback from their amygdala response to negative pictures. Activation and functional connectivity were analyzed to disentangle the role of brain regions in different processes. Feedback monitoring was mapped to the thalamus, ventromedial prefrontal cortex (vmPFC), ventral striatum (VS), and rostral PFC. The VS responded to feedback corresponding to instructions while rPFC activity differentiated between conditions and predicted amygdala regulation. Control involved the lateral PFC, anterior cingulate, and insula. Monitoring and control activity overlapped in the VS and thalamus. Extending current neural models of neurofeedback, this study introduces monitoring and control of feedback as anatomically dissociated processes, and suggests their important role in voluntary neuromodulation. © 2018 Wiley Periodicals, Inc.

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex

PubMed Central

McGarry, Laura M.

2016-01-01

Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. PMID:27605614

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex.

PubMed

McGarry, Laura M; Carter, Adam G

2016-09-07

Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. Copyright © 2016 the authors 0270-6474/16/369391-16$15.00/0.

Differences in resting corticolimbic functional connectivity in bipolar I euthymia

PubMed Central

Torrisi, Salvatore; Moody, Teena D; Vizueta, Nathalie; Thomason, Moriah E; Monti, Martin M; Townsend, Jennifer D; Bookheimer, Susan Y; Altshuler, Lori L

2012-01-01

Objective We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. Methods Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically-defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. Results The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). Conclusions Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically-important imaging biomarker. PMID:23347587

Basolateral amygdala-ventromedial prefrontal cortex connectivity predicts cognitive behavioural therapy outcome in adults with obsessive-compulsive disorder.

PubMed

Fullana, Miquel A; Zhu, Xi; Alonso, Pino; Cardoner, Narcís; Real, Eva; López-Solà, Clara; Segalàs, Cinto; Subirà, Marta; Galfalvy, Hanga; Menchón, José M; Simpson, H Blair; Marsh, Rachel; Soriano-Mas, Carles

2017-11-01

Cognitive behavioural therapy (CBT), including exposure and ritual prevention, is a first-line treatment for obsessive-compulsive disorder (OCD), but few reliable predictors of CBT outcome have been identified. Based on research in animal models, we hypothesized that individual differences in basolateral amygdala-ventromedial prefrontal cortex (BLA-vmPFC) communication would predict CBT outcome in patients with OCD. We investigated whether BLA-vmPFC resting-state functional connectivity (rs-fc) predicts CBT outcome in patients with OCD. We assessed BLA-vmPFC rs-fc in patients with OCD on a stable dose of a selective serotonin reuptake inhibitor who then received CBT and in healthy control participants. We included 73 patients with OCD and 84 healthy controls in our study. Decreased BLA-vmPFC rs-fc predicted a better CBT outcome in patients with OCD and was also detected in those with OCD compared with healthy participants. Additional analyses revealed that decreased BLA-vmPFC rs-fc uniquely characterized the patients with OCD who responded to CBT. We used a sample of convenience, and all patients were receiving pharmacological treatment for OCD. In this large sample of patients with OCD, BLA-vmPFC functional connectivity predicted CBT outcome. These results suggest that future research should investigate the potential of BLA-vmPFC pathways to inform treatment selection for CBT across patients with OCD and anxiety disorders.

Amygdala reactivity in healthy adults is correlated with prefrontal cortical thickness.

PubMed

Foland-Ross, Lara C; Altshuler, Lori L; Bookheimer, Susan Y; Lieberman, Matthew D; Townsend, Jennifer; Penfold, Conor; Moody, Teena; Ahlf, Kyle; Shen, Jim K; Madsen, Sarah K; Rasser, Paul E; Toga, Arthur W; Thompson, Paul M

2010-12-08

Recent evidence suggests that putting feelings into words activates the prefrontal cortex (PFC) and suppresses the response of the amygdala, potentially helping to alleviate emotional distress. To further elucidate the relationship between brain structure and function in these regions, structural and functional magnetic resonance imaging (MRI) data were collected from a sample of 20 healthy human subjects. Structural MRI data were processed using cortical pattern-matching algorithms to produce spatially normalized maps of cortical thickness. During functional scanning, subjects cognitively assessed an emotional target face by choosing one of two linguistic labels (label emotion condition) or matched geometric forms (control condition). Manually prescribed regions of interest for the left amygdala were used to extract percentage signal change in this region occurring during the contrast of label emotion versus match forms. A correlation analysis between left amygdala activation and cortical thickness was then performed along each point of the cortical surface, resulting in a color-coded r value at each cortical point. Correlation analyses revealed that gray matter thickness in left ventromedial PFC was inversely correlated with task-related activation in the amygdala. These data add support to a general role of the ventromedial PFC in regulating activity of the amygdala.

Oxytocin in the amygdala and not the prefrontal cortex enhances fear and impairs extinction in the juvenile rat.

PubMed

Kritman, Milly; Lahoud, Nisrine; Maroun, Mouna

2017-05-01

A growing body of evidence suggests that the hypothalamic neuropeptide oxytocin (OT), aside from its central role in the regulation of social behavior, reduces fear and anxiety. The functional and opposing interactions of the medial prefrontal cortex (mPFC) and the amygdala in regulation of fear provide a unique experimental setting to examine the effects of OT on fear and extinction. Recent evidence suggests that in the adult animal OT can play a dual role in the regulation of fear leading to contrasting effects on fear depending on the manipulated brain region and the time of manipulations. The OT system is one of the systems that undergoes major changes throughout development, however, its role in regulating fear in young animals has not been widely explored. We recently showed that the mechanisms of extinction, and specifically engagement of the mPFC in extinction, are not identical in adult and juvenile animals. Thus, the purpose of this study was to elucidate the effects of OT on fear and extinction in juvenile animals. To that end, we determine extinction, by measuring freezing at different time points, following microinjection of the OT agonist, TGOT, into the mPFC, the basolateral and the central nuclei of the amygdala (BLA and CeA, respectively). The results show that whereas TGOT microinjections into the IL-mPFC did not affect extinction, microinjections into the amygdala were mainly associated with enhanced fear and impaired extinction. These results further emphasize the differences between adult and juvenile brains. Copyright © 2017. Published by Elsevier Inc.

How stable is activation in the amygdala and prefrontal cortex in adolescence? A study of emotional face processing across three measurements.

PubMed

van den Bulk, Bianca G; Koolschijn, P Cédric M P; Meens, Paul H F; van Lang, Natasja D J; van der Wee, Nic J A; Rombouts, Serge A R B; Vermeiren, Robert R J M; Crone, Eveline A

2013-04-01

Prior developmental functional magnetic resonance imaging (fMRI) studies have demonstrated elevated activation patterns in the amygdala and prefrontal cortex (PFC) in response to viewing emotional faces. As adolescence is a time of substantial variability in mood and emotional responsiveness, the stability of activation patterns could be fluctuating over time. In the current study, 27 healthy adolescents (age: 12-19 years) were scanned three times over a period of six months (mean test-retest interval of three months; final samples N=27, N=22, N=18). At each session, participants performed the same emotional faces task. At first measurement the presentation of emotional faces resulted in heightened activation in bilateral amygdala, bilateral lateral PFC and visual areas including the fusiform face area. Average activation did not differ across test-sessions over time, indicating that at the group level activation patterns in this network do not vary significantly over time. However, using the Intraclass Correlation Coefficient (ICC), fMRI reliability demonstrated only fair reliability for PFC (ICC=0.41-0.59) and poor reliability for the amygdala (ICC<0.4). These findings suggest substantial variability of brain activity over time and may have implications for studies investigating the influence of treatment effects on changes in neural levels in adolescents with psychiatric disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Model of Amygdala-Hippocampal-Prefrontal Interaction in Fear Conditioning and Extinction in Animals

ERIC Educational Resources Information Center

Moustafa, Ahmed A.; Gilbertson, Mark W.; Orr, Scott P.; Herzallah, Mohammad M.; Servatius, Richard J.; Myers, Catherine E.

2013-01-01

Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus…

Effects of a single bilateral infusion of R-ketamine in the rat brain regions of a learned helplessness model of depression.

PubMed

Shirayama, Yukihiko; Hashimoto, Kenji

2017-03-01

Effects of a single bilateral infusion of R-enantiomer of ketamine in rat brain regions of learned helplessness model of depression were examined. A single bilateral infusion of R-ketamine into infralimbic (IL) portion of medial prefrontal cortex (mPFC), CA3 and dentate gyrus (DG) of the hippocampus showed antidepressant effects. By contrast, a single bilateral infusion of R-ketamine into prelimbic (PL) portion of mPFC, shell and core of nucleus accumbens, basolateral amygdala and central nucleus of the amygdala had no effect. This study suggests that IL of mPFC, CA3 and DG of hippocampus might be involved in the antidepressant actions of R-ketamine.

Clinically Anxious Individuals Show Disrupted Feedback between Inferior Frontal Gyrus and Prefrontal-Limbic Control Circuit.

PubMed

Cha, Jiook; DeDora, Daniel; Nedic, Sanja; Ide, Jaime; Greenberg, Tsafrir; Hajcak, Greg; Mujica-Parodi, Lilianne Rivka

2016-04-27

Clinical anxiety is associated with generalization of conditioned fear, in which innocuous stimuli elicit alarm. Using Pavlovian fear conditioning (electric shock), we quantify generalization as the degree to which subjects' neurobiological responses track perceptual similarity gradients to a conditioned stimulus. Previous studies show that the ventromedial prefrontal cortex (vmPFC) inversely and ventral tegmental area directly track the gradient of perceptual similarity to the conditioned stimulus in healthy individuals, whereas clinically anxious individuals fail to discriminate. Here, we extend this work by identifying specific functional roles within the prefrontal-limbic circuit. We analyzed fMRI time-series acquired from 57 human subjects during a fear generalization task using entropic measures of circuit-wide regulation and feedback (power spectrum scale invariance/autocorrelation), in combination with structural (diffusion MRI-probabilistic tractography) and functional (stochastic dynamic causal modeling) measures of prefrontal-limbic connectivity within the circuit. Group comparison and correlations with anxiety severity across 57 subjects revealed dysregulatory dynamic signatures within the inferior frontal gyrus (IFG), which our prior work has linked to impaired feedback within the circuit. Bayesian model selection then identified a fully connected prefrontal-limbic model comprising the IFG, vmPFC, and amygdala. Dysregulatory IFG dynamics were associated with weaker reciprocal excitatory connectivity between the IFG and the vmPFC. The vmPFC exhibited inhibitory influence on the amygdala. Our current results, combined with our previous work across a threat-perception spectrum of 137 subjects and a meta-analysis of 366 fMRI studies, dissociate distinct roles for three prefrontal-limbic regions, wherein the IFG provides evaluation of stimulus meaning, which then informs the vmPFC in inhibiting the amygdala. Affective neuroscience has generally treated prefrontal regions (orbitofrontal cortex, dorsolateral prefrontal cortex, inferior frontal gyrus, ventromedial prefrontal cortex) equivalently as inhibitory components of the prefrontal-limbic system. Yet research across the anxiety spectrum suggests that the inferior frontal gyrus may have a more complex role in emotion regulation, as this region shows abnormal function in disorders of both hyperarousal and hypoarousal. Using entropic measures of circuit-wide regulation and feedback, in combination with measures of structural and functional connectivity, we dissociate distinct roles for three prefrontal-limbic regions, wherein the inferior frontal gyrus provides evaluation of stimulus meaning, which then informs the ventromedial prefrontal cortex in inhibiting the amygdala. This reconfiguration coheres with studies of conceptual disambiguation also implicating the inferior frontal gyrus. Copyright © 2016 the authors 0270-6474/16/364708-11$15.00/0.

Decreased uncinate fasciculus tract integrity in male and female patients with PTSD: a diffusion tensor imaging study.

PubMed

Koch, Saskia B J; van Zuiden, Mirjam; Nawijn, Laura; Frijling, Jessie L; Veltman, Dick J; Olff, Miranda

2017-09-01

Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that has been associated with lower white matter integrity of tracts connecting the prefrontal cortex with limbic regions. However, previous diffusion tensor imaging (DTI) findings have been inconsistent, showing high variability in the exact location and direction of effects. We performed probabilistic tractography of the bilateral uncinate fasciculus, cingulum and superior longitudinal fasciculus (both temporal and parietal projections) in male and female police officers with and without PTSD. We included 38 (21 men) police officers with and 39 (20 men) without PTSD in our analyses. Compared with trauma-exposed controls, patients with PTSD showed significantly higher mean diffusivity of the right uncinate fasciculus, the major white matter tract connecting the amygdala to the prefrontal cortex ( p = 0.012). No other significant between-group or group × sex differences were observed. Mean diffusivity of the right uncinate fasciculus was positively associated with anxiety symptoms ( r = 0.410, p = 0.013) in patients with PTSD as well as with amygdala activity ( r = 0.247, p = 0.038) and ventromedial prefrontal cortex (vmPFC) activity ( r = 0.283, p = 0.016) in all participants in response to happy and neutral faces. Our specific sample of trauma-exposed police officers limits the generalizability of our findings to other PTSD patient groups (e.g., civilian trauma). Patients with PTSD showed diminished structural connectivity between the amygdala and vmPFC, which was correlated with higher anxiety symptoms and increased functional activity of these brain regions. Our findings provide additional evidence for the prevailing neurocircuitry model of PTSD, postulating that ineffective communication between the amygdala and vmPFC underlies decreased top-down control over fear responses.

Decreased uncinate fasciculus tract integrity in male and female patients with PTSD: a diffusion tensor imaging study

PubMed Central

Koch, Saskia B.J.; van Zuiden, Mirjam; Nawijn, Laura; Frijling, Jessie L.; Veltman, Dick J.; Olff, Miranda

2017-01-01

Background Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that has been associated with lower white matter integrity of tracts connecting the prefrontal cortex with limbic regions. However, previous diffusion tensor imaging (DTI) findings have been inconsistent, showing high variability in the exact location and direction of effects. Methods We performed probabilistic tractography of the bilateral uncinate fasciculus, cingulum and superior longitudinal fasciculus (both temporal and parietal projections) in male and female police officers with and without PTSD. Results We included 38 (21 men) police officers with and 39 (20 men) without PTSD in our analyses. Compared with trauma-exposed controls, patients with PTSD showed significantly higher mean diffusivity of the right uncinate fasciculus, the major white matter tract connecting the amygdala to the prefrontal cortex (p = 0.012). No other significant between-group or group × sex differences were observed. Mean diffusivity of the right uncinate fasciculus was positively associated with anxiety symptoms (r = 0.410, p = 0.013) in patients with PTSD as well as with amygdala activity (r = 0.247, p = 0.038) and ventromedial prefrontal cortex (vmPFC) activity (r = 0.283, p = 0.016) in all participants in response to happy and neutral faces. Limitations Our specific sample of trauma-exposed police officers limits the generalizability of our findings to other PTSD patient groups (e.g., civilian trauma). Conclusion Patients with PTSD showed diminished structural connectivity between the amygdala and vmPFC, which was correlated with higher anxiety symptoms and increased functional activity of these brain regions. Our findings provide additional evidence for the prevailing neurocircuitry model of PTSD, postulating that ineffective communication between the amygdala and vmPFC underlies decreased top–down control over fear responses. PMID:28452713

Basomedial amygdala mediates top-down control of anxiety and fear.

PubMed

Adhikari, Avishek; Lerner, Talia N; Finkelstein, Joel; Pak, Sally; Jennings, Joshua H; Davidson, Thomas J; Ferenczi, Emily; Gunaydin, Lisa A; Mirzabekov, Julie J; Ye, Li; Kim, Sung-Yon; Lei, Anna; Deisseroth, Karl

2015-11-12

Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.

The consolidation of inhibitory avoidance memory in mice depends on the intensity of the aversive stimulus: The involvement of the amygdala, dorsal hippocampus and medial prefrontal cortex.

PubMed

Canto-de-Souza, L; Mattioli, R

2016-04-01

Several studies using inhibitory avoidance models have demonstrated the importance of limbic structures, such as the amygdala, dorsal hippocampus and medial prefrontal cortex, in the consolidation of emotional memory. However, we aimed to investigate the role of the amygdala (AMG), dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) of mice in the consolidation of step-down inhibitory avoidance and whether this avoidance would be conditioned relative to the intensity of the aversive stimulus. To test this, we bilaterally infused anisomycin (ANI-40μg/μl, a protein synthesis inhibitor) into one of these three brain areas in mice. These mice were then exposed to one of two different intensities (moderate: 0.5mA or intense: 1.5mA) in a step-down inhibitory avoidance task. We found that consolidation of both of the aversive experiences was mPFC dependent, while the AMG and DH were only required for the consolidation of the intense experience. We suggest that in moderately aversive situations, which do not represent a severe physical risk to the individual, the consolidation of aversive experiences does not depend on protein synthesis in the AMG or the DH, but only the mPFC. However, for intense aversive stimuli all three of these limbic structures are essential for the consolidation of the experience. Copyright © 2016 Elsevier Inc. All rights reserved.

Neural foundations to moral reasoning and antisocial behavior

PubMed Central

Yang, Yaling

2006-01-01

A common feature of the antisocial, rule-breaking behavior that is central to criminal, violent and psychopathic individuals is the failure to follow moral guidelines. This review summarizes key findings from brain imaging research on both antisocial behavior and moral reasoning, and integrates these findings into a neural moral model of antisocial behavior. Key areas found to be functionally or structurally impaired in antisocial populations include dorsal and ventral regions of the prefrontal cortex (PFC), amygdala, hippocampus, angular gyrus, anterior cingulate and temporal cortex. Regions most commonly activated in moral judgment tasks consist of the polar/medial and ventral PFC, amygdala, angular gyrus and posterior cingulate. It is hypothesized that the rule-breaking behavior common to antisocial, violent and psychopathic individuals is in part due to impairments in some of the structures (dorsal and ventral PFC, amygdala and angular gyrus) subserving moral cognition and emotion. Impairments to the emotional component that comprises the feeling of what is moral is viewed as the primary deficit in antisocials, although some disruption to the cognitive and cognitive-emotional components of morality (particularly self-referential thinking and emotion regulation) cannot be ruled out. While this neurobiological predisposition is likely only one of several biosocial processes involved in the etiology of antisocial behavior, it raises significant moral issues for the legal system and neuroethics. PMID:18985107

The transition from childhood to adolescence is marked by a general decrease in amygdala reactivity and an affect-specific ventral-to-dorsal shift in medial prefrontal recruitment.

PubMed

Silvers, Jennifer A; Insel, Catherine; Powers, Alisa; Franz, Peter; Helion, Chelsea; Martin, Rebecca; Weber, Jochen; Mischel, Walter; Casey, B J; Ochsner, Kevin N

2017-06-01

Understanding how and why affective responses change with age is central to characterizing typical and atypical emotional development. Prior work has emphasized the role of the amygdala and prefrontal cortex (PFC), which show age-related changes in function and connectivity. However, developmental neuroimaging research has only recently begun to unpack whether age effects in the amygdala and PFC are specific to affective stimuli or may be found for neutral stimuli as well, a possibility that would support a general, rather than affect-specific, account of amygdala-PFC development. To examine this, 112 individuals ranging from 6 to 23 years of age viewed aversive and neutral images while undergoing fMRI scanning. Across age, participants reported more negative affect and showed greater amygdala responses for aversive than neutral stimuli. However, children were generally more sensitive to both neutral and aversive stimuli, as indexed by affective reports and amygdala responses. At the same time, the transition from childhood to adolescence was marked by a ventral-to-dorsal shift in medial prefrontal responses to aversive, but not neutral, stimuli. Given the role that dmPFC plays in executive control and higher-level representations of emotion, these results suggest that adolescence is characterized by a shift towards representing emotional events in increasingly cognitive terms. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome

PubMed Central

Huang, Wen-Chin; Chen, Youjun; Page, Damon T.

2016-01-01

Multiple autism risk genes converge on the regulation of mTOR signalling, which is a key effector of neuronal growth and connectivity. We show that mTOR signalling is dysregulated during early postnatal development in the cerebral cortex of germ-line heterozygous Pten mutant mice (Pten+/−), which model macrocephaly/autism syndrome. The basolateral amygdala (BLA) receives input from subcortical-projecting neurons in the medial prefrontal cortex (mPFC). Analysis of mPFC to BLA axonal projections reveals that Pten+/− mice exhibit increased axonal branching and connectivity, which is accompanied by increased activity in the BLA in response to social stimuli and social behavioural deficits. The latter two phenotypes can be suppressed by pharmacological inhibition of S6K1 during early postnatal life or by reducing the activity of mPFC–BLA circuitry in adulthood. These findings identify a mechanism of altered connectivity that has potential relevance to the pathophysiology of macrocephaly/autism syndrome and autism spectrum disorders featuring dysregulated mTOR signalling. PMID:27845329

Trace Eyeblink Conditioning in Mice Is Dependent upon the Dorsal Medial Prefrontal Cortex, Cerebellum, and Amygdala: Behavioral Characterization and Functional Circuitry1,2,3

PubMed Central

Taylor, William; Kalmbach, Brian; Desai, Niraj S.

2015-01-01

Abstract Trace eyeblink conditioning is useful for studying the interaction of multiple brain areas in learning and memory. The goal of the current work was to determine whether trace eyeblink conditioning could be established in a mouse model in the absence of elicited startle responses and the brain circuitry that supports this learning. We show here that mice can acquire trace conditioned responses (tCRs) devoid of startle while head-restrained and permitted to freely run on a wheel. Most mice (75%) could learn with a trace interval of 250 ms. Because tCRs were not contaminated with startle-associated components, we were able to document the development and timing of tCRs in mice, as well as their long-term retention (at 7 and 14 d) and flexible expression (extinction and reacquisition). To identify the circuitry involved, we made restricted lesions of the medial prefrontal cortex (mPFC) and found that learning was prevented. Furthermore, inactivation of the cerebellum with muscimol completely abolished tCRs, demonstrating that learned responses were driven by the cerebellum. Finally, inactivation of the mPFC and amygdala in trained animals nearly abolished tCRs. Anatomical data from these critical regions showed that mPFC and amygdala both project to the rostral basilar pons and overlap with eyelid-associated pontocerebellar neurons. The data provide the first report of trace eyeblink conditioning in mice in which tCRs were driven by the cerebellum and required a localized region of mPFC for acquisition. The data further reveal a specific role for the amygdala as providing a conditioned stimulus-associated input to the cerebellum. PMID:26464998

Long-Term Synaptic Changes in Two Input Pathways into the Lateral Nucleus of the Amygdala Underlie Fear Extinction

ERIC Educational Resources Information Center

Park, Junchol; Choi, June-Seek

2010-01-01

Plasticity in two input pathways into the lateral nucleus of the amygdala (LA), the medial prefrontal cortex (mPFC) and the sensory thalamus, have been suggested to underlie extinction, suppression of a previously acquired conditioned response (CR) following repeated presentations of the conditioned stimulus (CS). However, little is known about…

Distinct phasic and sustained brain responses and connectivity of amygdala and bed nucleus of the stria terminalis during threat anticipation in panic disorder.

PubMed

Brinkmann, L; Buff, C; Feldker, K; Tupak, S V; Becker, M P I; Herrmann, M J; Straube, T

2017-11-01

Panic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD. Using functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations. PD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks. We demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.

Medial prefrontal pathways for the contextual regulation of extinguished fear in humans

PubMed Central

Åhs, Fredrik; Kragel, Philip A.; Zielinski, David J.; Brady, Rachael; LaBar, Kevin S.

2015-01-01

The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS−. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations. PMID:26220745

Neural Correlates of Hostile Jokes: Cognitive and Motivational Processes in Humor Appreciation

PubMed Central

Chan, Yu-Chen; Liao, Yi-Jun; Tu, Cheng-Hao

2016-01-01

Hostile jokes (HJs) provide aggressive catharsis and a feeling of superiority. Behavioral research has found that HJs are perceived as funnier than non-hostile jokes (NJs). The purpose of the present study was to identify the neural correlates of the interaction between type and humor by comparing HJs, NJs, and their corresponding hostile sentences (HSs) and non-hostile sentences (NSs). HJs primarily showed activation in the dorsomedial prefrontal cortex (dmPFC) and midbrain compared with the corresponding hostile baseline. Conversely, NJs primarily revealed activation in the ventromedial PFC (vmPFC), amygdala, midbrain, ventral anterior cingulate cortex, and nucleus accumbens (NAcc) compared with the corresponding non-hostile baseline. These results support the critical role of the medial PFC (mPFC) for the neural correlates of social cognition and socio-emotional processing in response to different types of jokes. Moreover, the processing of HJs showed increased activation in the dmPFC, which suggested cognitive operations of social motivation, whereas the processing of NJs displayed increased activation in the vmPFC, which suggested social-affective engagement. HJs versus NJs primarily showed increased activation in the dmPFC and midbrain, whereas NJs versus HJs primarily displayed greater activation in the amygdala and midbrain. The psychophysiological interaction (PPI) analysis demonstrated functional coupling of the dmPFC–dlPFC and midbrain–dmPFC for HJs and functional coupling of the vmPFC–midbrain and amygdala–midbrain–NAcc for NJs. Surprisingly, HJs were not perceived as funnier than NJs. Future studies could further investigate the neural correlates of potentially important traits of high-hostility tendencies in humor appreciation based on the psychoanalytic and superiority theories of humor. PMID:27840604

Blunted neural response to implicit negative facial affect in anorexia nervosa.

PubMed

Leppanen, Jenni; Cardi, Valentina; Paloyelis, Yannis; Simmons, Andy; Tchanturia, Kate; Treasure, Janet

2017-09-01

People with anorexia nervosa (AN) have difficulties in a wide range of social-emotional processes. Previous work suggests atypical involvement of the prefrontal cortex (PFC), amygdala, insula, and fusiform gyri during social-emotional processing in AN. Twenty women with AN and twenty healthy comparison (HC) women were presented with happy, fearful, and neutral faces during a functional magnetic resonance imaging study. Group differences were investigated in the following regions of interest: lateral PFC, amygdala, insula, and fusiform gyri. The HC participants showed significantly increased recruitment of the ventrolateral PFC and amygdala in the fearful > neutral contrast relative to the AN participants. The AN participants showed a significantly increased recruitment of a small cluster in the right posterior insula in the happy > neutral contrast. These findings are in line with the hypothesis that people with AN have a blunted response to negative and atypical exaggerated response to positive emotionally provoking stimuli. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Blunted amygdala functional connectivity during a stress task in alcohol dependent individuals: A pilot study.

PubMed

Wade, Natasha E; Padula, Claudia B; Anthenelli, Robert M; Nelson, Erik; Eliassen, James; Lisdahl, Krista M

2017-12-01

Scant research has been conducted on neural mechanisms underlying stress processing in individuals with alcohol dependence (AD). We examined neural substrates of stress in AD individuals compared with controls using an fMRI task previously shown to induce stress, assessing amygdala functional connectivity to medial prefrontal cortex (mPFC). For this novel pilot study, 10 abstinent AD individuals and 11 controls completed a modified Trier stress task while undergoing fMRI acquisition. The amygdala was used as a seed region for whole-brain seed-based functional connectivity analysis. After controlling for family-wise error (p = 0.05), there was significantly decreased left and right amygdala connectivity with frontal (specifically mPFC), temporal, parietal, and cerebellar regions. Subjective stress, but not craving, increased from pre-to post-task. This study demonstrated decreased connectivity between the amygdala and regions important for stress and emotional processing in long-term abstinent individuals with AD. These results suggest aberrant stress processing in individuals with AD even after lengthy periods of abstinence.

Neuroanatomical correlates of personality in the elderly.

PubMed

Wright, Christopher I; Feczko, Eric; Dickerson, Bradford; Williams, Danielle

2007-03-01

Extraversion and neuroticism are two important and frequently studied dimensions of human personality. They describe individual differences in emotional responding that are quite stable across the adult lifespan. Neuroimaging research has begun to provide evidence that neuroticism and extraversion have specific neuroanatomical correlates within the cerebral cortex and amygdala of young adults. However, these brain areas undergo alterations in size with aging, which may influence the nature of these personality factor-brain structure associations in the elderly. One study in the elderly demonstrated associations between perisylvian cortex structure and measures of self transcendence [Kaasinen, V., Maguire, R.P., Kurki, T., Bruck, A., Rinne, J.O., 2005. Mapping brain structure and personality in late adulthood. NeuroImage 24, 315-322], but the neuroanatomical correlates of extraversion and neuroticism, or other measures of the Five Factor Model of personality have not been explored. The purpose of the present study was to investigate the structural correlates of neuroticism and extraversion in healthy elderly subjects (n=29) using neuroanatomic measures of the cerebral cortex and amygdala. We observed that the thickness of specific lateral prefrontal cortex (PFC) regions, but not amygdala volume, correlates with measures of extraversion and neuroticism. The results suggest differences in the regional neuroanatomic correlates of specific personality traits with aging. We speculate that this relates to the influences of age-related structural changes in the PFC.

Tyramide Signal Amplification Permits Immunohistochemical Analyses of Androgen Receptors in the Rat Prefrontal Cortex

PubMed Central

Low, Katelyn L.; Ma, Chunqi; Soma, Kiran K.

2017-01-01

Research on neural androgen receptors (ARs) has traditionally focused on brain regions that regulate reproductive and aggressive behaviors, such as the hypothalamus and amygdala. Although many cells in the prefrontal cortex (PFC) also express ARs, the number of ARs per cell appears to be much lower, and thus, AR immunostaining is often hard to detect and quantify in the PFC. Here, we demonstrate that biotin tyramide signal amplification (TSA) dramatically increases AR immunoreactivity in the rat brain, including critical regions of the PFC such as the medial PFC (mPFC) and orbitofrontal cortex (OFC). We show that TSA is useful for AR detection with both chromogenic and immunofluorescent immunohistochemistry. Double-labeling studies reveal that AR+ cells in the PFC and hippocampus are NeuN+ but not GFAP+ and thus primarily neuronal. Finally, in gonadally intact rats, more AR+ cells are present in the mPFC and OFC of males than of females. Future studies can use TSA to further examine AR immunoreactivity across ages, sexes, strains, and different procedures (e.g., fixation methods). In light of emerging evidence for the androgen regulation of executive function and working memory, these results may help understand the distribution and roles of ARs in the PFC. PMID:28438093

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model

PubMed Central

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-01-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction. PMID:27617747

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model.

PubMed

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-09-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction.

Individual Differences in Amygdala-Medial Prefrontal Anatomy Link Negative Affect, Impaired Social Functioning, and Polygenic Depression Risk

PubMed Central

Holmes, Avram J.; Lee, Phil H.; Hollinshead, Marisa O.; Bakst, Leah; Roffman, Joshua L.; Smoller, Jordan W.; Buckner, Randy L.

2013-01-01

Individual differences in affective and social processes may arise from variability in amygdala-medial prefrontal (mPFC) circuitry and related genetic heterogeneity. To explore this possibility in humans, we examined the structural correlates of trait negative affect in a sample of 1050 healthy young adults with no history of psychiatric illness. Analyses revealed that heightened negative affect was associated with increased amygdala volume and reduced thickness in a left mPFC region encompassing the subgenual and rostral anterior cingulate cortex. The most extreme individuals displayed an inverse correlation between amygdala volume and mPFC thickness, suggesting that imbalance between these structures is linked to negative affect in the general population. Subgroups of participants were further evaluated on social (n = 206) and emotional (n = 533) functions. Individuals with decreased mPFC thickness exhibited the poorest social cognition and were least able to correctly identify facial emotion. Given prior links between disrupted amygdala–mPFC circuitry and the presence of major depressive disorder (MDD), we explored whether the individual differences in anatomy observed here in healthy young adults were associated with polygenic risk for MDD (n = 438) using risk scores derived from a large genome-wide association analysis (n = 18,759). Analyses revealed associations between increasing polygenic burden for MDD and reduced cortical thickness in the left mPFC. These collective findings suggest that, within the healthy population, there is significant variability in amygdala–mPFC circuitry that is associated with poor functioning across affective and social domains. Individual differences in this circuitry may arise, in part, from common genetic variability that contributes to risk for MDD. PMID:23238724

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.

Reduced Prefrontal Connectivity in Psychopathy

PubMed Central

Motzkin, Julian C.; Newman, Joseph P.; Kiehl, Kent A.; Koenigs, Michael

2012-01-01

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. PMID:22131397

15. Amygdala pain mechanisms

PubMed Central

Neugebauer, Volker

2015-01-01

A limbic brain area the amygdala plays a key role in emotional responses and affective states and disorders such as learned fear, anxiety and depression. The amygdala has also emerged as an important brain center for the emotional-affective dimension of pain and for pain modulation. Hyperactivity in the laterocapsular division of the central nucleus of the amygdala (CeLC, also termed the “nociceptive amygdala”) accounts for pain-related emotional responses and anxiety-like behavior. Abnormally enhanced output from the CeLC is the consequence of an imbalance between excitatory and inhibitory mechanisms. Impaired inhibitory control mediated by a cluster of GABAergic interneurons in the intercalated cell masses (ITC) allows the development of glutamate- and neuropeptide-driven synaptic plasticity of excitatory inputs from the brainstem (parabrachial area) and from the lateral-basolateral amygdala network (LA-BLA, site of integration of polymodal sensory information). BLA hyperactivity also generates abnormally enhanced feedforward inhibition of principal cells in the medial prefrontal cortex (mPFC), a limbic cortical area that is strongly interconnected with the amygdala. Pain-related mPFC deactivation results in cognitive deficits and failure to engage cortically driven ITC-mediated inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms. PMID:25846623

Testosterone Modulates Altered Prefrontal Control of Emotional Actions in Psychopathic Offenders(1,2,3).

PubMed

Volman, Inge; von Borries, Anna Katinka Louise; Bulten, Berend Hendrik; Verkes, Robbert Jan; Toni, Ivan; Roelofs, Karin

2016-01-01

Psychopathic individuals are notorious for their controlled goal-directed aggressive behavior. Yet, during social challenges, they often show uncontrolled emotional behavior. Healthy individuals can control their social emotional behavior through anterior prefrontal cortex (aPFC) downregulation of neural activity in the amygdala, with testosterone modulating aPFC-amygdala coupling. This study tests whether individual differences in this neuroendocrine system relate to the paradoxical lack of emotional control observed in human psychopathic offenders. Emotional control was operationalized with an fMRI-adapted approach-avoidance task requiring rule-driven control over rapid emotional responses. Fifteen psychopathic offenders and 19 matched healthy control subjects made approaching and avoiding movements in response to emotional faces. Control of social emotional behavior was required during affect-incongruent trials, when participants had to override affect-congruent, automatic action tendencies and select the opposite response. Psychopathic offenders showed less control-related aPFC activity and aPFC-amygdala coupling during trials requiring control of emotional actions, when compared with healthy control subjects. This pattern was particularly pronounced in psychopathic individuals with high endogenous testosterone levels. These findings suggest that reduced prefrontal coordination underlies reduced behavioral control in psychopathic offenders during emotionally provoking situations. Even though the modest sample size warrants replication, the modulatory role of endogenous testosterone on the aPFC-amygdala circuit suggests a neurobiological substrate of individual differences that is relevant for the advancement of treatment and the reduction of recidivism.

Alter spontaneous activity in amygdala and vmPFC during fear consolidation following 24 h sleep deprivation.

PubMed

Feng, Pan; Becker, Benjamin; Feng, Tingyong; Zheng, Yong

2018-05-15

Sleep deprivation (SD) has been associated with cognitive and emotional disruptions, however its impact on the acquisition of fear and subsequent fear memory consolidation remain unknown. To address this question, we measured human brain activity before and after fear acquisition under conditions of 24 h sleep deprivation versus normal sleep using resting-state functional magnetic resonance imaging (rs-fMRI). Additionally, we explored whether the fear acquisition-induced change of brain activity during the fear memory consolidation window can be predicted by subjective fear ratings and autonomic fear response, assessed by skin conductance responses (SCR) during acquisition. Behaviorally, the SD group demonstrated increased subjective and autonomic fear responses compared to controls at the stage of fear acquisition. During the stage of fear consolidation, the SD group displayed decreased ventromedial prefrontal cortex (vmPFC) activity and concomitantly increased amygdala activity. Moreover, in the SD group fear acquisition-induced brain activity changes in amygdala were positively correlated with both, subjective and autonomic fear indices during acquisition, whereas in controls changes vmPFC activity were positively correlated with fear indices during acquisition. Together, the present findings suggested that SD may weaken the top-down ability of the vmPFC to regulate amygdala activity during fear memory consolidation. Moreover, subjective and objective fear at fear acquisition stage can predict the change of brain activity in amygdala in fear memory consolidation following SD. Copyright © 2018 Elsevier Inc. All rights reserved.

Early Adolescent MK-801 Exposure Impairs the Maturation of Ventral Hippocampal Control of Basolateral Amygdala Drive in the Adult Prefrontal Cortex

PubMed Central

Thomases, Daniel R.; Cass, Daryn K.; Meyer, Jacqueline D.; Caballero, Adriana

2014-01-01

The adolescent susceptibility to the onset of psychiatric disorders is only beginning to be understood when factoring in the development of the prefrontal cortex (PFC). The functional maturation of the PFC is dependent upon proper integration of glutamatergic inputs from the ventral hippocampus (vHipp) and the basolateral amygdala (BLA). Here we assessed how transient NMDAR blockade during adolescence alters the functional interaction of vHipp–BLA inputs in regulating PFC plasticity. Local field potential recordings were used to determine changes in long-term depression (LTD) and long-term potentiation (LTP) of PFC responses resulting from vHipp and BLA high-frequency stimulation in adult rats that received repeated injections of saline or the NMDAR antagonist MK-801 from postnatal day 35 (P35) to P40. We found that early adolescent MK-801 exposure elicited an age- and input-specific dysregulation of vHipp–PFC plasticity, characterized by a shift from LTD to LTP without altering the BLA-induced LTP. Data also showed that the vHipp normally resets the LTP state of BLA transmission; however, this inhibitory regulation is absent following early adolescent MK-801 treatment. This deficit was reminiscent of PFC responses seen in drug-naive juveniles. Notably, local prefrontal upregulation of GABAAα1 function completely restored vHipp functionality and its regulation of BLA plasticity in MK-801-treated rats. Thus, NMDAR signaling is critical for the periadolescent acquisition of a GABA-dependent hippocampal control of PFC plasticity, which enables the inhibitory control of the prefrontal output by the vHipp. A dysregulation of this pathway can alter PFC processing of other converging afferents such as those from the BLA. PMID:24990926

The Development of Human Amygdala Functional Connectivity at Rest from 4 to 23 Years: a cross-sectional study

PubMed Central

Gabard-Durnam, Laurel J.; Flannery, Jessica; Goff, Bonnie; Gee, Dylan G.; Humphreys, Kathryn L.; Telzer, Eva; Hare, Todd; Tottenham, Nim

2014-01-01

Functional connections (FC) between the amygdala and cortical and subcortical regions underlie a range of affective and cognitive processes. Despite the central role amygdala networks have in these functions, the normative developmental emergence of FC between the amygdala and the rest of the brain is still largely undefined. This study employed amygdala subregion maps and resting-state functional magnetic resonance imaging to characterize the typical development of human amygdala FC from age 4 to 23 years old (n = 58). Amygdala FC with subcortical and limbic regions was largely stable across this developmental period. However, three cortical regions exhibited age-dependent changes in FC: amygdala FC with the medial prefrontal cortex (mPFC) increased with age, while amygdala FC with a region including the insula and superior temporal sulcus decreased with age, and amygdala FC with a region encompassing the parahippocampal gyrus and posterior cingulate also decreased with age. The transition from childhood to adolescence (around age 10 years) marked an important change-point in the nature of amygdala-cortical FC. We distinguished unique developmental patterns of coupling for three amygdala subregions and found particularly robust convergence of FC for all subregions with the mPFC. These findings suggest that there are extensive changes in amygdala-cortical functional connectivity that emerge between childhood and adolescence. PMID:24662579

Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders.

PubMed

Bukalo, Olena; Pinard, Courtney R; Holmes, Andrew

2014-10-01

The burden of anxiety disorders is growing, but the efficacy of available anxiolytic treatments remains inadequate. Cognitive behavioural therapy for anxiety disorders focuses on identifying and modifying maladaptive patterns of thinking and behaving, and has a testable analogue in rodents in the form of fear extinction. A large preclinical literature has amassed in recent years describing the neural and molecular basis of fear extinction in rodents. In this review, we discuss how this work is being harnessed to foster translational research on anxiety disorders and facilitate the search for new anxiolytic treatments. We begin by summarizing the anatomical and functional connectivity of a medial prefrontal cortex (mPFC)-amygdala circuit that subserves fear extinction, including new insights from optogenetics. We then cover some of the approaches that have been taken to model impaired fear extinction and associated impairments with mPFC-amygdala dysfunction. The principal goal of the review is to evaluate evidence that various neurotransmitter and neuromodulator systems mediate fear extinction by modulating the mPFC-amygdala circuitry. To that end, we describe studies that have tested how fear extinction is impaired or facilitated by pharmacological manipulations of dopamine, noradrenaline, 5-HT, GABA, glutamate, neuropeptides, endocannabinoids and various other systems, which either directly target the mPFC-amygdala circuit, or produce behavioural effects that are coincident with functional changes in the circuit. We conclude that there are good grounds to be optimistic that the progress in defining the molecular substrates of mPFC-amygdala circuit function can be effectively leveraged to identify plausible candidates for extinction-promoting therapies for anxiety disorders. © 2014 The British Pharmacological Society.

Optogenetic dissection of medial prefrontal cortex circuitry

PubMed Central

Riga, Danai; Matos, Mariana R.; Glas, Annet; Smit, August B.; Spijker, Sabine; Van den Oever, Michel C.

2014-01-01

The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders. PMID:25538574

Optogenetic dissection of medial prefrontal cortex circuitry.

PubMed

Riga, Danai; Matos, Mariana R; Glas, Annet; Smit, August B; Spijker, Sabine; Van den Oever, Michel C

2014-01-01

The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders.

Role of the medial prefrontal cortex in cataplexy.

PubMed

Oishi, Yo; Williams, Rhiannan H; Agostinelli, Lindsay; Arrigoni, Elda; Fuller, Patrick M; Mochizuki, Takatoshi; Saper, Clifford B; Scammell, Thomas E

2013-06-05

Narcolepsy is characterized by chronic sleepiness and cataplexy, episodes of profound muscle weakness that are often triggered by strong, positive emotions. Narcolepsy with cataplexy is caused by a loss of orexin (also known as hypocretin) signaling, but almost nothing is known about the neural mechanisms through which positive emotions trigger cataplexy. Using orexin knock-out mice as a model of narcolepsy, we found that palatable foods, especially chocolate, markedly increased cataplexy and activated neurons in the medial prefrontal cortex (mPFC). Reversible suppression of mPFC activity using an engineered chloride channel substantially reduced cataplexy induced by chocolate but did not affect spontaneous cataplexy. In addition, neurons in the mPFC innervated parts of the amygdala and lateral hypothalamus that contain neurons active during cataplexy and that innervate brainstem regions known to regulate motor tone. These observations indicate that the mPFC is a critical site through which positive emotions trigger cataplexy.

Role of the medial prefrontal cortex in cataplexy

PubMed Central

Oishi, Yo; Williams, Rhiannan H.; Agostinelli, Lindsay; Arrigoni, Elda; Fuller, Patrick M.; Mochizuki, Takatoshi; Saper, Clifford B.; Scammell, Thomas E.

2013-01-01

Narcolepsy is characterized by chronic sleepiness and cataplexy - episodes of profound muscle weakness that are often triggered by strong, positive emotions. Narcolepsy with cataplexy is caused by a loss of orexin (also known as hypocretin) signaling, but almost nothing is known about the neural mechanisms through which positive emotions trigger cataplexy. Using orexin knockout mice as a model of narcolepsy, we found that palatable foods, especially chocolate, markedly increased cataplexy and activated neurons in the medial prefrontal cortex (mPFC). Reversible suppression of mPFC activity using an engineered chloride channel substantially reduced cataplexy induced by chocolate but did not affect spontaneous cataplexy. In addition, neurons in the mPFC innervated parts of the amygdala and lateral hypothalamus that contain neurons active during cataplexy, and that innervate brainstem regions known to regulate motor tone. These observations indicate that the mPFC is a critical site through which positive emotions trigger cataplexy. PMID:23739971

Morphological, structural, and functional alterations of the prefrontal cortex and the basolateral amygdala after early lesion of the rat mediodorsal thalamus.

PubMed

Ouhaz, Zakaria; Ba-M'hamed, Saadia; Bennis, Mohamed

2017-08-01

Early postnatal damage to the mediodorsal thalamus (MD) produces deficits in cognition and behavior believed to be associated with early prefrontal cortical maldevelopment. We assessed the role of MD afferents during development on the morphological and functional maturation of the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Sprague-Dawley rat pups (n = 56) received a bilateral electrolytic lesion of the MD or a MD Sham lesion on postnatal day 4. 7 weeks later, all rats were tested in anxiety-related and cognitive paradigms using the elevated plus maze and novel object recognition tests. Following behavioral testing (P70), rats were killed and the baseline expression of C-Fos protein and the number of GABAergic neurons were evaluated in the PFC and the BLA. The dendritic morphology and spine density in the PFC using Golgi-Cox staining was also evaluated. Adult rats with early postnatal bilateral MD damage exhibited disrupted recognition memory and increased anxiety-like behaviors. The lesion also caused a significant diminution of C-Fos immunolabeling and an increase of the number of GABAergic neurons in the PFC. In the BLA, the number of GABAergic neurons was significantly reduced, associated with an increase in C-Fos immunolabeling. Furthermore, in the PFC the lesion induced a significant reduction in dendritic branching and spine density. Our data are consistent with the hypothesis that the MD plays a role in the development of the PFC and, therefore, may be a good animal model to investigate cognitive symptoms associated with schizophrenia.

Hypoactive medial prefrontal cortex functioning in adults reporting childhood emotional maltreatment.

PubMed

van Harmelen, Anne-Laura; van Tol, Marie-José; Dalgleish, Tim; van der Wee, Nic J A; Veltman, Dick J; Aleman, André; Spinhoven, Philip; Penninx, Brenda W J H; Elzinga, Bernet M

2014-12-01

Childhood emotional maltreatment (CEM) has adverse effects on medial prefrontal cortex (mPFC) morphology, a structure that is crucial for cognitive functioning and (emotional) memory and which modulates the limbic system. In addition, CEM has been linked to amygdala hyperactivity during emotional face processing. However, no study has yet investigated the functional neural correlates of neutral and emotional memory in adults reporting CEM. Using functional magnetic resonance imaging, we investigated CEM-related differential activations in mPFC during the encoding and recognition of positive, negative and neutral words. The sample (N = 194) consisted of patients with depression and/or anxiety disorders and healthy controls (HC) reporting CEM (n = 96) and patients and HC reporting no abuse (n = 98). We found a consistent pattern of mPFC hypoactivation during encoding and recognition of positive, negative and neutral words in individuals reporting CEM. These results were not explained by psychopathology or severity of depression or anxiety symptoms, or by gender, level of neuroticism, parental psychopathology, negative life events, antidepressant use or decreased mPFC volume in the CEM group. These findings indicate mPFC hypoactivity in individuals reporting CEM during emotional and neutral memory encoding and recognition. Our findings suggest that CEM may increase individuals' risk to the development of psychopathology on differential levels of processing in the brain; blunted mPFC activation during higher order processing and enhanced amygdala activation during automatic/lower order emotion processing. These findings are vital in understanding the long-term consequences of CEM. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

GABA content within the ventromedial prefrontal cortex is related to trait anxiety.

PubMed

Delli Pizzi, Stefano; Padulo, Caterina; Brancucci, Alfredo; Bubbico, Giovanna; Edden, Richard A; Ferretti, Antonio; Franciotti, Raffaella; Manippa, Valerio; Marzoli, Daniele; Onofrj, Marco; Sepede, Gianna; Tartaro, Armando; Tommasi, Luca; Puglisi-Allegra, Stefano; Bonanni, Laura

2016-05-01

The ventromedial prefrontal cortex (vmPFC) plays a key role in emotion processing and regulation. vmPFC dysfunction may lead to disinhibition of amygdala causing high anxiety levels. γ-Aminobutyric acid (GABA) inter-neurons within vmPFC shape the information flow to amygdala. Thus, we hypothesize that GABA content within vmPFC could be relevant to trait anxiety. Forty-three healthy volunteers aged between 20 and 88 years were assessed for trait anxiety with the Subscale-2 of the State-Trait-Anxiety Inventory (STAI-Y2) and were studied with proton magnetic resonance spectroscopy to investigate GABA and Glx (glutamate+glutamine) contents within vmPFC. Total creatine (tCr) was used as internal reference. Partial correlations assessed the association between metabolite levels and STAI-Y2 scores, removing the effect of possible nuisance factors including age, educational level, volumes of gray matter and white matter within magnetic resonance spectroscopy voxel. We observed a positive relationship between GABA/tCr and STAI-Y2 scores. No significant relationships were found between Glx/tCr and STAI-Y2 and between tCr/water and STAI-Y2. No differences were found between males and females as regards to age, STAI-Y2, GABA/tCr, Glx/tCr, tCr/water, gray matter and white matter volumes. We suggest a close relationship between GABA content within vmPFC and trait anxiety providing new insights in the physiology of emotional brain. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Basomedial amygdala mediates top–down control of anxiety and fear

PubMed Central

Adhikari, Avishek; Lerner, Talia N.; Finkelstein, Joel; Pak, Sally; Jennings, Joshua H.; Davidson, Thomas J.; Ferenczi, Emily; Gunaydin, Lisa A.; Mirzabekov, Julie J.; Ye, Li; Kim, Sung-Yon; Lei, Anna; Deisseroth, Karl

2016-01-01

Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC–BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway. PMID:26536109

Brain regulation of food craving: relationships with weight status and eating behavior.

PubMed

Dietrich, A; Hollmann, M; Mathar, D; Villringer, A; Horstmann, A

2016-06-01

Food craving is a driving force for overeating and obesity. However, the relationship between brain mechanisms involved in its regulation and weight status is still an open issue. Gaps in the studied body mass index (BMI) distributions and focusing on linear analyses might have contributed to this lack of knowledge. Here, we investigated brain mechanisms of craving regulation using functional magnetic resonance imaging in a balanced sample including normal-weight, overweight and obese participants. We investigated associations between characteristics of obesity, eating behavior and regulatory brain function focusing on nonlinear relationships. Forty-three hungry female volunteers (BMI: 19.4-38.8 kg m(-2), mean: 27.5±5.3 s.d.) were presented with visual food stimuli individually pre-rated according to tastiness and healthiness. The participants were instructed to either admit to the upcoming craving or regulate it. We analyzed the relationships between regulatory brain activity as well as functional connectivity and BMI or eating behavior (Three-Factor Eating Questionnaire, scales: Cognitive Restraint, Disinhibition). During regulation, BMI correlated with brain activity in the left putamen, amygdala and insula in an inverted U-shaped manner. Functional connectivity between the putamen and the dorsolateral prefrontal cortex (dlPFC) correlated positively with BMI, whereas that of amygdala with pallidum and lingual gyrus was nonlinearly (U-shaped) associated with BMI. Disinhibition correlated negatively with the strength of functional connectivity between amygdala and dorsomedial prefrontal (dmPFC) cortex as well as caudate. This study is the first to reveal quadratic relationships of food-related brain processes and BMI. Reported nonlinear associations indicate inverse relationships between regulation-related motivational processing in the range of normal weight/overweight compared with the obese range. Connectivity analyses suggest that the need for top-down (dlPFC) adjustment of striatal value representations increases with BMI, whereas the interplay of self-monitoring (dmPFC) or eating-related strategic action planning (caudate) and salience processing (amygdala) might be hampered with high Disinhibition.

Functional Connectivity of Multiple Brain Regions Required for the Consolidation of Social Recognition Memory.

PubMed

Tanimizu, Toshiyuki; Kenney, Justin W; Okano, Emiko; Kadoma, Kazune; Frankland, Paul W; Kida, Satoshi

2017-04-12

Social recognition memory is an essential and basic component of social behavior that is used to discriminate familiar and novel animals/humans. Previous studies have shown the importance of several brain regions for social recognition memories; however, the mechanisms underlying the consolidation of social recognition memory at the molecular and anatomic levels remain unknown. Here, we show a brain network necessary for the generation of social recognition memory in mice. A mouse genetic study showed that cAMP-responsive element-binding protein (CREB)-mediated transcription is required for the formation of social recognition memory. Importantly, significant inductions of the CREB target immediate-early genes c-fos and Arc were observed in the hippocampus (CA1 and CA3 regions), medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and amygdala (basolateral region) when social recognition memory was generated. Pharmacological experiments using a microinfusion of the protein synthesis inhibitor anisomycin showed that protein synthesis in these brain regions is required for the consolidation of social recognition memory. These findings suggested that social recognition memory is consolidated through the activation of CREB-mediated gene expression in the hippocampus/mPFC/ACC/amygdala. Network analyses suggested that these four brain regions show functional connectivity with other brain regions and, more importantly, that the hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas the ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. We have found that a brain network composed of the hippocampus/mPFC/ACC/amygdala is required for the consolidation of social recognition memory. SIGNIFICANCE STATEMENT Here, we identify brain networks composed of multiple brain regions for the consolidation of social recognition memory. We found that social recognition memory is consolidated through CREB-meditated gene expression in the hippocampus, medial prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Importantly, network analyses based on c-fos expression suggest that functional connectivity of these four brain regions with other brain regions is increased with time spent in social investigation toward the generation of brain networks to consolidate social recognition memory. Furthermore, our findings suggest that hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. Copyright © 2017 the authors 0270-6474/17/374103-14$15.00/0.

Rapid treatment-induced brain changes in pediatric CRPS.

PubMed

Erpelding, Nathalie; Simons, Laura; Lebel, Alyssa; Serrano, Paul; Pielech, Melissa; Prabhu, Sanjay; Becerra, Lino; Borsook, David

2016-03-01

To date, brain structure and function changes in children with complex regional pain syndrome (CRPS) as a result of disease and treatment remain unknown. Here, we investigated (a) gray matter (GM) differences between patients with CRPS and healthy controls and (b) GM and functional connectivity (FC) changes in patients following intensive interdisciplinary psychophysical pain treatment. Twenty-three patients (13 females, 9 males; average age ± SD = 13.3 ± 2.5 years) and 21 healthy sex- and age-matched controls underwent magnetic resonance imaging. Compared to controls, patients had reduced GM in the primary motor cortex, premotor cortex, supplementary motor area, midcingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex, precuneus, basal ganglia, thalamus, and hippocampus. Following treatment, patients had increased GM in the dlPFC, thalamus, basal ganglia, amygdala, and hippocampus, and enhanced FC between the dlPFC and the periaqueductal gray, two regions involved in descending pain modulation. Accordingly, our results provide novel evidence for GM abnormalities in sensory, motor, emotional, cognitive, and pain modulatory regions in children with CRPS. Furthermore, this is the first study to demonstrate rapid treatment-induced GM and FC changes in areas implicated in sensation, emotion, cognition, and pain modulation.

Activation of beta- and alpha-2-adrenoceptors in the basolateral amygdala has opposing effects on hippocampal-prefrontal long-term potentiation.

PubMed

Lim, Ee Peng; Dawe, Gavin S; Jay, Thérèse M

2017-01-01

Noradrenaline (NA), released by the locus coeruleus (LC), plays a key role in mediating the effects of stress on memory functions. The LC provides diffuse projections to many forebrain nuclei including the hippocampus, the prefrontal cortex (PFC), and the basolateral amygdala (BLA). These three structures are intricately interlinked. The hippocampal-prefrontal (H-PFC) pathway is involved in various cognitive functions. The first aim of this study was to examine the role of BLA in H-PFC plasticity by infusion of drugs to activate and inactivate the BLA and studying the effects on H-PFC long-term potentiation (LTP) in the rat in vivo. Activation of the BLA with glutamate impaired, while inactivation with muscimol augmented, H-PFC LTP. This study also aimed to demonstrate how directly applying noradrenaline and other noradrenergic agents in the BLA can affect H-PFC LTP. Noradrenaline at 1μg/0.2μl enhanced H-PFC LTP. Stimulating alpha-2-adrenoceptors in the BLA with clonidine enhanced LTP while blocking alpha-2 adrenoceptors with idazoxan impaired it. Propranolol, a non-selective beta antagonist, enhanced H-PFC LTP while isoprenaline, a non-selective beta agonist, decreased H-PFC LTP. These results suggest that the BLA regulates H-PFC plasticity negatively and also provide a mechanism by which noradrenaline in the BLA can affect H-PFC plasticity via alpha-2 and beta adrenoceptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Social scaffolding of human amygdala-mPFCcircuit development.

PubMed

Tottenham, Nim

2015-01-01

Strong evidence indicates that reciprocal connections between the amygdala and the medial prefrontal cortex (mPFC) support fundamental aspects of emotional behavior in adulthood. However, this circuitry is slow to develop in humans, exhibiting immaturity in childhood. The argument is made that the development of this circuitry in humans is intimately associated with caregiving, such that parental availability during childhood provides important and enduring scaffolding of neuroaffective processes that ultimately form of the nature of the adult phenotype.

Agomelatine (S20098) modulates the expression of cytoskeletal microtubular proteins, synaptic markers and BDNF in the rat hippocampus, amygdala and PFC.

PubMed

Ladurelle, Nataly; Gabriel, Cecilia; Viggiano, Adela; Mocaër, Elisabeth; Baulieu, Etienne E; Bianchi, Massimiliano

2012-06-01

Agomelatine is described as a novel and clinical effective antidepressant drug with melatonergic (MT(1)/MT(2)) agonist and 5-HT(2C) receptor antagonist properties. Previous studies suggest that modulation of neuronal plasticity and microtubule dynamics may be involved in the treatment of depression. The present study investigated the effects of agomelatine on microtubular, synaptic and brain-derived neurotrophic factor (BDNF) proteins in selected rat brain regions. Adult male rats received agomelatine (40 mg/kg i.p.) once a day for 22 days. The pro-cognitive effect of agomelatine was tested in the novel object recognition task and antidepressant activity in the forced swimming test. Microtubule dynamics markers, microtubule-associated protein type 2 (MAP-2), phosphorylated MAP-2, synaptic markers [synaptophysin, postsynaptic density-95 (PSD-95) and spinophilin] and BDNF were measured by Western blot in the hippocampus, amygdala and prefrontal cortex (PFC). Agomelatine exerted pro-cognitive and antidepressant activity and induced molecular changes in the brain areas examined. Agomelatine enhanced microtubule dynamics in the hippocampus and to a higher magnitude in the amygdala. By contrast, in the PFC, a decrease in microtubule dynamics was observed. Spinophilin (dendritic spines marker) was decreased, and BDNF increased in the hippocampus. Synaptophysin (presynaptic) and spinophilin were increased in the PFC and amygdala, while PSD-95 (postsynaptic marker) was increased in the amygdala, consistent with the phenomena of synaptic remodelling. Agomelatine modulates cytoskeletal microtubule dynamics and synaptic markers. This may play a role in its pharmacological behavioural effects and may result from the melatonergic agonist and 5-HT(2C) antagonist properties of the compound.

Decreasing GABA function within the medial prefrontal cortex or basolateral amygdala decreases sociability.

PubMed

Paine, Tracie A; Swedlow, Nathan; Swetschinski, Lucien

2017-01-15

Decreased sociability is a symptom of psychiatric conditions including autism-spectrum disorder and schizophrenia. Both of these conditions are associated with decreases in GABA function, particularly in the medial prefrontal cortex (PFC) and the basolateral amygdala (BLA); structures that are components of the social brain. Here, we determined if decreasing GABA transmission within either the PFC or the BLA decreases social behavior. Rats were implanted with cannulae aimed at either the medial PFC or the BLA and then were tested on up to 4 behavioral tests following bilateral infusions of 0.5μl bicuculline methiodide (BMI, a GABA A receptor antagonist) at doses of 0, 25, or 50ng/μl. Rats were tested in the social interaction test, the social preference test, the sucrose preference test and for locomotor activity (BLA infusions only). Intra-BLA or PFC BMI infusions decreased the amount of time and the number of social interactions in the social interaction test. Further, in the social preference test, rats infused with 50ng BMI no longer exhibited a preference to explore a social over a non-social stimulus. The change in sociability was not due to a change in reward processing or locomotor behavior. Decreasing GABA transmission in either the medial PFC or BLA decreased sociability. Thus, changes in GABA signaling observed in conditions such as autism or schizophrenia may mediate the social withdrawal characteristic of these conditions. Moreover, they suggest that social withdrawal may be treated by drugs that potentiate GABA transmission. Copyright © 2016 Elsevier B.V. All rights reserved.

Increased Prefrontal Cortical Thickness Is Associated with Enhanced Abilities to Regulate Emotions in PTSD-Free Women with Borderline Personality Disorder

PubMed Central

Bruehl, Hannah; Preißler, Sandra; Heuser, Isabella; Heekeren, Hauke R.

2013-01-01

Previous studies suggest that amygdala, insula and prefrontal cortex (PFC) disintegrity play a crucial role in the failure to adequately regulate emotions in Borderline Personality Disorder (BPD). However, prior results are confounded by the high rate of comorbidity with Posttraumatic Stress Disorder (PTSD), which itself has been associated with changes in frontolimbic circuitry. We thus scrutinized the link between PFC, amygdala, insula, and the ability to regulate emotions, contrasting 17 women with BPD without comorbid PTSD to 27 non-clinical control women and in addition to those with BPD and PTSD (n = 14). BPD women without PTSD, but not those with comorbid PTSD, had increased cortical thickness in the dorsolateral PFC (DLPFC) in comparison to control women. Furthermore, cortical thickness in the DLPFC of BPD women without PTSD positively correlated with emotion regulation scores and furthermore was positively associated with amygdala volume, as well as cortical thickness of the insula. Our findings highlight the importance of disentangling the impact of BPD and PTSD on the brain and suggest possible compensatory mechanisms for the impaired emotion regulation in BPD women without PTSD. PMID:23755254

Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex.

PubMed

López-Ramos, Juan Carlos; Guerra-Narbona, Rafael; Delgado-García, José M

2015-01-01

Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals' avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations.

Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex

PubMed Central

López-Ramos, Juan Carlos; Guerra-Narbona, Rafael; Delgado-García, José M.

2015-01-01

Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals’ avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations. PMID:25688195

Playing it safe but losing anyway – serotonergic signaling of aversive outcomes in dorsomedial prefrontal cortex in the context of risk-aversion

PubMed Central

Macoveanu, Julian; Rowe, James B; Hornboll, Bettina; Elliott, Rebecca; Paulson, Olaf B; Knudsen, Gitte M; Siebner, Hartwig R

2015-01-01

Risk avoidance is an important determinant of human behavior. The neurotransmitter serotonin has long been implicated in processing aversive outcomes caused by risky decisions. However, it is unclear whether serotonin provides a neurobiological link between making a risk aversive decision and the response to an aversive outcome. Using pharmacological fMRI, we manipulated the availability of serotonin in healthy volunteers while performing a gambling task. The same group of participants was studied in three fMRI sessions: (i) during intravenous administration of the SSRI citalopram to increase the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopran had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased and citalopram decreased the neural response to aversive outcomes in dmPFC. Conversely, ATD decreased and citalopram increased the neural response to aversive outcomes in left amygdala. Critically, these pharmacological effects were restricted to aversive outcomes that were caused by low-risk decision and led to a high missed reward. ATD and citalopram did not alter the neural response to positive outcomes in dmPFC, but relative to ATD, citalopram produced a bilateral increase in the amygdala response to large wins caused by high-risk choices. The results show a selective involvement of the serotonergic system in neocortical processing of aversive outcomes resulting from risk-averse decisions, thereby linking risk aversion and processing of aversive outcomes in goal-directed behaviors. PMID:23051938

Spontaneous brain activity following fear reminder of fear conditioning by using resting-state functional MRI

PubMed Central

Feng, Pan; Zheng, Yong; Feng, Tingyong

2015-01-01

Although disrupting reconsolidation may be a promising approach to attenuate or erase the expression of fear memory, it is not clear how the neural state following fear reminder contribute to the following fear extinction. To address this question, we used resting-state functional magnetic resonance imaging (rs-fMRI) to measure spontaneous neuronal activity and functional connectivity (RSFC) following fear reminder. Some brain regions such as dorsal anterior cingulate (dACC) and ventromedial prefrontal cortex (vmPFC) showed increased amplitude of LFF (ALFF) in the fear reminder group than the no reminder group following fear reminder. More importantly, there was much stronger functional connectivity between the amygdala and vmPFC in the fear reminder group than those in the no reminder group. These findings suggest that the strong functional connectivity between vmPFC and amygdala following a fear reminder could serve as a key role in the followed-up fear extinction stages, which may contribute to the erasing of fear memory. PMID:26576733

Spontaneous brain activity following fear reminder of fear conditioning by using resting-state functional MRI.

PubMed

Feng, Pan; Zheng, Yong; Feng, Tingyong

2015-11-18

Although disrupting reconsolidation may be a promising approach to attenuate or erase the expression of fear memory, it is not clear how the neural state following fear reminder contribute to the following fear extinction. To address this question, we used resting-state functional magnetic resonance imaging (rs-fMRI) to measure spontaneous neuronal activity and functional connectivity (RSFC) following fear reminder. Some brain regions such as dorsal anterior cingulate (dACC) and ventromedial prefrontal cortex (vmPFC) showed increased amplitude of LFF (ALFF) in the fear reminder group than the no reminder group following fear reminder. More importantly, there was much stronger functional connectivity between the amygdala and vmPFC in the fear reminder group than those in the no reminder group. These findings suggest that the strong functional connectivity between vmPFC and amygdala following a fear reminder could serve as a key role in the followed-up fear extinction stages, which may contribute to the erasing of fear memory.

Enhancement of fear memory by retrieval through reconsolidation

PubMed Central

Fukushima, Hotaka; Zhang, Yue; Archbold, Georgia; Ishikawa, Rie; Nader, Karim; Kida, Satoshi

2014-01-01

Memory retrieval is considered to have roles in memory enhancement. Recently, memory reconsolidation was suggested to reinforce or integrate new information into reactivated memory. Here, we show that reactivated inhibitory avoidance (IA) memory is enhanced through reconsolidation under conditions in which memory extinction is not induced. This memory enhancement is mediated by neurons in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) through the simultaneous activation of calcineurin-induced proteasome-dependent protein degradation and cAMP responsive element binding protein-mediated gene expression. Interestingly, the amygdala is required for memory reconsolidation and enhancement, whereas the hippocampus and mPFC are required for only memory enhancement. Furthermore, memory enhancement triggered by retrieval utilizes distinct mechanisms to strengthen IA memory by additional learning that depends only on the amygdala. Our findings indicate that reconsolidation functions to strengthen the original memory and show the dynamic nature of reactivated memory through protein degradation and gene expression in multiple brain regions. DOI: http://dx.doi.org/10.7554/eLife.02736.001 PMID:24963141

Dynamic neural activity during stress signals resilient coping

PubMed Central

Sinha, Rajita; Lacadie, Cheryl M.; Constable, R. Todd; Seo, Dongju

2016-01-01

Active coping underlies a healthy stress response, but neural processes supporting such resilient coping are not well-known. Using a brief, sustained exposure paradigm contrasting highly stressful, threatening, and violent stimuli versus nonaversive neutral visual stimuli in a functional magnetic resonance imaging (fMRI) study, we show significant subjective, physiologic, and endocrine increases and temporally related dynamically distinct patterns of neural activation in brain circuits underlying the stress response. First, stress-specific sustained increases in the amygdala, striatum, hypothalamus, midbrain, right insula, and right dorsolateral prefrontal cortex (DLPFC) regions supported the stress processing and reactivity circuit. Second, dynamic neural activation during stress versus neutral runs, showing early increases followed by later reduced activation in the ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dACC), left DLPFC, hippocampus, and left insula, suggested a stress adaptation response network. Finally, dynamic stress-specific mobilization of the ventromedial prefrontal cortex (VmPFC), marked by initial hypoactivity followed by increased VmPFC activation, pointed to the VmPFC as a key locus of the emotional and behavioral control network. Consistent with this finding, greater neural flexibility signals in the VmPFC during stress correlated with active coping ratings whereas lower dynamic activity in the VmPFC also predicted a higher level of maladaptive coping behaviors in real life, including binge alcohol intake, emotional eating, and frequency of arguments and fights. These findings demonstrate acute functional neuroplasticity during stress, with distinct and separable brain networks that underlie critical components of the stress response, and a specific role for VmPFC neuroflexibility in stress-resilient coping. PMID:27432990

Neural Activation to Emotional Faces in Adolescents with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Weng, Shih-Jen; Carrasco, Melisa; Swartz, Johnna R.; Wiggins, Jillian Lee; Kurapati, Nikhil; Liberzon, Israel; Risi, Susan; Lord, Catherine; Monk, Christopher S.

2011-01-01

Background: Autism spectrum disorders (ASD) involve a core deficit in social functioning and impairments in the ability to recognize face emotions. In an emotional faces task designed to constrain group differences in attention, the present study used functional MRI to characterize activation in the amygdala, ventral prefrontal cortex (vPFC), and…

Altered structure and function in the hippocampus and medial prefrontal cortex in patients with burning mouth syndrome.

PubMed

Khan, Shariq A; Keaser, Michael L; Meiller, Timothy F; Seminowicz, David A

2014-08-01

Burning mouth syndrome (BMS) is a debilitating, idiopathic chronic pain condition. For many BMS patients, burning oral pain begins in late morning and becomes more intense throughout the day, peaking by late afternoon or evening. We investigated brain gray matter volume (GMV) with voxel-based morphometry (VBM), white matter fractional anisotropy (FA) with diffusion tensor imaging (DTI), and functional connectivity in resting state functional MRI (rsfMRI) in a tightly screened, homogeneous sample of 9 female, postmenopausal/perimenopausal BMS patients and 9 matched healthy control subjects. Patients underwent 2 scanning sessions in the same day: in the morning, when ongoing pain/burning was low, and in the afternoon, when pain/burning was significantly higher. Patients had increased GMV and lower FA in the hippocampus (Hc), and decreased GMV in the medial prefrontal cortex (mPFC). rsfMRI revealed altered connectivity patterns in different states of pain/burning, with increased connectivity between mPFC (a node in the default mode network) and anterior cingulate cortex, occipital cortex, ventromedial PFC, and bilateral Hc/amygdala in the afternoon compared with the morning session. Furthermore, mPFC-Hc connectivity was higher in BMS patients than control subjects for the afternoon but not the morning session. mPFC-Hc connectivity was related to Beck depression inventory scores both between groups and between burning states within patients, suggesting that depression and anxiety partially explain pain-related brain dysfunction in BMS. Overall, we provide multiple lines of evidence supporting aberrant structure and function in the mPFC and Hc, and implicate a circuit involving the mPFC and Hc in regulating mood and depressive symptoms in BMS. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Trace Fear Conditioning Differentially Modulates Intrinsic Excitability of Medial Prefrontal Cortex-Basolateral Complex of Amygdala Projection Neurons in Infralimbic and Prelimbic Cortices.

PubMed

Song, Chenghui; Ehlers, Vanessa L; Moyer, James R

2015-09-30

Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC-BLA projection neurons in adult rats. Trace fear conditioning significantly enhanced the intrinsic excitability of regular spiking infralimbic (IL) projection neurons, as evidenced by an increase in the number of action potentials after current injection. These changes were also associated with a reduction in spike threshold and an increase in h current. In contrast, trace fear conditioning reduced the excitability of regular spiking prelimbic (PL) projection neurons, through a learning-related decrease of input resistance. Interestingly, the amount of conditioned freezing was (1) positively correlated with excitability of IL-BLA projection neurons after conditioning and (2) negatively correlated with excitability of PL-BLA projection neurons after extinction. Trace fear conditioning also significantly enhanced the excitability of burst spiking PL-BLA projection neurons. In both regions, conditioning-induced plasticity was learning specific (observed in conditioned but not in pseudoconditioned rats), flexible (reversed by extinction), and transient (lasted <10 d). Together, these data suggest that intrinsic plasticity within mPFC-BLA projection neurons occurs in a subregion- and cell-type-specific manner during acquisition, consolidation, and extinction of trace fear conditioning. Significance statement: Frontal lobe-related function is vital for a variety of important behaviors, some of which decline during aging. This study involves a novel combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during behavior. This is the first study to demonstrate that trace fear conditioning significantly alters the intrinsic excitability of mPFC-to-amygdala projection neurons in a subregion- and cell-type-specific manner, which is also transient and reversed by extinction. These data are of broad interest to the neuroscientific community, and the results will inspire additional studies investigating the cellular mechanisms underlying circuit-specific changes within the brain as a result of associative learning and memory. Copyright © 2015 the authors 0270-6474/15/3513511-14$15.00/0.

Substrates of neuropsychological functioning in stimulant dependence: a review of functional neuroimaging research

PubMed Central

Crunelle, Cleo L; Veltman, Dick J; Booij, Jan; Emmerik – van Oortmerssen, Katelijne; den Brink, Wim

2012-01-01

Stimulant dependence is associated with neuropsychological impairments. Here, we summarize and integrate the existing neuroimaging literature on the neural substrates of neuropsychological (dys)function in stimulant dependence, including cocaine, (meth-)amphetamine, ecstasy and nicotine dependence, and excessive caffeine use, comparing stimulant abusers (SAs) to nondrug using healthy controls (HCs). Despite some inconsistencies, most studies indicated altered brain activation in prefrontal cortex (PFC) and insula in response to reward and punishment, and higher limbic and anterior cingulate cortex (ACC)/PFC activation during craving and attentional bias paradigms in SAs compared with HCs. Impulsivity in SAs was associated with lower ACC and presupplementary motor area activity compared with HCs, and related to both ventral (amygdala, ventrolateral PFC, insula) and dorsal (dorsolateral PFC, dorsal ACC, posterior parietal cortex) systems. Decision making in SAs was associated with low dorsolateral PFC activity and high orbitofrontal activity. Finally, executive function in SAs was associated with lower activation in frontotemporal regions and higher activation in premotor cortex compared with HCs. It is concluded that the lower activations compared with HCs are likely to reflect the neural substrate of impaired neurocognitive functions, whereas higher activations in SAs compared with HCs are likely to reflect compensatory cognitive control mechanisms to keep behavioral task performance to a similar level as in HCs. However, before final conclusions can be drawn, additional research is needed using neuroimaging in SAs and HCs using larger and more homogeneous samples as well as more comparable task paradigms, study designs, and statistical analyses. PMID:22950052

Interpersonal violence in posttraumatic women: brain networks triggered by trauma-related pictures.

PubMed

Neumeister, Paula; Feldker, Katharina; Heitmann, Carina Y; Helmich, Ruth; Gathmann, Bettina; Becker, Michael P I; Straube, Thomas

2017-04-01

Interpersonal violence (IPV) is one of the most frequent causes for the development of posttraumatic stress disorder (PTSD) in women. Trauma-related triggers have been proposed to evoke automatic emotional responses in PTSD. The present functional magnetic resonance study investigated the neural basis of trauma-related picture processing in women with IPV-PTSD (n = 18) relative to healthy controls (n = 18) using a newly standardized trauma-related picture set and a non-emotional vigilance task. We aimed to identify brain activation and connectivity evoked by trauma-related pictures, and associations with PTSD symptom severity. We found hyperactivation during trauma-related vs neutral picture processing in both subcortical [basolateral amygdala (BLA), thalamus, brainstem] and cortical [anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), insula, occipital cortex] regions in IPV-PTSD. In patients, brain activation in amygdala, ACC, insula, occipital cortex and brainstem correlated positively with symptom severity. Furthermore, connectivity analyses revealed hyperconnectivity between BLA and dorsal ACC/mPFC. Results show symptom severity-dependent brain activation and hyperconnectivity in response to trauma-related pictures in brain regions related to fear and visual processing in women suffering from IPV-PTSD. These brain mechanisms appear to be associated with immediate responses to trauma-related triggers presented in a non-emotional context in this PTSD subgroup. © The Author (2016). Published by Oxford University Press.

A Testosterone-Related Structural Brain Phenotype Predicts Aggressive Behavior From Childhood to Adulthood

PubMed Central

Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N.; Hudziak, James J; Ducharme, Simon

2015-01-01

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6 to 22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. PMID:26431805

A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood.

PubMed

Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N; Hudziak, James J; Ducharme, Simon

2016-01-01

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here, we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6-22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sad mood induction has an opposite effect on amygdala response to emotional stimuli in euthymic patients with bipolar disorder and healthy controls.

PubMed

Horacek, Jiri; Mikolas, Pavol; Tintera, Jaroslav; Novak, Tomas; Palenicek, Tomas; Brunovsky, Martin; Höschl, Cyril; Alda, Martin

2014-12-16

Aberrant amygdala reactivity to affective stimuli represents a candidate factor predisposing patients with bipolar disorder (BD) to relapse, but it is unclear to what extent amygdala reactivity is state-dependent. We evaluated the modulatory influence of mood on amygdala reactivity and functional connectivity in patients with remitted BD and healthy controls. Amygdala response to sad versus neutral faces was investigated using fMRI during periods of normal and sad mood induced by autobiographical scripts. We assessed the functional connectivity of the amygdala to characterize the influence of mood state on the network responsible for the amygdala response. We included 20 patients with remitted BD and 20 controls in our study. The sad and normal mood exerted opposite effects on the amygdala response to emotional faces in patients compared with controls ( F 1,38 = 5.85, p = 0.020). Sad mood amplified the amygdala response to sad facial stimuli in controls but attenuated the amygdala response in patients. The groups differed in functional connectivity between the amygdala and the inferior prefrontal gyrus ( p ≤ 0.05, family-wise error-corrected) of ventrolateral prefrontal cortex (vlPFC) corresponding to Brodmann area 47. The sad mood challenge increased connectivity during the period of processing sad faces in patients but decreased connectivity in controls. Limitations to our study included long-term medication use in the patient group and the fact that we mapped only depressive (not manic) reactivity. Our results support the role of the amygdala-vlPFC as the system of dysfunctional contextual affective processing in patients with BD. Opposite amygdala reactivity unmasked by the mood challenge paradigm could represent a trait marker of altered mood regulation in patients with BD.

Sad mood induction has an opposite effect on amygdala response to emotional stimuli in euthymic patients with bipolar disorder and healthy controls.

PubMed

Horacek, Jiri; Mikolas, Pavol; Tintera, Jaroslav; Novak, Tomas; Palenicek, Tomas; Brunovsky, Martin; Höschl, Cyril; Alda, Martin

2015-03-01

Aberrant amygdala reactivity to affective stimuli represents a candidate factor predisposing patients with bipolar disorder (BD) to relapse, but it is unclear to what extent amygdala reactivity is state-dependent. We evaluated the modulatory influence of mood on amygdala reactivity and functional connectivity in patients with remitted BD and healthy controls. Amygdala response to sad versus neutral faces was investigated using fMRI during periods of normal and sad mood induced by autobiographical scripts. We assessed the functional connectivity of the amygdala to characterize the influence of mood state on the network responsible for the amygdala response. We included 20 patients with remitted BD and 20 controls in our study. The sad and normal mood exerted opposite effects on the amygdala response to emotional faces in patients compared with controls (F1,38 = 5.85, p = 0.020). Sad mood amplified the amygdala response to sad facial stimuli in controls but attenuated the amygdala response in patients. The groups differed in functional connectivity between the amygdala and the inferior prefrontal gyrus (p ≤ 0.05, family-wise error-corrected) of ventrolateral prefrontal cortex (vlPFC) corresponding to Brodmann area 47. The sad mood challenge increased connectivity during the period of processing sad faces in patients but decreased connectivity in controls. Limitations to our study included long-term medication use in the patient group and the fact that we mapped only depressive (not manic) reactivity. Our results support the role of the amygdala-vlPFC as the system of dysfunctional contextual affective processing in patients with BD. Opposite amygdala reactivity unmasked by the mood challenge paradigm could represent a trait marker of altered mood regulation in patients with BD.

Neural response to pictorial health warning labels can predict smoking behavioral change

PubMed Central

Riddle, Philip J.; Newman-Norlund, Roger D.; Baer, Jessica; Thrasher, James F.

2016-01-01

In order to improve our understanding of how pictorial health warning labels (HWLs) influence smoking behavior, we examined whether brain activity helps to explain smoking behavior above and beyond self-reported effectiveness of HWLs. We measured the neural response in the ventromedial prefrontal cortex (vmPFC) and the amygdala while adult smokers viewed HWLs. Two weeks later, participants’ self-reported smoking behavior and biomarkers of smoking behavior were reassessed. We compared multiple models predicting change in self-reported smoking behavior (cigarettes per day [CPD]) and change in a biomarkers of smoke exposure (expired carbon monoxide [CO]). Brain activity in the vmPFC and amygdala not only predicted changes in CO, but also accounted for outcome variance above and beyond self-report data. Neural data were most useful in predicting behavioral change as quantified by the objective biomarker (CO). This pattern of activity was significantly modulated by individuals’ intention to quit. The finding that both cognitive (vmPFC) and affective (amygdala) brain areas contributed to these models supports the idea that smokers respond to HWLs in a cognitive-affective manner. Based on our findings, researchers may wish to consider using neural data from both cognitive and affective networks when attempting to predict behavioral change in certain populations (e.g. cigarette smokers). PMID:27405615

Functional Neuroimaging of Emotionally Intense Autobiographical Memories in Post-Traumatic Stress Disorder

PubMed Central

St. Jacques, Peggy L.; Botzung, Anne; Miles, Amanda; Rubin, David C.

2010-01-01

Post-traumatic stress disorder (PTSD) affects regions that support autobiographical memory (AM) retrieval, such as the hippocampus, amygdala and ventral medial prefrontal cortex (PFC). However, it is not well understood how PTSD may impact the neural mechanisms of memory retrieval for the personal past. We used a generic cue method combined with parametric modulation analysis and functional MRI (fMRI) to investigate the neural mechanisms affected by PTSD symptoms during the retrieval of a large sample of emotionally intense AMs. There were three main results. First, the PTSD group showed greater recruitment of the amygdala/hippocampus during the construction of negative versus positive emotionally intense AMs, when compared to controls. Second, across both the construction and elaboration phases of retrieval the PTSD group showed greater recruitment of the ventral medial PFC for negatively intense memories, but less recruitment for positively intense memories. Third, the PTSD group showed greater functional coupling between the ventral medial PFC and the amygdala for negatively intense memories, but less coupling for positively intense memories. In sum, the fMRI data suggest that there was greater recruitment and coupling of emotional brain regions during the retrieval of negatively intense AMs in the PTSD group when compared to controls. PMID:21109253

Neural response to pictorial health warning labels can predict smoking behavioral change.

PubMed

Riddle, Philip J; Newman-Norlund, Roger D; Baer, Jessica; Thrasher, James F

2016-11-01

In order to improve our understanding of how pictorial health warning labels (HWLs) influence smoking behavior, we examined whether brain activity helps to explain smoking behavior above and beyond self-reported effectiveness of HWLs. We measured the neural response in the ventromedial prefrontal cortex (vmPFC) and the amygdala while adult smokers viewed HWLs. Two weeks later, participants' self-reported smoking behavior and biomarkers of smoking behavior were reassessed. We compared multiple models predicting change in self-reported smoking behavior (cigarettes per day [CPD]) and change in a biomarkers of smoke exposure (expired carbon monoxide [CO]). Brain activity in the vmPFC and amygdala not only predicted changes in CO, but also accounted for outcome variance above and beyond self-report data. Neural data were most useful in predicting behavioral change as quantified by the objective biomarker (CO). This pattern of activity was significantly modulated by individuals' intention to quit. The finding that both cognitive (vmPFC) and affective (amygdala) brain areas contributed to these models supports the idea that smokers respond to HWLs in a cognitive-affective manner. Based on our findings, researchers may wish to consider using neural data from both cognitive and affective networks when attempting to predict behavioral change in certain populations (e.g. cigarette smokers). © The Author (2016). Published by Oxford University Press.

Neurobehavioral assessment of maternal odor in developing rat pups: implications for social buffering.

PubMed

Al Aïn, Syrina; Perry, Rosemarie E; Nuñez, Bestina; Kayser, Kassandra; Hochman, Chase; Brehman, Elizabeth; LaComb, Miranda; Wilson, Donald A; Sullivan, Regina M

2017-02-01

Social support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother's social buffering of the infant is one of the more robust examples; yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14 C 2-deoxyglucose (2-DG) and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (Basolateral Amygdala [BLA]), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC, or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering.

Sad mood induction has an opposite effect on amygdala response to emotional stimuli in euthymic patients with bipolar disorder and healthy controls

PubMed Central

Horacek, Jiri; Mikolas, Pavol; Tintera, Jaroslav; Novak, Tomas; Palenicek, Tomas; Brunovsky, Martin; Höschl, Cyril; Alda, Martin

2015-01-01

Background Aberrant amygdala reactivity to affective stimuli represents a candidate factor predisposing patients with bipolar disorder (BD) to relapse, but it is unclear to what extent amygdala reactivity is state-dependent. We evaluated the modulatory influence of mood on amygdala reactivity and functional connectivity in patients with remitted BD and healthy controls. Methods Amygdala response to sad versus neutral faces was investigated using fMRI during periods of normal and sad mood induced by autobiographical scripts. We assessed the functional connectivity of the amygdala to characterize the influence of mood state on the network responsible for the amygdala response. Results We included 20 patients with remitted BD and 20 controls in our study. The sad and normal mood exerted opposite effects on the amygdala response to emotional faces in patients compared with controls (F1,38 = 5.85, p = 0.020). Sad mood amplified the amygdala response to sad facial stimuli in controls but attenuated the amygdala response in patients. The groups differed in functional connectivity between the amygdala and the inferior prefrontal gyrus (p ≤ 0.05, family-wise error–corrected) of ventrolateral prefrontal cortex (vlPFC) corresponding to Brodmann area 47. The sad mood challenge increased connectivity during the period of processing sad faces in patients but decreased connectivity in controls. Limitations Limitations to our study included long-term medication use in the patient group and the fact that we mapped only depressive (not manic) reactivity. Conclusion Our results support the role of the amygdala–vlPFC as the system of dysfunctional contextual affective processing in patients with BD. Opposite amygdala reactivity unmasked by the mood challenge paradigm could represent a trait marker of altered mood regulation in patients with BD. PMID:25703646

Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders.

PubMed

Wilcox, Claire E; Pommy, Jessica M; Adinoff, Bryon

2016-04-01

Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.

Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders

PubMed Central

Wilcox, Claire E.; Pommy, Jessica M.; Adinoff, Bryon

2016-01-01

Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity. PMID:26771738

Functional grouping and cortical–subcortical interactions in emotion: A meta-analysis of neuroimaging studies

PubMed Central

Kober, Hedy; Barrett, Lisa Feldman; Joseph, Josh; Bliss-Moreau, Eliza; Lindquist, Kristen; Wager, Tor D.

2009-01-01

We performed an updated quantitative meta-analysis of 162 neuroimaging studies of emotion using a novel multi-level kernel-based approach, focusing on locating brain regions consistently activated in emotional tasks and their functional organization into distributed functional groups, independent of semantically defined emotion category labels (e.g., “anger,” “fear”). Such brain-based analyses are critical if our ways of labeling emotions are to be evaluated and revised based on consistency with brain data. Consistent activations were limited to specific cortical sub-regions, including multiple functional areas within medial, orbital, and inferior lateral frontal cortices. Consistent with a wealth of animal literature, multiple subcortical activations were identified, including amygdala, ventral striatum, thalamus, hypothalamus, and periaqueductal gray. We used multivariate parcellation and clustering techniques to identify groups of co-activated brain regions across studies. These analyses identified six distributed functional groups, including medial and lateral frontal groups, two posterior cortical groups, and paralimbic and core limbic/brainstem groups. These functional groups provide information on potential organization of brain regions into large-scale networks. Specific follow-up analyses focused on amygdala, periaqueductal gray (PAG), and hypothalamic (Hy) activations, and identified frontal cortical areas co-activated with these core limbic structures. While multiple areas of frontal cortex co-activated with amygdala sub-regions, a specific region of dorsomedial prefrontal cortex (dmPFC, Brodmann’s Area 9/32) was the only area co-activated with both PAG and Hy. Subsequent mediation analyses were consistent with a pathway from dmPFC through PAG to Hy. These results suggest that medial frontal areas are more closely associated with core limbic activation than their lateral counterparts, and that dmPFC may play a particularly important role in the cognitive generation of emotional states. PMID:18579414

Electroencephalographic coupling in the amygdala and prefrontal cortex in relation to the estrous cycle and duration of vaginocervical stimulation in the rat.

PubMed

Hernández-González, Marisela; Reynoso-Orozco, Orlando; Guevara, Miguel Angel; García Abascal, Diego Radberto Chapa; Ågmo, Anders

2016-12-01

The influence of the duration of vaginocervical stimulation (VCS) on the electroencephalographic activity (EEG) of medial amygdala (MeA) and prefrontal cortex (PFC) in rats during proestrus-estrus (P-E) and diestrus (D) was examined. Using a glass syringe plunger, a constant force of 300g was exerted against the cervix during 60s. Relative power (RP) and correlation of three EEG band frequencies were compared between the first and last 30s intervals of VCS. A higher RP of the 4-7Hz band and a lower RP of the fast frequencies were observed in the MeA and PFC in P-E females during the first 30s of VCS as compared to the last 30s. Only during P-E, a higher interamygdaline correlation in the 8-12Hz band and a lower correlation in the 13-21Hz band during the first 30s were observed. Similarly, a higher interamygdaline correlation in the 8-12Hz band was observed during the first 30s of VCS during P-E as compared to D. During the last 30s of VCS there was no difference between phases. The VCS evoked EEG changes in the MeA that varied between phases of the estrous cycle and depended on the duration of the stimulation. These effects could be associated with the quantification processes of VCS that has been proposed to occur in the amygdala. These findings show differential responsiveness of the MeA and PFC according to the amount of VCS received, and that the response varies according to the estrous cycle. Copyright © 2016 Elsevier B.V. All rights reserved.

Playing it safe but losing anyway--serotonergic signaling of negative outcomes in dorsomedial prefrontal cortex in the context of risk-aversion.

PubMed

Macoveanu, Julian; Rowe, James B; Hornboll, Bettina; Elliott, Rebecca; Paulson, Olaf B; Knudsen, Gitte M; Siebner, Hartwig R

2013-08-01

Risk avoidance is an important determinant of human behavior. The neurotransmitter serotonin has been implicated in processing negative outcomes caused by risky decisions. However, it is unclear whether serotonin provides a neurobiological link between making a risk aversive decision and the response to a negative outcome. Using pharmacological fMRI, we manipulated the availability of serotonin in healthy volunteers while performing a gambling task. The same group of participants was studied in three fMRI sessions: (i) during intravenous administration of the SSRI citalopram to increase the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopram had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased and citalopram decreased the neural response to negative outcomes in dmPFC. Conversely, ATD decreased and citalopram increased the neural response to negative outcomes in left amygdala. Critically, these pharmacological effects were restricted to negative outcomes that were caused by low-risk decisions and led to a high missed reward. ATD and citalopram did not alter the neural response to positive outcomes in dmPFC, but relative to ATD, citalopram produced a bilateral increase in the amygdala response to large wins caused by high-risk choices. The results show a selective involvement of the serotonergic system in neocortical processing of negative outcomes resulting from risk-averse decisions, thereby linking risk aversion and processing of negative outcomes in goal-directed behaviors. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Emotion processing in the aging brain is modulated by semantic elaboration

PubMed Central

Ritchey, Maureen; Bessette-Symons, Brandy; Hayes, Scott M.; Cabeza, Roberto

2010-01-01

The neural correlates of emotion processing have been shown to vary with age: older adults (OAs) exhibit increased frontal activations and, under some circumstances, decreased amygdala activations relative to young adults (YAs) during emotion processing. Some of these differences are additionally modulated by valence, with age-related biases toward positive versus negative stimuli, and are thought to depend on OAs’ capacity for controlled elaboration. However, the role of semantic elaboration in mediating valence effects in the aging brain has not yet been explicitly tested. In the present study, YAs and OAs were scanned while they viewed negative, neutral, and positive pictures during either a deep, elaborative task or a shallow, perceptual task. FMRI results reveal that emotion-related activity in the amygdala is preserved in aging and insensitive to elaboration demands. This study provides novel evidence that differences in valence processing are modulated by elaboration: relative to YAs, OAs show enhanced activity in the medial prefrontal cortex (PFC) and ventrolateral PFC in response to positive versus negative stimuli, but only during elaborative processing. These positive valence effects are predicted by individual differences in executive function in OAs for the deep but not shallow task. Finally, psychophysiological interaction analyses reveal age effects on valence-dependent functional connectivity between medial PFC and ventral striatum, as well as age and task effects on medial PFC-retrosplenial cortex interactions. Altogether, these findings provide support for the hypothesis that valence shifts in the aging brain are mediated by controlled processes such as semantic elaboration, self-referential processing, and emotion regulation. PMID:20869375

Altered neural processing of emotional faces in remitted Cushing's disease.

PubMed

Bas-Hoogendam, Janna Marie; Andela, Cornelie D; van der Werff, Steven J A; Pannekoek, J Nienke; van Steenbergen, Henk; Meijer, Onno C; van Buchem, Mark A; Rombouts, Serge A R B; van der Mast, Roos C; Biermasz, Nienke R; van der Wee, Nic J A; Pereira, Alberto M

2015-09-01

Patients with long-term remission of Cushing's disease (CD) demonstrate residual psychological complaints. At present, it is not known how previous exposure to hypercortisolism affects psychological functioning in the long-term. Earlier magnetic resonance imaging (MRI) studies demonstrated abnormalities of brain structure and resting-state connectivity in patients with long-term remission of CD, but no data are available on functional alterations in the brain during the performance of emotional or cognitive tasks in these patients. We performed a cross-sectional functional MRI study, investigating brain activation during emotion processing in patients with long-term remission of CD. Processing of emotional faces versus a non-emotional control condition was examined in 21 patients and 21 matched healthy controls. Analyses focused on activation and connectivity of two a priori determined regions of interest: the amygdala and the medial prefrontal-orbitofrontal cortex (mPFC-OFC). We also assessed psychological functioning, cognitive failure, and clinical disease severity. Patients showed less mPFC activation during processing of emotional faces compared to controls, whereas no differences were found in amygdala activation. An exploratory psychophysiological interaction analysis demonstrated decreased functional coupling between the ventromedial PFC and posterior cingulate cortex (a region structurally connected to the PFC) in CD-patients. The present study is the first to show alterations in brain function and task-related functional coupling in patients with long-term remission of CD relative to matched healthy controls. These alterations may, together with abnormalities in brain structure, be related to the persisting psychological morbidity in patients with CD after long-term remission. Copyright © 2015 Elsevier Ltd. All rights reserved.

Emotion processing in the aging brain is modulated by semantic elaboration.

PubMed

Ritchey, Maureen; Bessette-Symons, Brandy; Hayes, Scott M; Cabeza, Roberto

2011-03-01

The neural correlates of emotion processing have been shown to vary with age: older adults (OAs) exhibit increased frontal activations and, under some circumstances, decreased amygdala activations relative to young adults (YAs) during emotion processing. Some of these differences are additionally modulated by valence, with age-related biases toward positive versus negative stimuli, and are thought to depend on OAs' capacity for controlled elaboration. However, the role of semantic elaboration in mediating valence effects in the aging brain has not yet been explicitly tested. In the present study, YAs and OAs were scanned while they viewed negative, neutral, and positive pictures during either a deep, elaborative task or a shallow, perceptual task. fMRI results reveal that emotion-related activity in the amygdala is preserved in aging and insensitive to elaboration demands. This study provides novel evidence that differences in valence processing are modulated by elaboration: relative to YAs, OAs show enhanced activity in the medial prefrontal cortex (PFC) and ventrolateral PFC in response to positive versus negative stimuli, but only during elaborative processing. These positive valence effects are predicted by individual differences in executive function in OAs for the deep but not shallow task. Finally, psychophysiological interaction analyses reveal age effects on valence-dependent functional connectivity between medial PFC and ventral striatum, as well as age and task effects on medial PFC-retrosplenial cortex interactions. Altogether, these findings provide support for the hypothesis that valence shifts in the aging brain are mediated by controlled processes such as semantic elaboration, self-referential processing, and emotion regulation. Copyright © 2010 Elsevier Ltd. All rights reserved.

Neural activation to emotional faces in adolescents with autism spectrum disorders.

PubMed

Weng, Shih-Jen; Carrasco, Melisa; Swartz, Johnna R; Wiggins, Jillian Lee; Kurapati, Nikhil; Liberzon, Israel; Risi, Susan; Lord, Catherine; Monk, Christopher S

2011-03-01

Autism spectrum disorders (ASD) involve a core deficit in social functioning and impairments in the ability to recognize face emotions. In an emotional faces task designed to constrain group differences in attention, the present study used functional MRI to characterize activation in the amygdala, ventral prefrontal cortex (vPFC), and striatum, three structures involved in socio-emotional processing in adolescents with ASD. Twenty-two adolescents with ASD and 20 healthy adolescents viewed facial expressions (happy, fearful, sad and neutral) that were briefly presented (250 ms) during functional MRI acquisition. To monitor attention, subjects pressed a button to identify the gender of each face. The ASD group showed greater activation to the faces relative to the control group in the amygdala, vPFC and striatum. Follow-up analyses indicated that the ASD relative to control group showed greater activation in the amygdala, vPFC and striatum (p < .05 small volume corrected), particularly to sad faces. Moreover, in the ASD group, there was a negative correlation between developmental variables (age and pubertal status) and mean activation from the whole bilateral amygdala; younger adolescents showed greater activation than older adolescents. There were no group differences in accuracy or reaction time in the gender identification task. When group differences in attention to facial expressions were limited, adolescents with ASD showed greater activation in structures involved in socio-emotional processing. © 2010 The Authors. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health.

Dorsolateral prefrontal cortex activation during emotional anticipation and neuropsychological performance in posttraumatic stress disorder.

PubMed

Aupperle, Robin L; Allard, Carolyn B; Grimes, Erin M; Simmons, Alan N; Flagan, Taru; Behrooznia, Michelle; Cissell, Shadha H; Twamley, Elizabeth W; Thorp, Steven R; Norman, Sonya B; Paulus, Martin P; Stein, Murray B

2012-04-01

Posttraumatic stress disorder (PTSD) has been associated with executive or attentional dysfunction and problems in emotion processing. However, it is unclear whether these two domains of dysfunction are related to common or distinct neurophysiological substrates. To examine the hypothesis that greater neuropsychological impairment in PTSD relates to greater disruption in prefrontal-subcortical networks during emotional anticipation. Case-control, cross-sectional study. General community and hospital and community psychiatric clinics. Volunteer sample of 37 women with PTSD related to intimate partner violence and 34 age-comparable healthy control women. We used functional magnetic resonance imaging (fMRI) to examine neural responses during anticipation of negative and positive emotional images. The Clinician-Administered PTSD Scale was used to characterize PTSD symptom severity. The Wechsler Adult Intelligence Scale, Third Edition, Digit Symbol Test, Delis-Kaplan Executive Function System Color-Word Interference Test, and Wisconsin Card Sorting Test were used to characterize neuropsychological performance. Women with PTSD performed worse on complex visuomotor processing speed (Digit Symbol Test) and executive function (Color-Word Interference Inhibition/Switching subtest) measures compared with control subjects. Posttraumatic stress disorder was associated with greater anterior insula and attenuated lateral prefrontal cortex (PFC) activation during emotional anticipation. Greater dorsolateral PFC activation (anticipation of negative images minus anticipation of positive images) was associated with lower PTSD symptom severity and better visuomotor processing speed and executive functioning. Greater medial PFC and amygdala activation related to slower visuomotor processing speed. During emotional anticipation, women with PTSD show exaggerated activation in the anterior insula, a region important for monitoring internal bodily state. Greater dorsolateral PFC response in PTSD patients during emotional anticipation may reflect engagement of cognitive control networks that are beneficial for emotional and cognitive functioning. Novel treatments could be aimed at strengthening the balance between cognitive control (dorsolateral PFC) and affective processing (medial PFC and amygdala) networks to improve overall functioning for PTSD patients.

Typical and atypical neurodevelopment for face specialization: An fMRI study

PubMed Central

Joseph, Jane E.; Zhu, Xun; Gundran, Andrew; Davies, Faraday; Clark, Jonathan D.; Ruble, Lisa; Glaser, Paul; Bhatt, Ramesh S.

2014-01-01

Individuals with Autism Spectrum Disorder (ASD) and their relatives process faces differently from typically developed (TD) individuals. In an fMRI face-viewing task, TD and undiagnosed sibling (SIB) children (5–18 years) showed face specialization in the right amygdala and ventromedial prefrontal cortex (vmPFC), with left fusiform and right amygdala face specialization increasing with age in TD subjects. SIBs showed extensive antero-medial temporal lobe activation for faces that was not present in any other group, suggesting a potential compensatory mechanism. In ASD, face specialization was minimal but increased with age in the right fusiform and decreased with age in the left amygdala, suggesting atypical development of a frontal-amygdala-fusiform system which is strongly linked to detecting salience and processing facial information. PMID:25479816

Stimulus-Elicited Connectivity Influences Resting-State Connectivity Years Later in Human Development: A Prospective Study.

PubMed

Gabard-Durnam, Laurel Joy; Gee, Dylan Grace; Goff, Bonnie; Flannery, Jessica; Telzer, Eva; Humphreys, Kathryn Leigh; Lumian, Daniel Stephen; Fareri, Dominic Stephen; Caldera, Christina; Tottenham, Nim

2016-04-27

Although the functional architecture of the brain is indexed by resting-state connectivity networks, little is currently known about the mechanisms through which these networks assemble into stable mature patterns. The current study posits and tests the long-term phasic molding hypothesis that resting-state networks are gradually shaped by recurring stimulus-elicited connectivity across development by examining how both stimulus-elicited and resting-state functional connections of the human brain emerge over development at the systems level. Using a sequential design following 4- to 18-year-olds over a 2 year period, we examined the predictive associations between stimulus-elicited and resting-state connectivity in amygdala-cortical circuitry as an exemplar case (given this network's protracted development across these ages). Age-related changes in amygdala functional connectivity converged on the same regions of medial prefrontal cortex (mPFC) and inferior frontal gyrus when elicited by emotional stimuli and when measured at rest. Consistent with the long-term phasic molding hypothesis, prospective analyses for both connections showed that the magnitude of an individual's stimulus-elicited connectivity unidirectionally predicted resting-state functional connectivity 2 years later. For the amygdala-mPFC connection, only stimulus-elicited connectivity during childhood and the transition to adolescence shaped future resting-state connectivity, consistent with a sensitive period ending with adolescence for the amygdala-mPFC circuit. Together, these findings suggest that resting-state functional architecture may arise from phasic patterns of functional connectivity elicited by environmental stimuli over the course of development on the order of years. A fundamental issue in understanding the ontogeny of brain function is how resting-state (intrinsic) functional networks emerge and relate to stimulus-elicited functional connectivity. Here, we posit and test the long-term phasic molding hypothesis that resting-state network development is influenced by recurring stimulus-elicited connectivity through prospective examination of the developing human amygdala-cortical functional connections. Our results provide critical insight into how early environmental events sculpt functional network architecture across development and highlight childhood as a potential developmental period of heightened malleability for the amygdala-medial prefrontal cortex circuit. These findings have implications for how both positive and adverse experiences influence the developing brain and motivate future investigations of whether this molding mechanism reflects a general phenomenon of brain development. Copyright © 2016 the authors 0270-6474/16/364772-14$15.00/0.

Stimulus-Elicited Connectivity Influences Resting-State Connectivity Years Later in Human Development: A Prospective Study

PubMed Central

Gee, Dylan Grace; Goff, Bonnie; Flannery, Jessica; Telzer, Eva; Humphreys, Kathryn Leigh; Lumian, Daniel Stephen; Fareri, Dominic Stephen; Caldera, Christina; Tottenham, Nim

2016-01-01

Although the functional architecture of the brain is indexed by resting-state connectivity networks, little is currently known about the mechanisms through which these networks assemble into stable mature patterns. The current study posits and tests the long-term phasic molding hypothesis that resting-state networks are gradually shaped by recurring stimulus-elicited connectivity across development by examining how both stimulus-elicited and resting-state functional connections of the human brain emerge over development at the systems level. Using a sequential design following 4- to 18-year-olds over a 2 year period, we examined the predictive associations between stimulus-elicited and resting-state connectivity in amygdala-cortical circuitry as an exemplar case (given this network's protracted development across these ages). Age-related changes in amygdala functional connectivity converged on the same regions of medial prefrontal cortex (mPFC) and inferior frontal gyrus when elicited by emotional stimuli and when measured at rest. Consistent with the long-term phasic molding hypothesis, prospective analyses for both connections showed that the magnitude of an individual's stimulus-elicited connectivity unidirectionally predicted resting-state functional connectivity 2 years later. For the amygdala-mPFC connection, only stimulus-elicited connectivity during childhood and the transition to adolescence shaped future resting-state connectivity, consistent with a sensitive period ending with adolescence for the amygdala-mPFC circuit. Together, these findings suggest that resting-state functional architecture may arise from phasic patterns of functional connectivity elicited by environmental stimuli over the course of development on the order of years. SIGNIFICANCE STATEMENT A fundamental issue in understanding the ontogeny of brain function is how resting-state (intrinsic) functional networks emerge and relate to stimulus-elicited functional connectivity. Here, we posit and test the long-term phasic molding hypothesis that resting-state network development is influenced by recurring stimulus-elicited connectivity through prospective examination of the developing human amygdala-cortical functional connections. Our results provide critical insight into how early environmental events sculpt functional network architecture across development and highlight childhood as a potential developmental period of heightened malleability for the amygdala-medial prefrontal cortex circuit. These findings have implications for how both positive and adverse experiences influence the developing brain and motivate future investigations of whether this molding mechanism reflects a general phenomenon of brain development. PMID:27122035

Advancing understanding of affect labeling with dynamic causal modeling

PubMed Central

Torrisi, Salvatore J.; Lieberman, Matthew D.; Bookheimer, Susan Y.; Altshuler, Lori L.

2013-01-01

Mechanistic understandings of forms of incidental emotion regulation have implications for basic and translational research in the affective sciences. In this study we applied Dynamic Causal Modeling (DCM) for fMRI to a common paradigm of labeling facial affect to elucidate prefrontal to subcortical influences. Four brain regions were used to model affect labeling, including right ventrolateral prefrontal cortex (vlPFC), amygdala and Broca’s area. 64 models were compared, for each of 45 healthy subjects. Family level inference split the model space to a likely driving input and Bayesian Model Selection within the winning family of 32 models revealed a strong pattern of endogenous network connectivity. Modulatory effects of labeling were most prominently observed following Bayesian Model Averaging, with the dampening influence on amygdala originating from Broca’s area but much more strongly from right vlPFC. These results solidify and extend previous correlation and regression-based estimations of negative corticolimbic coupling. PMID:23774393

Self-regulation via neural simulation

PubMed Central

Gilead, Michael; Boccagno, Chelsea; Silverman, Melanie; Hassin, Ran R.; Weber, Jochen; Ochsner, Kevin N.

2016-01-01

Can taking the perspective of other people modify our own affective responses to stimuli? To address this question, we examined the neurobiological mechanisms supporting the ability to take another person’s perspective and thereby emotionally experience the world as they would. We measured participants’ neural activity as they attempted to predict the emotional responses of two individuals that differed in terms of their proneness to experience negative affect. Results showed that behavioral and neural signatures of negative affect (amygdala activity and a distributed multivoxel pattern reflecting affective negativity) simulated the presumed affective state of the target person. Furthermore, the anterior medial prefrontal cortex (mPFC)—a region implicated in mental state inference—exhibited a perspective-dependent pattern of connectivity with the amygdala, and the multivoxel pattern of activity within the mPFC differentiated between the two targets. We discuss the implications of these findings for research on perspective-taking and self-regulation. PMID:27551094

Prefrontal cortex, caloric restriction and stress during aging: studies on dopamine and acetylcholine release, BDNF and working memory.

PubMed

Del Arco, Alberto; Segovia, Gregorio; de Blas, Marta; Garrido, Pedro; Acuña-Castroviejo, Dario; Pamplona, Reinald; Mora, Francisco

2011-01-01

This study was designed to investigate whether long-term caloric restriction during the life span of the rat changes the effects of an acute mild stress on the release of dopamine and acetylcholine in the prefrontal cortex (PFC) and on working memory performance. Spontaneous motor activity was also monitored and levels of BDNF measured in the prefrontal cortex, amygdala and hippocampus. Male Wistar rats (3 months of age) were housed during 3, 12, 21 and 27 months (6, 15, 24 and 30 months of age at the end of housing) in caloric restriction (CR; 40% food intake restriction) or control conditions. After behavioural testing, animals were further subdivided into two other groups. In one of the groups BDNF protein levels were determined. In the other group rats were implanted with guide cannulas into the PFC to perform microdialysis experiments. In CR rats the release of dopamine produced by handling stress did not differ from the response found in control rats of 6, 15 and 24 months of age. The release of acetylcholine was not changed at the ages of 6 and 15 months but reduced at the age of 24 months. Stress did not change dopamine or acetylcholine release in CR and control rats of 30 months of age. BDNF levels were increased in the hippocampus and amygdala, but not in the PFC, of 6 and 15 months CR rats. Spontaneous motor activity was increased in all groups of CR rats. Age, however, decreased motor activity in CR and control rats. Both experimental groups showed similar working memory performance in a delayed alternation task in basal conditions and after a situation of acute stress. These results suggest that CR does not modify the function of the PFC in response to an acute stress nor the changes found as a result of the normal process of aging. Copyright © 2010 Elsevier B.V. All rights reserved.

Vigilance in the Laboratory Predicts Avoidance in the Real World: A Dimensional Analysis of Neural, Behavioral, and Ecological Momentary Data in Anxious Youth

PubMed Central

Silk, Jennifer S.; Ladouceur, Cecile D.; Ryan, Neal D.; Dahl, Ronald E.; Forbes, Erika E.; Siegle, Greg J.

2016-01-01

Vigilance and avoidance of threat are observed in anxious adults during laboratory tasks, and are posited to have real-world clinical relevance, but data are mixed in anxious youth. We propose that vigilance-avoidance patterns will become evident in anxious youth through a focus on individual differences and real-world strategic avoidance. Decreased functional connectivity between the amygdala and prefrontal cortex (PFC) could play a mechanistic role in this link. 78 clinically anxious youth completed a dot-probe task to assess vigilance to threat while undergoing fMRI. Real-world avoidance was assessed using Ecological Momentary Assessment (EMA) of self-reported suppression and distraction during negative life events. Vigilance towards threat was positively associated with EMA distraction and suppression. Functional connectivity between a right amygdala seed region and dorsomedial and right dorsolateral PFC regions was inversely related to EMA distraction. Dorsolateral PFC-amygdalar connectivity statistically mediated the relationship between attentional vigilance and real-world distraction. Findings suggest anxious youth showing attentional vigilance toward threat are more likely to use suppression and distraction to regulate negative emotions. Reduced PFC control over limbic reactivity is a possible neural substrate of this pattern. These findings lend ecological validity to laboratory vigilance assessments and suggest PFC-amygdalar connectivity is a neural mechanism bridging laboratory and naturalistic contexts. PMID:27010577

Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder

PubMed Central

Sripada, Rebecca K.; King, Anthony P.; Garfinkel, Sarah N.; Wang, Xin; Sripada, Chandra S.; Welsh, Robert C.; Liberzon, Israel

2012-01-01

Background Converging neuroimaging research suggests altered emotion neurocircuitry in individuals with posttraumatic stress disorder (PTSD). Emotion activation studies in these individuals have shown hyperactivation in emotion-related regions, including the amygdala and insula, and hypoactivation in emotion-regulation regions, including the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). However, few studies have examined patterns of connectivity at rest in individuals with PTSD, a potentially powerful method for illuminating brain network structure. Methods Using the amygdala as a seed region, we measured resting-state brain connectivity using 3 T functional magnetic resonance imaging in returning male veterans with PTSD and combat controls without PTSD. Results Fifteen veterans with PTSD and 14 combat controls enrolled in our study. Compared with controls, veterans with PTSD showed greater positive connectivity between the amygdala and insula, reduced positive connectivity between the amygdala and hippocampus, and reduced anticorrelation between the amygdala and dorsal ACC and rostral ACC. Limitations Only male veterans with combat exposure were tested, thus our findings cannot be generalized to women or to individuals with non–combat related PTSD. Conclusion These results demonstrate that studies of functional connectivity during resting state can discern aberrant patterns of coupling within emotion circuits and suggest a possible brain basis for emotion-processing and emotion-regulation deficits in individuals with PTSD. PMID:22313617

The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers.

PubMed

Rzepa, Ewelina; Tudge, Luke; McCabe, Ciara

2015-09-10

The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown. We examined the effects of a single 10mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales. Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv. Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Neural Mechanisms Underlying Hyperphagia in Prader-Willi Syndrome

PubMed Central

Holsen, Laura M.; Zarcone, Jennifer R.; Brooks, William M.; Butler, Merlin G.; Thompson, Travis I.; Ahluwalia, Jasjit S.; Nollen, Nicole L.; Savage, Cary R.

2006-01-01

Objective Prader-Willi syndrome (PWS) is a genetic disorder associated with developmental delay, obesity, and obsessive behavior related to food consumption. The most striking symptom of PWS is hyperphagia; as such, PWS may provide important insights into factors leading to overeating and obesity in the general population. We used functional magnetic resonance imaging to study the neural mechanisms underlying responses to visual food stimuli, before and after eating, in individuals with PWS and a healthy weight control (HWC) group. Research Methods and Procedures Participants were scanned once before (pre-meal) and once after (post-meal) eating a standardized meal. Pictures of food, animals, and blurred control images were presented in a block design format during acquisition of functional magnetic resonance imaging data. Results Statistical contrasts in the HWC group showed greater activation to food pictures in the pre-meal condition compared with the post-meal condition in the amygdala, orbitofrontal cortex, medial prefrontal cortex (medial PFC), and frontal operculum. In comparison, the PWS group exhibited greater activation to food pictures in the post-meal condition compared with the pre-meal condition in the orbitofrontal cortex, medial PFC, insula, hippocampus, and parahippocampal gyrus. Between-group contrasts in the pre- and post-meal conditions confirmed group differences, with the PWS group showing greater activation than the HWC group after the meal in food motivation networks. Discussion Results point to distinct neural mechanisms associated with hyperphagia in PWS. After eating a meal, the PWS group showed hyperfunction in limbic and para-limbic regions that drive eating behavior (e.g., the amygdala) and in regions that suppress food intake (e.g., the medial PFC). PMID:16861608

Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions.

PubMed

Moscarello, Justin M; LeDoux, Joseph E

2013-02-27

Signaled active avoidance (AA) paradigms train subjects to prevent an aversive outcome by performing a learned behavior during the presentation of a conditioned cue. This complex form of conditioning involves pavlovian and instrumental components, which produce competing behavioral responses that must be reconciled for the subject to successfully avoid an aversive stimulus. In signaled AA paradigm for rat, we tested the hypothesis that the instrumental component of AA training recruits infralimbic prefrontal cortex (ilPFC) to inhibit central amygdala (CeA)-mediated Pavlovian reactions. Pretraining lesions of ilPFC increased conditioned freezing while causing a corresponding decrease in avoidance; lesions of CeA produced opposite effects, reducing freezing and facilitating avoidance behavior. Pharmacological inactivation experiments demonstrated that ilPFC is relevant to both acquisition and expression phases of AA learning. Inactivation experiments also revealed that AA produces an ilPFC-mediated diminution of pavlovian reactions that extends beyond the training context, even when the conditioned stimulus is presented in an environment that does not allow the avoidance response. Finally, injection of a protein synthesis inhibitor into either ilPFC or CeA impaired or facilitated AA, respectively, showing that avoidance training produces two opposing memory traces in these regions. These data support a model in which AA learning recruits ilPFC to inhibit CeA-mediated defense behaviors, leading to a robust suppression of freezing that generalizes across environments. Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat.

Neurobehavioral assessment of maternal odor in developing rat pups: implications for social buffering

PubMed Central

Al Aïn, Syrina; Perry, Rosemarie E.; Nuñez, Bestina; Kayser, Kassandra; Hochman, Chase; Brehman, Elizabeth; LaComb, Miranda; Wilson, Donald A.; Sullivan, Regina M.

2016-01-01

Social support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother’s social buffering of the infant is one of the more robust examples; yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14C 2-deoxyglucose (2-DG) and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (Basolateral Amygdala [BLA]), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC, or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering. PMID:26934130

Brain glutamic acid decarboxylase-67kDa alterations induced by magnesium treatment in olfactory bulbectomy and chronic mild stress models in rats.

PubMed

Pochwat, Bartłomiej; Nowak, Gabriel; Szewczyk, Bernadeta

2016-10-01

The preclinical results indicate that magnesium, an N-methyl-d-aspartate receptor (NMDAR) blocker has anxiolytic and antidepressant-like activity. One of the mechanisms involved in these activities is modulation of glutamate, γ-aminobutyric acid (GABA) system. Based on this, the aim of the present study was to investigate the effect of magnesium on the level of glutamic acid decarboxylase-67kDa (GAD-67) in the different brain areas in the chronic mild stress (CMS) and olfactory bulbectomy (OB) models of depression in rats. Magnesium (15mg/kg) was administered intraperitonealy once daily for 14 days in the OB model and for 35 days in the CMS model. 24h after the last dose, the prefrontal cortex (PFC), hippocampus and amygdala were collected and the GAD-67 protein level was determined by the western blotting method. In the OB model, chronic magnesium treatment normalized decreased by OB protein level of GAD-67 in PFC. CMS did not influence the GAD-67 protein level, however magnesium increased GAD-67 protein expression in amygdala and PFC of stress rats when compared to vehicle-treated stress group. OB or CMS models as well as magnesium treatment did not affect GAD-67 protein level in the hippocampus. Obtained results indicate that the antidepressant-like activity of magnesium in CMS and OB models of depression is associated with an enhanced expression of GAD-67 in the PFC and amygdala. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory.

PubMed

Akirav, Irit; Maroun, Mouna

2006-12-01

Once consolidated, a long-term memory item could regain susceptibility to consolidation blockers, that is, reconsolidate, upon its reactivation. Both consolidation and reconsolidation require protein synthesis, but it is not yet known how similar these processes are in terms of molecular, cellular, and neural circuit mechanisms. Whereas most previous studies focused on aversive conditioning in the amygdala and the hippocampus, here we examine the role of the ventromedial prefrontal cortex (vmPFC) in consolidation and reconsolidation of object recognition memory. Object recognition memory is the ability to discriminate the familiarity of previously encountered objects. We found that microinfusion of the protein synthesis inhibitor anisomycin or the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonovaleric acid (APV) into the vmPFC, immediately after training, resulted in impairment of long-term (24 h) but not short-term (3 h) recognition memory. Similarly, microinfusion of anisomycin or APV into the vmPFC immediately after reactivation of the long-term memory impaired recognition memory 24 h, but not 3 h, post-reactivation. These results indicate that both protein synthesis and NMDA receptors are required for consolidation and reconsolidation of recognition memory in the vmPFC.

Within-session effect of repeated stress exposure on extinction circuitry function in social anxiety disorder.

PubMed

Åhs, Fredrik; Gingnell, Malin; Furmark, Tomas; Fredrikson, Mats

2017-03-30

Anxiety reduction following repeated exposure to stressful experiences is generally held to depend on neural processes involved in extinction of conditioned fear. We predicted that repeated exposure to stressful experiences would change activity throughout the circuitry serving extinction, including ventromedial prefrontal cortex (vmPFC), the hippocampus and the amygdala. To test this prediction, 36 participants diagnosed with SAD performed two successive speeches in front of an observing audience while regional cerebral blood flow (rCBF) was recorded using positron emission tomography. To control for non-anxiolytic effects of repeated exposure, rCBF was also measured during repeated presentations of neutral and angry facial expressions. Results showed that anxiety ratings and heart rate decreased from the first to the second speech, indicating an anxiolytic effect of repeated exposure. Exposure attenuated rCBF in the amygdala whereas no change in rCBF was observed in the vmPFC or hippocampus. The rCBF-reductions in the amygdala were greater following repetition of the speech task than repetition of face exposure indicating that they were specific to anxiety attenuation and not due to a reduced novelty. Our findings suggest that amygdala-related attenuation processes are key to understanding the working mechanisms of exposure therapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Emotion introspection and regulation in depression.

PubMed

Herwig, Uwe; Opialla, Sarah; Cattapan, Katja; Wetter, Thomas C; Jäncke, Lutz; Brühl, Annette B

2018-07-30

Depressed patients suffer from an impairment to voluntarily influence and regulate their unpleasant emotional state. Strengthening the mental ability to interfere with dysfunctional emotion processing may be beneficial in treating depression. According to models of emotion processing this may be done by successful down-regulation of enhanced amygdala activity. We investigated short periods of intentional emotion-introspection compared with cognitive self-reflection as two domains of self-awareness in terms of effects on emotion regulation. Thirty depressed patients performed twelve second periods of emotion-introspection, self-reflection and a neutral condition during functional magnetic resonance imaging. We analyzed brain activation in the patients with depression by means of whole brain, region of interest and connectivity analyses. Amygdala activity decreased during emotion-introspection relative to self-reflection and to the neutral condition, whereby left amygdala was inversely activated relative to the left insula. Insula activity itself was correlated with medial and dorsolateral prefrontal cortex (PFC) activation. In conclusion, depressed patients are able to down-regulate amygdala activity by emotion-introspection. This may be interpreted as well-working emotion regulation supposedly induced by PFC connections mediated via insula. The finding supports the application of emotion-introspection, a mindfulness-related process, in a clinical setting as an element of psychotherapy to train and improve emotion regulation. Copyright © 2018 Elsevier B.V. All rights reserved.

Developmental sex differences in resting state functional connectivity of amygdala sub-regions

PubMed Central

Alarcón, Gabriela; Cservenka, Anita; Rudolph, Marc D.; Fair, Damien A.; Nagel, Bonnie J.

2015-01-01

During adolescence, considerable social and biological changes occur that interact with functional brain maturation, some of which are sex-specific. The amygdala is one brain area that has displayed sexual dimorphism, specifically in socio-affective (superficial amygdala [SFA]), stress (centromedial amygdala [CMA]), and learning and memory (basolateral amygdala [BLA]) processing. The amygdala has also been implicated in mood and anxiety disorders which also display sex-specific features, most prominently observed during adolescence. Using functional magnetic resonance imaging (fMRI), the present study examined the interaction of age and sex on resting state functional connectivity (RSFC) of amygdala sub-regions, BLA and SFA, in a sample of healthy adolescents between the ages 10-16 years (n=122, 71 boys). Whole-brain, voxel-wise partial correlation analyses were conducted to determine RSFC of bilateral BLA and SFA seed regions, created using the Eickhoff-Zilles maximum probability maps based on cytoarchitectonic mapping and FMRIB's Integrated Registration and Segmentation Tool (FIRST). Monte Carlo simulation was implemented to correct for multiple comparisons (threshold of 53 contiguous voxels with a z-value ≥ 2.25). Results indicated that with increasing age, there was a corresponding decrease in RSFC between both amygdala sub-regions and parieto-occipital cortices, with a concurrent increase in RSFC with medial prefrontal cortex (mPFC). Specifically, boys and girls demonstrated increased coupling of mPFC and left and right SFA with age, respectively; however, neither sex showed increased connectivity between mPFC and BLA, which could indicate relative immaturity of fronto-limbic networks that is similar across sex. A dissociation in connectivity between BLA- and SFA- parieto-occipital RSFC emerged, in which girls had weaker negative RSFC between SFA and parieto-occipital regions and boys had weaker negative RSFC of BLA and parieto-occipital regions with increased age, both standing in contrast to adult patterns of amygdala sub-regional RSFC. The present findings suggest relative immaturity of amygdala sub-regional RSFC with parieto-occipital cortices during adolescence, with unique patterns in both sexes that may support memory and socio-affective processing in boys and girls, respectively. Understanding the underlying normative functional architecture of brain networks associated with the amygdala during adolescence may better inform future research of the neural features associated with increased risk for internalizing psychopathology. PMID:25887261

Developmental sex differences in resting state functional connectivity of amygdala sub-regions.

PubMed

Alarcón, Gabriela; Cservenka, Anita; Rudolph, Marc D; Fair, Damien A; Nagel, Bonnie J

2015-07-15

During adolescence, considerable social and biological changes occur that interact with functional brain maturation, some of which are sex-specific. The amygdala is one brain area that has displayed sexual dimorphism, specifically in socio-affective (superficial amygdala [SFA]), stress (centromedial amygdala [CMA]), and learning and memory (basolateral amygdala [BLA]) processing. The amygdala has also been implicated in mood and anxiety disorders which display sex-specific features, most prominently observed during adolescence. Using functional magnetic resonance imaging (fMRI), the present study examined the interaction of age and sex on resting state functional connectivity (RSFC) of amygdala sub-regions, BLA and SFA, in a sample of healthy adolescents between the ages 10 and 16 years (n = 122, 71 boys). Whole-brain, voxel-wise partial correlation analyses were conducted to determine RSFC of bilateral BLA and SFA seed regions, created using the Eickhoff-Zilles maximum probability maps based on cytoarchitectonic mapping and FMRIB's Integrated Registration and Segmentation Tool (FIRST). Monte Carlo simulation was implemented to correct for multiple comparisons (threshold of 53 contiguous voxels with a z-value ≥ 2.25). Results indicated that with increasing age, there was a corresponding decrease in RSFC between both amygdala sub-regions and parieto-occipital cortices, with a concurrent increase in RSFC with medial prefrontal cortex (mPFC). Specifically, boys and girls demonstrated increased coupling of mPFC and left and right SFA with age, respectively; however, neither sex showed increased connectivity between mPFC and BLA, which could indicate relative immaturity of fronto-limbic networks that is similar across sex. A dissociation in connectivity between BLA- and SFA-parieto-occipital RSFC emerged, in which girls had weaker negative RSFC between SFA and parieto-occipital regions and boys had weaker negative RSFC of BLA and parieto-occipital regions with increased age, both standing in contrast to adult patterns of amygdala sub-regional RSFC. The present findings suggest relative immaturity of amygdala sub-regional RSFC with parieto-occipital cortices during adolescence, with unique patterns in both sexes that may support memory and socio-affective processing in boys and girls, respectively. Understanding the underlying normative functional architecture of brain networks associated with the amygdala during adolescence may better inform future research of the neural features associated with increased risk for internalizing psychopathology. Copyright © 2015 Elsevier Inc. All rights reserved.

Structural Covariance of the Prefrontal-Amygdala Pathways Associated with Heart Rate Variability.

PubMed

Wei, Luqing; Chen, Hong; Wu, Guo-Rong

2018-01-01

The neurovisceral integration model has shown a key role of the amygdala in neural circuits underlying heart rate variability (HRV) modulation, and suggested that reciprocal connections from amygdala to brain regions centered on the central autonomic network (CAN) are associated with HRV. To provide neuroanatomical evidence for these theoretical perspectives, the current study used covariance analysis of MRI-based gray matter volume (GMV) to map structural covariance network of the amygdala, and then determined whether the interregional structural correlations related to individual differences in HRV. The results showed that covariance patterns of the amygdala encompassed large portions of cortical (e.g., prefrontal, cingulate, and insula) and subcortical (e.g., striatum, hippocampus, and midbrain) regions, lending evidence from structural covariance analysis to the notion that the amygdala was a pivotal node in neural pathways for HRV modulation. Importantly, participants with higher resting HRV showed increased covariance of amygdala to dorsal medial prefrontal cortex and anterior cingulate cortex (dmPFC/dACC) extending into adjacent medial motor regions [i.e., pre-supplementary motor area (pre-SMA)/SMA], demonstrating structural covariance of the prefrontal-amygdala pathways implicated in HRV, and also implying that resting HRV may reflect the function of neural circuits underlying cognitive regulation of emotion as well as facilitation of adaptive behaviors to emotion. Our results, thus, provide anatomical substrates for the neurovisceral integration model that resting HRV may index an integrative neural network which effectively organizes emotional, cognitive, physiological and behavioral responses in the service of goal-directed behavior and adaptability.

Functional gene polymorphisms in the serotonin system and traumatic life events modulate the neural basis of fear acquisition and extinction.

PubMed

Hermann, Andrea; Küpper, Yvonne; Schmitz, Anja; Walter, Bertram; Vaitl, Dieter; Hennig, Jürgen; Stark, Rudolf; Tabbert, Katharina

2012-01-01

Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.

Neural Correlates of Emotion Regulation in the Ventral Prefrontal Cortex and the Encoding of Subjective Value and Economic Utility

PubMed Central

Viviani, Roberto

2014-01-01

In many studies of the interaction between cognitive control and emotion, the orbitofrontal cortex/ventromedial prefrontal cortex (mOFC/vmPFC) has been associated with an inhibitory function on limbic areas activated by emotionally arousing stimuli, such as the amygdala. This has led to the hypothesis of an inhibitory or regulatory role of mOFC/vmPFC. In studies of cognition and executive function, however, this area is deactivated by focused effort, raising the issue of the nature of the putative regulatory process associated with mOFC/vmPFC. This issue is here revisited in light of findings in the neuroeconomics field demonstrating the importance of mOFC/vmPFC to encoding the subjective value of stimuli or their economic utility. Many studies show that mOFC/vmPFC activity may affect response by activating personal preferences, instead of resorting to effortful control mechanisms typically associated with emotion regulation. Based on these findings, I argue that a simple automatic/controlled dichotomy is insufficient to describe the data on emotion and control of response adequately. Instead, I argue that the notion of subjective value from neuroeconomics studies and the notion of attentional orienting may play key roles in integrating emotion and cognition. mOFC/vmPFC may work together with the inferior parietal lobe, the cortical region associated with attentional orienting, to convey information about motivational priorities and facilitate processing of inputs that are behaviorally relevant. I also suggest that the dominant mode of function of this ventral network may be a distinct type of process with intermediate properties between the automatic and the controlled, and which may co-operate with effortful control processes in order to steer response. PMID:25309459

Vigilance in the laboratory predicts avoidance in the real world: A dimensional analysis of neural, behavioral, and ecological momentary data in anxious youth.

PubMed

Price, Rebecca B; Allen, Kristy Benoit; Silk, Jennifer S; Ladouceur, Cecile D; Ryan, Neal D; Dahl, Ronald E; Forbes, Erika E; Siegle, Greg J

2016-06-01

Vigilance and avoidance of threat are observed in anxious adults during laboratory tasks, and are posited to have real-world clinical relevance, but data are mixed in anxious youth. We propose that vigilance-avoidance patterns will become evident in anxious youth through a focus on individual differences and real-world strategic avoidance. Decreased functional connectivity between the amygdala and prefrontal cortex (PFC) could play a mechanistic role in this link. 78 clinically anxious youth completed a dot-probe task to assess vigilance to threat while undergoing fMRI. Real-world avoidance was assessed using Ecological Momentary Assessment (EMA) of self-reported suppression and distraction during negative life events. Vigilance toward threat was positively associated with EMA distraction and suppression. Functional connectivity between a right amygdala seed region and dorsomedial and right dorsolateral PFC regions was inversely related to EMA distraction. Dorsolateral PFC-amygdalar connectivity statistically mediated the relationship between attentional vigilance and real-world distraction. Findings suggest anxious youth showing attentional vigilance toward threat are more likely to use suppression and distraction to regulate negative emotions. Reduced PFC control over limbic reactivity is a possible neural substrate of this pattern. These findings lend ecological validity to laboratory vigilance assessments and suggest PFC-amygdalar connectivity is a neural mechanism bridging laboratory and naturalistic contexts. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Comparison of the adolescent and adult mouse prefrontal cortex proteome

PubMed Central

Small, Amanda T.; Spanos, Marina; Burrus, Brainard M.

2017-01-01

Adolescence is a developmental period characterized by unique behavioral phenotypes (increased novelty seeking, risk taking, sociability and impulsivity) and increased risk for destructive behaviors, impaired decision making and psychiatric illness. Adaptive and maladaptive adolescent traits have been associated with development of the medial prefrontal cortex (mPFC), a brain region that mediates regulatory control of behavior. However, the molecular changes that underlie brain development and behavioral vulnerability have not been fully characterized. Using high-throughput 2D DIGE spot profiling with identification by MALDI-TOF mass spectrometry, we identified 62 spots in the PFC that exhibited age-dependent differences in expression. Identified proteins were associated with diverse cellular functions, including intracellular signaling, synaptic plasticity, cellular organization and metabolism. Separate Western blot analyses confirmed age-related changes in DPYSL2, DNM1, STXBP1 and CFL1 in the mPFC and expanded these findings to the dorsal striatum, nucleus accumbens, motor cortex, amygdala and ventral tegmental area. Ingenuity Pathway Analysis (IPA) identified functional interaction networks enriched with proteins identified in the proteomics screen, linking age-related alterations in protein expression to cellular assembly and development, cell signaling and behavior, and psychiatric illness. These results provide insight into potential molecular components of adolescent cortical development, implicating structural processes that begin during embryonic development as well as plastic adaptations in signaling that may work in concert to bring the cortex, and other brain regions, into maturity. PMID:28570644

Aniracetam enhances glutamatergic transmission in the prefrontal cortex of stroke-prone spontaneously hypertensive rats.

PubMed

Togashi, Hiroko; Nakamura, Kazuo; Matsumoto, Machiko; Ueno, Ken-ichi; Ohashi, Satoshi; Saito, Hideya; Yoshioka, Mitsuhiro

2002-03-08

The effects of aniracetam, a cognition enhancer, on extracellular levels of glutamate (Glu), gamma-aminobutyric acid (GABA) and nitric oxide metabolites (NOx) were examined in the prefrontal cortex (PFC) and the basolateral amygdala (AMG) in stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal release of Glu, was lower in the AMG of SHRSP than in normotensive Wistar Kyoto rats, whereas no difference in GABA and NOx was noted. Aniracetam (100 mg/kg, p.o.) significantly increased the area under the curve of Glu levels in the PFC, but not in the AMG, of SHRSP. Aniracetam failed to exert any remarkable effects on GABA or NOx levels in either brain region. Our findings suggest that aniracetam enhances cortical glutamatergic release, which may be the mechanism involved in the ameliorating effects of aniracetam on various neuronal dysfunctions.

PI[subscript 3]-Kinase Cascade Has a Differential Role in Acquisition and Extinction of Conditioned Fear Memory in Juvenile and Adult Rats

ERIC Educational Resources Information Center

Slouzkey, Ilana; Maroun, Mouna

2016-01-01

The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (P[subscript 3]K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear…

Neural Correlates of Graphic Cigarette Warning Labels Predict Smoking Cessation Relapse

PubMed Central

Owens, Max M.; MacKillop, James; Gray, Joshua C.; Hawkshead, Brittany E.; Murphy, Cara M.; Sweet, Lawrence H.

2017-01-01

Exposure to graphic warning labels (GWLs) on cigarette packaging has been found to produce heightened activity in brain regions central to emotional processing and higher-order cognitive processes. The current study extends this literature by using functional magnetic resonance imaging (fMRI) to investigate neural activation in response to GWLs and use it to predict relapse in an evidence-based smoking cessation treatment program. Participants were 48 treatment-seeking nicotine-dependent smokers who completed an fMRI paradigm in which they were exposed to GWLs, text-only warning labels (TOLs), and matched control stimuli. Subsequently, they enrolled in smoking cessation treatment and their smoking behavior was monitored. Activation in bilateral amygdala, right dorsolateral prefrontal cortex, right inferior frontal gyrus, left medial temporal gyrus, bilateral occipital lobe, and bilateral fusiform gyrus was greater during GWLs than TOLs. Neural response in the ventromedial prefrontal cortex (vmPFC) during exposure to GWLs (relative to a visual control image) predicted relapse during treatment beyond baseline demographic and dependence severity, but response in the amygdala to GWLs did not. These findings suggest that neurocognitive processes in the vmPFC may be critical to understanding how GWL’s induce behavior change and may be useful as a predictor of smoking cessation treatment prognosis. PMID:28236714

Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits.

PubMed

Rossignoli, Matheus Teixeira; Lopes-Aguiar, Cleiton; Ruggiero, Rafael Naime; Do Val da Silva, Raquel Araujo; Bueno-Junior, Lezio Soares; Kandratavicius, Ludmyla; Peixoto-Santos, José Eduardo; Crippa, José Alexandre; Cecilio Hallak, Jaime Eduardo; Zuardi, Antonio Waldo; Szawka, Raphael Escorsim; Anselmo-Franci, Janete; Leite, João Pereira; Romcy-Pereira, Rodrigo Neves

2017-05-14

The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network.

PubMed

Childs, Jessica E; DeLeon, Jaime; Nickel, Emily; Kroener, Sven

2017-01-01

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug- and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects. © 2016 Childs et al.; Published by Cold Spring Harbor Laboratory Press.

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

PubMed Central

Childs, Jessica E.; DeLeon, Jaime; Nickel, Emily

2017-01-01

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug- and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects. PMID:27980074

Ventromedial prefrontal cortex activity and rapid eye movement sleep are associated with subsequent fear expression in human subjects.

PubMed

Spoormaker, V I; Gvozdanovic, G A; Sämann, P G; Czisch, M

2014-05-01

In humans, activity patterns in the ventromedial prefrontal cortex (vmPFC) have been found to be predictive of subsequent fear memory consolidation. Pioneering work in rodents has further shown that vmPFC-amygdala theta synchronization is correlated with fear memory consolidation. We aimed to evaluate whether vmPFC activity during fear conditioning is (1) correlated with fear expression the subsequent day and whether (2) this relationship is mediated by rapid eye movement (REM) sleep. We analyzed data from 17 young healthy subjects undergoing a fear conditioning task, followed by a fear extinction task 24 h later, both recorded with simultaneous skin conductance response (SCR) and functional magnetic resonance imaging measurements, with a polysomnographically recorded night sleep in between. Our results showed a correlation between vmPFC activity during fear conditioning and subsequent REM sleep amount, as well as between REM sleep amount and SCR to the conditioned stimulus 24 h later. Moreover, we observed a significant correlation between vmPFC activity during fear conditioning and SCR responses during extinction, which was no longer significant after controlling for REM sleep amount. vmPFC activity during fear conditioning was further correlated with sleep latency. Interestingly, hippocampus activity during fear conditioning was correlated with stage 2 and stage 4 sleep amount. Our results provide preliminary evidence that the relationship between REM sleep and fear conditioning and extinction observed in rodents can be modeled in healthy human subjects, highlighting an interrelated set of potentially relevant trait markers.

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.

Dual neurocircuitry dysfunctions in disruptive behavior disorders: emotional responding and response inhibition.

PubMed

Hwang, S; Nolan, Z T; White, S F; Williams, W C; Sinclair, S; Blair, R J R

2016-05-01

To determine the functional integrity of the neural systems involved in emotional responding/regulation and response control/inhibition in youth (age 10-18 years) with disruptive behavioral disorders (DBDs: conduct disorder and/or oppositional defiant disorder) as a function of callous-unemotional (CU) traits. Twenty-eight healthy youths and 35 youths with DBD [high CU (HCU), n = 18; low CU (LCU), n = 17] performed the fMRI Affective Stroop task. Participants viewed positive, neutral, and negative images under varying levels of cognitive load. A 3-way ANOVA (group×emotion by task) was conducted on the BOLD response data. Youth with DBD-HCU showed significantly less activation of ventromedial prefrontal cortex (vmPFC) and amygdala in response to negative stimuli, compared to healthy youth and youth with DBD-LCU. vmPFC responsiveness was inversely related to CU symptoms in DBD. Youth with DBD-LCU showed decreased functional connectivity between amygdala and regions including inferior frontal gyrus in response to emotional stimuli. Youth with DBD (LCU and HCU) additionally showed decreased insula responsiveness to high load (incongruent trials) compared to healthy youth. Insula responsiveness was inversely related to ADHD symptoms in DBD. These data reveal two forms of pathophysiology in DBD. One associated with reduced amygdala and vmPFC responses to negative stimuli and related to increased CU traits. Another associated with reduced insula responses during high load task trials and related to ADHD symptoms. Appropriate treatment will need to be individualized according to the patient's specific pathophysiology.

Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress

PubMed Central

Licznerski, Pawel; Duric, Vanja; Banasr, Mounira; Alavian, Kambiz N.; Ota, Kristie T.; Kang, Hyo Jung; Jonas, Elizabeth A.; Ursano, Robert; Krystal, John H.; Duman, Ronald S.

2015-01-01

Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology. PMID:26506154

Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea.

PubMed

Fatouleh, Rania H; Hammam, Elie; Lundblad, Linda C; Macey, Paul M; McKenzie, David K; Henderson, Luke A; Macefield, Vaughan G

2014-01-01

Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnoea (OSA) during daytime wakefulness, leading to hypertension, but the underlying mechanisms are poorly understood. By recording MSNA concurrently with functional Magnetic Resonance Imaging (fMRI) of the brain we aimed to identify the central processes responsible for the sympathoexcitation. Spontaneous fluctuations in MSNA were recorded via tungsten microelectrodes inserted percutaneously into the common peroneal nerve in 17 OSA patients and 15 healthy controls lying in a 3 T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast gradient echo, echo-planar images were continuously collected in a 4 s ON, 4 s OFF (200 volumes) sampling protocol. Fluctuations in BOLD signal intensity covaried with the intensity of the concurrently recorded bursts of MSNA. In both groups there was a positive correlation between MSNA and signal intensity in the left and right insulae, dorsolateral prefrontal cortex (dlPFC), dorsal precuneus, sensorimotor cortex and posterior temporal cortex, and the right mid-cingulate cortex and hypothalamus. In OSA the left and right dlPFC, medial PFC (mPFC), dorsal precuneus, anterior cingulate cortex, retrosplenial cortex and caudate nucleus showed augmented signal changes compared with controls, while the right hippocampus/parahippocampus signal intensity decreased in controls but did not change in the OSA subjects. In addition, there were significant increases in grey matter volume in the left mid-insula, the right insula, left and right primary motor cortices, left premotor cortex, left hippocampus and within the brainstem and cerebellum, and significant decreases in the mPFC, occipital lobe, right posterior cingulate cortex, left cerebellar cortex and the left and right amygdala in OSA, but there was no overlap between these structural changes and the functional changes in OSA. These data suggest that the elevated muscle vasoconstrictor drive in OSA may result from functional changes within these brain regions, which are known to be directly or indirectly involved in the modulation of sympathetic outflow via the brainstem. That there was no overlap in the structural and functional changes suggests that asphyxic damage due to repeated episodes of nocturnal obstructive apnoea is not the main cause of the sympathoexcitation.

Region-specific Alterations in Glucocorticoid Receptor Expression in the Postmortem Brain of Teenage Suicide Victims

PubMed Central

Pandey, Ghanshyam N.; Rizavi, Hooriyah S.; Ren, Xinguo; Dwivedi, Yogesh; Palkovits, Miklós

2013-01-01

Introduction Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of depression and suicide. The purpose of this study was to test the hypothesis that the reported dysregulation of the HPA axis in suicide may be related to a disturbed feedback inhibition caused by decreased corticoid receptors in the brain. We therefore determined the protein and gene expression of glucocorticoid (GR) and mineralocorticoid receptors (MR) in the postmortem brain of teenage suicide victims and matched normal controls. Methods Protein and mRNA expression of GR (GR-α and GR-β) and MR and the mRNA expression of glucocorticoid-induced leucine zipper (GILZ), a target gene for GR were determined by immunolabeling using Western blot technique and the real-time RT-polymerase chain reaction (qPCR) technique in the prefrontal cortex (PFC), hippocampus, subiculum, and amygdala obtained from 24 teenage suicide victims and 24 teenage control subjects. Results We observed that protein and gene expression of GR-α was significantly decreased in the PFC and amygdala, but not in the hippocampus or subiculum, of teenage suicide victims compared with normal control subjects. Also, the mRNA levels of GR inducible target gene GILZ was significantly decreased in PFC and amygdaloid nuclei but not in hippocampus compared with controls. In contrast, no significant differences were observed in protein or gene expression of MR in any of the areas studied between teenage suicide victims and normal control subjects. There was no difference in the expression of GR-β in the PFC between suicide victims and normal controls. Conclusions These results suggested that the observed dysregulation of the HPA axis in suicide may be related to a decreased expression of GR-α and GR inducible genes in the PFC and amygdala of teenage suicide victims. The reason why GR receptors are not dysregulated in the hippocampus or subiculum, presumably two sites of stress action, are not clear at this time. PMID:23845513

Structural Covariance of the Prefrontal-Amygdala Pathways Associated with Heart Rate Variability

PubMed Central

Wei, Luqing; Chen, Hong; Wu, Guo-Rong

2018-01-01

The neurovisceral integration model has shown a key role of the amygdala in neural circuits underlying heart rate variability (HRV) modulation, and suggested that reciprocal connections from amygdala to brain regions centered on the central autonomic network (CAN) are associated with HRV. To provide neuroanatomical evidence for these theoretical perspectives, the current study used covariance analysis of MRI-based gray matter volume (GMV) to map structural covariance network of the amygdala, and then determined whether the interregional structural correlations related to individual differences in HRV. The results showed that covariance patterns of the amygdala encompassed large portions of cortical (e.g., prefrontal, cingulate, and insula) and subcortical (e.g., striatum, hippocampus, and midbrain) regions, lending evidence from structural covariance analysis to the notion that the amygdala was a pivotal node in neural pathways for HRV modulation. Importantly, participants with higher resting HRV showed increased covariance of amygdala to dorsal medial prefrontal cortex and anterior cingulate cortex (dmPFC/dACC) extending into adjacent medial motor regions [i.e., pre-supplementary motor area (pre-SMA)/SMA], demonstrating structural covariance of the prefrontal-amygdala pathways implicated in HRV, and also implying that resting HRV may reflect the function of neural circuits underlying cognitive regulation of emotion as well as facilitation of adaptive behaviors to emotion. Our results, thus, provide anatomical substrates for the neurovisceral integration model that resting HRV may index an integrative neural network which effectively organizes emotional, cognitive, physiological and behavioral responses in the service of goal-directed behavior and adaptability. PMID:29545744

Prelimbic cortex extracellular signal-regulated kinase 1/2 activation is required for memory retrieval of long-term inhibitory avoidance.

PubMed

Luo, Fei; Zheng, Jian; Sun, Xuan; Deng, Wei-Ke; Li, Bao Ming; Liu, Fang

2017-04-15

Neural mechanism underlying memory retrieval has been extensively studied in the hippocampus and amygdala. However, little is known about the role of medial prefrontal cortex in long-term memory retrieval. We evaluate this issue in one-trial step-through inhibitory avoidance (IA) paradigm. Our results showed that, 1) inactivation of mPFC by local infusion of GABA A -receptor agonist muscimol caused severe deficits in retrieval of 1-day and 7-day but had no effects on 2-h inhibitory avoidance memory; 2) the protein level of phosphorylated-ERK1/2 in mPFC were significantly increased following retrieval of 1-day and 7-day IA memory, so did the numbers of phosphorylated-ERK (pERK) and phosphorylated-CREB (pCREB) labeled neurons; 3) intra-mPFC infusion of ERK kinase inhibitor PD98095 significantly reduced phosphorylated ERK1/2 levels and phosphorylated-ERK1/2 and phosphorylated-CREB labeled cells, and severely impaired retrieval of 7-day IA memory when the drugs were administrated 30min prior to test. The present study provides evidence that retrieval of long-lasting memory for inhibitory avoidance requires mPFC and involves the ERK-CREB signaling cascade. Copyright © 2017 Elsevier B.V. All rights reserved.

Medial Prefrontal Cortex: Adding Value to Imagined Scenarios

PubMed Central

Lin, Wen-Jing; Horner, Aidan J.; Bisby, James A.; Burgess, Neil

2016-01-01

The medial prefrontal cortex (mPFC) is consistently implicated in the network supporting autobiographical memory. Whereas more posterior regions in this network have been related to specific processes, such as the generation of visuospatial imagery or the association of items and contexts, the functional contribution of the mPFC remains unclear. However, the involvement of mPFC in estimation of value during decision-making suggests that it might play a similar role in memory. We investigated whether mPFC activity reflects the subjective value of elements in imagined scenarios. Participants in an MRI scanner imagined scenarios comprising a spatial context, a physiological state of need (e.g., thirst), and two items that could be congruent (e.g., drink) or incongruent (e.g., food) with the state of need. Memory for the scenarios was tested outside the scanner. Our manipulation of subjective value by imagined need was verified by increased subjective ratings of value for congruent items and improved subsequent memory for them. Consistent with our hypothesis, fMRI signal in mPFC reflected the modulation of an item’s subjective value by the imagined physiological state, suggesting the mPFC selectively tracked subjective value within our imagination paradigm. Further analyses showed uncorrected effects in non-mPFC regions, including increased activity in the insula when imagining states of need, the caudate nucleus when imagining congruent items, and the anterior hippocampus/amygdala when imagining subsequently remembered items. We therefore provide evidence that the mPFC plays a role in constructing the subjective value of the components of imagined scenarios and thus potentially in reconstructing the value of components of autobiographical recollection. PMID:26042501

Common and distinct networks underlying reward valence and processing stages: A meta-analysis of functional neuroimaging studies

PubMed Central

Liu, Xun; Hairston, Jacqueline; Schrier, Madeleine; Fan, Jin

2011-01-01

To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior (ACC) and posterior (PCC) cingulate cortex, as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore distributed and interrelated representations of reward valuation and valence assessment into account. PMID:21185861

Disentangling brain activity related to the processing of emotional visual information and emotional arousal.

PubMed

Kuniecki, Michał; Wołoszyn, Kinga; Domagalik, Aleksandra; Pilarczyk, Joanna

2018-05-01

Processing of emotional visual information engages cognitive functions and induces arousal. We aimed to examine the modulatory role of emotional valence on brain activations linked to the processing of visual information and those linked to arousal. Participants were scanned and their pupil size was measured while viewing negative and neutral images. The visual noise was added to the images in various proportions to parametrically manipulate the amount of visual information. Pupil size was used as an index of physiological arousal. We show that arousal induced by the negative images, as compared to the neutral ones, is primarily related to greater amygdala activity while increasing visibility of negative content to enhanced activity in the lateral occipital complex (LOC). We argue that more intense visual processing of negative scenes can occur irrespective of the level of arousal. It may suggest that higher areas of the visual stream are fine-tuned to process emotionally relevant objects. Both arousal and processing of emotional visual information modulated activity within the ventromedial prefrontal cortex (vmPFC). Overlapping activations within the vmPFC may reflect the integration of these aspects of emotional processing. Additionally, we show that emotionally-evoked pupil dilations are related to activations in the amygdala, vmPFC, and LOC.

Neural functional architecture and modulation during decision making under uncertainty in individuals with generalized anxiety disorder.

PubMed

Assaf, Michal; Rabany, Liron; Zertuche, Luis; Bragdon, Laura; Tolin, David; Goethe, John; Diefenbach, Gretchen

2018-06-21

Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) might be effective in treating generalized anxiety disorder (GAD). Cognitive models of GAD highlight the role of intolerance of uncertainty (IU) in precipitating and maintaining worry, and it has been hypothesized that patients with GAD exhibit decision-making deficits under uncertain conditions. Improving understanding of the neural mechanisms underlying cognitive deficits associated with IU may lead to the identification of novel rTMS treatment targets and optimization of treatment parameters. The current report describes two interrelated studies designed to identify and verify a potential neural target for rTMS treatment of GAD. Study I explored the integrity of prefrontal cortex (PFC) and amygdala neural networks, which underlie decision making under conditions of uncertainty, in GAD. Individuals diagnosed with GAD (n = 31) and healthy controls (n = 20) completed a functional magnetic resonance imaging (fMRI) gambling task that manipulated uncertainty using high versus low error rates. In a subsequent randomized-controlled trial (Study II), a subset of the GAD sample (n = 16) completed the fMRI gambling task again after 30 sessions of active versus sham rTMS (1 Hz, right dorsolateral prefrontal cortex) to investigate the modulation of functional networks and symptoms. In Study I, participants with GAD demonstrated impairments in PFC-PFC and PFC-amygdala functional connectivity (FC) mostly during the high uncertainty condition. In Study II, one region of interest pair, dorsal anterior cingulate (ACC) - subgenual ACC, showed "normalization" of FC following active, but not sham, rTMS, and neural changes were associated with improvement in worry symptoms. These results outline a possible treatment mechanism of rTMS in GAD, and pave the way for future studies of treatment optimization. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala.

PubMed

Keistler, Colby R; Hammarlund, Emma; Barker, Jacqueline M; Bond, Colin W; DiLeone, Ralph J; Pittenger, Christopher; Taylor, Jane R

2017-04-26

The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC→NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA→NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections. SIGNIFICANCE STATEMENT The vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic structures that regulate alcohol intake, it has been difficult to disentangle how separate projections between them may control different aspects of these complex behaviors. Here, we demonstrate a new approach for noninvasively ablating each of these pathways and testing their necessity for both extinction and relapse. We show that inputs to the nucleus accumbens from medial prefrontal cortex and amygdala regulate alcohol-seeking behaviors differentially, adding to our understanding of the neural control of alcoholism. Copyright © 2017 the authors 0270-6474/17/374462-10$15.00/0.

Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala

PubMed Central

Bond, Colin W.; DiLeone, Ralph J.

2017-01-01

The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC→NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA→NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections. SIGNIFICANCE STATEMENT The vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic structures that regulate alcohol intake, it has been difficult to disentangle how separate projections between them may control different aspects of these complex behaviors. Here, we demonstrate a new approach for noninvasively ablating each of these pathways and testing their necessity for both extinction and relapse. We show that inputs to the nucleus accumbens from medial prefrontal cortex and amygdala regulate alcohol-seeking behaviors differentially, adding to our understanding of the neural control of alcoholism. PMID:28336571

Rescue of Impaired mGluR5-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats.

PubMed

Kiritoshi, Takaki; Ji, Guangchen; Neugebauer, Volker

2016-01-20

The medial prefrontal cortex (mPFC) serves executive functions that are impaired in neuropsychiatric disorders and pain. Underlying mechanisms remain to be determined. Here we advance the novel concept that metabotropic glutamate receptor 5 (mGluR5) fails to engage endocannabinoid (2-AG) signaling to overcome abnormal synaptic inhibition in pain, but restoring endocannabinoid signaling allows mGluR5 to increase mPFC output hence inhibit pain behaviors and mitigate cognitive deficits. Whole-cell patch-clamp recordings were made from layer V pyramidal cells in the infralimbic mPFC in rat brain slices. Electrical and optogenetic stimulations were used to analyze amygdala-driven mPFC activity. A selective mGluR5 activator (VU0360172) increased pyramidal output through an endocannabinoid-dependent mechanism because intracellular inhibition of the major 2-AG synthesizing enzyme diacylglycerol lipase or blockade of CB1 receptors abolished the facilitatory effect of VU0360172. In an arthritis pain model mGluR5 activation failed to overcome abnormal synaptic inhibition and increase pyramidal output. mGluR5 function was rescued by restoring 2-AG-CB1 signaling with a CB1 agonist (ACEA) or inhibitors of postsynaptic 2-AG hydrolyzing enzyme ABHD6 (intracellular WWL70) and monoacylglycerol lipase MGL (JZL184) or by blocking GABAergic inhibition with intracellular picrotoxin. CB1-mediated depolarization-induced suppression of synaptic inhibition (DSI) was also impaired in the pain model but could be restored by coapplication of VU0360172 and ACEA. Stereotaxic coadministration of VU0360172 and ACEA into the infralimbic, but not anterior cingulate, cortex mitigated decision-making deficits and pain behaviors of arthritic animals. The results suggest that rescue of impaired endocannabinoid-dependent mGluR5 function in the mPFC can restore mPFC output and cognitive functions and inhibit pain. Significance statement: Dysfunctions in prefrontal cortical interactions with subcortical brain regions, such as the amygdala, are emerging as important players in neuropsychiatric disorders and pain. This study identifies a novel mechanism and rescue strategy for impaired medial prefrontal cortical function in an animal model of arthritis pain. Specifically, an integrative approach of optogenetics, pharmacology, electrophysiology, and behavior is used to advance the novel concept that a breakdown of metabotropic glutamate receptor subtype mGluR5 and endocannabinoid signaling in infralimbic pyramidal cells fails to control abnormal amygdala-driven synaptic inhibition in the arthritis pain model. Restoring endocannabinoid signaling allows mGluR5 activation to increase infralimbic output hence inhibit pain behaviors and mitigate pain-related cognitive deficits. Copyright © 2016 the authors 0270-6474/16/360837-14$15.00/0.

Reduced functional connectivity within and between ‘social’ resting state networks in autism spectrum conditions

PubMed Central

Stoyanova, Raliza S.; Baron-Cohen, Simon; Calder, Andrew J.

2013-01-01

Individuals with Autism Spectrum Conditions (ASC) have difficulties in social interaction and communication, which is reflected in hypoactivation of brain regions engaged in social processing, such as medial prefrontal cortex (mPFC), amygdala and insula. Resting state studies in ASC have identified reduced connectivity of the default mode network (DMN), which includes mPFC, suggesting that other resting state networks incorporating ‘social’ brain regions may also be abnormal. Using Seed-based Connectivity and Group Independent Component Analysis (ICA) approaches, we looked at resting functional connectivity in ASC between specific ‘social’ brain regions, as well as within and between whole networks incorporating these regions. We found reduced functional connectivity within the DMN in individuals with ASC, using both ICA and seed-based approaches. Two further networks identified by ICA, the salience network, incorporating the insula and a medial temporal lobe network, incorporating the amygdala, showed reduced inter-network connectivity. This was underlined by reduced seed-based connectivity between the insula and amygdala. The results demonstrate significantly reduced functional connectivity within and between resting state networks incorporating ‘social’ brain regions. This reduced connectivity may result in difficulties in communication and integration of information across these networks, which could contribute to the impaired processing of social signals in ASC. PMID:22563003

Differentiating between bipolar and unipolar depression in functional and structural MRI studies.

PubMed

Han, Kyu-Man; De Berardis, Domenico; Fornaro, Michele; Kim, Yong-Ku

2018-03-28

Distinguishing depression in bipolar disorder (BD) from unipolar depression (UD) solely based on clinical clues is difficult, which has led to the exploration of promising neural markers in neuroimaging measures for discriminating between BD depression and UD. In this article, we review structural and functional magnetic resonance imaging (MRI) studies that directly compare UD and BD depression based on neuroimaging modalities including functional MRI studies on regional brain activation or functional connectivity, structural MRI on gray or white matter morphology, and pattern classification analyses using a machine learning approach. Numerous studies have reported distinct functional and structural alterations in emotion- or reward-processing neural circuits between BD depression and UD. Different activation patterns in neural networks including the amygdala, anterior cingulate cortex (ACC), prefrontal cortex (PFC), and striatum during emotion-, reward-, or cognition-related tasks have been reported between BD and UD. A stronger functional connectivity pattern in BD was pronounced in default mode and in frontoparietal networks and brain regions including the PFC, ACC, parietal and temporal regions, and thalamus compared to UD. Gray matter volume differences in the ACC, hippocampus, amygdala, and dorsolateral prefrontal cortex (DLPFC) have been reported between BD and UD, along with a thinner DLPFC in BD compared to UD. BD showed reduced integrity in the anterior part of the corpus callosum and posterior cingulum compared to UD. Several studies performed pattern classification analysis using structural and functional MRI data to distinguish between UD and BD depression using a supervised machine learning approach, which yielded a moderate level of accuracy in classification. Copyright © 2018 Elsevier Inc. All rights reserved.

Novelty and fear conditioning induced gene expression in high and low states of anxiety.

PubMed

Donley, Melanie P; Rosen, Jeffrey B

2017-09-01

Emotional states influence how stimuli are interpreted. High anxiety states in humans lead to more negative, threatening interpretations of novel information, typically accompanied by activation of the amygdala. We developed a handling protocol that induces long-lasting high and low anxiety-like states in rats to explore the role of state anxiety on brain activation during exposure to a novel environment and fear conditioning. In situ hybridization of the inducible transcription factor Egr-1 found increased gene expression in the lateral nucleus of the amygdala (LA) following exposure to a novel environment and contextual fear conditioning in high anxiety-like rats. In contrast, low state anxiety-like rats did not generate Egr-1 increases in LA when placed in a novel chamber. Egr-1 expression was also examined in the dorsal hippocampus and prefrontal cortex. In CA1 of the hippocampus and medial prefrontal cortex (mPFC), Egr-1 expression increased in response to novel context exposure and fear conditioning, independent of state anxiety level. Furthermore, in mPFC, Egr-1 in low anxiety-like rats was increased more with fear conditioning than novel exposure. The current series of experiments show that brain areas involved in fear and anxiety-like states do not respond uniformly to novelty during high and low states of anxiety. © 2017 Donley and Rosen; Published by Cold Spring Harbor Laboratory Press.

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.

Traumatic stress causes distinctive effects on fear circuit catecholamines and the fear extinction profile in a rodent model of posttraumatic stress disorder.

PubMed

Lin, Chen-Cheng; Tung, Che-Se; Lin, Pin-Hsuan; Huang, Chuen-Lin; Liu, Yia-Ping

2016-09-01

Central catecholamines regulate fear memory across the medial prefrontal cortex (mPFC), amygdala (AMYG), and hippocampus (HPC). However, inadequate evidence exists to address the relationships among these fear circuit areas in terms of the fear symptoms of posttraumatic stress disorder (PTSD). By examining the behavioral profile in a Pavlovian fear conditioning paradigm together with tissue/efflux levels of dopamine (DA) and norepinephrine (NE) and their reuptake abilities across the fear circuit areas in rats that experienced single prolonged stress (SPS, a rodent model of PTSD), we demonstrated that SPS-impaired extinction retrieval was concomitant with the changes of central DA/NE in a dissociable manner. For tissue levels, diminished DA and increased NE were both observed in the mPFC and AMYG. DA efflux and synaptosomal DA transporter were consistently reduced in the AMYG/vHPC, whereas SPS reduced NE efflux in the infralimbic cortex and synaptosomal NE transporter in the mPFC. Furthermore, a lower expression of synaptosomal VMAT2 was observed in the mPFC, AMYG, and vHPC after SPS. Finally, negative correlations were observed between retrieval freezing and DA in the mPFC/AMYG; nevertheless, the phenomena became invalid after SPS. Our results suggest that central catecholamines are crucially involved in the retrieval of fear extinction in which DA and NE play distinctive roles across the fear circuit areas. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Neurocognitive correlates of the effects of yoga meditation practice on emotion and cognition: a pilot study

PubMed Central

Froeliger, Brett E.; Garland, Eric L.; Modlin, Leslie A.; McClernon, F. Joseph

2012-01-01

Mindfulness meditation involves attending to emotions without cognitive fixation of emotional experience. Over time, this practice is held to promote alterations in trait affectivity and attentional control with resultant effects on well-being and cognition. However, relatively little is known regarding the neural substrates of meditation effects on emotion and cognition. The present study investigated the neurocognitive correlates of emotion interference on cognition in Yoga practitioners and a matched control group (CG) underwent fMRI while performing an event-related affective Stroop task. The task includes image viewing trials and Stroop trials bracketed by neutral or negative emotional distractors. During image viewing trials, Yoga practitioners exhibited less reactivity in right dorsolateral prefrontal cortex (dlPFC) to negative as compared to neutral images; whereas the CG had the opposite pattern. A main effect of valence (negative > neutral) was observed in limbic regions (e.g., amygdala), of which the magnitude was inversely related to dlPFC activation. Exploratory analyses revealed that the magnitude of amygdala activation predicted decreased self-reported positive affect in the CG, but not among Yoga practitioners. During Stroop trials, Yoga practitioners had greater activation in ventrolateral prefrontal cortex (vlPFC) during Stroop trials when negative, compared to neutral, emotional distractor were presented; the CG exhibited the opposite pattern. Taken together, these data suggest that though Yoga practitioners exhibit limbic reactivity to negative emotional stimuli, such reactivity does not have downstream effects on later mood state. This uncoupling of viewing negative emotional images and affect among Yoga practitioners may be occasioned by their selective implementation of frontal executive-dependent strategies to reduce emotional interference during competing cognitive demands and not during emotional processing per se. PMID:22855674

Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder

PubMed Central

Milad, Mohammed R.; Pitman, Roger K.; Ellis, Cameron B.; Gold, Andrea L.; Shin, Lisa M; Lasko, Natasha B.; Zeidan, Mohamed A.; Handwerger, Kathryn; Orr, Scott P.; Rauch, Scott L.

2009-01-01

Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. Results: SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment. PMID:19748076

Sex differences in stress response circuitry activation dependent on female hormonal cycle.

PubMed

Goldstein, Jill M; Jerram, Matthew; Abbs, Brandon; Whitfield-Gabrieli, Susan; Makris, Nikos

2010-01-13

Understanding sex differences in stress regulation has important implications for understanding basic physiological differences in the male and female brain and their impact on vulnerability to sex differences in chronic medical disorders associated with stress response circuitry. In this functional magnetic resonance imaging study, we demonstrated that significant sex differences in brain activity in stress response circuitry were dependent on women's menstrual cycle phase. Twelve healthy Caucasian premenopausal women were compared to a group of healthy men from the same population, based on age, ethnicity, education, and right handedness. Subjects were scanned using negative valence/high arousal versus neutral visual stimuli that we demonstrated activated stress response circuitry [amygdala, hypothalamus, hippocampus, brainstem, orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and anterior cingulate gyrus (ACG)]. Women were scanned twice based on normal variation in menstrual cycle hormones [i.e., early follicular (EF) compared with late follicular-midcycle (LF/MC) menstrual phases]. Using SPM8b, there were few significant differences in blood oxygenation level-dependent (BOLD) signal changes in men compared to EF women, except ventromedial nucleus (VMN), lateral hypothalamic area (LHA), left amygdala, and ACG. In contrast, men exhibited significantly greater BOLD signal changes compared to LF/MC women on bilateral ACG and OFC, mPFC, LHA, VMN, hippocampus, and periaqueductal gray, with largest effect sizes in mPFC and OFC. Findings suggest that sex differences in stress response circuitry are hormonally regulated via the impact of subcortical brain activity on the cortical control of arousal, and demonstrate that females have been endowed with a natural hormonal capacity to regulate the stress response that differs from males.

Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia.

PubMed

Zoladz, Phillip R; Park, Collin R; Halonen, Joshua D; Salim, Samina; Alzoubi, Karem H; Srivareerat, Marisa; Fleshner, Monika; Alkadhi, Karim A; Diamond, David M

2012-03-01

We have studied the effects of spatial learning and predator stress-induced amnesia on the expression of calcium/calmodulin-dependent protein kinase II (CaMKII), brain-derived neurotrophic factor (BDNF) and calcineurin in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adult male rats were given a single training session in the radial-arm water maze (RAWM) composed of 12 trials followed by a 30-min delay period, during which rats were either returned to their home cages or given inescapable exposure to a cat. Immediately following the 30-min delay period, the rats were given a single test trial in the RAWM to assess their memory for the hidden platform location. Under control (no stress) conditions, rats exhibited intact spatial memory and an increase in phosphorylated CaMKII (p-CaMKII), total CaMKII, and BDNF in dorsal CA1. Under stress conditions, rats exhibited impaired spatial memory and a suppression of all measured markers of molecular plasticity in dorsal CA1. The molecular profiles observed in the BLA, mPFC, and ventral CA1 were markedly different from those observed in dorsal CA1. Stress exposure increased p-CaMKII in the BLA, decreased p-CaMKII in the mPFC, and had no effect on any of the markers of molecular plasticity in ventral CA1. These findings provide novel observations regarding rapidly induced changes in the expression of molecular plasticity in response to spatial learning, predator exposure, and stress-induced amnesia in brainregions involved in different aspects of memory processing. Copyright © 2011 Wiley Periodicals, Inc.

β-Adrenoceptor Blockade in the Basolateral Amygdala, But Not the Medial Prefrontal Cortex, Rescues the Immediate Extinction Deficit.

PubMed

Giustino, Thomas F; Seemann, Jocelyn R; Acca, Gillian M; Goode, Travis D; Fitzgerald, Paul J; Maren, Stephen

2017-12-01

Early psychological interventions, such as exposure therapy, rely on extinction learning to reduce the development of stress- and trauma-related disorders. However, recent research suggests that extinction often fails to reduce fear when administered soon after trauma. This immediate extinction deficit (IED) may be due to stress-induced dysregulation of neural circuits involved in extinction learning. We have shown that systemic β-adrenoceptor blockade with propranolol rescues the IED, but impairs delayed extinction. Here we sought to determine the neural locus of these effects. Rats underwent auditory fear conditioning and then received either immediate (30 min) or delayed (24 h) extinction training. We used bilateral intracranial infusions of propranolol into either the infralimbic division of the medial prefrontal cortex (mPFC) or the basolateral amygdala (BLA) to examine the effects of β-adrenoceptor blockade on immediate and delayed extinction learning. Interestingly, intra-BLA, but not intra-mPFC, propranolol rescued the IED; animals receiving intra-BLA propranolol prior to immediate extinction showed less spontaneous recovery of fear during extinction retrieval. Importantly, this was not due to impaired consolidation of the conditioning memory. In contrast, neither intra-BLA nor intra-mPFC propranolol affected delayed extinction learning. Overall, these data contribute to a growing literature suggesting dissociable roles for key nodes in the fear extinction circuit depending on the timing of extinction relative to conditioning. These data also suggest that heightened noradrenergic activity in the BLA underlies stress-induced extinction deficits. Propranolol may be a useful adjunct to behavioral therapeutic interventions in recently traumatized individuals who are at risk for developing trauma-related disorders.

Emotion dysregulation and functional connectivity in children with and without a history of major depressive disorder.

PubMed

Lopez, Katherine C; Luby, Joan L; Belden, Andy C; Barch, Deanna M

2018-04-01

Recent interest has emerged in understanding the neural mechanisms by which deficits in emotion regulation (ER) early in development may relate to later depression. Corticolimbic alterations reported in emotion dysregulation and depression may be one possible link. We examined the relationships between emotion dysregulation in school age, corticolimbic resting-state functional connectivity (rs-FC) in preadolescence, and depressive symptoms in adolescence. Participants were 143 children from a longitudinal preschool onset depression study who completed the Children Sadness Management Scale (CSMS; measuring ER), Child Depression Inventory (CDI-C; measuring depressive symptoms), and two resting-state MRI scans. Rs-FC between four primary regions of interest (ROIs; bilateral dorsolateral prefrontal cortex [dlPFC] and amygdala) and six target ROIs thought to contribute to ER were examined. Findings showed that ER in school age did not predict depressive symptoms in adolescence, but did predict preadolescent increases in dlPFC-insula and dlPFC-ventromedial PFC rs-FC across diagnosis, as well as increased dlPFC-dorsal anterior cingulate cortex (dACC) rs-FC in children with a history of depression. Of these profiles, only dlPFC-dACC rs-FC in preadolescence predicted depressive symptoms in adolescence. However, dlPFC-dACC connectivity did not mediate the relationship between ER in school age and depressive symptoms in adolescence. Despite the absence of a direct relationship between ER and depressive symptoms and no significant rs-FC mediation, the rs-FC profiles predicted by ER are consistent with the hypothesis that emotion dysregulation is associated with abnormalities in top-down control functions. The extent to which these relationships might confer greater risk for later depression, however, remains unclear.

Altered brain activation and connectivity during anticipation of uncertain threat in trait anxiety.

PubMed

Geng, Haiyang; Wang, Yi; Gu, Ruolei; Luo, Yue-Jia; Xu, Pengfei; Huang, Yuxia; Li, Xuebing

2018-06-08

In the research field of anxiety, previous studies generally focus on emotional responses following threat. A recent model of anxiety proposes that altered anticipation prior to uncertain threat is related with the development of anxiety. Behavioral findings have built the relationship between anxiety and distinct anticipatory processes including attention, estimation of threat, and emotional responses. However, few studies have characterized the brain organization underlying anticipation of uncertain threat and its role in anxiety. In the present study, we used an emotional anticipation paradigm with functional magnetic resonance imaging (fMRI) to examine the aforementioned topics by employing brain activation and general psychophysiological interactions (gPPI) analysis. In the activation analysis, we found that high trait anxious individuals showed significantly increased activation in the thalamus, middle temporal gyrus (MTG), and dorsomedial prefrontal cortex (dmPFC), as well as decreased activation in the precuneus, during anticipation of uncertain threat compared to the certain condition. In the gPPI analysis, the key regions including the amygdala, dmPFC, and precuneus showed altered connections with distributed brain areas including the ventromedial prefrontal cortex (vmPFC), dorsolateral prefrontal cortex (dlPFC), inferior parietal sulcus (IPS), insula, para-hippocampus gyrus (PHA), thalamus, and MTG involved in anticipation of uncertain threat in anxious individuals. Taken together, our findings indicate that during the anticipation of uncertain threat, anxious individuals showed altered activations and functional connectivity in widely distributed brain areas, which may be critical for abnormal perception, estimation, and emotion reactions during the anticipation of uncertain threat. © 2018 Wiley Periodicals, Inc.

Polymorphisms of the OXTR gene explain why sales professionals love to help customers

PubMed Central

Verbeke, Willem; Bagozzi, Richard P.; van den Berg, Wouter E.; Lemmens, Aurelie

2013-01-01

Polymorphisms of the OXTR gene affect people's social interaction styles in various social encounters: carriers of the OXTR GG, compared to the OXTR AA/AG in general, are more motivated to interact socially and detect social salience. We focus on sales professionals operating in knowledge intensive organizations. Study 1, with a sample of 141 sales people, shows that carriers of the OXTR GG allele, compared to the OXTR AA/AG allele, are more motivated to help customers than to manipulatively impose goods/services on them. Study 2, using genomic functional magnetic resonance imaging (fMRI) on a sample of 21 sales professionals processing facial pictures with different emotional valences, investigates key nuclei of social brain regions (SBRs). Compared to OXTR AA/AG carriers, OXTR GG carriers experience greater effective connectivity between SBRs of interest measured by Granger causality tests using univariate Haugh tests. In addition, the multivariate El-Himdi and Roy tests demonstrate that the amygdala, prefrontal cortex, and pars opercularis (inferior frontal gyrus) play key roles when processing emotional expressions. The bilateral amygdala and medial prefrontal cortex (mPFC) show significantly greater clout—influence on other brain regions—for GG allele carriers than non-carriers; likewise, the bilateral pars opercularis, left amygdala, and left mPFC are more receptive to activity in other brain regions among GG allele carriers than AG/AA allele carriers are. Thus, carriers of the OXTR GG allele are more sensitive to changes in emotional cues, enhancing social salience. To our knowledge, this is the first study on how insights from imaging genetics help understanding of the social motivation of people operating in a professional setting. PMID:24348351

Polymorphisms of the OXTR gene explain why sales professionals love to help customers.

PubMed

Verbeke, Willem; Bagozzi, Richard P; van den Berg, Wouter E; Lemmens, Aurelie

2013-01-01

Polymorphisms of the OXTR gene affect people's social interaction styles in various social encounters: carriers of the OXTR GG, compared to the OXTR AA/AG in general, are more motivated to interact socially and detect social salience. We focus on sales professionals operating in knowledge intensive organizations. Study 1, with a sample of 141 sales people, shows that carriers of the OXTR GG allele, compared to the OXTR AA/AG allele, are more motivated to help customers than to manipulatively impose goods/services on them. Study 2, using genomic functional magnetic resonance imaging (fMRI) on a sample of 21 sales professionals processing facial pictures with different emotional valences, investigates key nuclei of social brain regions (SBRs). Compared to OXTR AA/AG carriers, OXTR GG carriers experience greater effective connectivity between SBRs of interest measured by Granger causality tests using univariate Haugh tests. In addition, the multivariate El-Himdi and Roy tests demonstrate that the amygdala, prefrontal cortex, and pars opercularis (inferior frontal gyrus) play key roles when processing emotional expressions. The bilateral amygdala and medial prefrontal cortex (mPFC) show significantly greater clout-influence on other brain regions-for GG allele carriers than non-carriers; likewise, the bilateral pars opercularis, left amygdala, and left mPFC are more receptive to activity in other brain regions among GG allele carriers than AG/AA allele carriers are. Thus, carriers of the OXTR GG allele are more sensitive to changes in emotional cues, enhancing social salience. To our knowledge, this is the first study on how insights from imaging genetics help understanding of the social motivation of people operating in a professional setting.

Neural and Behavioral Correlates of Alcohol-Induced Aggression Under Provocation

PubMed Central

Gan, Gabriela; Sterzer, Philipp; Marxen, Michael; Zimmermann, Ulrich S; Smolka, Michael N

2015-01-01

Although alcohol consumption is linked to increased aggression, its neural correlates have not directly been studied in humans so far. Based on a comprehensive neurobiological model of alcohol-induced aggression, we hypothesized that alcohol-induced aggression would go along with increased amygdala and ventral striatum reactivity and impaired functioning of the prefrontal cortex (PFC) under alcohol. We measured neural and behavioral correlates of alcohol-induced aggression in a provoking vs non-provoking condition with a variant of the Taylor aggression paradigm (TAP) allowing to differentiate between reactive (provoked) and proactive (unprovoked) aggression. In a placebo-controlled cross-over design with moderate alcohol intoxication (~0.6 g/kg), 35 young healthy adults performed the TAP during functional magnetic resonance imaging (fMRI). Analyses revealed that provoking vs non-provoking conditions and alcohol vs placebo increased aggression and decreased brain responses in the anterior cingulate cortex/dorso-medial PFC (provoking

Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment

PubMed Central

Burgos-Robles, Anthony; Kimchi, Eyal Y.; Izadmehr, Ehsan M.; Porzenheim, Mary Jane; Ramos-Guasp, William A.; Nieh, Edward H.; Felix-Ortiz, Ada C.; Namburi, Praneeth; Leppla, Christopher A.; Presbrey, Kara N.; Anandalingam, Kavitha K.; Pagan-Rivera, Pablo A.; Anahtar, Melodi; Beyeler, Anna; Tye, Kay M.

2017-01-01

Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral amygdala (BLA) and prelimbic (PL) medial prefrontal cortex (mPFC) have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally-connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task where in shock- and sucrose-predictive cues were simultaneously presented to induce competition. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, the majority of optogenetically-identified PL-projecting BLA neurons recorded encoded the shock-associated cue, and more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally, BLA→PL photostimulation increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. The BLA→PL circuit plays a critical role in governing the selection of behavioral responses in the face of competing signals. PMID:28436980

Social Defeat: Impact on Fear Extinction and Amygdala-Prefrontal Cortical Theta Synchrony in 5-HTT Deficient Mice

PubMed Central

Narayanan, Venu; Heiming, Rebecca S.; Jansen, Friederike; Lesting, Jörg; Sachser, Norbert; Pape, Hans-Christian; Seidenbecher, Thomas

2011-01-01

Emotions, such as fear and anxiety, can be modulated by both environmental and genetic factors. One genetic factor is for example the genetically encoded variation of the serotonin transporter (5-HTT) expression. In this context, the 5-HTT plays a key role in the regulation of central 5-HT neurotransmission, which is critically involved in the physiological regulation of emotions including fear and anxiety. However, a systematic study which examines the combined influence of environmental and genetic factors on fear-related behavior and the underlying neurophysiological basis is missing. Therefore, in this study we used the 5-HTT-deficient mouse model for studying emotional dysregulation to evaluate consequences of genotype specific disruption of 5-HTT function and repeated social defeat for fear-related behaviors and corresponding neurophysiological activities in the lateral amygdala (LA) and infralimbic region of the medial prefrontal cortex (mPFC) in male 5-HTT wild-type (+/+), homo- (−/−) and heterozygous (+/−) mice. Naive males and experienced losers (generated in a resident-intruder paradigm) of all three genotypes, unilaterally equipped with recording electrodes in LA and mPFC, underwent a Pavlovian fear conditioning. Fear memory and extinction of conditioned fear was examined while recording neuronal activity simultaneously with fear-related behavior. Compared to naive 5-HTT+/+ and +/− mice, 5-HTT−/− mice showed impaired recall of extinction. In addition, 5-HTT−/− and +/− experienced losers showed delayed extinction learning and impaired recall of extinction. Impaired behavioral responses were accompanied by increased theta synchronization between the LA and mPFC during extinction learning in 5-HTT-/− and +/− losers. Furthermore, impaired extinction recall was accompanied with increased theta synchronization in 5-HTT−/− naive and in 5-HTT−/− and +/− loser mice. In conclusion, extinction learning and memory of conditioned fear can be modulated by both the 5-HTT gene activity and social experiences in adulthood, accompanied by corresponding alterations of the theta activity in the amygdala-prefrontal cortex network. PMID:21818344

Distinct roles of three frontal cortical areas in reward-guided behavior

PubMed Central

Noonan, M.P.; Mars, R.B.; Rushworth, M.F.S

2011-01-01

Functional magnetic resonance imaging (fMRI) was used to measure activity in three frontal cortical areas, lateral orbitofrontal cortex (lOFC), medial orbitofrontal cortex/ventromedial frontal cortex (mOFC/vmPFC), and anterior cingulate cortex (ACC) when expectations about type of reward, and not just reward presence or absence, could be learned. Two groups of human subjects learned twelve stimulus-response pairings. In one group (Consistent), correct performances of a given pairing were always reinforced with a specific reward outcome whereas in the other group (Inconsistent), correct performances were reinforced with randomly selected rewards. MOFC/vmPFC and lOFC were not distinguished by simple differences in relative preference for positive and negative outcomes. Instead lOFC activity reflected updating of reward-related associations specific to reward type; lOFC was active whenever informative outcomes allowed updating of reward-related associations regardless of whether the outcomes were positive or negative and the effects were greater when consistent stimulus-outcome and response-outcome mappings were present. A psycho-physiological interaction (PPI) analysis demonstrated changed coupling between lOFC and brain areas for visual object representation, such as perirhinal cortex, and reward-guided learning, such as amygdala, ventral striatum, and habenula /mediodorsal thalamus. By contrast mOFC/vmPFC activity reflected expected values of outcomes and occurrence of positive outcomes, irrespective of consistency of outcome mappings. The third frontal cortical region, ACC, reflected the use of reward type information to guide response selection. ACC activity reflected the probability of selecting the correct response, was greater when consistent outcome mappings were present, and was related to individual differences in propensity to select the correct response. PMID:21976525

Expression of the PPM1F Gene Is Regulated by Stress and Associated With Anxiety and Depression.

PubMed

Wingo, Aliza P; Velasco, Eric R; Florido, Antonio; Lori, Adriana; Choi, Dennis C; Jovanovic, Tanja; Ressler, Kerry J; Andero, Raül

2018-02-01

Molecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as posttraumatic stress disorder (PTSD) and depression, are not well understood. Using convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression and anxiety after traumatic experiences. From a transcriptome-wide analysis in mice, we found the Ppm1f gene to be differentially expressed in the amygdala and medial prefrontal cortex (mPFC) a week after immobilization stress. Next, we found that PPM1F messenger RNA levels in human blood were downregulated in cases with symptoms of comorbid PTSD and depression and consistently in cases with anxiety symptoms in a separate human dataset. Furthermore, we showed that a genetic variant of PPM1F, rs17759843, was associated with comorbid PTSD and depression and with PPM1F expression in both human brain and blood. Given prior reported mechanistic links between PPM1F and CAMK2 (CAMKII), we examined blood messenger RNA level of CAMK2G in humans and found it to be lower in cases with comorbid PTSD and depression. We also found that PPM1F protein levels and colocalization with CAMK2G were altered in amygdala and mPFC of male mice. Additionally, we found that a systemic dose of corticosterone blocked the depressive-like phenotype elicited by stress in female mice. Lastly, corticosterone rescued the anxiety-like phenotype and messenger RNA levels of Ppm1f in amygdala and mPFC in male mice and in mPFC of female mice. Taken together, our data suggest a mechanistic pathway involving PPM1F and CAMK2G in stress- and trauma-related manifestation of anxiety and depression across species. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Neural substrates of decision-making.

PubMed

Broche-Pérez, Y; Herrera Jiménez, L F; Omar-Martínez, E

2016-06-01

Decision-making is the process of selecting a course of action from among 2 or more alternatives by considering the potential outcomes of selecting each option and estimating its consequences in the short, medium and long term. The prefrontal cortex (PFC) has traditionally been considered the key neural structure in decision-making process. However, new studies support the hypothesis that describes a complex neural network including both cortical and subcortical structures. The aim of this review is to summarise evidence on the anatomical structures underlying the decision-making process, considering new findings that support the existence of a complex neural network that gives rise to this complex neuropsychological process. Current evidence shows that the cortical structures involved in decision-making include the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). This process is assisted by subcortical structures including the amygdala, thalamus, and cerebellum. Findings to date show that both cortical and subcortical brain regions contribute to the decision-making process. The neural basis of decision-making is a complex neural network of cortico-cortical and cortico-subcortical connections which includes subareas of the PFC, limbic structures, and the cerebellum. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Recovery from Posttraumatic Stress Requires Dynamic and Sequential Shifts in Amygdalar Connectivities

PubMed Central

Yoon, Sujung; Kim, Jieun E; Hwang, Jaeuk; Kang, Ilhyang; Jeon, Saerom; Im, Jooyeon J; Kim, Bori R; Lee, Sunho; Kim, Geon Ha; Rhim, Hyewhon; Lim, Soo Mee; Lyoo, In Kyoon

2017-01-01

The neural mechanisms underlying the development and maintenance of posttraumatic stress disorder (PTSD) have long been studied. However, little is known about the neural correlates of the recovery process from PTSD. A 5-year longitudinal study was conducted to investigate the trajectory of structural connectivities of the amygdala in disaster survivors with PTSD. Thirty disaster survivors, who were diagnosed with PTSD, and 29 healthy individuals, who were not exposed to trauma, underwent three waves of assessments including neuroimaging scanning over a 5-year period from the time of the disaster at approximately 1.3-year intervals. All disaster survivors showed significant improvements in PTSD symptoms over time. Using diffusion tensor imaging analysis, a 5-year trajectory of amygdalar structural connectivities with key brain regions was assessed. The amygdala–insula connection was initially strengthened and then normalized during recovery, while the amygdala–prefrontal cortex (PFC) connection was at first unaffected, then strengthened, and eventually normalized. The lower tract strength of the amygdala–thalamus connection normalized during recovery, while that of amygdala–hippocampus connection remained low. The greater amygdala–PFC connectivity was associated with less PTSD symptom severity. The present longitudinal study revealed that recovery from PTSD parallels dynamic and sequential shifts in amygdalar connectivities with multiple brain regions, suggesting the expanded view of fear circuitry including the insula and thalamus, beyond the traditional model which primarily involves the amygdala, PFC, and hippocampus. PMID:27461083

MRI Shows that Exhaustion Syndrome Due to Chronic Occupational Stress is Associated with Partially Reversible Cerebral Changes.

PubMed

Savic, I; Perski, A; Osika, W

2018-03-01

The present study investigates the cerebral effects of chronic occupational stress and its possible reversibility. Forty-eight patients with occupational exhaustion syndrome (29 women) and 80 controls (47 women) underwent structural magnetic resonance imaging (MRI) and neuropsychological testing. Forty-four participants (25 patients, 19 controls) also completed a second MRI scan after 1-2 years. Only patients received cognitive therapy. The stressed group at intake had reduced thickness in the right prefrontal cortex (PFC) and left superior temporal gyrus (STG), enlarged amygdala volumes, and reduced caudate volumes. Except for the caudate volume, these abnormalities were more pronounced in females. They were all related to perceived stress, which was similar for both genders. Thickness of the PFC also correlated with an impaired ability to down-modulate negative emotions. Thinning of PFC and reduction of caudate volume normalized in the follow-up. The amygdala enlargement and the left STG thinning remained. Longitudinal changes were not detected among controls. Chronic occupational stress was associated with partially reversible structural abnormalities in key regions for stress processing. These changes were dynamically correlated with the degree of perceived stress, highlighting a possible causal link. They seem more pronounced in women, and could be a substrate for an increased cerebral vulnerability to stress-related psychiatric disorders. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Association of stigma resistance with emotion regulation - functional magnetic resonance imaging and neuropsychological findings.

PubMed

Raij, Tuukka T; Korkeila, Jyrki; Joutsenniemi, Kaisla; Saarni, Samuli I; Riekki, Tapani J J

2014-04-01

[corrected] Personal characteristics contribute to whether negative attitudes in society are internalized as deteriorating self-stigma. Studies in healthy subjects suggest that resilience is associated with the regulation of amygdala activation by the medial prefrontal cortex (mPFC), but little is known about the factors that contribute to individual stigma resistance in psychiatric patients. We assessed stigma (by measuring association strengths between social inferiority and schizophrenia by an implicit association test) in 20 patients with schizophrenia and in 16 age- and sex-matched healthy control subjects. The brain activation strengths were measured by functional magnetic resonance imaging during evaluation of schizophrenia-related statements and of control statements. Association strengths between social inferiority and schizophrenia were inversely related to the strength of the activation of the rostro-ventral mPFC. This inverse correlation survived adjustment for global functioning, depression symptom scores, and insight. Activation of the rostro-ventral mPFC was negatively correlated with activation of the amygdala. The association strengths between social inferiority and schizophrenia correlated with the compromised performance in a Stroop task, which is a measure of cognitive regulation. Our findings suggest that individual stigma resistance is associated with emotion regulation. These findings may help to understand better stigma resistance and thereby aid the development of patient interventions that add to the public anti-stigma work in reducing devastating effects of stigma. © 2014.

Distinct patterns of outcome valuation and amygdala-prefrontal cortex synaptic remodeling in adolescence and adulthood

PubMed Central

Stolyarova, Alexandra; Izquierdo, Alicia

2015-01-01

Adolescent behavior is typified by increased risk-taking, reward- and novelty-seeking, as well as an augmented need for social and environmental stimulation. This behavioral phenotype may result from alterations in outcome valuation or reward learning. In the present set of experiments, we directly compared adult and adolescent animals on tasks measuring both of these processes. Additionally, we examined developmental differences in dopamine D1-like receptor (D1R), dopamine D2-like receptor (D2R), and polysialylated neural cell adhesion molecule (PSA-NCAM) expression in animals that were trained on an effortful reward valuation task, given that these proteins play an important role in the functional development of the amygdala-prefrontocortical (PFC) circuit and mesocorticolimbic dopamine system. We found that adolescent animals were not different from adults in appetitive associative learning, but exhibited distinct pattern of responses to differences in outcome values, which was paralleled by an enhanced motivation to invest effort to obtain larger rewards. There were no differences in D2 receptor expression, but D1 receptor expression was significantly reduced in the striatum of animals that had experiences with reward learning during adolescence compared to animals that went through the same experiences in adulthood. We observed increased levels of PSA-NCAM expression in both PFC and amygdala of late adolescents compared to adults that were previously trained on an effortful reward valuation task. PSA-NCAM levels in PFC were strongly and positively associated with high effort/reward (HER) choices in adolescents, but not in adult animals. Increased levels of PSA-NCAM expression in adolescents may index increased structural plasticity and represent a neural correlate of a reward sensitive endophenotype. PMID:25999830

The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives.

PubMed

Lelli-Chiesa, G; Kempton, M J; Jogia, J; Tatarelli, R; Girardi, P; Powell, J; Collier, D A; Frangou, S

2011-04-01

The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala-prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action. We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls. Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls. Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.

Sex differences in neural responses to stress and alcohol context cues.

PubMed

Seo, Dongju; Jia, Zhiru; Lacadie, Cheryl M; Tsou, Kristen A; Bergquist, Keri; Sinha, Rajita

2011-11-01

Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. This study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue, and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (P < 0.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum, and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the left dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala, and hippocampus than women, whereas women showed greater alcohol-cue-related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion-modulation regions, including the medial OFC, ventromedial PFC, left superior-mPFC, and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal, and ventral) in men, supporting its involvement in alcohol "urge" in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders. Copyright © 2010 Wiley-Liss, Inc.

Projection specificity in heterogeneous locus coeruleus cell populations: implications for learning and memory

PubMed Central

Uematsu, Akira; Tan, Bao Zhen

2015-01-01

Noradrenergic neurons in the locus coeruleus (LC) play a critical role in many functions including learning and memory. This relatively small population of cells sends widespread projections throughout the brain including to a number of regions such as the amygdala which is involved in emotional associative learning and the medial prefrontal cortex which is important for facilitating flexibility when learning rules change. LC noradrenergic cells participate in both of these functions, but it is not clear how this small population of neurons modulates these partially distinct processes. Here we review anatomical, behavioral, and electrophysiological studies to assess how LC noradrenergic neurons regulate these different aspects of learning and memory. Previous work has demonstrated that subpopulations of LC noradrenergic cells innervate specific brain regions suggesting heterogeneity of function in LC neurons. Furthermore, noradrenaline in mPFC and amygdala has distinct effects on emotional learning and cognitive flexibility. Finally, neural recording data show that LC neurons respond during associative learning and when previously learned task contingencies change. Together, these studies suggest a working model in which distinct and potentially opposing subsets of LC neurons modulate particular learning functions through restricted efferent connectivity with amygdala or mPFC. This type of model may provide a general framework for understanding other neuromodulatory systems, which also exhibit cell type heterogeneity and projection specificity. PMID:26330494

Complexity of VTA DA neural activities in response to PFC transection in nicotine treated rats.

PubMed

Chen, Ting Y; Zhang, Die; Dragomir, Andrei; Akay, Yasemin M; Akay, Metin

2011-02-27

The dopaminergic (DA) neurons in the ventral tegmental area (VTA) are widely implicated in the addiction and natural reward circuitry of the brain. These neurons project to several areas of the brain, including prefrontal cortex (PFC), nucleus accubens (NAc) and amygdala. The functional coupling between PFC and VTA has been demonstrated, but little is known about how PFC mediates nicotinic modulation in VTA DA neurons. The objectives of this study were to investigate the effect of acute nicotine exposure on the VTA DA neuronal firing and to understand how the disruption of communication from PFC affects the firing patterns of VTA DA neurons. Extracellular single-unit recordings were performed on Sprague-Dawley rats and nicotine was administered after stable recording was established as baseline. In order to test how input from PFC affects the VTA DA neuronal firing, bilateral transections were made immediate caudal to PFC to mechanically delete the interaction between VTA and PFC. The complexity of the recorded neural firing was subsequently assessed using a method based on the Lempel-Ziv estimator. The results were compared with those obtained when computing the entropy of neural firing. Exposure to nicotine triggered a significant increase in VTA DA neurons firing complexity when communication between PFC and VTA was present, while transection obliterated the effect of nicotine. Similar results were obtained when entropy values were estimated. Our findings suggest that PFC plays a vital role in mediating VTA activity. We speculate that increased firing complexity with acute nicotine administration in PFC intact subjects is due to the close functional coupling between PFC and VTA. This hypothesis is supported by the fact that deletion of PFC results in minor alterations of VTA DA neural firing when nicotine is acutely administered.

Hunger is the best spice: an fMRI study of the effects of attention, hunger and calorie content on food reward processing in the amygdala and orbitofrontal cortex.

PubMed

Siep, Nicolette; Roefs, Anne; Roebroeck, Alard; Havermans, Remco; Bonte, Milene L; Jansen, Anita

2009-03-02

Research indicates that dysfunctional food reward processing may contribute to pathological eating behaviour. It is widely recognized that both the amygdala and the orbitofrontal cortex (OFC) are essential parts of the brain's reward circuitry. The aims of this fMRI study were (1) to examine the effects of food deprivation and calorie content on reward processing in the amygdala and the OFC, and (2) to examine whether an explicit evaluation of foods is necessary for OFC, but not amygdalar activity. Addressing the first aim, healthy females were presented with high and low calorie food pictures while being either hungry or satiated. For the second aim, attention focus was manipulated by directing participants' attention either to the food or to a neutral aspect. This study shows that hunger interacts with the energy content of foods, modulating activity in the posterior cingulate cortex, medial OFC, insula, caudate putamen and fusiform gyrus. Results show that satiated healthy females show an increased reward processing in response to low calorie foods. Confirming our hypothesis, food deprivation increased activity following the presentation of high calorie foods, which may explain why treatments of obesity energy restricting diets often are unsuccessful. Interestingly, activity in both the amygdala and mOFC was only evident when participants explicitly evaluated foods. However, attention independent activity was found in the mPFC following the high calorie foods cues when participants where hungry. Current findings indicate that research on how attention modulates food reward processing might prove especially insightful in the study of the neural substrates of healthy and pathological eating behaviour.

Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex.

PubMed

Abelaira, Helena M; Réus, Gislaine Z; Ignácio, Zuleide M; Dos Santos, Maria Augusta B; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Michels, Monique; Abatti, Mariane; Sonai, Beatriz; Dal Pizzol, Felipe; Carvalho, André F; Quevedo, João

2017-04-01

Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures. Copyright © 2016 Elsevier Ltd. All rights reserved.

microRNA-206 in Rat Medial Prefrontal Cortex Regulates BDNF Expression and Alcohol Drinking

PubMed Central

Barbier, Estelle; Flanigan, Meghan; Solomon, Matthew; Pincus, Alexandra; Pilling, Andrew; Sun, Hui; Schank, Jesse R.; King, Courtney; Heilig, Markus

2014-01-01

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3′-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR. In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3′-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3′-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action. PMID:24672003

Emotion reactivity and regulation in late-life generalized anxiety disorder: Functional connectivity at baseline and post-treatment

PubMed Central

Andreescu, Carmen; Sheu, Lei K.; Tudorascu, Dana; Gross, James J.; Walker, Sarah; Banihashemi, Layla; Aizenstein, Howard

2014-01-01

Objectives Generalized Anxiety Disorder (GAD) is one of the most prevalent mental disorders in the elderly, but its functional neuroanatomy is not well understood. Given the role of emotion dysregulation in GAD, we sought to describe the neural bases of emotion regulation in late-life GAD by analyzing the functional connectivity (FC) in the Salience Network and the Executive Control Network during worry induction and worry reappraisal. Design, setting and participants Twenty-eight elderly GAD and thirty-one non-anxious comparison participants were included. Twelve elderly GAD completed a 12-week pharmacotherapy trial. We used an in-scanner worry script that alternates blocks of worry induction and reappraisal. We assessed network FC, employing the following seeds: anterior insula (AI), dorso-lateral prefrontal cortex (dlPFC), the bed nucleus of stria terminalis (BNST), the paraventricular nucleus (PVN). Results GAD participants exhibited greater FC during worry induction between the left AI and the right orbito-frontal cortex (OFC), and between the BNST and the subgenual cingulate. During worry reappraisal, the non-anxious participants had greater FC between the left dlPFC and the medial PFC, as well as between the left AI and the medial PFC, while elderly GAD had greater FC between the PVN and the amygdala. Following twelve weeks of pharmacotherapy, GAD participants had greater connectivity between the dlPFC and several prefrontal regions during worry reappraisal. Conclusion FC during worry induction and reappraisal points toward abnormalities in both worry generation and worry reappraisal. Following successful pharmacologic treatment, we observed greater connectivity in the prefrontal nodes of the Executive Control Network during reappraisal of worry. PMID:24996397

microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking.

PubMed

Tapocik, Jenica D; Barbier, Estelle; Flanigan, Meghan; Solomon, Matthew; Pincus, Alexandra; Pilling, Andrew; Sun, Hui; Schank, Jesse R; King, Courtney; Heilig, Markus

2014-03-26

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3'-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR. In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3'-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3'-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action.

Do you make a difference? Social context in a betting task

PubMed Central

Nelson, Eric E.; Pine, Daniel S.; Ernst, Monique

2008-01-01

Social context strongly influences human motivated behavior. The triadic model implicates three major nodes in the regulation of motivated behavior, i.e. amygdala, medial prefrontal cortex (mPFC) and striatum. The present work examines how social context modulates this system. Nineteen healthy subjects completed an event-related functional magnetic resonance imaging study of a monetary betting task in the presence (social trials) and in the absence of a social peer (nonsocial trials). In the social trials, the scanned subject played along with another subject, although their performances were independent from one another. In the nonsocial trials the scanned subject played alone. Although behavioral performance did not differ between social and nonsocial trials, BOLD signal changes during betting were significantly greater in the amygdala bilaterally and the right dorsolateral prefrontal cortex (BA 9) in the social condition relative to the nonsocial condition. In contrast, activation was greater in ventral striatum in the nonsocial condition relative to the social condition. These findings suggest that social context modulates the triadic neural-systems ensemble to adjust motivated behavior to the unique demands associated with the presence of conspecifics. PMID:19015081

Sex differences in corticolimbic dopamine and serotonin systems in the rat and the effect of postnatal handling.

PubMed

Duchesne, Annie; Dufresne, Marc M; Sullivan, Ron M

2009-03-17

Stress-related psychopathology is particularly prevalent in women, although the neurobiological reason(s) for this are unclear. Dopamine (DA) and serotonin (5-HT) systems however, are known to play important adaptive roles in stress and emotion regulation. The aims of the present study included examination of sex differences in stress-related behaviour and neuroendocrine function as well as post mortem neurochemistry, with the main hypothesis that corticolimbic DA and 5-HT systems would show greater functional activity in males than females. Long-Evans rats of both sexes were employed. Additional factors incorporated included differential postnatal experience (handled vs. nonhandled) and adult mild stress experience (acute vs. repeated (5) restraint). Regional neurochemistry measures were conducted separately for left and right hemispheres. Behaviourally, females showed more exploratory behaviour than males in the elevated plus maze and an openfield/holeboard apparatus. Females also exhibited significantly higher levels of adrenocorticotrophic hormone and corticosterone at all time points in response to restraint stress than males across treatment conditions, although both sexes showed similar habituation in stress-induced ACTH activation with repeated mild stress. Neurochemically, females had significantly higher levels of DA (in ventromedial prefrontal cortex (vmPFC), insular cortex and n. accumbens) and 5-HT (in vmPFC, amygdala, dorsal hippocampus and insula) than males. In contrast, males had higher levels of the DA metabolite DOPAC or DOPAC/DA ratios than females in all five regions and higher levels of the 5-HT metabolite 5-HIAA or 5-HIAA/5-HT ratios in vmPFC, amygdala and insula, suggesting greater neurotransmitter utilization in males. Moreover, handling treatment induced a significant male-specific upregulation of 5-HT metabolism in all regions except n. accumbens. Given the adaptive role of 5-HT and DAergic neurotransmission in stress and emotion regulation, the intrinsic sex differences we report in the functional status of these systems across conditions, may be highly relevant to the differential vulnerability to disorders of stress and emotion regulation.

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment.

PubMed

Vahid-Ansari, Faranak; Albert, Paul R

2018-01-01

Poststroke depression (PSD) is a common outcome of stroke that limits recovery and is only partially responsive to chronic antidepressant treatment. In order to elucidate changes in the cortical-limbic circuitry associated with PSD and its treatment, we examined a novel mouse model of persistent PSD. Focal endothelin-1-induced ischemia of the left medial prefrontal cortex (mPFC) in male C57BL6 mice resulted in a chronic anxiety and depression phenotype. Here, we show severe cognitive impairment in spatial learning and memory in the stroke mice. The behavioral and cognitive phenotypes were reversed by chronic (4-week) treatment with fluoxetine, alone or with voluntary exercise (free-running wheel), but not by exercise alone. To assess chronic cellular activation, FosB + cells were co-labeled for markers of glutamate/pyramidal (VGluT1-3/CaMKIIα), γ-aminobutyric acid (GAD67), and serotonin (TPH). At 6 weeks poststroke versus sham (or 4 days poststroke), left mPFC stroke induced widespread FosB activation, more on the right (contralesional) than on the left side. Stroke activated glutamate cells of the mPFC, nucleus accumbens, amygdala, hippocampus, and raphe serotonin neurons. Chronic fluoxetine balanced bilateral neuronal activity, reducing total FosB and FosB/CamKII + cells (mPFC, nucleus accumbens), and unlike exercise, increasing FosB/GAD67 + cells (septum, amygdala) or both (hippocampus, raphe). In summary, chronic antidepressant but not exercise mediates recovery in this unilateral ischemic PSD model that is associated with region-specific reversal of stroke-induced pyramidal cell hyperactivity and increase in γ-aminobutyric acidergic activity. Targeted brain stimulation to restore brain activity could provide a rational approach for treating clinical PSD.

Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles.

PubMed

Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Vialou, Vincent; Heller, Elizabeth A; Yieh, Lynn; LaBonté, Benoit; Peña, Catherine J; Shen, Li; Wittenberg, Gayle M; Nestler, Eric J

2017-02-15

Examining transcriptional regulation by antidepressants in key neural circuits implicated in depression and understanding the relation to transcriptional mechanisms of susceptibility and natural resilience may help in the search for new therapeutic agents. Given the heterogeneity of treatment response in human populations, examining both treatment response and nonresponse is critical. We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine, and a rapidly acting, non-monoamine-based antidepressant, ketamine, in mice subjected to chronic social defeat stress, a validated depression model, and used RNA sequencing to analyze transcriptional profiles associated with susceptibility, resilience, and antidepressant response and nonresponse in the prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. We identified similar numbers of responders and nonresponders after ketamine or imipramine treatment. Ketamine induced more expression changes in the hippocampus; imipramine induced more expression changes in the nucleus accumbens and amygdala. Transcriptional profiles in treatment responders were most similar in the PFC. Nonresponse reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptibility-associated transcriptional changes and induced resilience-associated transcription in the PFC. We generated a uniquely large resource of gene expression data in four interconnected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by antidepressant drugs and in both reversing susceptibility- and inducing resilience-associated molecular adaptations. In addition, we found region-specific effects of each drug, suggesting both common and unique effects of imipramine versus ketamine. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses.

PubMed

Goldstein, Jill M; Lancaster, Katie; Longenecker, Julia M; Abbs, Brandon; Holsen, Laura M; Cherkerzian, Sara; Whitfield-Gabrieli, Susan; Makris, Nicolas; Tsuang, Ming T; Buka, Stephen L; Seidman, Larry J; Klibanski, Anne

2015-06-30

Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Transdiagnostic deviant facial recognition for implicit negative emotion in autism and schizophrenia.

PubMed

Ciaramidaro, Angela; Bölte, Sven; Schlitt, Sabine; Hainz, Daniela; Poustka, Fritz; Weber, Bernhard; Freitag, Christine; Walter, Henrik

2018-02-01

Impaired facial affect recognition (FAR) is observed in schizophrenia and autism spectrum disorder (ASD) and has been linked to amygdala and fusiform gyrus dysfunction. ASD patient's impairments seem to be more pronounced during implicit rather than explicit FAR, whereas for schizophrenia data are inconsistent. However, there are no studies comparing both patient groups in an identical design. The aim of this three-group study was to identify (i) whether FAR alterations are equally present in both groups, (ii) whether they are present rather during implicit or explicit FAR, (iii) and whether they are conveyed by similar or disorder-specific neural mechanisms. Using fMRI, we investigated neural activation during explicit and implicit negative and neutral FAR in 33 young-adult individuals with ASD, 20 subjects with paranoid-schizophrenia and 25 IQ- and gender-matched controls individuals. Differences in activation patterns between each clinical group and controls, respectively were found exclusively for implicit FAR in amygdala and fusiform gyrus. In addition, the ASD group additionally showed reduced activations in medial prefrontal cortex (PFC), bilateral dorso-lateral PFC, ventro-lateral PFC, posterior-superior temporal sulcus and left temporo-parietal junction. Although subjects with ASD showed more widespread altered activation patterns, a direct comparison between both patient groups did not show disorder-specific deficits in neither patient group. In summary, our findings are consistent with a common neural deficit during implicit negative facial affect recognition in schizophrenia and autism spectrum disorders. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Diazepam reduces excitability of amygdala and further influences auditory cortex following sodium salicylate treatment in rats.

PubMed

Song, Yu; Liu, Junxiu; Ma, Furong; Mao, Lanqun

2016-12-01

Diazepam can reduce the excitability of lateral amygdala and eventually suppress the excitability of the auditory cortex in rats following salicylate treatment, indicating the regulating effect of lateral amygdala to the auditory cortex in the tinnitus procedure. To study the spontaneous firing rates (SFR) of the auditory cortex and lateral amygdala regulated by diazepam in the tinnitus rat model induced by sodium salicylate. This study first created a tinnitus rat modal induced by sodium salicylate, and recorded SFR of both auditory cortex and lateral amygdala. Then diazepam was intraperitoneally injected and the SFR changes of lateral amygdala recorded. Finally, diazepam was microinjected on lateral amygdala and the SFR changes of the auditory cortex recorded. Both SFRs of the auditory cortex and lateral amygdala increased after salicylate treatment. SFR of lateral amygdala decreased after intraperitoneal injection of diazepam. Microinjecting diazepam to lateral amygdala decreased SFR of the auditory cortex ipsilaterally and contralaterally.

Context-Dependent Encoding of Fear and Extinction Memories in a Large-Scale Network Model of the Basal Amygdala

PubMed Central

Vlachos, Ioannis; Herry, Cyril; Lüthi, Andreas; Aertsen, Ad; Kumar, Arvind

2011-01-01

The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories. PMID:21437238

Neural Correlates of Sex/Gender Differences in Humor Processing for Different Joke Types.

PubMed

Chan, Yu-Chen

2016-01-01

Humor operates through a variety of techniques, which first generate surprise and then amusement and laughter once the unexpected incongruity is resolved. As different types of jokes use different techniques, the corresponding humor processes also differ. The present study builds on the framework of the 'tri-component theory of humor,' which details the mechanisms involved in cognition (comprehension), affect (appreciation), and laughter (expression). This study seeks to identify differences among joke types and between sexes/genders in the neural mechanisms underlying humor processing. Three types of verbal jokes, bridging-inference jokes (BJs), exaggeration jokes (EJs), and ambiguity jokes (AJs), were used as stimuli. The findings revealed differences in brain activity for an interaction between sex/gender and joke type. For BJs, women displayed greater activation in the temporoparietal-mesocortical-motor network than men, demonstrating the importance of the temporoparietal junction (TPJ) presumably for 'theory of mind' processing, the orbitofrontal cortex for motivational functions and reward coding, and the supplementary motor area for laughter. Women also showed greater activation than men in the frontal-mesolimbic network associated with EJs, including the anterior (frontopolar) prefrontal cortex (aPFC, BA 10) for executive control processes, and the amygdala and midbrain for reward anticipation and salience processes. Conversely, AJs elicited greater activation in men than women in the frontal-paralimbic network, including the dorsal prefrontal cortex (dPFC) and parahippocampal gyrus. All joke types elicited greater activation in the aPFC of women than of men, whereas men showed greater activation than women in the dPFC. To confirm the findings related to sex/gender differences, random group analysis and within group variance analysis were also performed. These findings help further establish the mechanisms underlying the processing of different joke types for the sexes/genders and provide a neural foundation for a theory of sex/gender differences in humor.

Neural Correlates of Sex/Gender Differences in Humor Processing for Different Joke Types

PubMed Central

Chan, Yu-Chen

2016-01-01

Humor operates through a variety of techniques, which first generate surprise and then amusement and laughter once the unexpected incongruity is resolved. As different types of jokes use different techniques, the corresponding humor processes also differ. The present study builds on the framework of the ‘tri-component theory of humor,’ which details the mechanisms involved in cognition (comprehension), affect (appreciation), and laughter (expression). This study seeks to identify differences among joke types and between sexes/genders in the neural mechanisms underlying humor processing. Three types of verbal jokes, bridging-inference jokes (BJs), exaggeration jokes (EJs), and ambiguity jokes (AJs), were used as stimuli. The findings revealed differences in brain activity for an interaction between sex/gender and joke type. For BJs, women displayed greater activation in the temporoparietal–mesocortical-motor network than men, demonstrating the importance of the temporoparietal junction (TPJ) presumably for ‘theory of mind’ processing, the orbitofrontal cortex for motivational functions and reward coding, and the supplementary motor area for laughter. Women also showed greater activation than men in the frontal-mesolimbic network associated with EJs, including the anterior (frontopolar) prefrontal cortex (aPFC, BA 10) for executive control processes, and the amygdala and midbrain for reward anticipation and salience processes. Conversely, AJs elicited greater activation in men than women in the frontal-paralimbic network, including the dorsal prefrontal cortex (dPFC) and parahippocampal gyrus. All joke types elicited greater activation in the aPFC of women than of men, whereas men showed greater activation than women in the dPFC. To confirm the findings related to sex/gender differences, random group analysis and within group variance analysis were also performed. These findings help further establish the mechanisms underlying the processing of different joke types for the sexes/genders and provide a neural foundation for a theory of sex/gender differences in humor. PMID:27199791

Neural substrates of framing effects in social contexts: A meta-analytical approach.

PubMed

Wang, X T; Rao, Li-Lin; Zheng, Hongming

2017-06-01

We hypothesize that framing effects (risk-averse in the positive frame and risk-seeking in the negative frame) are likely to occur when ambiguous social contexts result in ambiguous or ambivalent risk preferences, leading the decision-maker to search for more subtle cues, such as verbal framing. In a functional magnetic resonance imaging (fMRI) study, we examined framing effects in both unambiguous homogeneous group and more ambiguous heterogeneous group contexts. We began by conducting a meta-analysis and identified three regions of interest: the right inferior frontal gyrus, the left anterior cingulate (ACC)/ventromedial prefrontal cortex (vmPFC), and the left amygdala. Our own fMRI data were collected while the participants made choices between a sure option and a gamble framed in terms of the number of lives to either save or die. The framing effect was evident in a heterogeneous context with a mixture of kin and strangers, but disappeared in a homogeneous group of either all kin-members or all strangers. The fMRI results revealed a greater activation in the right middle/inferior frontal gyrus under the negative than the positive framing, and less ACC/vmPFC deactivation under positive framing in the heterogamous/ambiguous context. The activation of the amygdala was correlated with greater risk-seeking preference in homogeneous kinship contexts.

The effect of hippocampal NMDA receptor blockade by MK-801 on cued fear extinction.

PubMed

Zhang, Bo; Li, Chuan-Yu; Wang, Xiu-Song

2017-08-14

Extinction of conditioned fear has been suggested to be a new form of learning instead of erasure of what was originally learned, and the process is NMDA (N-methyl d-aspartate) receptor (NMDAR) dependent. Most of studies have so far revealed the important roles of NMDARs in the amygdala and medial prefrontal cortex (mPFC) in cued fear extinction. Although the ventral hippocampus has intimately reciprocal connections with the amygdala and mPFC, the role of its NMDARs in cued fear extinction remains unclear. The present experiment explored the issue by bilateral pre-extinction microinjection of the noncompetitive NMDAR antagonist MK-801 into the ventral hippocampus. Four groups of rats were given habituation, tone cued fear conditioning, fear extinction training and extinction test. Prior to extinction training, rats received bilateral infusions of either MK-801 (1.5, 3, or 6μg/0.5μl) or saline. Our results showed that MK-801 reduced freezing on the first trial of extinction training with no impact on within-session acquisition of extinction, and that the lower doses of MK-801 resulted in increased freezing on the extinction retrieval test. These findings suggest that ventral hippocampal NMDARs are necessary for the consolidation of tone cued fear extinction. Copyright © 2017 Elsevier B.V. All rights reserved.

Anxiolytic effect of music exposure on BDNFMet/Met transgenic mice.

PubMed

Li, Wen-Jing; Yu, Hui; Yang, Jian-Min; Gao, Jing; Jiang, Hong; Feng, Min; Zhao, Yu-Xia; Chen, Zhe-Yu

2010-08-06

Brain-derived neurotrophic factor (BDNF) has been reported to play important roles in the modulation of anxiety, mood stabilizers, and pathophysiology of affective disorders. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (Val66Met) has been found to be associated with depression and anxiety disorders. The humanized BDNF(Met/Met) knock-in transgenic mice exhibited increased anxiety-related behaviors that were unresponsive to serotonin reuptake inhibitors, fluoxetine. Music is known to be able to elicit emotional changes, including anxiolytic effects. In this study, we found that music treatment could significantly decrease anxiety state in BDNF(Met/Met) mice, but not in BDNF(+/)(-), mice compared with white noise exposure in open field and elevated plus maze test. Moreover, in contrast to white noise exposure, BDNF expression levels in the prefrontal cortex (PFC), amygdala and hippocampus were significantly increased in music-exposed adult BDNF(Met/Met) mice. However, music treatment could not upregulate BDNF levels in the PFC, amygdala, and hippocampus in BDNF(+/)(-) mice, which suggests the essential role of BDNF in the anxiolytic effect of music. Together, our results imply that music may provide an effective therapeutic intervention for anxiety disorders in humans with this genetic BDNF(Met) variant. Copyright 2010 Elsevier B.V. All rights reserved.

Cortico-limbic connectivity in MAOA-L carriers is vulnerable to acute tryptophan depletion.

PubMed

Eisner, Patrick; Klasen, Martin; Wolf, Dhana; Zerres, Klaus; Eggermann, Thomas; Eisert, Albrecht; Zvyagintsev, Mikhail; Sarkheil, Pegah; Mathiak, Krystyna A; Zepf, Florian; Mathiak, Klaus

2017-03-01

A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Dopaminergic system and dream recall: An MRI study in Parkinson's disease patients.

PubMed

De Gennaro, Luigi; Lanteri, Olimpia; Piras, Fabrizio; Scarpelli, Serena; Assogna, Francesca; Ferrara, Michele; Caltagirone, Carlo; Spalletta, Gianfranco

2016-03-01

We investigated the role of the dopamine system [i.e., subcortical-medial prefrontal cortex (mPFC) network] in dreaming, by studying patients with Parkinson's Disease (PD) as a model of altered dopaminergic transmission. Subcortical volumes and cortical thickness were extracted by 3T-MR images of 27 PD patients and 27 age-matched controls, who were asked to fill out a dream diary upon morning awakening for one week. PD patients do not substantially differ from healthy controls with respect to the sleep, dream, and neuroanatomical measures. Multivariate correlational analyses in PD patients show that dopamine agonist dosage is associated to qualitatively impoverished dreams, as expressed by lower bizarreness and lower emotional load values. Visual vividness (VV) of their dream reports positively correlates with volumes of both the amygdalae and with thickness of the left mPFC. Emotional load also positively correlates with hippocampal volume. Beside the replication of our previous finding on the role of subcortical nuclei in dreaming experience of healthy subjects, this represents the first evidence of a specific role of the amygdala-mPFC dopaminergic network system in dream recall. The association in PD patients between higher dopamine agonist dosages and impoverished dream reports, however, and the significant correlations between VV and mesolimbic regions, however, provide an empirical support to the hypothesis that a dopamine network plays a key role in dream generation. The causal relation is however precluded by the intrinsic limitation of assuming the dopamine agonist dosage as a measure of the hypodopaminergic state in PD. Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.

PubMed

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-12-06

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.

Functional states of rat cortical circuits during the unpredictable availability of a reward-related cue

PubMed Central

Fernández-Lamo, Iván; Sánchez-Campusano, Raudel; Gruart, Agnès; Delgado-García M, José M.

2016-01-01

Proper performance of acquired abilities can be disturbed by the unexpected occurrence of external changes. Rats trained with an operant conditioning task (to press a lever in order to obtain a food pellet) using a fixed-ratio (1:1) schedule were subsequently placed in a Skinner box in which the lever could be removed randomly. Field postsynaptic potentials (fPSPs) were chronically evoked in perforant pathway-hippocampal CA1 (PP-CA1), CA1-subiculum (CA1-SUB), CA1-medial prefrontal cortex (CA1-mPFC), mPFC-nucleus accumbens (mPFC-NAc), and mPFC-basolateral amygdala (mPFC-BLA) synapses during lever IN and lever OUT situations. While lever presses were accompanied by a significant increase in fPSP slopes at the five synapses, the unpredictable absence of the lever were accompanied by decreased fPSP slopes in all, except PP-CA1 synapses. Spectral analysis of local field potentials (LFPs) recorded when the animal approached the corresponding area in the lever OUT situation presented lower spectral powers than during lever IN occasions for all recording sites, apart from CA1. Thus, the unpredictable availability of a reward-related cue modified the activity of cortical and subcortical areas related with the acquisition of operant learning tasks, suggesting an immediate functional reorganization of these neural circuits to address the changed situation and to modify ongoing behaviors accordingly. PMID:27869181

Previous Institutionalization Is Followed by Broader Amygdala-Hippocampal-PFC Network Connectivity during Aversive Learning in Human Development.

PubMed

Silvers, Jennifer A; Lumian, Daniel S; Gabard-Durnam, Laurel; Gee, Dylan G; Goff, Bonnie; Fareri, Dominic S; Caldera, Christina; Flannery, Jessica; Telzer, Eva H; Humphreys, Kathryn L; Tottenham, Nim

2016-06-15

Early institutional care can be profoundly stressful for the human infant, and, as such, can lead to significant alterations in brain development. In animal models, similar variants of early adversity have been shown to modify amygdala-hippocampal-prefrontal cortex development and associated aversive learning. The current study examined this rearing aberration in human development. Eighty-nine children and adolescents who were either previously institutionalized (PI youth; N = 46; 33 females and 13 males; age range, 7-16 years) or were raised by their biological parents from birth (N = 43; 22 females and 21 males; age range, 7-16 years) completed an aversive-learning paradigm while undergoing functional neuroimaging, wherein visual cues were paired with either an aversive sound (CS+) or no sound (CS-). For the PI youth, better aversive learning was associated with higher concurrent trait anxiety. Both groups showed robust learning and amygdala activation for CS+ versus CS- trials. However, PI youth also exhibited broader recruitment of several regions and increased hippocampal connectivity with prefrontal cortex. Stronger connectivity between the hippocampus and ventromedial PFC predicted significant improvements in future anxiety (measured 2 years later), and this was particularly true within the PI group. These results suggest that for humans as well as for other species, early adversity alters the neurobiology of aversive learning by engaging a broader prefrontal-subcortical circuit than same-aged peers. These differences are interpreted as ontogenetic adaptations and potential sources of resilience. Prior institutionalization is a significant form of early adversity. While nonhuman animal research suggests that early adversity alters aversive learning and associated neurocircuitry, no prior work has examined this in humans. Here, we show that youth who experienced prior institutionalization, but not comparison youth, recruit the hippocampus during aversive learning. Among youth who experienced prior institutionalization, individual differences in aversive learning were associated with worse current anxiety. However, connectivity between the hippocampus and prefrontal cortex prospectively predicted significant improvements in anxiety 2 years following scanning for previously institutionalized youth. Among youth who experienced prior institutionalization, age-atypical engagement of a distributed set of brain regions during aversive learning may serve a protective function. Copyright © 2016 the authors 0270-6474/16/366421-11$15.00/0.

Cell Type-Specific Expression of Corticotropin-Releasing Hormone-Binding Protein in GABAergic Interneurons in the Prefrontal Cortex

PubMed Central

Ketchesin, Kyle D.; Huang, Nicholas S.; Seasholtz, Audrey F.

2017-01-01

Corticotropin-releasing hormone-binding protein (CRH-BP) is a secreted glycoprotein that binds CRH with very high affinity to modulate CRH receptor activity. CRH-BP is widely expressed throughout the brain, with particularly high expression in regions such as the amygdala, hippocampus, ventral tegmental area and prefrontal cortex (PFC). Recent studies suggest a role for CRH-BP in stress-related psychiatric disorders and addiction, with the PFC being a potential site of interest. However, the molecular phenotype of CRH-BP-expressing cells in this region has not been well-characterized. In the current study, we sought to determine the cell type-specific expression of CRH-BP in the PFC to begin to define the neural circuits in which this key regulator is acting. To characterize the expression of CRH-BP in excitatory and/or inhibitory neurons, we utilized dual in situ hybridization to examine the cellular colocalization of CRH-BP mRNA with vesicular glutamate transporter (VGLUT) or glutamic acid decarboxylase (GAD) mRNA in different subregions of the PFC. We show that CRH-BP is expressed predominantly in GABAergic interneurons of the PFC, as revealed by the high degree of colocalization (>85%) between CRH-BP and GAD. To further characterize the expression of CRH-BP in this heterogenous group of inhibitory neurons, we examined the colocalization of CRH-BP with various molecular markers of GABAergic interneurons, including parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP) and cholecystokinin (CCK). We demonstrate that CRH-BP is colocalized predominantly with SST in the PFC, with lower levels of colocalization in PV- and CCK-expressing neurons. Our results provide a more comprehensive characterization of the cell type-specific expression of CRH-BP and begin to define its potential role within circuits of the PFC. These results will serve as the basis for future in vivo studies to manipulate CRH-BP in a cell type-specific manner to better understand its role in stress-related psychiatric disorders, including anxiety, depression and addiction. PMID:29066956

Multiple mechanisms of consciousness: the neural correlates of emotional awareness.

PubMed

Amting, Jayna M; Greening, Steven G; Mitchell, Derek G V

2010-07-28

Emotional stimuli, including facial expressions, are thought to gain rapid and privileged access to processing resources in the brain. Despite this access, we are conscious of only a fraction of the myriad of emotion-related cues we face everyday. It remains unclear, therefore, what the relationship is between activity in neural regions associated with emotional representation and the phenomenological experience of emotional awareness. We used functional magnetic resonance imaging and binocular rivalry to delineate the neural correlates of awareness of conflicting emotional expressions in humans. Behaviorally, fearful faces were significantly more likely to be perceived than disgusted or neutral faces. Functionally, increased activity was observed in regions associated with facial expression processing, including the amygdala and fusiform gyrus during emotional awareness. In contrast, awareness of neutral faces and suppression of fearful faces were associated with increased activity in dorsolateral prefrontal and inferior parietal cortices. The amygdala showed increased functional connectivity with ventral visual system regions during fear awareness and increased connectivity with perigenual prefrontal cortex (pgPFC; Brodmann's area 32/10) when fear was suppressed. Despite being prioritized for awareness, emotional items were associated with reduced activity in areas considered critical for consciousness. Contributions to consciousness from bottom-up and top-down neural regions may be additive, such that increased activity in specialized regions within the extended ventral visual system may reduce demands on a frontoparietal system important for awareness. The possibility is raised that interactions between pgPFC and the amygdala, previously implicated in extinction, may also influence whether or not an emotional stimulus is accessible to consciousness.

Neural substrates of context- and person-dependent altruistic punishment.

PubMed

Wang, Lili; Lu, Xiaping; Gu, Ruolei; Zhu, Ruida; Xu, Rui; Broster, Lucas S; Feng, Chunliang

2017-11-01

Human altruistic behaviors are heterogeneous across both contexts and people, whereas the neural signatures underlying the heterogeneity remain to be elucidated. To address this issue, we examined the neural signatures underlying the context- and person-dependent altruistic punishment, conjoining event-related fMRI with both task-based and resting-state functional connectivity (RSFC). Acting as an impartial third party, participants decided how to punish norm violators either alone or in the presence of putative others. We found that the presence of others decreased altruistic punishment due to diffusion of responsibility. Those behavioral effects paralleled altered neural responses in the dorsal anterior cingulate cortex (dACC) and putamen. Further, we identified modulation of responsibility diffusion on task-based functional connectivity of dACC with the brain regions implicated in reward processing (i.e., posterior cingulate cortex and amygdala/orbital frontal cortex). Finally, the RSFC results revealed that (i) increased intrinsic connectivity strengths of the putamen with temporoparietal junction and dorsolateral PFC were associated with attenuated responsibility diffusion in altruistic punishment and (ii) increased putamen-dorsomedial PFC connectivity strengths were associated with reduced responsibility diffusion in self-reported responsibility. Taken together, our findings elucidate the context- and person-dependent altruistic behaviors as well as associated neural substrates and thus provide a potential neurocognitive mechanism of heterogeneous human altruistic behaviors. Hum Brain Mapp 38:5535-5550, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Interactive effects of genetic polymorphisms and childhood adversity on brain morphologic changes in depression.

PubMed

Kim, Yong-Ku; Ham, Byung-Joo; Han, Kyu-Man

2018-03-10

The etiology of depression is characterized by the interplay of genetic and environmental factors and brain structural alteration. Childhood adversity is a major contributing factor in the development of depression. Interactions between childhood adversity and candidate genes for depression could affect brain morphology via the modulation of neurotrophic factors, serotonergic neurotransmission, or the hypothalamus-pituitary-adrenal (HPA) axis, and this pathway may explain the subsequent onset of depression. Childhood adversity is associated with structural changes in the hippocampus, amygdala, anterior cingulate cortex (ACC), and prefrontal cortex (PFC), as well as white matter tracts such as the corpus callosum, cingulum, and uncinate fasciculus. Childhood adversity showed an interaction with the brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism, serotonin transporter-linked promoter region (5-HTTLPR), and FK506 binding protein 51 (FKBP5) gene rs1360780 in brain morphologic changes in patients with depression and in a non-clinical population. Individuals with the Met allele of BDNF Val66Met and a history of childhood adversity had reduced volume in the hippocampus and its subfields, amygdala, and PFC and thinner rostral ACC in a study of depressed patients and healthy controls. The S allele of 5-HTTLPR combined with exposure to childhood adversity or a poorer parenting environment was associated with a smaller hippocampal volume and subsequent onset of depression. The FKBP5 gene rs160780 had a significant interaction with childhood adversity in the white matter integrity of brain regions involved in emotion processing. This review identified that imaging genetic studies on childhood adversity may deepen our understanding on the neurobiological background of depression by scrutinizing complicated pathways of genetic factors, early psychosocial environments, and the accompanying morphologic changes in emotion-processing neural circuitry. Copyright © 2018 Elsevier Inc. All rights reserved.

TRANSDIAGNOSTIC DIMENSIONS OF ANXIETY AND DEPRESSION MODERATE MOTIVATION-RELATED BRAIN NETWORKS DURING GOAL MAINTENANCE

PubMed Central

Spielberg, Jeffrey M.; Miller, Gregory A.; Warren, Stacie L.; Sutton, Bradley P.; Banich, Marie; Heller, Wendy

2015-01-01

Background Advancing research on the etiology, prevention, and treatment of psychopathology requires the field to move beyond modular conceptualizations of neural dysfunction toward understanding disturbance in key brain networks. Although some studies of anxiety and depression have begun doing so, they typically suffer from several drawbacks, including: (1) a categorical approach ignoring transdiagnostic processes, (2) failure to account for substantial anxiety and depression comorbidity, (3) examination of networks at rest, which overlooks disruption manifesting only when networks are challenged. Accordingly, the present study examined relationships between transdiagnostic dimensions of anxiety/depression and patterns of functional connectivity while goal maintenance was challenged. Methods Participants (n = 179, unselected community members and undergraduates selected to be high/low on anxiety/depression) performed a task in which goal maintenance was challenged (color-word Stroop) while fMRI data were collected. Analyses examined moderation by anxiety/depression of condition-dependent coupling between regions of dorsolateral prefrontal cortex (dlPFC) previously associated with approach and avoidance motivation and amygdala/orbitofrontal cortex (OFC). Results Anxious arousal was positively associated with amygdala↔right dlPFC coupling. Depression was positively associated with OFC↔right dlPFC coupling and negatively associated with OFC↔left dlPFC coupling. Conclusions Findings advance the field toward an integrative model of the neural instantiation of anxiety/depression by identifying specific, distinct dysfunctions associated with anxiety and depression in networks important for maintaining approach and avoidance goals. Specifically, findings shed light on potential neural mechanisms involved in attentional biases in anxiety and valuation biases in depression and underscore the importance of examining transdiagnostic dimensions of anxiety/depression while networks are challenged. PMID:24753242

Neural substrates of approach-avoidance conflict decision-making.

PubMed

Aupperle, Robin L; Melrose, Andrew J; Francisco, Alex; Paulus, Martin P; Stein, Murray B

2015-02-01

Animal approach-avoidance conflict paradigms have been used extensively to operationalize anxiety, quantify the effects of anxiolytic agents, and probe the neural basis of fear and anxiety. Results from human neuroimaging studies support that a frontal-striatal-amygdala neural circuitry is important for approach-avoidance learning. However, the neural basis of decision-making is much less clear in this context. Thus, we combined a recently developed human approach-avoidance paradigm with functional magnetic resonance imaging (fMRI) to identify neural substrates underlying approach-avoidance conflict decision-making. Fifteen healthy adults completed the approach-avoidance conflict (AAC) paradigm during fMRI. Analyses of variance were used to compare conflict to nonconflict (avoid-threat and approach-reward) conditions and to compare level of reward points offered during the decision phase. Trial-by-trial amplitude modulation analyses were used to delineate brain areas underlying decision-making in the context of approach/avoidance behavior. Conflict trials as compared to the nonconflict trials elicited greater activation within bilateral anterior cingulate cortex, anterior insula, and caudate, as well as right dorsolateral prefrontal cortex (PFC). Right caudate and lateral PFC activation was modulated by level of reward offered. Individuals who showed greater caudate activation exhibited less approach behavior. On a trial-by-trial basis, greater right lateral PFC activation related to less approach behavior. Taken together, results suggest that the degree of activation within prefrontal-striatal-insula circuitry determines the degree of approach versus avoidance decision-making. Moreover, the degree of caudate and lateral PFC activation related to individual differences in approach-avoidance decision-making. Therefore, the approach-avoidance conflict paradigm is ideally suited to probe anxiety-related processing differences during approach-avoidance decision-making. © 2014 Wiley Periodicals, Inc.

Transdiagnostic dimensions of anxiety and depression moderate motivation-related brain networks during goal maintenance.

PubMed

Spielberg, Jeffrey M; Miller, Gregory A; Warren, Stacie L; Sutton, Bradley P; Banich, Marie; Heller, Wendy

2014-10-01

Advancing research on the etiology, prevention, and treatment of psychopathology requires the field to move beyond modular conceptualizations of neural dysfunction toward understanding disturbance in key brain networks. Although some studies of anxiety and depression have begun doing so, they typically suffer from several drawbacks, including: (1) a categorical approach ignoring transdiagnostic processes, (2) failure to account for substantial anxiety and depression comorbidity, (3) examination of networks at rest, which overlooks disruption manifesting only when networks are challenged. Accordingly, the present study examined relationships between transdiagnostic dimensions of anxiety/depression and patterns of functional connectivity while goal maintenance was challenged. Participants (n = 179, unselected community members and undergraduates selected to be high/low on anxiety/depression) performed a task in which goal maintenance was challenged (color-word Stroop) while fMRI data were collected. Analyses examined moderation by anxiety/depression of condition-dependent coupling between regions of dorsolateral prefrontal cortex (dlPFC) previously associated with approach and avoidance motivation and amygdala/orbitofrontal cortex (OFC). Anxious arousal was positively associated with amygdala↔right dlPFC coupling. Depression was positively associated with OFC↔right dlPFC coupling and negatively associated with OFC↔left dlPFC coupling. Findings advance the field toward an integrative model of the neural instantiation of anxiety/depression by identifying specific, distinct dysfunctions associated with anxiety and depression in networks important for maintaining approach and avoidance goals. Specifically, findings shed light on potential neural mechanisms involved in attentional biases in anxiety and valuation biases in depression and underscore the importance of examining transdiagnostic dimensions of anxiety/depression while networks are challenged. © 2014 Wiley Periodicals, Inc.

An Integrative Neuroscience Framework for the Treatment of Chronic Pain: From Cellular Alterations to Behavior.

PubMed

Greenwald, Jess D; Shafritz, Keith M

2018-01-01

Chronic pain can result from many pain syndromes including complex regional pain syndrome (CRPS), phantom limb pain and chronic low back pain, among others. On a molecular level, chronic pain syndromes arise from hypersensitization within the dorsal horn of the spinal cord, a process known as central sensitization. Central sensitization involves an upregulation of ionotropic and metabotropic glutamate receptors (mGluRs) similar to that of long-term potentiation (LTP). Regions of the brain in which LTP occurs, such as the amygdala and hippocampus, are implicated in fear- and memory-related brain circuity. Chronic pain dramatically influences patient quality of life. Individuals with chronic pain may develop pain-related anxiety and pain-related fear. The syndrome also alters functional connectivity in the default-mode network (DMN) and salience network. On a cellular/molecular level, central sensitization may be reversed through degradative glutamate receptor pathways. This, however, rarely happens. Instead, cortical brain regions may serve in a top-down regulatory capacity for the maintenance or alleviation of pain. Specifically, the medial prefrontal cortex (mPFC), which plays a critical role in fear-related brain circuits, the DMN, and salience network may be the driving forces in this process. On a cellular level, the mPFC may form new neural circuits through LTP that may cause extinction of pre-existing pain pathways found within fear-related brain circuits, the DMN, and salience network. In order to promote new LTP connections between the mPFC and other key brain structures, such as the amygdala and insula, we propose a holistic rehabilitation program including cognitive behavioral therapy (CBT) and revolving around: (1) cognitive reappraisals; (2) mindfulness meditation; and (3) functional rehabilitation. Unlike current medical interventions focusing upon pain-relieving medications, we do not believe that chronic pain treatment should focus on reversing the effects of central sensitization. Instead, we propose here that it is critical to focus on non-invasive efforts to promote new neural circuits originating from the mPFC.

Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit.

PubMed

Ganon-Elazar, Eti; Akirav, Irit

2013-09-01

Considerable evidence suggests that cannabinoids modulate the behavioral and physiological response to stressful events. We have recently shown that activating the cannabinoid system using the CB1/CB2 receptor agonist WIN55,212-2 (WIN) in proximity to exposure to single-prolonged stress (SPS), a rat model of emotional trauma, prevented the stress-induced enhancement of acoustic startle response, the impairment in avoidance extinction and the enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis (Ganon-Elazar and Akirav, 2012). Some of the effects were found to be mediated by CB1 receptors in the basolateral amygdala (BLA). Here we examined whether cannabinoid receptor activation in a putative brain circuit that includes the BLA, hippocampus and prefrontal cortex (PFC), could prevent the effects of traumatic stress on contextual fear extinction and alterations in glucocorticoid receptor (GR) protein levels. We found that: (i) SPS impaired contextual fear extinction tested one week after trauma exposure and that WIN prevented the stress-induced impairment of extinction when microinjected immediately after trauma exposure into the BLA or hippocampus (5 μg), but not when microinjected into the PFC, (ii) the ameliorating effects of WIN on contextual extinction were prevented by blocking GRs in the BLA and hippocampus, and (iii) SPS up regulated GRs in the BLA, PFC and hippocampus and systemic WIN administration (0.5 mg/kg) after trauma exposure normalized GR levels in the BLA and hippocampus, but not in the PFC. Cannabinoid receptor activation in the aftermath of trauma exposure may regulate the emotional response to the trauma and prevent stress-induced impairment of extinction and GR up regulation through the mediation of CB1 receptors in the BLA and hippocampus. Taken together, the findings suggest that the interaction between the cannabinoid and glucocorticoid systems is crucial in the modulation of emotional trauma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder.

PubMed

Månsson, Kristoffer N T; Carlbring, Per; Frick, Andreas; Engman, Jonas; Olsson, Carl-Johan; Bodlund, Owe; Furmark, Tomas; Andersson, Gerhard

2013-12-30

Randomized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear.

PubMed

Marek, Roger; Jin, Jingji; Goode, Travis D; Giustino, Thomas F; Wang, Qian; Acca, Gillian M; Holehonnur, Roopashri; Ploski, Jonathan E; Fitzgerald, Paul J; Lynagh, Timothy; Lynch, Joseph W; Maren, Stephen; Sah, Pankaj

2018-03-01

The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin-expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.

Hyper-modulation of brain networks by the amygdala among women with Borderline Personality Disorder: Network signatures of affective interference during cognitive processing.

PubMed

Soloff, Paul H; Abraham, Kristy; Ramaseshan, Karthik; Burgess, Ashley; Diwadkar, Vaibhav A

2017-05-01

Emotion dysregulation is a core characteristic of patients with Borderline Personality Disorder (BPD), and is often attributed to an imbalance in fronto-limbic network function. Hyperarousal of amygdala, especially in response to negative affective stimuli, results in affective interference with cognitive processing of executive functions. Clinical consequences include the impulsive-aggression, suicidal and self-injurious behaviors which characterize BPD. Dysfunctional interactions between amygdala and its network targets have not been well characterized during cognitive task performance. Using psychophysiological interaction analysis (PPI), we mapped network profiles of amygdala interaction with key regulatory regions during a Go No-Go task, modified to use negative, positive and neutral Ekman faces as targets. Fifty-six female subjects, 31 BPD and 25 healthy controls (HC), completed the affectively valenced Go No-Go task during fMRI scanning. In the negative affective condition, the amygdala exerted greater modulation of its targets in BPD compared to HC subjects in Rt. OFC, Rt. dACC, Rt. Parietal cortex, Rt. Basal Ganglia, and Rt. dlPFC. Across the spectrum of affective contrasts, hypermodulation in BPD subjects observed the following ordering: Negative > Neutral > Positive contrast. The amygdala seed exerted modulatory effects on specific target regions important in processing response inhibition and motor impulsiveness. The vulnerability of BPD subjects to affective interference with impulse control may be due to specific network dysfunction related to amygdala hyper-arousal and its effects on prefrontal regulatory regions such as the OFC and dACC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Time Determines the Neural Circuit Underlying Associative Fear Learning

PubMed Central

Guimarãis, Marta; Gregório, Ana; Cruz, Andreia; Guyon, Nicolas; Moita, Marta A.

2011-01-01

Ultimately associative learning is a function of the temporal features and relationships between experienced stimuli. Nevertheless how time affects the neural circuit underlying this form of learning remains largely unknown. To address this issue, we used single-trial auditory trace fear conditioning and varied the length of the interval between tone and foot-shock. Through temporary inactivation of the amygdala, medial prefrontal-cortex (mPFC), and dorsal-hippocampus in rats, we tested the hypothesis that different temporal intervals between the tone and the shock influence the neuronal structures necessary for learning. With this study we provide the first experimental evidence showing that temporarily inactivating the amygdala before training impairs auditory fear learning when there is a temporal gap between the tone and the shock. Moreover, imposing a short interval (5 s) between the two stimuli also relies on the mPFC, while learning the association across a longer interval (40 s) becomes additionally dependent on a third structure, the dorsal-hippocampus. Thus, our results suggest that increasing the interval length between tone and shock leads to the involvement of an increasing number of brain areas in order for the association between the two stimuli to be acquired normally. These findings demonstrate that the temporal relationship between events is a key factor in determining the neuronal mechanisms underlying associative fear learning. PMID:22207842

Evidence for the triadic model of adolescent brain development: Cognitive load and task-relevance of emotion differentially affect adolescents and adults.

PubMed

Mueller, Sven C; Cromheeke, Sofie; Siugzdaite, Roma; Nicolas Boehler, C

2017-08-01

In adults, cognitive control is supported by several brain regions including the limbic system and the dorsolateral prefrontal cortex (dlPFC) when processing emotional information. However, in adolescents, some theories hypothesize a neurobiological imbalance proposing heightened sensitivity to affective material in the amygdala and striatum within a cognitive control context. Yet, direct neurobiological evidence is scarce. Twenty-four adolescents (12-16) and 28 adults (25-35) completed an emotional n-back working memory task in response to happy, angry, and neutral faces during fMRI. Importantly, participants either paid attention to the emotion (task-relevant condition) or judged the gender (task-irrelevant condition). Behaviorally, for both groups, when happy faces were task-relevant, performance improved relative to when they were task-irrelevant, while performance decrements were seen for angry faces. In the dlPFC, angry faces elicited more activation in adults during low relative to high cognitive load (2-back vs. 0-back). By contrast, happy faces elicited more activation in the amygdala in adolescents when they were task-relevant. Happy faces also generally increased nucleus accumbens activity (regardless of relevance) in adolescents relative to adults. Together, the findings are consistent with neurobiological models of adolescent brain development and identify neurodevelopmental differences in cognitive control emotion interactions. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effects of Optogenetic inhibition of BLA on Sleep Brief Optogenetic Inhibition of the Basolateral Amygdala in Mice Alters Effects of Stressful Experiences on Rapid Eye Movement Sleep.

PubMed

Machida, Mayumi; Wellman, Laurie L; Fitzpatrick Bs, Mairen E; Hallum Bs, Olga; Sutton Bs, Amy M; Lonart, György; Sanford, Larry D

2017-04-01

Stressful events can directly produce significant alterations in subsequent sleep, in particular rapid eye movement sleep (REM); however, the neural mechanisms underlying the process are not fully known. Here, we investigated the role of the basolateral nuclei of the amygdala (BLA) in regulating the effects of stressful experience on sleep. We used optogenetics to briefly inhibit glutamatergic cells in BLA during the presentation of inescapable footshock (IS) and assessed effects on sleep, the acute stress response, and fear memory. c-Fos expression was also assessed in the amygdala and the medial prefrontal cortex (mPFC), both regions involved in coping with stress, and in brain stem regions implicated in the regulation of REM. Compared to control mice, peri-shock inhibition of BLA attenuated an immediate reduction in REM after IS and produced a significant overall increase in REM. Moreover, upon exposure to the shock context alone, mice receiving peri-shock inhibition of BLA during training showed increased REM without altered freezing (an index of fear memory) or stress-induced hyperthermia (an index of acute stress response). Inhibition of BLA during REM under freely sleeping conditions enhanced REM only when body temperature was high, suggesting the effect was influenced by stress. Peri-shock inhibition of BLA also led to elevated c-Fos expression in the central nucleus of the amygdala and mPFC and differentially altered c-Fos activity in the selected brain stem regions. Glutamatergic cells in BLA can modulate the effects of stress on REM and can mediate effects of fear memory on sleep that can be independent of behavioral fear. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

PubMed Central

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-01-01

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory. PMID:27922638

Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle.

PubMed

Dandekar, Manoj P; Luse, Dustin; Hoffmann, Carson; Cotton, Patrick; Peery, Travis; Ruiz, Christian; Hussey, Caroline; Giridharan, Vijayasree V; Soares, Jair C; Quevedo, Joao; Fenoy, Albert J

2017-08-01

Among several potential neuroanatomical targets pursued for deep brain stimulation (DBS) for treating those with treatment-resistant depression (TRD), the superolateral-branch of the medial forebrain bundle (MFB) is emerging as a privileged location. We investigated the antidepressant-like phenotypic and chemical changes associated with reward-processing dopaminergic systems in rat brains after MFB-DBS. Male Wistar rats were divided into three groups: sham-operated, DBS-Off, and DBS-On. For DBS, a concentric bipolar electrode was stereotactically implanted into the right MFB. Exploratory activity and depression-like behavior were evaluated using the open-field and forced-swimming test (FST), respectively. MFB-DBS effects on the dopaminergic system were evaluated using immunoblotting for tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine receptors (D1-D5), and high-performance liquid chromatography for quantifying dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in brain homogenates of prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc). Animals receiving MFB-DBS showed a significant increase in swimming time without alterations in locomotor activity, relative to the DBS-Off (p<0.039) and sham-operated groups (p<0.014), indicating an antidepressant-like response. MFB-DBS led to a striking increase in protein levels of dopamine D2 receptors and DAT in the PFC and hippocampus, respectively. However, we did not observe appreciable differences in the expression of other dopamine receptors, TH, or in the concentrations of dopamine, DOPAC, and HVA in PFC, hippocampus, amygdala, and NAc. This study was not performed on an animal model of TRD. MFB-DBS rescues the depression-like phenotypes and selectively activates expression of dopamine receptors in brain regions distant from the target area of stimulation. Copyright © 2017. Published by Elsevier B.V.

A critical role for prefrontocortical endocannabinoid signaling in the regulation of stress and emotional behavior.

PubMed

McLaughlin, Ryan J; Hill, Matthew N; Gorzalka, Boris B

2014-05-01

The prefrontal cortex (PFC) provides executive control of the brain in humans and rodents, coordinating cognitive, emotional, and behavioral responses to threatening stimuli and subsequent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. The endocannabinoid system has emerged as a fundamental regulator of HPA axis feedback inhibition and an important modulator of emotional behavior. However, the precise role of endocannabinoid signaling within the PFC with respect to stress coping and emotionality has only recently been investigated. This review discusses the current state of knowledge regarding the localization and function of the endocannabinoid system in the PFC, its sensitivity to stress and its role in modulating the neuroendocrine and behavioral responses to aversive stimuli. We propose a model whereby steady-state endocannabinoid signaling in the medial PFC indirectly regulates the outflow of pyramidal neurons by fine-tuning GABAergic inhibition. Local activation of this population of CB1 receptors increases the downstream targets of medial PFC activation, which include inhibitory interneurons in the basolateral amygdala, inhibitory relay neurons in the bed nucleus of the stria terminalis and monoamine cell bodies such as the dorsal raphe nucleus. This ultimately produces beneficial effects on emotionality (active coping responses to stress and reduced anxiety) and assists in constraining activation of the HPA axis. Under conditions of chronic stress, or in individuals suffering from mood disorders, this system may be uniquely recruited to help maintain appropriate function in the face of adversity, while breakdown of the endocannabinoid system in the medial PFC may be, in and of itself, sufficient to produce neuropsychiatric illness. Thus, we suggest that endocannabinoid signaling in the medial PFC may represent an attractive target for the treatment of stress-related disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lateral Orbitofrontal Cortical Modulation on the Medial Prefrontal Cortex-Amygdala Pathway: Differential Regulation of Intra-Amygdala GABAA and GABAB Receptors.

PubMed

Chang, Chun-Hui

2017-07-01

The basolateral complex of the amygdala receives inputs from neocortical areas, including the medial prefrontal cortex and lateral orbitofrontal cortex. Earlier studies have shown that lateral orbitofrontal cortex activation exerts an inhibitory gating on medial prefrontal cortex-amygdala information flow. Here we examined the individual role of GABAA and GABAB receptors in this process. In vivo extracellular single-unit recordings were done in anesthetized rats. We searched amygdala neurons that fire in response to medial prefrontal cortex activation, tested lateral orbitofrontal cortex gating at different delays (lateral orbitofrontal cortex-medial prefrontal cortex delays: 25, 50, 100, 250, 500, and 1000 milliseconds), and examined differential contribution of GABAA and GABAB receptors with iontophoresis. Relative to baseline, lateral orbitofrontal cortex stimulation exerted an inhibitory modulatory gating on the medial prefrontal cortex-amygdala pathway and was effective up to a long delay of 500 ms (long-delay latencies at 100, 250, and 500 milliseconds). Moreover, blockade of intra-amygdala GABAA receptors with bicuculline abolished the lateral orbitofrontal cortex inhibitory gating at both short- (25 milliseconds) and long-delay (100 milliseconds) intervals, while blockade of GABAB receptors with saclofen reversed the inhibitory gating at long delay (100 milliseconds) only. Among the majority of the neurons examined (8 of 9), inactivation of either GABAA or GABAB receptors during baseline did not change evoked probability per se, suggesting that local feed-forward inhibitory mechanism is pathway specific. Our results suggest that the effect of lateral orbitofrontal cortex inhibitory modulatory gating was effective up to 500 milliseconds and that intra-amygdala GABAA and GABAB receptors differentially modulate the short- and long-delay lateral orbitofrontal cortex inhibitory gating on the medial prefrontal cortex-amygdala pathway. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Towards a mechanistic understanding of pathological anxiety: the dorsal medial prefrontal-amygdala ‘aversive amplification’ circuit in unmedicated generalized and social anxiety disorders

PubMed Central

Robinson, Oliver J; Krimsky, Marissa; Lieberman, Lynne; Allen, Phillip; Vytal, Katherine; Grillon, Christian

2014-01-01

Background We have delineated, across four prior studies, the role of positive dorsal medial prefrontal/anterior cingulate cortex (dmPFC/ACC)-amygdala circuit coupling during aversive processing in healthy individuals under stress. This translational circuit, termed the ‘aversive amplification circuit’, is thought to drive adaptive, harm-avoidant behavior in threatening environments. Here, in a natural progression of this prior work, we confirm that this circuit also plays a role in the pathological manifestation of anxiety disorders. Methods Forty-five unmedicated participants (N=22 generalized and social anxiety disorder/N=23 controls) recruited from Washington DC metropolitan area completed a simple emotion identification task during functional magnetic resonance imaging at the National Institutes of Health, Bethesda, MD, USA. Findings As predicted, a diagnosis by valence interaction was seen in whole-brain amygdala connectivity within the dmPFC/ACC clusters identified in our prior study; driven by significantly greater circuit coupling during fearful versus happy face processing in anxious, but not healthy, participants. Critically, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, providing evidence of a continuous circuit-subjective symptomatology relationship. Interpretation We track the functional role of a single neural circuit from its involvement in adaptive threat-biases under stress, to its chronic engagement in anxiety disorders in the absence of experimentally induced stress. Thus, we uniquely map a mood and anxiety related circuit across its adaptive and maladaptive stages. Clinically, this may provide a step towards a more mechanistic spectrum-based approach to anxiety disorder diagnosis and may ultimately lead to more targeted treatments. PMID:25722962

Towards a mechanistic understanding of pathological anxiety: the dorsal medial prefrontal-amygdala 'aversive amplification' circuit in unmedicated generalized and social anxiety disorders.

PubMed

Robinson, Oliver J; Krimsky, Marissa; Lieberman, Lynne; Allen, Phillip; Vytal, Katherine; Grillon, Christian

2014-09-01

We have delineated, across four prior studies, the role of positive dorsal medial prefrontal/anterior cingulate cortex (dmPFC/ACC)-amygdala circuit coupling during aversive processing in healthy individuals under stress. This translational circuit, termed the 'aversive amplification circuit', is thought to drive adaptive, harm-avoidant behavior in threatening environments. Here, in a natural progression of this prior work, we confirm that this circuit also plays a role in the pathological manifestation of anxiety disorders. Forty-five unmedicated participants (N=22 generalized and social anxiety disorder/N=23 controls) recruited from Washington DC metropolitan area completed a simple emotion identification task during functional magnetic resonance imaging at the National Institutes of Health, Bethesda, MD, USA. As predicted, a diagnosis by valence interaction was seen in whole-brain amygdala connectivity within the dmPFC/ACC clusters identified in our prior study; driven by significantly greater circuit coupling during fearful versus happy face processing in anxious, but not healthy, participants. Critically, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, providing evidence of a continuous circuit-subjective symptomatology relationship. We track the functional role of a single neural circuit from its involvement in adaptive threat-biases under stress, to its chronic engagement in anxiety disorders in the absence of experimentally induced stress. Thus, we uniquely map a mood and anxiety related circuit across its adaptive and maladaptive stages. Clinically, this may provide a step towards a more mechanistic spectrum-based approach to anxiety disorder diagnosis and may ultimately lead to more targeted treatments.

Extinction of Contextual Fear with Timed Exposure to Enriched Environment: A Differential Effect

PubMed Central

Hegde, Preethi; O'Mara, Shane; Laxmi, Thenkanidiyoor Rao

2017-01-01

Background Extinction of fear memory depends on the environmental and emotional cues. Furthermore, consolidation of extinction is also dependent on the environmental exposure. But, the relationship of the time of the exposure to a variety of environmental cues is not well known. The important region involved in facilitation of extinction of fear memory is through diversion of the flow of information leaving the lateral nucleus of amygdala. Purpose The study aimed to address a question to explain how these brain regions react to environmental stimulation during the retention and extinction of fear memory. Methods An enriched environment (EE) is assumed to mediate extinction of fear memory, we examined the apparent discrepancy between the effects of defensive response, the freezing behavior induced by Pavlovian classical fear conditioning by subjecting them to variance in the timing to EE. The different timing of EE exposure was 10 days of EE either before fear conditioning and/or after extinction training to the rats. The local field potentials was recorded from CA1 hippocampus, lateral nucleus of amygdala and infralimbic region of medial prefrontal cortex (mPFC) during the fear learning and extinction from the control rats and rats exposed to EE before and after fear conditioning. Results Exposure to EE before the fear conditioning and after extinction training was more effective in the extinction fear memory. In addition, we also found switching from exploratory locomotion to freezing during retention of contextual fear memory which was associated with decreased theta power and reduced synchronized theta oscillations in CA1-hippocampus, lateral nucleus of amygdala, and infralimbic region of mPFC. Conclusion Thus, we propose that the timing of exposure to EE play a key role in the extinction of fear memory. PMID:28588364

Repeated social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus.

PubMed

Patel, D; Anilkumar, S; Chattarji, S; Buwalda, B

2018-03-23

Previous studies have demonstrated that repeated immobilization and restraint stress cause contrasting patterns of dendritic reorganization as well as alterations in spine density in amygdalar and hippocampal neurons. Whether social and ethologically relevant stressors can induce similar patterns of morphological plasticity remains largely unexplored. Hence, we assessed the effects of repeated social defeat stress on neuronal morphology in basolateral amygdala (BLA), hippocampal CA1 and infralimbic medial prefrontal cortex (mPFC). Male Wistar rats experienced social defeat stress on 5 consecutive days during confrontation in the resident-intruder paradigm with larger and aggressive Wild-type Groningen rats. This resulted in clear social avoidance behavior one day after the last confrontation. To assess the morphological consequences of repeated social defeat, 2 weeks after the last defeat, animals were sacrificed and brains were stained using a Golgi-Cox procedure. Morphometric analyses revealed that, compared to controls, defeated Wistar rats showed apical dendritic decrease in spine density on CA1 but not BLA. Sholl analysis demonstrated a significant dendritic atrophy of CA1 basal dendrites in defeated animals. In contrast, basal dendrites of BLA pyramidal neurons exhibited enhanced dendritic arborization in defeated animals. Social stress failed to induce lasting structural changes in mPFC neurons. Our findings demonstrate for the first time that social defeat stress elicits divergent patterns of structural plasticity in the hippocampus versus amygdala, similar to what has previously been reported with repeated physical stressors. Therefore, brain region specific variations may be a universal feature of stress-induced plasticity that is shared by both physical and social stressors. Copyright © 2018 Elsevier B.V. All rights reserved.

Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making

PubMed Central

Bechara, A.; Damasio, H.; Aitken, M. R. F.; Sahakian, B. J.; Robbins, T. W.

2008-01-01

The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear whether vmPFC is also necessary for decision-making under risk, when outcome probabilities are explicit. It is not known whether the effect of insular damage is analogous to the effect of vmPFC damage, or whether these regions contribute differentially to choice behaviour. Four groups of participants were compared on the Cambridge Gamble Task, a well-characterized measure of risky decision-making where outcome probabilities are presented explicitly, thus minimizing additional learning and working memory demands. Patients with focal, stable lesions to the vmPFC (n = 20) and the insular cortex (n = 13) were compared against healthy subjects (n = 41) and a group of lesion controls (n = 12) with damage predominantly affecting the dorsal and lateral frontal cortex. The vmPFC and insular cortex patients showed selective and distinctive disruptions of betting behaviour. VmPFC damage was associated with increased betting regardless of the odds of winning, consistent with a role of vmPFC in biasing healthy individuals towards conservative options under risk. In contrast, patients with insular cortex lesions failed to adjust their bets by the odds of winning, consistent with a role of the insular cortex in signalling the probability of aversive outcomes. The insular group attained a lower point score on the task and experienced more ‘bankruptcies’. There were no group differences in probability judgement. These data confirm the necessary role of the vmPFC and insular regions in decision-making under risk. Poor decision-making in clinical populations can arise via multiple routes, with functionally dissociable effects of vmPFC and insular cortex damage. PMID:18390562

Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making.

PubMed

Clark, L; Bechara, A; Damasio, H; Aitken, M R F; Sahakian, B J; Robbins, T W

2008-05-01

The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear whether vmPFC is also necessary for decision-making under risk, when outcome probabilities are explicit. It is not known whether the effect of insular damage is analogous to the effect of vmPFC damage, or whether these regions contribute differentially to choice behaviour. Four groups of participants were compared on the Cambridge Gamble Task, a well-characterized measure of risky decision-making where outcome probabilities are presented explicitly, thus minimizing additional learning and working memory demands. Patients with focal, stable lesions to the vmPFC (n = 20) and the insular cortex (n = 13) were compared against healthy subjects (n = 41) and a group of lesion controls (n = 12) with damage predominantly affecting the dorsal and lateral frontal cortex. The vmPFC and insular cortex patients showed selective and distinctive disruptions of betting behaviour. VmPFC damage was associated with increased betting regardless of the odds of winning, consistent with a role of vmPFC in biasing healthy individuals towards conservative options under risk. In contrast, patients with insular cortex lesions failed to adjust their bets by the odds of winning, consistent with a role of the insular cortex in signalling the probability of aversive outcomes. The insular group attained a lower point score on the task and experienced more 'bankruptcies'. There were no group differences in probability judgement. These data confirm the necessary role of the vmPFC and insular regions in decision-making under risk. Poor decision-making in clinical populations can arise via multiple routes, with functionally dissociable effects of vmPFC and insular cortex damage.

Differential neural circuitry and self-interest in real vs hypothetical moral decisions

PubMed Central

Dalgleish, Tim; Thompson, Russell; Evans, Davy; Schweizer, Susanne; Mobbs, Dean

2012-01-01

Classic social psychology studies demonstrate that people can behave in ways that contradict their intentions—especially within the moral domain. We measured brain activity while subjects decided between financial self-benefit (earning money) and preventing physical harm (applying an electric shock) to a confederate under both real and hypothetical conditions. We found a shared neural network associated with empathic concern for both types of decisions. However, hypothetical and real moral decisions also recruited distinct neural circuitry: hypothetical moral decisions mapped closely onto the imagination network, while real moral decisions elicited activity in the bilateral amygdala and anterior cingulate—areas essential for social and affective processes. Moreover, during real moral decision-making, distinct regions of the prefrontal cortex (PFC) determined whether subjects make selfish or pro-social moral choices. Together, these results reveal not only differential neural mechanisms for real and hypothetical moral decisions but also that the nature of real moral decisions can be predicted by dissociable networks within the PFC. PMID:22711879

Neural Basis of Emotional Decision Making in Trait Anxiety

PubMed Central

Xu, Pengfei; Gu, Ruolei; Broster, Lucas S.; Wu, Runguo; Van Dam, Nicholas T.; Jiang, Yang; Fan, Jin

2013-01-01

Although trait anxiety has been associated with risk decision making, whether it is related to risk per se or to the feeling of the risk, as well as the underlying neurocognitive mechanisms, remains unclear. Using a decision-making task with a manipulation of frame (i.e., written description of options as a potential gain or loss) and functional magnetic resonance imaging, we investigated the neurocognitive relationship between trait anxiety and decision making. The classic framing effect was observed: participants chose the safe option when it was described as a potential gain, but they avoided the same option when it was described as a potential loss. Most importantly, trait anxiety was positively correlated with this behavioral bias. Trait anxiety was also positively correlated with amygdala-based “emotional” system activation and its coupling with the ventromedial prefrontal cortex (vmPFC) when decisions were consistent with the framing effect, but negatively correlated with the dorsal anterior cingulate cortex (dACC)-based “analytic” system activation and its connectivity to the vmPFC when decisions ran counter to the framing effect. Our findings suggest that trait anxiety is not associated with subjective risk preference but an evaluative bias of emotional information in decision making, underpinned by a hyperactive emotional system and a hypoactive analytic system in the brain. PMID:24259585

Neural basis of emotional decision making in trait anxiety.

PubMed

Xu, Pengfei; Gu, Ruolei; Broster, Lucas S; Wu, Runguo; Van Dam, Nicholas T; Jiang, Yang; Fan, Jin; Luo, Yue-jia

2013-11-20

Although trait anxiety has been associated with risk decision making, whether it is related to risk per se or to the feeling of the risk, as well as the underlying neurocognitive mechanisms, remains unclear. Using a decision-making task with a manipulation of frame (i.e., written description of options as a potential gain or loss) and functional magnetic resonance imaging, we investigated the neurocognitive relationship between trait anxiety and decision making. The classic framing effect was observed: participants chose the safe option when it was described as a potential gain, but they avoided the same option when it was described as a potential loss. Most importantly, trait anxiety was positively correlated with this behavioral bias. Trait anxiety was also positively correlated with amygdala-based "emotional" system activation and its coupling with the ventromedial prefrontal cortex (vmPFC) when decisions were consistent with the framing effect, but negatively correlated with the dorsal anterior cingulate cortex (dACC)-based "analytic" system activation and its connectivity to the vmPFC when decisions ran counter to the framing effect. Our findings suggest that trait anxiety is not associated with subjective risk preference but an evaluative bias of emotional information in decision making, underpinned by a hyperactive emotional system and a hypoactive analytic system in the brain.

Insulin sensitivity affects corticolimbic brain responses to visual food cues in polycystic ovary syndrome patients.

PubMed

Alsaadi, Hanin M; Van Vugt, Dean A

2015-11-01

This study examined the effect of insulin sensitivity on the responsiveness of appetite regulatory brain regions to visual food cues. Nineteen participants diagnosed with polycystic ovary syndrome (PCOS) were divided into insulin-sensitive (n=8) and insulin-resistant (n=11) groups based on the homeostatic model assessment of insulin resistance (HOMA2-IR). Subjects underwent functional magnetic resonance imaging (fMRI) while viewing food pictures following water or dextrose consumption. The corticolimbic blood oxygen level dependent (BOLD) responses to high-calorie (HC) or low-calorie (LC) food pictures were compared within and between groups. BOLD responses to food pictures were reduced during a glucose challenge in numerous corticolimbic brain regions in insulin-sensitive but not insulin-resistant subjects. Furthermore, the degree of insulin resistance positively correlated with the corticolimbic BOLD response in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate and ventral tegmental area (VTA) in response to HC pictures, and in the dorsolateral prefrontal cortex (DLPFC), mPFC, anterior cingulate, and insula in response to LC pictures following a glucose challenge. BOLD signal in the OFC, midbrain, hippocampus, and amygdala following a glucose challenge correlated with HOMA2-IR in response to HC-LC pictures. We conclude that the normal inhibition of corticolimbic brain responses to food pictures during a glucose challenge is compromised in insulin-resistant subjects. The increase in brain responsiveness to food pictures during postprandial hyperinsulinemia may lead to greater non-homeostatic eating and perpetuate obesity in insulin-resistant subjects.

Girls' challenging social experiences in early adolescence predict neural response to rewards and depressive symptoms.

PubMed

Casement, Melynda D; Guyer, Amanda E; Hipwell, Alison E; McAloon, Rose L; Hoffmann, Amy M; Keenan, Kathryn E; Forbes, Erika E

2014-04-01

Developmental models of psychopathology posit that exposure to social stressors may confer risk for depression in adolescent girls by disrupting neural reward circuitry. The current study tested this hypothesis by examining the relationship between early adolescent social stressors and later neural reward processing and depressive symptoms. Participants were 120 girls from an ongoing longitudinal study of precursors to depression across adolescent development. Low parental warmth, peer victimization, and depressive symptoms were assessed when the girls were 11 and 12 years old, and participants completed a monetary reward guessing fMRI task and assessment of depressive symptoms at age 16. Results indicate that low parental warmth was associated with increased response to potential rewards in the medial prefrontal cortex (mPFC), striatum, and amygdala, whereas peer victimization was associated with decreased response to potential rewards in the mPFC. Furthermore, concurrent depressive symptoms were associated with increased reward anticipation response in mPFC and striatal regions that were also associated with early adolescent psychosocial stressors, with mPFC and striatal response mediating the association between social stressors and depressive symptoms. These findings are consistent with developmental models that emphasize the adverse impact of early psychosocial stressors on neural reward processing and risk for depression in adolescence. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

The topology of connections between rat prefrontal and temporal cortices

PubMed Central

Bedwell, Stacey A.; Billett, E. Ellen; Crofts, Jonathan J.; MacDonald, Danielle M.; Tinsley, Chris J.

2015-01-01

Understanding the structural organization of the prefrontal cortex (PFC) is an important step toward determining its functional organization. Here we investigated the organization of PFC using different neuronal tracers. We injected retrograde (Fluoro-Gold, 100 nl) and anterograde [Biotinylated dextran amine (BDA) or Fluoro-Ruby, 100 nl] tracers into sites within PFC subdivisions (prelimbic, ventral orbital, ventrolateral orbital, dorsolateral orbital) along a coronal axis within PFC. At each injection site one injection was made of the anterograde tracer and one injection was made of the retrograde tracer. The projection locations of retrogradely labeled neurons and anterogradely labeled axon terminals were then analyzed in the temporal cortex: area Te, entorhinal and perirhinal cortex. We found evidence for an ordering of both the anterograde (anterior-posterior, dorsal-ventral, and medial-lateral axes: p < 0.001) and retrograde (anterior-posterior, dorsal-ventral, and medial-lateral axes: p < 0.001) connections of PFC. We observed that anterograde and retrograde labeling in ipsilateral temporal cortex (i.e., PFC inputs and outputs) often occurred reciprocally (i.e., the same brain region, such as area 35d in perirhinal cortex, contained anterograde and retrograde labeling). However, often the same specific columnar temporal cortex regions contained only either labeling of retrograde or anterograde tracer, indicating that PFC inputs and outputs are frequently non-matched. PMID:26042005

Capturing the temporal evolution of choice across prefrontal cortex

PubMed Central

Hunt, Laurence T; Behrens, Timothy EJ; Hosokawa, Takayuki; Wallis, Jonathan D; Kennerley, Steven W

2015-01-01

Activity in prefrontal cortex (PFC) has been richly described using economic models of choice. Yet such descriptions fail to capture the dynamics of decision formation. Describing dynamic neural processes has proven challenging due to the problem of indexing the internal state of PFC and its trial-by-trial variation. Using primate neurophysiology and human magnetoencephalography, we here recover a single-trial index of PFC internal states from multiple simultaneously recorded PFC subregions. This index can explain the origins of neural representations of economic variables in PFC. It describes the relationship between neural dynamics and behaviour in both human and monkey PFC, directly bridging between human neuroimaging data and underlying neuronal activity. Moreover, it reveals a functionally dissociable interaction between orbitofrontal cortex, anterior cingulate cortex and dorsolateral PFC in guiding cost-benefit decisions. We cast our observations in terms of a recurrent neural network model of choice, providing formal links to mechanistic dynamical accounts of decision-making. DOI: http://dx.doi.org/10.7554/eLife.11945.001 PMID:26653139

Dopamine in the medial amygdala network mediates human bonding.

PubMed

Atzil, Shir; Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M; Dickerson, Bradford C; Catana, Ciprian; Barrett, Lisa Feldman

2017-02-28

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers' dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the "medial amygdala network") that supports social functioning. We also measured the mothers' behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother's infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.

Affective and executive network processing associated with persuasive antidrug messages.

PubMed

Ramsay, Ian S; Yzer, Marco C; Luciana, Monica; Vohs, Kathleen D; MacDonald, Angus W

2013-07-01

Previous research has highlighted brain regions associated with socioemotional processes in persuasive message encoding, whereas cognitive models of persuasion suggest that executive brain areas may also be important. The current study aimed to identify lateral prefrontal brain areas associated with persuasive message viewing and understand how activity in these executive regions might interact with activity in the amygdala and medial pFC. Seventy adolescents were scanned using fMRI while they watched 10 strongly convincing antidrug public service announcements (PSAs), 10 weakly convincing antidrug PSAs, and 10 advertisements (ads) unrelated to drugs. Antidrug PSAs compared with nondrug ads more strongly elicited arousal-related activity in the amygdala and medial pFC. Within antidrug PSAs, those that were prerated as strongly persuasive versus weakly persuasive showed significant differences in arousal-related activity in executive processing areas of the lateral pFC. In support of the notion that persuasiveness involves both affective and executive processes, functional connectivity analyses showed greater coactivation between the lateral pFC and amygdala during PSAs known to be strongly (vs. weakly) convincing. These findings demonstrate that persuasive messages elicit activation in brain regions responsible for both emotional arousal and executive control and represent a crucial step toward a better understanding of the neural processes responsible for persuasion and subsequent behavior change.

FMRI Study of Neural Responses to Implicit Infant Emotion in Anorexia Nervosa

PubMed Central

Leppanen, Jenni; Cardi, Valentina; Paloyelis, Yannis; Simmons, Andy; Tchanturia, Kate; Treasure, Janet

2017-01-01

Difficulties in social–emotional processing have been proposed to play an important role in the development and maintenance of anorexia nervosa (AN). Few studies, thus far, have investigated neural processes that underlie these difficulties, including processing emotional facial expressions. However, the majority of these studies have investigated neural responses to adult emotional display, which may be confounded by elevated sensitivity to social rank and threat in AN. Therefore, the aim of this study was to investigate the neural processes underlying implicit processing of positively and negatively valenced infant emotional display in AN. Twenty-one adult women with AN and twenty-six healthy comparison (HC) women were presented with images of positively valenced, negatively valenced, and neutral infant faces during a fMRI scan. Significant differences between the groups in positive > neutral and negative > neutral contrasts were investigated in a priori regions of interest, including the bilateral amygdala, insula, and lateral prefrontal cortex (PFC). The findings revealed that the AN participants showed relatively increased recruitment while the HC participants showed relatively reduced recruitment of the bilateral amygdala and the right dorsolateral PFC in the positive > neutral contrast. In the negative > neutral contrast, the AN group showed relatively increased recruitment of the left posterior insula while the HC groups showed relatively reduced recruitment of this region. These findings suggest that people with AN may engage in implicit prefrontal down-regulation of elevated limbic reactivity to positively social–emotional stimuli. PMID:28567026

Increased antidepressant sensitivity after prefrontal cortex glucocorticoid receptor gene deletion in mice.

PubMed

Hussain, Rifat J; Jacobson, Lauren

2015-01-01

Our laboratory has previously shown that antidepressants regulate glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC). To determine if PFC GR are involved in antidepressant effects on behavior or hypothalamic-pituitary-adrenocortical (HPA) axis activity, we treated floxed GR male mice with saline or 15 or 30 mg/kg/d imipramine after PFC injection of adeno-associated virus 2/9 vectors transducing expression of Cre recombinase, to knock-down GR (PFC-GRKD), or green fluorescent protein (PFC-GFP), to serve as a control. The pattern of virally transduced GR deletion, common to all imipramine treatment groups, included the infralimbic, prelimbic, and medial anterior cingulate cortex at its largest extent, but was confined to the prelimbic and anterior cingulate cortex at its smallest extent. PFC GR knock-down increased behavioral sensitivity to imipramine, with imipramine-treated PFC-GRKD but not PFC-GFP mice exhibiting significant decreases in depression-like immobility during forced swim. PFC GR deletion did not alter general locomotor activity. The 30 mg/kg dose of imipramine increased plasma corticosterone levels immediately after a 5-min forced swim, but PFC GR knock-down had no significant effect on plasma corticosterone under these experimental conditions. We conclude that PFC GR knock-down, likely limited to the medial prelimbic and anterior cingulate cortices, can increase behavioral sensitivity to antidepressants. These findings indicate a novel role for PFC GR in influencing antidepressant response. Copyright © 2014 Elsevier Inc. All rights reserved.

Neural Correlates of Learning from Induced Insight: A Case for Reward-Based Episodic Encoding

PubMed Central

Kizilirmak, Jasmin M.; Thuerich, Hannes; Folta-Schoofs, Kristian; Schott, Björn H.; Richardson-Klavehn, Alan

2016-01-01

Experiencing insight when solving problems can improve memory formation for both the problem and its solution. The underlying neural processes involved in this kind of learning are, however, thus far insufficiently understood. Here, we conceptualized insight as the sudden understanding of a novel relationship between known stimuli that fits into existing knowledge and is accompanied by a positive emotional response. Hence, insight is thought to comprise associative novelty, schema congruency, and intrinsic reward, all of which are separately known to enhance memory performance. We examined the neural correlates of learning from induced insight with functional magnetic resonance imaging (fMRI) using our own version of the compound-remote-associates-task (CRAT) in which each item consists of three clue words and a solution word. (Pseudo-)Solution words were presented after a brief period of problem-solving attempts to induce either sudden comprehension (CRA items) or continued incomprehension (control items) at a specific time point. By comparing processing of the solution words of CRA with control items, we found induced insight to elicit activation of the rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) and left hippocampus. This pattern of results lends support to the role of schema congruency (rACC/mPFC) and associative novelty (hippocampus) in the processing of induced insight. We propose that (1) the mPFC not only responds to schema-congruent information, but also to the detection of novel schemata, and (2) that the hippocampus responds to a form of associative novelty that is not just a novel constellation of familiar items, but rather comprises a novel meaningful relationship between the items—which was the only difference between our insight and no insight conditions. To investigate episodic long-term memory encoding, we compared CRA items whose solution word was recognized 24 h after encoding to those with forgotten solutions. We found activation in the left striatum and parts of the left amygdala, pointing to a potential role of brain reward circuitry in the encoding of the solution words. We propose that learning from induced insight mainly relies on the amygdala evaluating the internal value (as an affective evaluation) of the suddenly comprehended information, and striatum-dependent reward-based learning. PMID:27847490

Neural Correlates of Learning from Induced Insight: A Case for Reward-Based Episodic Encoding.

PubMed

Kizilirmak, Jasmin M; Thuerich, Hannes; Folta-Schoofs, Kristian; Schott, Björn H; Richardson-Klavehn, Alan

2016-01-01

Experiencing insight when solving problems can improve memory formation for both the problem and its solution. The underlying neural processes involved in this kind of learning are, however, thus far insufficiently understood. Here, we conceptualized insight as the sudden understanding of a novel relationship between known stimuli that fits into existing knowledge and is accompanied by a positive emotional response. Hence, insight is thought to comprise associative novelty, schema congruency, and intrinsic reward, all of which are separately known to enhance memory performance. We examined the neural correlates of learning from induced insight with functional magnetic resonance imaging (fMRI) using our own version of the compound-remote-associates-task (CRAT) in which each item consists of three clue words and a solution word. (Pseudo-)Solution words were presented after a brief period of problem-solving attempts to induce either sudden comprehension (CRA items) or continued incomprehension (control items) at a specific time point. By comparing processing of the solution words of CRA with control items, we found induced insight to elicit activation of the rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) and left hippocampus. This pattern of results lends support to the role of schema congruency (rACC/mPFC) and associative novelty (hippocampus) in the processing of induced insight. We propose that (1) the mPFC not only responds to schema-congruent information, but also to the detection of novel schemata, and (2) that the hippocampus responds to a form of associative novelty that is not just a novel constellation of familiar items, but rather comprises a novel meaningful relationship between the items-which was the only difference between our insight and no insight conditions. To investigate episodic long-term memory encoding, we compared CRA items whose solution word was recognized 24 h after encoding to those with forgotten solutions. We found activation in the left striatum and parts of the left amygdala, pointing to a potential role of brain reward circuitry in the encoding of the solution words. We propose that learning from induced insight mainly relies on the amygdala evaluating the internal value (as an affective evaluation) of the suddenly comprehended information, and striatum-dependent reward-based learning.

Impact of the neural correlates of stress and cue reactivity on stress related binge eating in the natural environment.

PubMed

Fischer, Sarah; Breithaupt, Lauren; Wonderlich, Joseph; Westwater, Margaret L; Crosby, Ross D; Engel, Scott G; Thompson, James; Lavender, Jason; Wonderlich, Stephen

2017-09-01

Women with symptoms of bulimia nervosa (BN) exhibit decreased response to visual food cues in several limbic and frontal regions compared to controls. Stress causes decreased blood oxygenation level dependent (BOLD) response in these regions in non-clinical samples; there is a lack of data on this topic in BN. This study examined the impact of individual differences in neural reactivity to palatable food cues following acute stress on stress-binge trajectories in everyday life. 16 women with BN symptoms viewed palatable food cues prior to and immediately following an acute stress induction in the scanner. Participants then responded to a series of prompts assessing daily ratings of stress and binge episodes for a period of two weeks. Decreased BOLD signal was observed in response to food cues pre to post stress in the anterior cingulate cortex (ACC), amygdala, and ventromedial prefrontal cortex (vmPFC). Ecological momentary assessment data collection demonstrated that stress increased prior to binge episodes in the natural environment, and decreased following. Changes in activation in the ACC, precuneus, and dorsolateral prefrontal cortex (dlPFC) significantly moderated the relationship of stress to binge eating in daily life, such that women who exhibited decreased response reported significantly increasing stress prior to binges, while women who did not exhibit decreases reported no significant change in stress prior to binges. Individual differences in neural response to food cues under stress appear to underlie distinct antecedants to binge eating. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Brain Basis for Misophonia.

PubMed

Kumar, Sukhbinder; Tansley-Hancock, Olana; Sedley, William; Winston, Joel S; Callaghan, Martina F; Allen, Micah; Cope, Thomas E; Gander, Phillip E; Bamiou, Doris-Eva; Griffiths, Timothy D

2017-02-20

Misophonia is an affective sound-processing disorder characterized by the experience of strong negative emotions (anger and anxiety) in response to everyday sounds, such as those generated by other people eating, drinking, chewing, and breathing [1-8]. The commonplace nature of these sounds (often referred to as "trigger sounds") makes misophonia a devastating disorder for sufferers and their families, and yet nothing is known about the underlying mechanism. Using functional and structural MRI coupled with physiological measurements, we demonstrate that misophonic subjects show specific trigger-sound-related responses in brain and body. Specifically, fMRI showed that in misophonic subjects, trigger sounds elicit greatly exaggerated blood-oxygen-level-dependent (BOLD) responses in the anterior insular cortex (AIC), a core hub of the "salience network" that is critical for perception of interoceptive signals and emotion processing. Trigger sounds in misophonics were associated with abnormal functional connectivity between AIC and a network of regions responsible for the processing and regulation of emotions, including ventromedial prefrontal cortex (vmPFC), posteromedial cortex (PMC), hippocampus, and amygdala. Trigger sounds elicited heightened heart rate (HR) and galvanic skin response (GSR) in misophonic subjects, which were mediated by AIC activity. Questionnaire analysis showed that misophonic subjects perceived their bodies differently: they scored higher on interoceptive sensibility than controls, consistent with abnormal functioning of AIC. Finally, brain structural measurements implied greater myelination within vmPFC in misophonic individuals. Overall, our results show that misophonia is a disorder in which abnormal salience is attributed to particular sounds based on the abnormal activation and functional connectivity of AIC. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Amygdala lesions disrupt modulation of functional MRI activity evoked by facial expression in the monkey inferior temporal cortex

PubMed Central

Hadj-Bouziane, Fadila; Liu, Ning; Bell, Andrew H.; Gothard, Katalin M.; Luh, Wen-Ming; Tootell, Roger B. H.; Murray, Elisabeth A.; Ungerleider, Leslie G.

2012-01-01

We previously showed that facial expressions modulate functional MRI activity in the face-processing regions of the macaque monkey’s amygdala and inferior temporal (IT) cortex. Specifically, we showed that faces expressing emotion yield greater activation than neutral faces; we term this difference the “valence effect.” We hypothesized that amygdala lesions would disrupt the valence effect by eliminating the modulatory feedback from the amygdala to the IT cortex. We compared the valence effects within the IT cortex in monkeys with excitotoxic amygdala lesions (n = 3) with those in intact control animals (n = 3) using contrast agent-based functional MRI at 3 T. Images of four distinct monkey facial expressions—neutral, aggressive (open mouth threat), fearful (fear grin), and appeasing (lip smack)—were presented to the subjects in a blocked design. Our results showed that in monkeys with amygdala lesions the valence effects were strongly disrupted within the IT cortex, whereas face responsivity (neutral faces > scrambled faces) and face selectivity (neutral faces > non-face objects) were unaffected. Furthermore, sparing of the anterior amygdala led to intact valence effects in the anterior IT cortex (which included the anterior face-selective regions), whereas sparing of the posterior amygdala led to intact valence effects in the posterior IT cortex (which included the posterior face-selective regions). Overall, our data demonstrate that the feedback projections from the amygdala to the IT cortex mediate the valence effect found there. Moreover, these modulatory effects are consistent with an anterior-to-posterior gradient of projections, as suggested by classical tracer studies. PMID:23184972

Disrupted functional connectivity of the periaqueductal gray in chronic low back pain

PubMed Central

Yu, Rongjun; Gollub, Randy L.; Spaeth, Rosa; Napadow, Vitaly; Wasan, Ajay; Kong, Jian

2014-01-01

Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG–vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG–insula and PAG–amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest. PMID:25379421

The Essential Role of Primate Orbitofrontal Cortex in Conflict-Induced Executive Control Adjustment

PubMed Central

Buckley, Mark J.; Tanaka, Keiji

2014-01-01

Conflict in information processing evokes trial-by-trial behavioral modulations. Influential models suggest that adaptive tuning of executive control, mediated by mid-dorsal lateral prefrontal cortex (mdlPFC) and anterior cingulate cortex (ACC), underlies these modulations. However, mdlPFC and ACC are parts of distributed brain networks including orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), and superior-dorsal lateral prefrontal cortex (sdlPFC). Contributions of these latter areas in adaptive tuning of executive control are unknown. We trained monkeys to perform a matching task in which they had to resolve the conflict between two behavior-guiding rules. Here, we report that bilateral lesions in OFC, but not in PCC or sdlPFC, impaired selection between these competing rules. In addition, the behavioral adaptation that is normally induced by experiencing conflict disappeared in OFC-lesioned, but remained normal in PCC-lesioned or sdlPFC-lesioned monkeys. Exploring underlying neuronal processes, we found that the activity of neurons in OFC represented the conflict between behavioral options independent from the other aspects of the task. Responses of OFC neurons to rewards also conveyed information of the conflict level that the monkey had experienced along the course to obtain the reward. Our findings indicate dissociable functions for five closely interconnected cortical areas suggesting that OFC and mdlPFC, but not PCC or sdlPFC or ACC, play indispensable roles in conflict-dependent executive control of on-going behavior. Both mdlPFC and OFC support detection of conflict and its integration with the task goal, but in contrast to mdlPFC, OFC does not retain the necessary information for conflict-induced modulation of future decisions. PMID:25122901

Maladaptive Sexual Behavior Following Concurrent Methamphetamine and Sexual Experience in Male Rats is Associated with Altered Neural Activity in Frontal Cortex.

PubMed

Kuiper, Lindsey B; Frohmader, Karla S; Coolen, Lique M

2017-09-01

The use of psychostimulants is often associated with hypersexuality, and psychostimulant users have identified the effects of drug on sexual behavior as a reason for further use. It was previously demonstrated in male rats that methamphetamine (Meth), when administered concurrently with sexual behavior results in impairment of inhibition of sexual behavior in a conditioned sex aversion (CSA) paradigm where mating is paired with illness. This is indicative of maladaptive sex behavior following Meth and sex experience. The present study examined the neural pathways activated during inhibition of sexual behavior in male rats and the effects of concurrent Meth and sexual behavior on neural activity, using ERK phosphorylation (pERK). First, exposure to conditioned aversive stimuli in males trained to inhibit sexual behavior in the CSA paradigm increased pERK expression in medial prefrontal (mPFC), orbitofrontal cortex (OFC) and areas in striatum and amygdala. Second, effects of concurrent Meth and sex experience were tested in males that were exposed to four daily sessions of concurrent Meth (1 mg/kg) or saline and mating and subsequently exposed to CSA one week after last treatment. Meth and mating-treated males showed significant impairment of inhibition of mating, higher pERK expression under baseline conditions, and disrupted pERK induction by exposure to the conditioned aversive stimuli in mPFC and OFC. These alterations of pERK occurred in CaMKII-expressing neurons, suggesting changes in efferent projections of these areas. Altogether, these data show that concurrent Meth and mating experience causes maladapative sexual behavior that is associated with alterations in neural activation in mPFC and OFC.

Comprehensive neural networks for guilty feelings in young adults.

PubMed

Nakagawa, Seishu; Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Sekiguchi, Atsushi; Kotozaki, Yuka; Miyauchi, Carlos Makoto; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Kunitoki, Keiko; Sassa, Yuko; Kawashima, Ryuta

2015-01-15

Feelings of guilt are associated with widespread self and social cognitions, e.g., empathy, moral reasoning, and punishment. Neural correlates directly related to the degree of feelings of guilt have not been detected, probably due to the small numbers of subjects, whereas there are growing numbers of neuroimaging studies of feelings of guilt. We hypothesized that the neural networks for guilty feelings are widespread and include the insula, inferior parietal lobule (IPL), amygdala, subgenual cingulate cortex (SCC), and ventromedial prefrontal cortex (vmPFC), which are essential for cognitions of guilt. We investigated the association between regional gray matter density (rGMD) and feelings of guilt in 764 healthy young students (422 males, 342 females; 20.7 ± 1.8 years) using magnetic resonance imaging and the guilty feeling scale (GFS) for the younger generation which comprises interpersonal situation (IPS) and rule-breaking situation (RBS) scores. Both the IPS and RBS were negatively related to the rGMD in the right posterior insula (PI). The IPS scores were negatively correlated with rGMD in the left anterior insula (AI), right IPL, and vmPFC using small volume correction. A post hoc analysis performed on the significant clusters identified through these analyses revealed that rGMD activity in the right IPL showed a significant negative association with the empathy quotient. These findings at the whole-brain level are the widespread comprehensive neural network regions for guilty feelings. Interestingly, the novel finding in this study is that the PI was implicated as a common region for feelings of guilt with interaction between the IPS and RBS. Additionally, the neural networks including the IPL were associated with empathy and with regions implicated in moral reasoning (AI and vmPFC), and punishment (AI). Copyright © 2014 Elsevier Inc. All rights reserved.

Neural substrates of approach-avoidance conflict decision-making

PubMed Central

Aupperle, Robin L.; Melrose, Andrew J.; Francisco, Alex; Paulus, Martin P.; Stein, Murray B.

2014-01-01

Animal approach-avoidance conflict paradigms have been used extensively to operationalize anxiety, quantify the effects of anxiolytic agents, and probe the neural basis of fear and anxiety. Results from human neuroimaging studies support that a frontal-striatal-amygdala neural circuitry is important for approach-avoidance learning. However, the neural basis of decision-making is much less clear in this context. Thus, we combined a recently developed human approach-avoidance paradigm with functional magnetic resonance imaging (fMRI) to identify neural substrates underlying approach-avoidance conflict decision-making. Fifteen healthy adults completed the approach-avoidance conflict (AAC) paradigm during fMRI. Analyses of variance were used to compare conflict to non-conflict (avoid-threat and approach-reward) conditions and to compare level of reward points offered during the decision phase. Trial-by-trial amplitude modulation analyses were used to delineate brain areas underlying decision-making in the context of approach/avoidance behavior. Conflict trials as compared to the non-conflict trials elicited greater activation within bilateral anterior cingulate cortex (ACC), anterior insula, and caudate, as well as right dorsolateral prefrontal cortex. Right caudate and lateral PFC activation was modulated by level of reward offered. Individuals who showed greater caudate activation exhibited less approach behavior. On a trial-by-trial basis, greater right lateral PFC activation related to less approach behavior. Taken together, results suggest that the degree of activation within prefrontal-striatal-insula circuitry determines the degree of approach versus avoidance decision-making. Moreover, the degree of caudate and lateral PFC activation is related to individual differences in approach-avoidance decision-making. Therefore, the AAC paradigm is ideally suited to probe anxiety-related processing differences during approach-avoidance decision-making. PMID:25224633

Regional brain [(11)C]carfentanil binding following tobacco smoking.

PubMed

Domino, Edward F; Hirasawa-Fujita, Mika; Ni, Lisong; Guthrie, Sally K; Zubieta, Jon Kar

2015-06-03

To determine if overnight tobacco abstinent carriers of the AG or GG (*G) vs. the AA variant of the human mu opioid receptor (OPRM1) A118G polymorphism (rs1799971) differ in [(11)C]carfentanil binding after tobacco smoking. Twenty healthy American male smokers who abstained from tobacco overnight were genotyped and completed positron emission tomography (PET) scans with the mu opioid receptor agonist, [(11)C]carfentanil. They smoked deniconized (denic) and average nicotine (avnic) cigarettes during the PET scans. Smoking avnic cigarette decreased the binding potential (BPND) of [(11)C]carfentanil in the right medial prefrontal cortex (mPfc; 6, 56, 18), left anterior medial prefrontal cortex (amPfc; -2, 46, 44), right ventral striatum (vStr; 16, 3, -10), left insula (Ins; -42, 10, -12), right hippocampus (Hippo; 18, -6, -14) and left cerebellum (Cbl; -10, -88, -34), and increased the BPND in left amygdala (Amy; -20, 0, -22), left putamen (Put; -22, 10, -6) and left nucleus accumbens (NAcc; -10, 12, -8). In the AA allele carriers, avnic cigarette smoking significantly changed the BPND compared to after denic smoking in most brain areas listed above. However in the *G carriers the significant BPND changes were confirmed in only amPfc and vStr. Free mu opioid receptor availability was significantly less in the *G than the AA carriers in the Amy and NAcc. The present study demonstrates that BPND changes induced by avnic smoking in OPRM1 *G carriers were blunted compared to the AA carriers. Also *G smokers had less free mu opioid receptor availability in Amy and NAcc. Copyright © 2015 Elsevier Inc. All rights reserved.

Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP.

PubMed

Shirane, M; Nakamura, K

2001-10-19

Aniracetam, a cognition enhancer, has been recently found to preferentially increase extracellular levels of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex (PFC), basolateral amygdala and dorsal hippocampus of the mesocorticolimbic system in stroke-prone spontaneously hypertensive rats. In the present study, we aimed to identify actually active substances among aniracetam and its major metabolites and to clarify the mode of action in DA and 5-HT release in the PFC. Local perfusion of mecamylamine, a nicotinic acetylcholine (nACh) and N-methyl-D-aspartate (NMDA) receptor antagonist, into the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) completely blocked DA and 5-HT release, respectively, in the PFC elicited by orally administered aniracetam. The effects of aniracetam were mimicked by local perfusion of N-anisoyl-gamma-aminobutyric acid [corrected] (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN. The cortical DA release induced by N-anisoyl-GABA applied to the VTA was also completely abolished by co-perfusion of mecamylamine. Additionally, when p-anisic acid, another metabolite of aniracetam, and N-anisoyl-GABA were locally perfused into the PFC, they induced DA and 5-HT release in the same region, respectively. These results indicate that aniracetam enhances DA and 5-HT release by mainly mediating the action of N-anisoyl-GABA that targets not only somatodendritic nACh and NMDA receptors but also presynaptic nACh receptors.

Identifying the Neural Substrates of Procrastination: a Resting-State fMRI Study.

PubMed

Zhang, Wenwen; Wang, Xiangpeng; Feng, Tingyong

2016-09-12

Procrastination is a prevalent problematic behavior that brings serious consequences to individuals who suffer from it. Although this phenomenon has received increasing attention from researchers, the underpinning neural substrates of it is poorly studied. To examine the neural bases subserving procrastination, the present study employed resting-state fMRI. The main results were as follows: (1) the behavioral procrastination was positively correlated with the regional activity of the ventromedial prefrontal cortex (vmPFC) and the parahippocampal cortex (PHC), while negatively correlated with that of the anterior prefrontal cortex (aPFC). (2) The aPFC-seed connectivity with the anterior medial prefrontal cortex and the posterior cingulate cortex was positively associated with procrastination. (3) The connectivity between vmPFC and several other regions, such as the dorsomedial prefrontal cortex, the bilateral inferior prefrontal cortex showed a negative association with procrastination. These results suggested that procrastination could be attributed to, on the one hand, hyper-activity of the default mode network (DMN) that overrides the prefrontal control signal; while on the other hand, the failure of top-down control exerted by the aPFC on the DMN. Therefore, the present study unravels the biomarkers of procrastination and provides treatment targets for procrastination prevention.

Identifying the Neural Substrates of Procrastination: a Resting-State fMRI Study

PubMed Central

Zhang, Wenwen; Wang, Xiangpeng; Feng, Tingyong

2016-01-01

Procrastination is a prevalent problematic behavior that brings serious consequences to individuals who suffer from it. Although this phenomenon has received increasing attention from researchers, the underpinning neural substrates of it is poorly studied. To examine the neural bases subserving procrastination, the present study employed resting-state fMRI. The main results were as follows: (1) the behavioral procrastination was positively correlated with the regional activity of the ventromedial prefrontal cortex (vmPFC) and the parahippocampal cortex (PHC), while negatively correlated with that of the anterior prefrontal cortex (aPFC). (2) The aPFC-seed connectivity with the anterior medial prefrontal cortex and the posterior cingulate cortex was positively associated with procrastination. (3) The connectivity between vmPFC and several other regions, such as the dorsomedial prefrontal cortex, the bilateral inferior prefrontal cortex showed a negative association with procrastination. These results suggested that procrastination could be attributed to, on the one hand, hyper-activity of the default mode network (DMN) that overrides the prefrontal control signal; while on the other hand, the failure of top-down control exerted by the aPFC on the DMN. Therefore, the present study unravels the biomarkers of procrastination and provides treatment targets for procrastination prevention. PMID:27616687

Prefrontal single-unit firing associated with deficient extinction in mice

PubMed Central

Fitzgerald, Paul J; Whittle, Nigel; Flynn, Shaun M; Graybeal, Carolyn; Pinard, Courtney; Gunduz-Cinar, Ozge; Kravitz, Alexxai; Singewald, Nicolas; Holmes, Andrew

2014-01-01

The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal cortex (vmPFC) has been found to promote extinction, whereas the prelimbic cortex (PL) demonstrates an opposing, pro-fear, function. Studies employing in vivo electrophysiological recordings have observed that while increased IL single-unit firing and bursting predicts robust extinction retrieval, increased PL firing can correlate with sustained fear and poor extinction. These relationships between single-unit firing and extinction do not hold under all experimental conditions, however. In the current study, we further investigated the relationship between vmPFC and PL single-unit firing and extinction using inbred mouse models of intact (C57BL/6J, B6) and deficient (129S1/SvImJ, S1) extinction strains. Simultaneous single-unit recordings were made in the PL and vmPFC (encompassing IL) as B6 and S1 mice performed extinction training and retrieval. Impaired extinction retrieval in S1 mice was associated with elevated PL single-unit firing, as compared to firing in extinguishing B6 mice, consistent with the hypothesized pro-fear contribution of PL. Analysis of local field potentials also revealed significantly higher gamma power in the PL of Sthan B6 mice during extinction training and retrieval. In the vmPFC, impaired extinction in S1 mice was also associated with exaggerated single-unit firing, relative to B6 mice. This is in apparent contradiction to evidence that IL activity promotes extinction, but could reflect a (failed) compensatory effort by the vmPFC to mitigate fear-promoting activity in other regions, such as the PL or amygdala. In support of this hypothesis, augmenting IL activity via direct infusion of the GABAA receptor antagonist picrotoxin rescued impaired extinction retrieval in S1 mice. Chronic fluoxetine treatment produced modest reductions in fear during extinction retrieval and increased the number of Zif268-labeled cells in layer II of IL, but failed to increase vmPFC single-unit firing. Collectively, these findings further support the important contribution these cortical regions play in determining the balance between robust extinction on the one hand, and sustained fear on the other. Elucidating the precise nature of these roles could help inform understanding of the pathophysiology of fear-related anxiety disorders. PMID:24231425

Prefrontal Cortex and Drug Abuse Vulnerability: Translation to Prevention and Treatment Interventions

PubMed Central

Perry, Jennifer L.; Joseph, Jane E.; Jiang, Yang; Zimmerman, Rick S.; Kelly, Thomas H.; Darna, Mahesh; Huettl, Peter; Dwoskin, Linda P.; Bardo, Michael T.

2010-01-01

Vulnerability to drug abuse is related to both reward seeking and impulsivity, two constructs thought to have a biological basis in the prefrontal cortex (PFC). This review addresses similarities and differences in neuroanatomy, neurochemistry and behavior associated with PFC function in rodents and primates. Emphasis is placed on monoamine and amino acid neurotransmitter systems located in anatomically distinct subregions: medial prefrontal cortex (mPFC); lateral prefrontal cortex (lPFC); anterior cingulate cortex (ACC); and orbitofrontal cortex (OFC). While there are complex interconnections and overlapping functions among these regions, each is thought to be involved in various functions related to health-related risk behaviors and drug abuse vulnerability. Among the various functions implicated, evidence suggests that mPFC is involved in reward processing, attention and drug reinstatement; lPFC is involved in decision-making, behavioral inhibition and attentional gating; ACC is involved in attention, emotional processing and self-monitoring; and OFC is involved in behavioral inhibition, signaling of expected outcomes and reward/punishment sensitivity. Individual differences factors (e.g., age and sex) influence functioning of these regions, which, in turn, impacts drug abuse vulnerability. Implications for the development of drug abuse prevention and treatment strategies aimed at engaging PFC inhibitory processes that may reduce risk-related behaviors are discussed, including the design of effective public service announcements, cognitive exercises, physical activity, direct current stimulation, feedback control training and pharmacotherapies. A major challenge in drug abuse prevention and treatment rests with improving intervention strategies aimed at strengthening PFC inhibitory systems among at-risk individuals. PMID:20837060

Ventromedial prefrontal cortex modulates fatigue after penetrating traumatic brain injury

PubMed Central

Pardini, Matteo; Krueger, Frank; Raymont, Vanessa; Grafman, Jordan

2010-01-01

Background: Fatigue is a common and disabling symptom in neurologic disorders including traumatic penetrating brain injury (PBI). Despite fatigue's prevalence and impact on quality of life, its pathophysiology is not understood. Studies on effort perception in healthy subjects, animal behavioral paradigms, and recent evidence in different clinical populations suggest that ventromedial prefrontal cortex could play a significant role in fatigue pathophysiology in neurologic conditions. Methods: We enrolled 97 PBI patients and 37 control subjects drawn from the Vietnam Head Injury Study registry. Fatigue was assessed with a self-report questionnaire and a clinician-rated instrument; lesion location and volume were evaluated on CT scans. PBI patients were divided in 3 groups according to lesion location: a nonfrontal lesion group, a ventromedial prefrontal cortex lesion (vmPFC) group, and a dorso/lateral prefrontal cortex (d/lPFC) group. Fatigue scores were compared among the 3 PBI groups and the healthy controls. Results: Individuals with vmPFC lesions were significantly more fatigued than individuals with d/lPFC lesions, individuals with nonfrontal lesions, and healthy controls, while these 3 latter groups were equally fatigued. VmPFC volume was correlated with fatigue scores, showing that the larger the lesion volume, the higher the fatigue scores. Conclusions: We demonstrated that ventromedial prefrontal cortex lesion (vmPFC) plays a critical role in penetrating brain injury–related fatigue, providing a rationale to link fatigue to different vmPFC functions such as effort and reward perception. The identification of the anatomic and cognitive basis of fatigue can contribute to developing pathophysiology-based treatments for this disabling symptom. GLOSSARY AAL = Automated Anatomic Labeling; ANOVA = analysis of variance; BDI = Beck Depression Inventory; d/lPFC = dorso/lateral prefrontal cortex; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; NBRS = Neurobehavioral Rating Scale; NF = nonfrontal lesion; PBI = penetrating brain injury; ROI = region of interest; SCID-I = Structured Clinical Interview for DSM-IV, Axis I; VHIS = Vietnam Head Injury Study; vmPFC = ventromedial prefrontal cortex lesion. PMID:20194914

Dissociable patterns of medial prefrontal and amygdala activity to face identity versus emotion in bipolar disorder.

PubMed

Keener, M T; Fournier, J C; Mullin, B C; Kronhaus, D; Perlman, S B; LaBarbara, E; Almeida, J C; Phillips, M L

2012-09-01

Individuals with bipolar disorder demonstrate abnormal social function. Neuroimaging studies in bipolar disorder have shown functional abnormalities in neural circuitry supporting face emotion processing, but have not examined face identity processing, a key component of social function. We aimed to elucidate functional abnormalities in neural circuitry supporting face emotion and face identity processing in bipolar disorder. Twenty-seven individuals with bipolar disorder I currently euthymic and 27 healthy controls participated in an implicit face processing, block-design paradigm. Participants labeled color flashes that were superimposed on dynamically changing background faces comprising morphs either from neutral to prototypical emotion (happy, sad, angry and fearful) or from one identity to another identity depicting a neutral face. Whole-brain and amygdala region-of-interest (ROI) activities were compared between groups. There was no significant between-group difference looking across both emerging face emotion and identity. During processing of all emerging emotions, euthymic individuals with bipolar disorder showed significantly greater amygdala activity. During facial identity and also happy face processing, euthymic individuals with bipolar disorder showed significantly greater amygdala and medial prefrontal cortical activity compared with controls. This is the first study to examine neural circuitry supporting face identity and face emotion processing in bipolar disorder. Our findings of abnormally elevated activity in amygdala and medial prefrontal cortex (mPFC) during face identity and happy face emotion processing suggest functional abnormalities in key regions previously implicated in social processing. This may be of future importance toward examining the abnormal self-related processing, grandiosity and social dysfunction seen in bipolar disorder.

Importance of reward and prefrontal circuitry in hunger and satiety: Prader-Willi syndrome vs simple obesity.

PubMed

Holsen, L M; Savage, C R; Martin, L E; Bruce, A S; Lepping, R J; Ko, E; Brooks, W M; Butler, M G; Zarcone, J R; Goldstein, J M

2012-05-01

The majority of research on obesity (OB) has focused primarily on clinical features (eating behavior, adiposity measures) or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions that are associated with appetite-regulatory hormones are also involved in the development and maintenance of OB. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic OB. Simple (non-PWS) OB represents an OB-control state. This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (that is, hypothalamus, amygdala) and prefrontal regions associated with cognitive control (that is, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC) after eating. A total of 14 individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC and DLPFC. Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in the hypothalamus and hippocampus in response to food (vs non-food) images pre-meal. Post meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared with OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control. In PWS, compared with OB per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple OB.

Importance of Reward and Prefrontal Circuitry in Hunger and Satiety: Prader-Willi Syndrome vs. Simple Obesity

PubMed Central

Holsen, Laura M.; Savage, Cary R.; Martin, Laura E.; Bruce, Amanda S.; Lepping, Rebecca J.; Ko, Eunice; Brooks, William M.; Butler, Merlin G.; Zarcone, Jennifer R.; Goldstein, Jill M.

2011-01-01

Background The majority of research on obesity has focused primarily on clinical features (eating behavior, adiposity measures), or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions which are associated with appetite-regulatory hormones are also involved in the development and maintenance of obesity. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic obesity. Simple (non-PWS) obesity (OB) represents an obesity control state. Objective This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (i.e., hypothalamus, amygdala) and prefrontal regions associated with cognitive control [i.e., dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC)] after eating. Design and Participants Fourteen individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls (HWC) viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC, and DLPFC. Results Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in hypothalamus and hippocampus, in response to food (vs. non-food) images pre-meal. Post-meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared to OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control. Conclusion In PWS compared with obesity per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple obesity. PMID:22024642

Williams Syndrome Hypersociability: A Neuropsychological Study of the Amygdala and Prefrontal Cortex Hypotheses

ERIC Educational Resources Information Center

Capitao, Liliana; Sampaio, Adriana; Fernandez, Montse; Sousa, Nuno; Pinheiro, Ana; Goncalves, Oscar F.

2011-01-01

Individuals with Williams syndrome display indiscriminate approach towards strangers. Neuroimaging studies conducted so far have linked this social profile to structural and/or functional abnormalities in WS amygdala and prefrontal cortex. In this study, the neuropsychological hypotheses of amygdala and prefrontal cortex involvement in WS…

Neuropsychology of prefrontal cortex

PubMed Central

Siddiqui, Shazia Veqar; Chatterjee, Ushri; Kumar, Devvarta; Siddiqui, Aleem; Goyal, Nishant

2008-01-01

The history of clinical frontal lobe study is long and rich which provides valuable insights into neuropsychologic determinants of functions of prefrontal cortex (PFC). PFC is often classified as multimodal association cortex as extremely processed information from various sensory modalities is integrated here in a precise fashion to form the physiologic constructs of memory, perception, and diverse cognitive processes. Human neuropsychologic studies also support the notion of different functional operations within the PFC. The specification of the component ‘executive’ processes and their localization to particular regions of PFC have been implicated in a wide variety of psychiatric disorders. PMID:19742233

Differential neural correlates of autobiographical memory recall in bipolar and unipolar depression.

PubMed

Young, Kymberly D; Bodurka, Jerzy; Drevets, Wayne C

2016-11-01

Autobiographical memory (AM) recall is impaired in both bipolar depression (BD) and major depressive disorder (MDD). The current study used functional magnetic resonance imaging (fMRI) to investigate differences between healthy controls (HCs) and depressed participants with either BD or MDD as they recalled AMs that varied in emotional valence. Unmedicated adults in a current major depressive episode who met criteria for either MDD or BD and HCs (n=16/group) underwent fMRI while recalling AMs in response to emotionally valenced cue words. Control tasks involved generating examples from a given category and counting the number of risers in a letter string. Both participants with BD and those with MDD recalled fewer specific and more categorical memories than HC participants. During specific AM recall of positive memories, participants with BD showed increased hemodynamic activity in the ventrolateral prefrontal cortex, posterior cingulate cortex, anterior insula, middle temporal gyrus, parahippocampus, and amygdala relative to MDD and HC participants, as well as decreased dorsolateral prefrontal (DLPFC) activity relative to MDD participants. During specific AM recall of negative memories, participants with BD manifested decreased activity in the precuneus, amygdala, anterior cingulate, and DLPFC along with increased activity in the dorsomedial PFC relative to MDD participants. While depressed participants with BD and MDD exhibited similar depression ratings and memory deficits, the brain regions underlying successful AM recall significantly differentiated these patient groups. Differential amygdala activity during emotional memory recall (particularly increased activity in participants with BD for positive AMs) may prove useful in the differentiation of individuals with MDD and BD experiencing a depressive episode. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cortico-Amygdala Coupling as a Marker of Early Relapse Risk in Cocaine-Addicted Individuals

PubMed Central

McHugh, Meredith J.; Demers, Catherine H.; Salmeron, Betty Jo; Devous, Michael D.; Stein, Elliot A.; Adinoff, Bryon

2014-01-01

Addiction to cocaine is a chronic condition characterized by high rates of early relapse. This study builds on efforts to identify neural markers of relapse risk by studying resting-state functional connectivity (rsFC) in neural circuits arising from the amygdala, a brain region implicated in relapse-related processes including craving and reactivity to stress following acute and protracted withdrawal from cocaine. Whole-brain resting-state functional magnetic resonance imaging connectivity (6 min) was assessed in 45 cocaine-addicted individuals and 22 healthy controls. Cocaine-addicted individuals completed scans in the final week of a residential treatment episode. To approximate preclinical models of relapse-related circuitry, separate seeds were derived for the left and right basolateral (BLA) and corticomedial (CMA) amygdala. Participants also completed the Iowa Gambling Task, Wisconsin Card Sorting Test, Cocaine Craving Questionnaire, Obsessive-Compulsive Cocaine Use Scale and Personality Inventory. Relapse within the first 30 days post-treatment (n = 24) was associated with reduced rsFC between the left CMA and ventromedial prefrontal cortex/rostral anterior cingulate cortex (vmPFC/rACC) relative to cocaine-addicted individuals who remained abstinent (non-relapse, n = 21). Non-relapse participants evidenced reduced rsFC between the bilateral BLA and visual processing regions (lingual gyrus/cuneus) compared to controls and relapsed participants. Early relapse was associated with fewer years of education but unrelated to trait reactivity to stress, neurocognitive and clinical characteristics or cocaine use history. Findings suggest that rsFC within neural circuits implicated in preclinical models of relapse may provide a promising marker of relapse risk in cocaine-addicted individuals. Future efforts to replicate the current findings and alter connectivity within these circuits may yield novel interventions and improve treatment outcomes. PMID:24578695

Neurobiological dissociation of retrieval and reconsolidation of cocaine-associated memory

PubMed Central

Otis, James M.; Dashew, Kidane B.; Mueller, Devin

2013-01-01

Drug use is provoked by the presentation of drug-associated cues, even following long periods of abstinence. Disruption of these learned associations would therefore limit relapse susceptibility. Drug-associated memories are susceptible to long-term disruption during retrieval and shortly after, during memory reconsolidation. Recent evidence reveals that retrieval and reconsolidation are dependent on β-adrenergic receptor (β-AR) activation. Despite this, whether retrieval and reconsolidation are dependent on identical or distinct neural mechanisms is unknown. The prelimbic medial prefrontal cortex (PL-mPFC) and basolateral amygdala (BLA) have been implicated in the expression and reconsolidation of associative memories. Therefore, we investigated the necessity of β-AR activation within the PL-mPFC and BLA for cocaine-associated memory retrieval and reconsolidation in rats. Before or immediately after a cocaine-induced conditioned place preference (CPP) retrieval trial, β-AR antagonists were infused into the PL-mPFC or BLA, followed by daily testing. PL-mPFC infusions before, but not after, a CPP trial disrupted CPP memory retrieval and induced a persistent deficit in retrieval during subsequent trials. In contrast, BLA β-AR blockade had no effect on initial CPP memory retrieval, but prevented CPP expression during subsequent trials indicative of reconsolidation disruption. Our results reveal a distinct dissociation between the neural mechanisms required for cocaine-associated memory retrieval and reconsolidation. Using patch-clamp electrophysiology, we also show that application of a β-AR antagonist prevents NE-induced potentiation of PL-mPFC pyramidal and GABAergic neuronal excitability. Thus, targeted β-AR blockade could induce long-term deficits in drug-associated memory retrieval by reducing neuronal excitability, providing a novel method of preventing cue-elicited drug seeking and relapse. PMID:23325262

c-Fos induction in mesotelencephalic dopamine pathway projection targets and dorsal striatum following oral intake of sugars and fats in rats.

PubMed

Dela Cruz, J A D; Coke, T; Karagiorgis, T; Sampson, C; Icaza-Cukali, D; Kest, K; Ranaldi, R; Bodnar, R J

2015-02-01

Overconsumption of nutrients high in fats and sugars can lead to obesity. Previous studies indicate that sugar or fat consumption activate individual brain sites using Fos-like immunoreactivity (FLI). Sugars and fats also elicit conditioned flavor preferences (CFP) that are differentially mediated by flavor-flavor (orosensory: f/f) and flavor-nutrient (post-ingestive: f/n) processes. Dopamine (DA) signaling in the medial prefrontal cortex (mPFC), the amygdala (AMY) and the nucleus accumbens (NAc), has been implicated in acquisition and expression of fat- and sugar-CFP. The present study examined the effects of acute consumption of fat (corn oil: f/f and f/n), glucose (f/f and f/n), fructose, (f/f only), saccharin, xanthan gum or water upon simultaneous FLI activation of DA mesotelencephalic nuclei (ventral tegmental area (VTA)) and projections (infralimbic and prelimbic mPFC, basolateral and central-cortico-medial AMY, core and shell of NAc as well as the dorsal striatum). Consumption of corn oil solutions, isocaloric to glucose and fructose, significantly increased FLI in all sites except for the NAc shell. Glucose intake significantly increased FLI in both AMY areas, dorsal striatum and NAc core, but not in either mPFC area, VTA or Nac shell. Correspondingly, fructose intake significantly increased FLI in the both AMY areas, the infralimbic mPFC and dorsal striatum, but not the prelimbic mPFC, VTA or either NAc area. Saccharin and xanthan gum intake failed to activate FLI relative to water. When significant FLI activation occurred, highly positive relationships were observed among sites, supporting the idea of activation of a distributed brain network mediating sugar and fat intake. Copyright © 2014 Elsevier Inc. All rights reserved.

PI3-kinase cascade has a differential role in acquisition and extinction of conditioned fear memory in juvenile and adult rats.

PubMed

Slouzkey, Ilana; Maroun, Mouna

2016-12-01

The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (PI3K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear and extinction in juvenile animals and whether these mechanisms are distinctive from those in adult animals. In the present study, we examined (1) changes in phosphorylation of Akt in the BLA and mPFC after fear conditioning and extinction in juvenile and adult rats and (2) the effect of BLA and mPFC localized inhibition of the PI3K following acquisition and extinction of contextual fear memory. Our results show that Akt phosphorylation is increased following acquisition of contextual fear learning in the BLA but not in the mPFC in adult and juvenile rats. Extinction learning was not associated with changes in Akt phosphorylation. Although there were no differences in the pattern of phosphorylation of Akt either in adult or juvenile rats, microinjection of the PI3K inhibitor, LY294002, into the BLA or mPFC elicited differential effects on fear memory acquisition and extinction, depending on the site and timing of the microinjection, as well as on the age of the animal. These results suggest that PI3K/Akt has a differential role in formation, retrieval, and extinction of contextual fear memory in juvenile and adult animals, and point to developmental differences between adult and juvenile rats in mechanisms of extinction. © 2016 Slouzkey and Maroun; Published by Cold Spring Harbor Laboratory Press.

Neurobiological dissociation of retrieval and reconsolidation of cocaine-associated memory.

PubMed

Otis, James M; Dashew, Kidane B; Mueller, Devin

2013-01-16

Drug use is provoked by the presentation of drug-associated cues, even following long periods of abstinence. Disruption of these learned associations would therefore limit relapse susceptibility. Drug-associated memories are susceptible to long-term disruption during retrieval and shortly after, during memory reconsolidation. Recent evidence reveals that retrieval and reconsolidation are dependent on β-adrenergic receptor (β-AR) activation. Despite this, whether retrieval and reconsolidation are dependent on identical or distinct neural mechanisms is unknown. The prelimbic medial prefrontal cortex (PL-mPFC) and basolateral amygdala (BLA) have been implicated in the expression and reconsolidation of associative memories. Therefore, we investigated the necessity of β-AR activation within the PL-mPFC and BLA for cocaine-associated memory retrieval and reconsolidation in rats. Before or immediately after a cocaine-induced conditioned place preference (CPP) retrieval trial, β-AR antagonists were infused into the PL-mPFC or BLA, followed by daily testing. PL-mPFC infusions before, but not after, a CPP trial disrupted CPP memory retrieval and induced a persistent deficit in retrieval during subsequent trials. In contrast, BLA β-AR blockade had no effect on initial CPP memory retrieval, but prevented CPP expression during subsequent trials indicative of reconsolidation disruption. Our results reveal a distinct dissociation between the neural mechanisms required for cocaine-associated memory retrieval and reconsolidation. Using patch-clamp electrophysiology, we also show that application of a β-AR antagonist prevents norepinephrine-induced potentiation of PL-mPFC pyramidal cell and γ-aminobutyric-acid (GABA) interneuron excitability. Thus, targeted β-AR blockade could induce long-term deficits in drug-associated memory retrieval by reducing neuronal excitability, providing a novel method of preventing cue-elicited drug seeking and relapse.

Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury.

PubMed

Schneider, Brandy L; Ghoddoussi, Farhad; Charlton, Jennifer L; Kohler, Robert J; Galloway, Matthew P; Perrine, Shane A; Conti, Alana C

2016-09-01

Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD). Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, we examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using proton magnetic resonance spectroscopy ex vivo, we examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall.

Amygdala functional disconnection with the prefrontal-cingulate-temporal circuit in chronic tinnitus patients with depressive mood.

PubMed

Chen, Yu-Chen; Bo, Fan; Xia, Wenqing; Liu, Shenghua; Wang, Peng; Su, Wen; Xu, Jin-Jing; Xiong, Zhenyu; Yin, Xindao

2017-10-03

Chronic tinnitus is often accompanied with depressive symptom, which may arise from aberrant functional coupling between the amygdala and cerebral cortex. To explore this hypothesis, resting-state functional magnetic resonance imaging (fMRI) was used to investigate the disrupted amygdala-cortical functional connectivity (FC) in chronic tinnitus patients with depressive mood. Chronic tinnitus patients with depressive mood (n=20), without depressive mood (n=20), and well-matched healthy controls (n=23) underwent resting-state fMRI scanning. Amygdala-cortical FC was characterized using a seed-based whole-brain correlation method. The bilateral amygdala FC was compared among the three groups. Compared to non-depressed patients, depressive tinnitus patients showed decreased amygdala FC with the prefrontal cortex and anterior cingulate cortex as well as increased amygdala FC with the postcentral gyrus and lingual gyrus. Relative to healthy controls, depressive tinnitus patients revealed decreased amygdala FC with the superior and middle temporal gyrus, anterior and posterior cingulate cortex, and prefrontal cortex, as well as increased amygdala FC with the postcentral gyrus and lingual gyrus. The current study identified for the first time abnormal resting-state amygdala-cortical FC with the prefrontal-cingulate-temporal circuit in chronic tinnitus patients with depressive mood, which will provide novel insight into the underlying neuropathological mechanisms of tinnitus-induced depressive disorder. Copyright © 2017 Elsevier Inc. All rights reserved.

Dopamine in the medial amygdala network mediates human bonding

PubMed Central

Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M.; Dickerson, Bradford C.; Catana, Ciprian; Barrett, Lisa Feldman

2017-01-01

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted. PMID:28193868

The vomeronasal cortex - afferent and efferent projections of the posteromedial cortical nucleus of the amygdala in mice.

PubMed

Gutiérrez-Castellanos, Nicolás; Pardo-Bellver, Cecília; Martínez-García, Fernando; Lanuza, Enrique

2014-01-01

Most mammals possess a vomeronasal system that detects predominantly chemical signals of biological relevance. Vomeronasal information is relayed to the accessory olfactory bulb (AOB), whose unique cortical target is the posteromedial cortical nucleus of the amygdala. This cortical structure should therefore be considered the primary vomeronasal cortex. In the present work, we describe the afferent and efferent connections of the posteromedial cortical nucleus of the amygdala in female mice, using anterograde (biotinylated dextranamines) and retrograde (Fluorogold) tracers, and zinc selenite as a tracer specific for zinc-enriched (putative glutamatergic) projections. The results show that the posteromedial cortical nucleus of the amygdala is strongly interconnected not only with the rest of the vomeronasal system (AOB and its target structures in the amygdala), but also with the olfactory system (piriform cortex, olfactory-recipient nuclei of the amygdala and entorhinal cortex). Therefore, the posteromedial cortical nucleus of the amygdala probably integrates olfactory and vomeronasal information. In addition, the posteromedial cortical nucleus of the amygdala shows moderate interconnections with the associative (basomedial) amygdala and with the ventral hippocampus, which may be involved in emotional and spatial learning (respectively) induced by chemical signals. Finally, the posteromedial cortical nucleus of the amygdala gives rise to zinc-enriched projections to the ventrolateral septum and the ventromedial striatum (including the medial islands of Calleja). This pattern of intracortical connections (with the olfactory cortex and hippocampus, mainly) and cortico-striatal excitatory projections (with the olfactory tubercle and septum) is consistent with its proposed nature as the primary vomeronasal cortex. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Effects of Intermittent Alcohol Exposure on Emotion and Cognition: A Potential Role for the Endogenous Cannabinoid System and Neuroinflammation

PubMed Central

Sanchez-Marin, Laura; Pavon, Francisco J.; Decara, Juan; Suarez, Juan; Gavito, Ana; Castilla-Ortega, Estela; Rodriguez de Fonseca, Fernando; Serrano, Antonia

2017-01-01

Intermittent alcohol exposure is a common pattern of adolescent alcohol use that can lead to binge drinking episodes. Alcohol use is known to modulate the endocannabinoid system (ECS), which is involved in neuronal communication, neuroplasticity, neuroinflammation and behavior. Adolescent male Wistar rats were exposed to 4-week intermittent alcohol intoxication (3 g/kg injections for 4 days/week) or saline (N = 12 per group). After alcohol deprivation, adult rats were assessed for emotionality and cognition and the gene expression of the ECS and other factors related to behavior and neuroinflammation was examined in the brain. Alcohol-exposed rats exhibited anxiogenic-like responses and impaired recognition memory but no motor alterations. There were brain region-dependent changes in the mRNA levels of the ECS and molecular signals compared with control rats. Thus, overall, alcohol-exposed rats expressed higher mRNA levels of endocannabinoid synthetic enzymes (N-acyl-phosphatidylethanolamine phospholipase D and diacylglycerol lipases) in the medial-prefrontal cortex (mPFC) but lower mRNA levels in the amygdala. Furthermore, we observed lower mRNA levels of receptors CB1 CB2 and peroxisome proliferator-activated receptor-α in the striatum. Regarding neuropeptide signaling, alcohol-exposed rats displayed lower mRNA levels of the neuropeptide Y signaling, particularly NPY receptor-2, in the amygdala and hippocampus and higher mRNA levels of corticotropin-releasing factor in the hippocampus. Additionally, we observed changes of several neuroinflammation-related factors. Whereas, the mRNA levels of toll-like receptor-4, tumor necrosis factor-α, cyclooxygenase-2 and glial fibrillary acidic protein were significantly increased in the mPFC, the mRNA levels of cyclooxygenase-2 and glial fibrillary acidic protein were decreased in the striatum and hippocampus. However, nuclear factor-κβ mRNA levels were lower in the mPFC and striatum and allograft inflammatory factor-1 levels were differentially expressed in the amygdala and hippocampus. In conclusion, rats exposed to adolescent intermittent alcohol displayed anxiety-like behavior and cognitive deficits in adulthood and these alterations were accompanied by brain region-dependent changes in the gene expression of the ECS and other signals associated with neuroinflammation and behavior. An intermittent adolescent alcohol exposure has behavioral and molecular consequences in the adult brain, which might be linked to higher vulnerability to addictive behaviors and psychopathologies. PMID:28223925

Distinguishing the roles of dorsolateral and anterior PFC in visual metacognition.

PubMed

Shekhar, Medha; Rahnev, Dobromir

2018-05-02

Visual metacognition depends on regions within the prefrontal cortex. Two areas in particular have been repeatedly implicated: the dorsolateral prefrontal cortex (DLPFC) and the anterior prefrontal cortex (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we employed online transcranial magnetic stimulation (TMS) to causally interfere with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision-making task and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability but only for the second half of the experimental blocks. These results support a functional architecture where DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgement by potentially incorporating additional, non-perceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation. SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its sub-regions - dorsolateral PFC (DLPFC) and anterior PFC (aPFC) - have specifically been implicated in confidence generation. However, it is unclear if these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation (TMS), we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, while targeting aPFC specifically affected metacognitive scores. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation. Copyright © 2018 the authors.

The medial prefrontal and orbitofrontal cortices differentially regulate dopamine system function.

PubMed

Lodge, Daniel J

2011-05-01

The prefrontal cortex (PFC) is essential for top-down control over higher-order executive function. In this study we demonstrate that the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) differentially regulate VTA dopamine neuron activity, and furthermore, the pattern of activity in the PFC drastically alters the dopamine neuron response. Thus, although single-pulse activation of the mPFC either excites or inhibits equivalent numbers of dopamine neurons, activation of the OFC induces a primarily inhibitory response. Moreover, activation of the PFC with a pattern that mimics spontaneous burst firing of pyramidal neurons produces a strikingly different response. Specifically, burst-like activation of the mPFC induces a massive increase in dopamine neuron firing, whereas a similar pattern of OFC activation largely inhibits dopamine activity. Taken together, these data demonstrate that the mPFC and OFC differentially regulate dopamine neuron activity, and that the pattern of cortical activation is critical for determining dopamine system output.

Neural processing of negative word stimuli concerning body image in patients with eating disorders: an fMRI study.

PubMed

Miyake, Yoshie; Okamoto, Yasumasa; Onoda, Keiichi; Shirao, Naoko; Okamoto, Yuri; Otagaki, Yoko; Yamawaki, Shigeto

2010-04-15

Eating disorders (EDs) are associated with abnormalities of body image perception. The aim of the present study was to investigate the functional abnormalities in brain systems during processing of negative words concerning body images in patients with EDs. Brain responses to negative words concerning body images (task condition) and neutral words (control condition) were measured using functional magnetic resonance imaging in 36 patients with EDs (12 with the restricting type anorexia nervosa; AN-R, 12 with the binging-purging type anorexia nervosa; AN-BP, and 12 with bulimia nervosa; BN) and 12 healthy young women. Participants were instructed to select the most negative word from each negative body-image word set and to select the most neutral word from each neutral word set. In the task relative to the control condition, the right amygdala was activated both in patients with AN-R and in patients with AN-BP. The left medial prefrontal cortex (mPFC) was activated both in patients with BN and in patients with AN-BP. It is suggested that these brain activations may be associated with abnormalities of body image perception. Amygdala activation may be involved in fearful emotional processing of negative words concerning body image and strong fears of gaining weight. One possible interpretation of the finding of mPFC activation is that it may reflect an attempt to regulate the emotion invoked by the stimuli. These abnormal brain functions may help provide better accounts of the psychopathological mechanisms underlying EDs. Copyright 2009 Elsevier Inc. All rights reserved.

Ingestion of dried-bonito broth (dashi) facilitates PV-parvalbumin-immunoreactive neurons in the brain, and affects emotional behaviors in mice.

PubMed

Jargalsaikhan, Undarmaa; Nishimaru, Hiroshi; Matsumoto, Jumpei; Takamura, Yusaku; Nakamura, Tomoya; Hori, Etsuro; Kondoh, Takashi; Ono, Taketoshi; Nishijo, Hisao

2017-12-01

Emerging evidence suggests that traditional diets and nutrition have a significant impact on brain development, and could contribute to the promotion of mental health and prevention of psychiatric disorders in children and adolescents. Moreover, deficits in parvalbumin (PV)-immunoreactive and/or GABAergic neurons are closely associated with various psychiatric disorders in children and adolescents. To investigate the possible neural mechanisms of diet involvement in mental health, we analyzed the effects of dried-bonito dashi (Japanese fish broth) (DBD) on PV-immunoreactive neurons and emotional behaviors in young mice. Male mice after weaning were fed DBD for 60 days, and tested with a resident-intruder test for aggressiveness and a forced swimming test for depression-like symptoms. After the behavioral testing, PV-immunoreactive neurons in the brain were immunohistochemically analyzed. The results indicated that DBD intake decreased aggressiveness and depression-like symptoms, and increased the densities of PV-immunoreactive neurons in the medial prefrontal cortex (mPFC), amygdala, hippocampus, and superior colliculus. These behavioral changes were correlated with the densities of PV-immunoreactive neurons in the mPFC, amygdala, and hippocampus. However, subdiaphragmatic vagotomy did not affect the effects of DBD on emotional behaviors, although it nonspecifically decreased the densities of PV-immunoreactive neurons. The results suggest that DBD might modulate emotional behaviors by promoting PV-immunoreactive and/or GABAergic neuronal activity through parallel routes. The present results highlight a new mechanism for diet involvement in brain functions, and suggest that DBD might have therapeutic potential for the promotion of mental health.

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.

Mifepristone Decreases Depression-Like Behavior and Modulates Neuroendocrine and Central Hypothalamic-Pituitary-Adrenocortical Axis Responsiveness to Stress

PubMed Central

Wulsin, Aynara C.; Herman, James P.; Solomon, Matia B.

2010-01-01

Summary Glucocorticoid dyshomeostasis is observed in a proportion of depressed individuals. As a result, glucocorticoid receptor (GR) antagonists are currently being tested as potential anti-depressants. The current study was designed to test the efficacy of mifepristone, a GR antagonist, in mitigating behavioral, neuroendocrine and central nervous system (CNS) responses to an acute stressor. Adult male rats were treated for five days with mifepristone (10 mg/kg) and then exposed to the forced swim test (FST). Treatment with mifepristone decreased immobility and increased swimming (but not climbing) behavior in the FST, consistent with antidepressant action. In addition, mifepristone dampened the ACTH response to FST exposure. In the CNS, mifepristone increased c-Fos expression in all subdivisions of the medial prefrontal cortex (mPFC) and decreased neuronal activity in some subdivisions of the hippocampus including the CA2, CA3, and hilus region of the dentate gyrus in animals exposed to FST. In contrast, mifepristone increased neuronal activity in the ventral subiculum (output region of the hippocampus) and decreased c-Fos expression in the central amygdala (CeA) in animals exposed to FST. These data suggest that antidepressant efficacy and perhaps HPA dampening properties of RU486 are related to alterations in key limbic circuits mediating CNS stress responses, resulting in enhanced stress inhibition (via the mPFC and ventral subiculum) as well as decreased stress excitation (central amygdala). Overall the data suggest that drugs targeting the glucocorticoid receptor may ameliorate stress dysfunction associated with depressive illness. PMID:20149549

Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer.

PubMed

Eddy, Meghan C; Todd, Travis P; Bouton, Mark E; Green, John T

2016-02-01

Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction. Copyright © 2015 Elsevier Inc. All rights reserved.

The neural bases for devaluing radical political statements revealed by penetrating traumatic brain injury

PubMed Central

Cristofori, Irene; Viola, Vanda; Chau, Aileen; Zhong, Wanting; Krueger, Frank; Zamboni, Giovanna; Grafman, Jordan

2015-01-01

Given the determinant role of ventromedial prefrontal cortex (vmPFC) in valuation, we examined whether vmPFC lesions also modulate how people scale political beliefs. Patients with penetrating traumatic brain injury (pTBI; N = 102) and healthy controls (HCs; N = 31) were tested on the political belief task, where they rated 75 statements expressing political opinions concerned with welfare, economy, political involvement, civil rights, war and security. Each statement was rated for level of agreement and scaled along three dimensions: radicalism, individualism and conservatism. Voxel-based lesion-symptom mapping (VLSM) analysis showed that diminished scores for the radicalism dimension (i.e. statements were rated as less radical than the norms) were associated with lesions in bilateral vmPFC. After dividing the pTBI patients into three groups, according to lesion location (i.e. vmPFC, dorsolateral prefrontal cortex [dlPFC] and parietal cortex), we found that the vmPFC, but not the dlPFC, group had reduced radicalism scores compared with parietal and HC groups. These findings highlight the crucial role of the vmPFC in appropriately valuing political behaviors and may explain certain inappropriate social judgments observed in patients with vmPFC lesions. PMID:25656509

Encoding of contextual fear memory requires de novo proteins in the prelimbic cortex

PubMed Central

Rizzo, Valerio; Touzani, Khalid; Raveendra, Bindu L.; Swarnkar, Supriya; Lora, Joan; Kadakkuzha, Beena M.; Liu, Xin-An; Zhang, Chao; Betel, Doron; Stackman, Robert W.; Puthanveettil, Sathyanarayanan V.

2016-01-01

Background Despite our understanding of the significance of the prefrontal cortex in the consolidation of long-term memories (LTM), its role in the encoding of LTM remains elusive. Here we investigated the role of new protein synthesis in the mouse medial prefrontal cortex (mPFC) in encoding contextual fear memory. Methods Because a change in the association of mRNAs to polyribosomes is an indicator of new protein synthesis, we assessed the changes in polyribosome-associated mRNAs in the mPFC following contextual fear conditioning (CFC) in the mouse. Differential gene expression in mPFC was identified by polyribosome profiling (n = 18). The role of new protein synthesis in mPFC was determined by focal inhibition of protein synthesis (n = 131) and by intra-prelimbic cortex manipulation (n = 56) of Homer 3, a candidate identified from polyribosome profiling. Results We identified several mRNAs that are differentially and temporally recruited to polyribosomes in the mPFC following CFC. Inhibition of protein synthesis in the prelimbic (PL), but not in the anterior cingulate cortex (ACC) region of the mPFC immediately after CFC disrupted encoding of contextual fear memory. Intriguingly, inhibition of new protein synthesis in the PL 6 hours after CFC did not impair encoding. Furthermore, expression of Homer 3, an mRNA enriched in polyribosomes following CFC, in the PL constrained encoding of contextual fear memory. Conclusions Our studies identify several molecular substrates of new protein synthesis in the mPFC and establish that encoding of contextual fear memories require new protein synthesis in PL subregion of mPFC. PMID:28503670

Levels of integration in cognitive control and sequence processing in the prefrontal cortex.

PubMed

Bahlmann, Jörg; Korb, Franziska M; Gratton, Caterina; Friederici, Angela D

2012-01-01

Cognitive control is necessary to flexibly act in changing environments. Sequence processing is needed in language comprehension to build the syntactic structure in sentences. Functional imaging studies suggest that sequence processing engages the left ventrolateral prefrontal cortex (PFC). In contrast, cognitive control processes additionally recruit bilateral rostral lateral PFC regions. The present study aimed to investigate these two types of processes in one experimental paradigm. Sequence processing was manipulated using two different sequencing rules varying in complexity. Cognitive control was varied with different cue-sets that determined the choice of a sequencing rule. Univariate analyses revealed distinct PFC regions for the two types of processing (i.e. sequence processing: left ventrolateral PFC and cognitive control processing: bilateral dorsolateral and rostral PFC). Moreover, in a common brain network (including left lateral PFC and intraparietal sulcus) no interaction between sequence and cognitive control processing was observed. In contrast, a multivariate pattern analysis revealed an interaction of sequence and cognitive control processing, such that voxels in left lateral PFC and parietal cortex showed different tuning functions for tasks involving different sequencing and cognitive control demands. These results suggest that the difference between the process of rule selection (i.e. cognitive control) and the process of rule-based sequencing (i.e. sequence processing) find their neuronal underpinnings in distinct activation patterns in lateral PFC. Moreover, the combination of rule selection and rule sequencing can shape the response of neurons in lateral PFC and parietal cortex.

Levels of Integration in Cognitive Control and Sequence Processing in the Prefrontal Cortex

PubMed Central

Bahlmann, Jörg; Korb, Franziska M.; Gratton, Caterina; Friederici, Angela D.

2012-01-01

Cognitive control is necessary to flexibly act in changing environments. Sequence processing is needed in language comprehension to build the syntactic structure in sentences. Functional imaging studies suggest that sequence processing engages the left ventrolateral prefrontal cortex (PFC). In contrast, cognitive control processes additionally recruit bilateral rostral lateral PFC regions. The present study aimed to investigate these two types of processes in one experimental paradigm. Sequence processing was manipulated using two different sequencing rules varying in complexity. Cognitive control was varied with different cue-sets that determined the choice of a sequencing rule. Univariate analyses revealed distinct PFC regions for the two types of processing (i.e. sequence processing: left ventrolateral PFC and cognitive control processing: bilateral dorsolateral and rostral PFC). Moreover, in a common brain network (including left lateral PFC and intraparietal sulcus) no interaction between sequence and cognitive control processing was observed. In contrast, a multivariate pattern analysis revealed an interaction of sequence and cognitive control processing, such that voxels in left lateral PFC and parietal cortex showed different tuning functions for tasks involving different sequencing and cognitive control demands. These results suggest that the difference between the process of rule selection (i.e. cognitive control) and the process of rule-based sequencing (i.e. sequence processing) find their neuronal underpinnings in distinct activation patterns in lateral PFC. Moreover, the combination of rule selection and rule sequencing can shape the response of neurons in lateral PFC and parietal cortex. PMID:22952762

Temporal kinetics of prefrontal modulation of the extrastriate cortex during visual attention.

PubMed

Yago, Elena; Duarte, Audrey; Wong, Ting; Barceló, Francisco; Knight, Robert T

2004-12-01

Single-unit, event-related potential (ERP), and neuroimaging studies have implicated the prefrontal cortex (PFC) in top-down control of attention and working memory. We conducted an experiment in patients with unilateral PFC damage (n = 8) to assess the temporal kinetics of PFC-extrastriate interactions during visual attention. Subjects alternated attention between the left and the right hemifields in successive runs while they detected target stimuli embedded in streams of repetitive task-irrelevant stimuli (standards). The design enabled us to examine tonic (spatial selection) and phasic (feature selection) PFC-extrastriate interactions. PFC damage impaired performance in the visual field contralateral to lesions, as manifested by both larger reaction times and error rates. Assessment of the extrastriate P1 ERP revealed that the PFC exerts a tonic (spatial selection) excitatory input to the ipsilateral extrastriate cortex as early as 100 msec post stimulus delivery. The PFC exerts a second phasic (feature selection) excitatory extrastriate modulation from 180 to 300 msec, as evidenced by reductions in selection negativity after damage. Finally, reductions of the N2 ERP to target stimuli supports the notion that the PFC exerts a third phasic (target selection) signal necessary for successful template matching during postselection analysis of target features. The results provide electrophysiological evidence of three distinct tonic and phasic PFC inputs to the extrastriate cortex in the initial few hundred milliseconds of stimulus processing. Damage to this network appears to underlie the pervasive deficits in attention observed in patients with prefrontal lesions.

Contributions of primate prefrontal cortex and medial temporal lobe to temporal-order memory.

PubMed

Naya, Yuji; Chen, He; Yang, Cen; Suzuki, Wendy A

2017-12-19

Neuropsychological and neurophysiological studies have emphasized the role of the prefrontal cortex (PFC) in maintaining information about the temporal order of events or items for upcoming actions. However, the medial temporal lobe (MTL) has also been considered critical to bind individual events or items to their temporal context in episodic memory. Here we characterize the contributions of these brain areas by comparing single-unit activity in the dorsal and ventral regions of macaque lateral PFC (d-PFC and v-PFC) with activity in MTL areas including the hippocampus (HPC), entorhinal cortex, and perirhinal cortex (PRC) as well as in area TE during the encoding phase of a temporal-order memory task. The v-PFC cells signaled specific items at particular time periods of the task. By contrast, MTL cortical cells signaled specific items across multiple time periods and discriminated the items between time periods by modulating their firing rates. Analysis of the temporal dynamics of these signals showed that the conjunctive signal of item and temporal-order information in PRC developed earlier than that seen in v-PFC. During the delay interval between the two cue stimuli, while v-PFC provided prominent stimulus-selective delay activity, MTL areas did not. Both regions of PFC and HPC exhibited an incremental timing signal that appeared to represent the continuous passage of time during the encoding phase. However, the incremental timing signal in HPC was more prominent than that observed in PFC. These results suggest that PFC and MTL contribute to the encoding of the integration of item and timing information in distinct ways.

Amygdala and auditory cortex exhibit distinct sensitivity to relevant acoustic features of auditory emotions.

PubMed

Pannese, Alessia; Grandjean, Didier; Frühholz, Sascha

2016-12-01

Discriminating between auditory signals of different affective value is critical to successful social interaction. It is commonly held that acoustic decoding of such signals occurs in the auditory system, whereas affective decoding occurs in the amygdala. However, given that the amygdala receives direct subcortical projections that bypass the auditory cortex, it is possible that some acoustic decoding occurs in the amygdala as well, when the acoustic features are relevant for affective discrimination. We tested this hypothesis by combining functional neuroimaging with the neurophysiological phenomena of repetition suppression (RS) and repetition enhancement (RE) in human listeners. Our results show that both amygdala and auditory cortex responded differentially to physical voice features, suggesting that the amygdala and auditory cortex decode the affective quality of the voice not only by processing the emotional content from previously processed acoustic features, but also by processing the acoustic features themselves, when these are relevant to the identification of the voice's affective value. Specifically, we found that the auditory cortex is sensitive to spectral high-frequency voice cues when discriminating vocal anger from vocal fear and joy, whereas the amygdala is sensitive to vocal pitch when discriminating between negative vocal emotions (i.e., anger and fear). Vocal pitch is an instantaneously recognized voice feature, which is potentially transferred to the amygdala by direct subcortical projections. These results together provide evidence that, besides the auditory cortex, the amygdala too processes acoustic information, when this is relevant to the discrimination of auditory emotions. Copyright © 2016 Elsevier Ltd. All rights reserved.

The postnatal 5-HT1A receptor regulates adult anxiety and depression differently via multiple molecules.

PubMed

Ishikawa, Chihiro; Shiga, Takashi

2017-08-01

Serotonin (5-HT) and the 5-HT 1A receptor during development are known to modulate anxiety and depression in later life. However, the brain mechanisms linking the postnatal 5-HT system and adult behavior remain unknown. Here, we examined the effects of pharmacological 5-HT 1A receptor activation during the postnatal period on anxiety and depression-like behavior in adult BALB/c male mice. To elucidate the underlying mechanisms, we measured mRNA expression of the 5-HT 1A receptor, brain-derived neurotrophic factor (BDNF), GABA A receptor subunits, and AMPA receptor subunits in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Treatment with the selective 5-HT reuptake inhibitor (fluoxetine) and 5-HT 1A receptor agonist (8-OH-DPAT) during the postnatal period decreased anxiety-like behavior in adulthood, whereas only 8-OH-DPAT treatment increased depression-like behavior. Concomitantly with the behavioral effects, postnatal treatment with fluoxetine and 8-OH-DPAT decreased the mRNA expression of the GABA A receptor α3 subunit in the mPFC and ventral hippocampus in adulthood, while 8-OH-DPAT, but not fluoxetine, decreased the mRNA expression of the 5-HT 1A receptor and BDNF in the mPFC and the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. On the basis of the correlative changes between behavior and mRNA expression, these results suggest that the GABA A receptor α3 subunit in the mPFC and ventral hippocampus may regulate anxiety-like behavior. In contrast, depression-like behavior may be regulated by the 5-HT 1A receptor and BDNF in the mPFC and by the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. In summary, activation of the 5-HT 1A receptor during the postnatal period may reduce anxiety levels, but increase depression levels during adulthood via different multiple molecules in the mPFC and ventral hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Cognitive regulation during decision making shifts behavioral control between ventromedial and dorsolateral prefrontal value systems.

PubMed

Hutcherson, Cendri A; Plassmann, Hilke; Gross, James J; Rangel, Antonio

2012-09-26

Cognitive regulation is often used to influence behavioral outcomes. However, the computational and neurobiological mechanisms by which it affects behavior remain unknown. We studied this issue using an fMRI task in which human participants used cognitive regulation to upregulate and downregulate their cravings for foods at the time of choice. We found that activity in both ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) correlated with value. We also found evidence that two distinct regulatory mechanisms were at work: value modulation, which operates by changing the values assigned to foods in vmPFC and dlPFC at the time of choice, and behavioral control modulation, which operates by changing the relative influence of the vmPFC and dlPFC value signals on the action selection process used to make choices. In particular, during downregulation, activation decreased in the value-sensitive region of dlPFC (indicating value modulation) but not in vmPFC, and the relative contribution of the two value signals to behavior shifted toward the dlPFC (indicating behavioral control modulation). The opposite pattern was observed during upregulation: activation increased in vmPFC but not dlPFC, and the relative contribution to behavior shifted toward the vmPFC. Finally, ventrolateral PFC and posterior parietal cortex were more active during both upregulation and downregulation, and were functionally connected with vmPFC and dlPFC during cognitive regulation, which suggests that they help to implement the changes to the decision-making circuitry generated by cognitive regulation.

Cognitive Regulation during Decision Making Shifts Behavioral Control between Ventromedial and Dorsolateral Prefrontal Value Systems

PubMed Central

Plassmann, Hilke; Gross, James J.; Rangel, Antonio

2012-01-01

Cognitive regulation is often used to influence behavioral outcomes. However, the computational and neurobiological mechanisms by which it affects behavior remain unknown. We studied this issue using an fMRI task in which human participants used cognitive regulation to upregulate and downregulate their cravings for foods at the time of choice. We found that activity in both ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) correlated with value. We also found evidence that two distinct regulatory mechanisms were at work: value modulation, which operates by changing the values assigned to foods in vmPFC and dlPFC at the time of choice, and behavioral control modulation, which operates by changing the relative influence of the vmPFC and dlPFC value signals on the action selection process used to make choices. In particular, during downregulation, activation decreased in the value-sensitive region of dlPFC (indicating value modulation) but not in vmPFC, and the relative contribution of the two value signals to behavior shifted toward the dlPFC (indicating behavioral control modulation). The opposite pattern was observed during upregulation: activation increased in vmPFC but not dlPFC, and the relative contribution to behavior shifted toward the vmPFC. Finally, ventrolateral PFC and posterior parietal cortex were more active during both upregulation and downregulation, and were functionally connected with vmPFC and dlPFC during cognitive regulation, which suggests that they help to implement the changes to the decision-making circuitry generated by cognitive regulation. PMID:23015444

Individual Differences in Anticipatory Somatosensory Cortex Activity for Shock is Positively Related with Trait Anxiety and Multisensory Integration

PubMed Central

Greening, Steven G.; Lee, Tae-Ho; Mather, Mara

2016-01-01

Anxiety is associated with an exaggerated expectancy of harm, including overestimation of how likely a conditioned stimulus (CS+) predicts a harmful unconditioned stimulus (US). In the current study we tested whether anxiety-associated expectancy of harm increases primary sensory cortex (S1) activity on non-reinforced (i.e., no shock) CS+ trials. Twenty healthy volunteers completed a differential-tone trace conditioning task while undergoing fMRI, with shock delivered to the left hand. We found a positive correlation between trait anxiety and activity in right, but not left, S1 during CS+ versus CS− conditions. Right S1 activity also correlated with individual differences in both primary auditory cortices (A1) and amygdala activity. Lastly, a seed-based functional connectivity analysis demonstrated that trial-wise S1 activity was positively correlated with regions of dorsolateral prefrontal cortex (dlPFC), suggesting that higher-order cognitive processes contribute to the anticipatory sensory reactivity. Our findings indicate that individual differences in trait anxiety relate to anticipatory reactivity for the US during associative learning. This anticipatory reactivity is also integrated along with emotion-related sensory signals into a brain network implicated in fear-conditioned responding. PMID:26751483

Individual Differences in Anticipatory Somatosensory Cortex Activity for Shock is Positively Related with Trait Anxiety and Multisensory Integration.

PubMed

Greening, Steven G; Lee, Tae-Ho; Mather, Mara

2016-01-06

Anxiety is associated with an exaggerated expectancy of harm, including overestimation of how likely a conditioned stimulus (CS+) predicts a harmful unconditioned stimulus (US). In the current study we tested whether anxiety-associated expectancy of harm increases primary sensory cortex (S1) activity on non-reinforced (i.e., no shock) CS+ trials. Twenty healthy volunteers completed a differential-tone trace conditioning task while undergoing fMRI, with shock delivered to the left hand. We found a positive correlation between trait anxiety and activity in right, but not left, S1 during CS+ versus CS- conditions. Right S1 activity also correlated with individual differences in both primary auditory cortices (A1) and amygdala activity. Lastly, a seed-based functional connectivity analysis demonstrated that trial-wise S1 activity was positively correlated with regions of dorsolateral prefrontal cortex (dlPFC), suggesting that higher-order cognitive processes contribute to the anticipatory sensory reactivity. Our findings indicate that individual differences in trait anxiety relate to anticipatory reactivity for the US during associative learning. This anticipatory reactivity is also integrated along with emotion-related sensory signals into a brain network implicated in fear-conditioned responding.

Repeated microinjections into the medial prefrontal cortex (mPFC) impair extinction of conditioned place preference in mice.

PubMed

Groblewski, Peter A; Cunningham, Christopher L

2012-04-21

The medial prefrontal cortex (mPFC) is important for extinction of many behaviors including conditioned place preference (CPP). We examined the effects of intra-mPFC inactivation (with bupivacaine) on extinction of ethanol-induced CPP in mice. Injections of both bupivacaine and vehicle impaired extinction whereas no-surgery control mice extinguished normally. Consistent with recently reported effects of mPFC lesions, these data suggest that extinction was impaired by excessive mPFC damage induced by repeated intracranial infusions. Copyright © 2012 Elsevier B.V. All rights reserved.

On the Origin of Cortical Dopamine: Is it a Co-Transmitter in Noradrenergic Neurons?

PubMed Central

Devoto, Paola; Flore, Giovanna

2006-01-01

Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA. To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter. Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas. Systemic administration or intra-cortical perfusion of α2-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex. Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC. Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced. Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of α2-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex. Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in contrast with augmented dopaminergic neuronal activity; moreover, during morphine withdrawal both DA and NA levels increased, in spite of a diminished dopaminergic activity, both increases being antagonised by clonidine but not quinpirole administration. Extensive 6-hydroxy dopamine lesion of the ventral tegmental area (VTA) decreases below 95% of control both intra- and extracellular DA and DOPAC in the nucleus accumbens, but only partially or not significantly in the mPFC and parietal cortex. The above evidence points to a common origin for NA and DA in the cerebral cortex and suggests the possible utility of noradrenergic system modulation as a target for drugs with potential clinical efficacy on cognitive functions. PMID:18615131

On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons?

PubMed

Devoto, Paola; Flore, Giovanna

2006-04-01

Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA.To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter.Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas.Systemic administration or intra-cortical perfusion of alpha(2)-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex.Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC.Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced.Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of alpha(2)-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex.Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in contrast with augmented dopaminergic neuronal activity; moreover, during morphine withdrawal both DA and NA levels increased, in spite of a diminished dopaminergic activity, both increases being antagonised by clonidine but not quinpirole administration.Extensive 6-hydroxy dopamine lesion of the ventral tegmental area (VTA) decreases below 95% of control both intra- and extracellular DA and DOPAC in the nucleus accumbens, but only partially or not significantly in the mPFC and parietal cortex.The above evidence points to a common origin for NA and DA in the cerebral cortex and suggests the possible utility of noradrenergic system modulation as a target for drugs with potential clinical efficacy on cognitive functions.

Medial Prefrontal Cortex Is Selectively Involved in Response Selection Using Visual Context in the Background

ERIC Educational Resources Information Center

Lee, Inah; Shin, Ji Yun

2012-01-01

The exact roles of the medial prefrontal cortex (mPFC) in conditional choice behavior are unknown and a visual contextual response selection task was used for examining the issue. Inactivation of the mPFC severely disrupted performance in the task. mPFC inactivations, however, did not disrupt the capability of perceptual discrimination for visual…

Differential Effects of Insular and Ventromedial Prefrontal Cortex Lesions on Risky Decision-Making

ERIC Educational Resources Information Center

Clark, L.; Bechara, A.; Damasio, H.; Aitken, M. R. F.; Sahakian, B. J.; Robbins, T. W.

2008-01-01

The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear…

The neural bases for devaluing radical political statements revealed by penetrating traumatic brain injury.

PubMed

Cristofori, Irene; Viola, Vanda; Chau, Aileen; Zhong, Wanting; Krueger, Frank; Zamboni, Giovanna; Grafman, Jordan

2015-08-01

Given the determinant role of ventromedial prefrontal cortex (vmPFC) in valuation, we examined whether vmPFC lesions also modulate how people scale political beliefs. Patients with penetrating traumatic brain injury (pTBI; N = 102) and healthy controls (HCs; N = 31) were tested on the political belief task, where they rated 75 statements expressing political opinions concerned with welfare, economy, political involvement, civil rights, war and security. Each statement was rated for level of agreement and scaled along three dimensions: radicalism, individualism and conservatism. Voxel-based lesion-symptom mapping (VLSM) analysis showed that diminished scores for the radicalism dimension (i.e. statements were rated as less radical than the norms) were associated with lesions in bilateral vmPFC. After dividing the pTBI patients into three groups, according to lesion location (i.e. vmPFC, dorsolateral prefrontal cortex [dlPFC] and parietal cortex), we found that the vmPFC, but not the dlPFC, group had reduced radicalism scores compared with parietal and HC groups. These findings highlight the crucial role of the vmPFC in appropriately valuing political behaviors and may explain certain inappropriate social judgments observed in patients with vmPFC lesions. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Endocannabinoids in brain plasticity: Cortical maturation, HPA axis function and behavior.

PubMed

Dow-Edwards, Diana; Silva, Lindsay

2017-01-01

Marijuana use during adolescence has reached virtually every strata of society. The general population has the perception that marijuana use is safe for mature people and therefore is also safe for developing adolescents. However, both clinical and preclinical research shows that marijuana use, particularly prior to age 16, could have long-term effects on cognition, anxiety and stress-related behaviors, mood disorders and substance abuse. These effects derive from the role of the endocannabinoid system, the endogenous cannabinoid system, in the development of cortex, amygdala, hippocampus and hypothalamus during adolescence. Endocannabinoids are necessary for normal neuronal excitation and inhibition through actions at glutamate and GABA terminals. Synaptic pruning at excitatory synapses and sparing of inhibitory synapses likely results in changes in the balance of excitation/inhibition in individual neurons and within networks; processes which are necessary for normal cortical development. The interaction between prefrontal cortex (PFC), amygdala and hippocampus is responsible for emotional memory, anxiety-related behaviors and drug abuse and all utilize the endogenous cannabinoid system to maintain homeostasis. Also, endocannabinoids are required for fast and slow feedback in the normal stress response, processes which mature during adolescence. Therefore, exogenous cannabinoids, such as marijuana, have the potential to alter the course of development of each of these major systems (limbic, hypothalamic-pituitary-adrenal (HPA) axis and neocortex) if used during the critical period of brain development, adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.

Activation of beta2-Adrenoceptor Enhances Synaptic Potentiation and Behavioral Memory via cAMP-PKA Signaling in the Medial Prefrontal Cortex of Rats

ERIC Educational Resources Information Center

Zhou, Hou-Cheng; Sun, Yan-Yan; Cai, Wei; He, Xiao-Ting; Yi, Feng; Li, Bao-Ming; Zhang, Xue-Han

2013-01-01

The prefrontal cortex (PFC) plays a critical role in cognitive functions, including working memory, attention regulation, behavioral inhibition, as well as memory storage. The functions of PFC are very sensitive to norepinephrine (NE), and even low levels of endogenously released NE exert a dramatic influence on the functioning of the PFC.…

The differential contributions of pFC and temporo-parietal cortex to multimodal semantic control: exploring refractory effects in semantic aphasia.

PubMed

Gardner, Hannah E; Lambon Ralph, Matthew A; Dodds, Naomi; Jones, Theresa; Ehsan, Sheeba; Jefferies, Elizabeth

2012-04-01

Aphasic patients with multimodal semantic impairment following pFC or temporo-parietal (TP) cortex damage (semantic aphasia [SA]) have deficits characterized by poor control of semantic activation/retrieval, as opposed to loss of semantic knowledge per se. In line with this, SA patients show "refractory effects"; that is, declining accuracy in cyclical word-picture matching tasks when semantically related sets are presented rapidly and repeatedly. This is argued to follow a build-up of competition between targets and distractors. However, the link between poor semantic control and refractory effects is still controversial for two reasons. (1) Some theories propose that refractory effects are specific to verbal or auditory tasks, yet SA patients show poor control over semantic processing in both word and picture semantic tasks. (2) SA can result from lesions to either the left pFC or TP cortex, yet previous work suggests that refractory effects are specifically linked to the left inferior frontal cortex. For the first time, verbal, visual, and nonverbal auditory refractory effects were explored in nine SA patients who had pFC (pFC+) or TP cortex (TP-only) lesions. In all modalities, patient accuracy declined significantly over repetitions. This refractory effect at the group level was driven by pFC+ patients and was not shown by individuals with TP-only lesions. These findings support the theory that SA patients have reduced control over multimodal semantic retrieval and, additionally, suggest there may be functional specialization within the posterior versus pFC elements of the semantic control network.

Intrusive Memories of Distressing Information: An fMRI Study

PubMed Central

Battaglini, Eva; Liddell, Belinda; Das, Pritha; Malhi, Gin; Felmingham, Kim

2016-01-01

Although intrusive memories are characteristic of many psychological disorders, the neurobiological underpinning of these involuntary recollections are largely unknown. In this study we used functional magentic resonance imaging (fMRI) to identify the neural networks associated with encoding of negative stimuli that are subsequently experienced as intrusive memories. Healthy partipants (N = 42) viewed negative and neutral images during a visual/verbal processing task in an fMRI context. Two days later they were assessed on the Impact of Event Scale for occurrence of intrusive memories of the encoded images. A sub-group of participants who reported significant intrusions (n = 13) demonstrated stronger activation in the amygdala, bilateral ACC and parahippocampal gyrus during verbal encoding relative to a group who reported no intrusions (n = 13). Within-group analyses also revealed that the high intrusion group showed greater activity in the dorsomedial (dmPFC) and dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus and occipital regions during negative verbal processing compared to neutral verbal processing. These results do not accord with models of intrusions that emphasise visual processing of information at encoding but are consistent with models that highlight the role of inhibitory and suppression processes in the formation of subsequent intrusive memories. PMID:27685784

Thinning of the lateral prefrontal cortex during adolescence predicts emotion regulation in females.

PubMed

Vijayakumar, Nandita; Whittle, Sarah; Yücel, Murat; Dennison, Meg; Simmons, Julian; Allen, Nicholas B

2014-11-01

Adolescence is a crucial period for the development of adaptive emotion regulation strategies. Despite the fact that structural maturation of the prefrontal cortex during adolescence is often assumed to underlie the maturation of emotion regulation strategies, no longitudinal studies have directly assessed this relationship. This study examined whether use of cognitive reappraisal strategies during late adolescence was predicted by (i) absolute prefrontal cortical thickness during early adolescence and (ii) structural maturation of the prefrontal cortex between early and mid-adolescence. Ninety-two adolescents underwent baseline and follow-up magnetic resonance imaging scans when they were aged approximately 12 and 16 years, respectively. FreeSurfer software was used to obtain cortical thickness estimates for three prefrontal regions [anterior cingulate cortex; dorsolateral prefrontal cortex (dlPFC); ventrolateral prefrontal cortex (vlPFC)]. The Emotion Regulation Questionnaire was completed when adolescents were aged approximately 19 years. Results showed that greater cortical thinning of the left dlPFC and left vlPFC during adolescence was significantly associated with greater use of cognitive reappraisal in females, though no such relationship was evident in males. Furthermore, baseline left dlPFC thickness predicted cognitive reappraisal at trend level. These findings suggest that cortical maturation may play a role in the development of adaptive emotion regulation strategies during adolescence. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Role of the ventrolateral orbital cortex and medial prefrontal cortex in incentive downshift situations.

PubMed

Ortega, Leonardo A; Glueck, Amanda C; Uhelski, Megan; Fuchs, Perry N; Papini, Mauricio R

2013-05-01

The present research evaluated the role of two prefrontal cortex areas, the ventrolateral orbital cortex (VLO) and the medial prefrontal cortex (mPFC), on two situations involving incentive downshifts, consummatory successive negative contrast (cSNC) with sucrose solutions and Pavlovian autoshaping following continuous vs. partial reinforcement with food pellets. Animals received electrolytic lesions and then were tested on cSNC, autoshaping, open-field activity, and sucrose sensitivity. Lesions of the VLO reduced suppression of consummatory behavior after the incentive downshift, but only during the first downshift trial, and also eliminated the enhancement of anticipatory behavior during partial reinforcement, relative to continuous reinforcement, in autoshaping. There was no evidence of specific effects of mPFC lesions on incentive downshifts. Open-field activity was also reduced by VLO lesions, but only in the central area, whereas mPFC lesions had no observable effects on activity. Animals with mPFC lesions exhibited decreased consumption of the lowest sucrose concentration, whereas no effects were observed in animals with VLO lesions. These results suggest that the VLO may exert nonassociative (i.e., motivational, emotional) influences on behavior in situations involving incentive downshifts. No clear role on incentive downshift was revealed by mPFC lesions. Copyright © 2013 Elsevier B.V. All rights reserved.

Neurocognitive development of the ability to manipulate information in working memory.

PubMed

Crone, Eveline A; Wendelken, Carter; Donohue, Sarah; van Leijenhorst, Linda; Bunge, Silvia A

2006-06-13

The ability to manipulate information in working memory is a key factor in cognitive development. Here, we used event-related functional MRI to test the hypothesis that developmental improvements in manipulation, relative to pure maintenance, are associated with increased recruitment of dorsolateral (DL) prefrontal cortex (PFC) and superior parietal cortex. Three age groups (8-12 years old, 13-17 years old, and 18-25 years old) performed an object-working memory task with separate maintenance and manipulation conditions. We found that 8- to 12-year-olds did not perform the task as well as adolescents or adults, particularly on trials requiring manipulation in addition to maintenance. In this study, no age differences were observed in the activation profile of ventrolateral PFC, a region associated with online maintenance. In contrast, unlike the older participants, 8- to 12-year-olds failed to recruit right DL PFC and bilateral superior parietal cortex during the delay period for manipulation relative to maintenance. This group difference was observed specifically during the delay period, while participants reordered items in working memory, and could not be accounted for by group differences in performance. Across participants, activation levels in right DL PFC and superior parietal cortex, but not ventrolateral PFC, were positively correlated with performance on manipulation trials. These results indicate that increased recruitment of right DL PFC and bilateral parietal cortex during adolescence is associated with improvements in the ability to work with object representations.

Past makes future: role of pFC in prediction.

PubMed

Fuster, Joaquín M; Bressler, Steven L

2015-04-01

The pFC enables the essential human capacities for predicting future events and preadapting to them. These capacities rest on both the structure and dynamics of the human pFC. Structurally, pFC, together with posterior association cortex, is at the highest hierarchical level of cortical organization, harboring neural networks that represent complex goal-directed actions. Dynamically, pFC is at the highest level of the perception-action cycle, the circular processing loop through the cortex that interfaces the organism with the environment in the pursuit of goals. In its predictive and preadaptive roles, pFC supports cognitive functions that are critical for the temporal organization of future behavior, including planning, attentional set, working memory, decision-making, and error monitoring. These functions have a common future perspective and are dynamically intertwined in goal-directed action. They all utilize the same neural infrastructure: a vast array of widely distributed, overlapping, and interactive cortical networks of personal memory and semantic knowledge, named cognits, which are formed by synaptic reinforcement in learning and memory acquisition. From this cortex-wide reservoir of memory and knowledge, pFC generates purposeful, goal-directed actions that are preadapted to predicted future events.

Medial Prefrontal Cortex Reduces Memory Interference by Modifying Hippocampal Encoding

PubMed Central

Guise, Kevin G.; Shapiro, Matthew L.

2017-01-01

Summary The prefrontal cortex (PFC) is crucial for accurate memory performance when prior knowledge interferes with new learning, but the mechanisms that minimize proactive interference are unknown. To investigate these, we assessed the influence of medial PFC (mPFC) activity on spatial learning and hippocampal coding in a plus maze task that requires both structures. mPFC inactivation did not impair spatial learning or retrieval per se, but impaired the ability to follow changing spatial rules. mPFC and CA1 ensembles recorded simultaneously predicted goal choices and tracked changing rules; inactivating mPFC attenuated CA1 prospective coding. mPFC activity modified CA1 codes during learning, which in turn predicted how quickly rats adapted to subsequent rule changes. The results suggest that task rules signaled by the mPFC become incorporated into hippocampal representations and support prospective coding. By this mechanism, mPFC activity prevents interference by “teaching” the hippocampus to retrieve distinct representations of similar circumstances. PMID:28343868

INCREASES IN FUNCTIONAL CONNECTIVITY BETWEEN PREFRONTAL CORTEX AND STRIATUM DURING CATEGORY LEARNING

PubMed Central

Antzoulatos, Evan G.; Miller, Earl K.

2014-01-01

SUMMARY Functional connectivity between the prefrontal cortex (PFC) and striatum (STR) is thought critical for cognition, and has been linked to conditions like autism and schizophrenia. We recorded from multiple electrodes in PFC and STR while monkeys acquired new categories. Category learning was accompanied by an increase in beta-band synchronization of LFPs between, but not within, the PFC and STR. After learning, different pairs of PFC-STR electrodes showed stronger synchrony for one or the other category, suggesting category-specific functional circuits. This category-specific synchrony was also seen between PFC spikes and STR LFPs, but not the reverse, reflecting the direct monosynaptic connections from the PFC to STR. However, causal connectivity analyses suggested that the polysynaptic connections from STR to the PFC exerted a stronger overall influence. This supports models positing that the basal ganglia “train” the PFC. Category learning may depend on the formation of functional circuits between the PFC and STR. PMID:24930701

The behavioral and molecular evaluation of effects of social instability stress as a model of stress-related disorders in adult female rats.

PubMed

Nowacka-Chmielewska, Marta Maria; Kasprowska-Liśkiewicz, Daniela; Barski, Jarosław Jerzy; Obuchowicz, Ewa; Małecki, Andrzej

2017-11-01

The study aimed to test the hypotheses that chronic social instability stress (CSIS) alters behavioral and physiological parameters and expression of selected genes important for stress response and social behaviors. Adult female Sprague-Dawley rats were subjected to the 4-week CSIS procedure, which involves unpredictable rotation between phases of isolation and overcrowding. Behavioral analyses (Experiment 1) were performed on the same rats before and after CSIS (n = 16) and physiological and biochemical measurements (Experiment 2) were made on further control (CON; n = 7) and stressed groups (CSIS; n = 8). Behaviors in the open field test (locomotor and exploratory activities) and elevated-plus maze (anxiety-related behaviors) indicated anxiety after CSIS. CSIS did not alter the physiological parameters measured, i.e. body weight gain, regularity of estrous cycles, and circulating concentrations of stress hormones and sex steroids. QRT-PCR analysis of mRNA expression levels was performed on amygdala, hippocampus, prefrontal cortex (PFC), and hypothalamus. The main finding is that CSIS alters the mRNA levels for the studied genes in a region-specific manner. Hence, expression of POMC (pro-opiomelanocortin), AVPR1a (arginine vasopressin receptor), and OXTR (oxytocin receptor) significantly increased in the amygdala following CSIS, while in PFC and/or hypothalamus, POMC, AVPR1a, AVPR1b, OXTR, and ERβ (estrogen receptor beta) expression decreased. CSIS significantly reduced expression of CRH-R1 (corticotropin-releasing hormone receptor type 1) in the hippocampus. The directions of change in gene expression and the genes and regions affected indicate a molecular basis for the behavior changes. In conclusion, CSIS may be valuable for further analyzing the neurobiology of stress-related disorders in females.

Fear conditioning is associated with dynamic directed functional interactions between and within the human amygdala, hippocampus, and frontal lobe.

PubMed

Liu, C C; Crone, N E; Franaszczuk, P J; Cheng, D T; Schretlen, D S; Lenz, F A

2011-08-25

The current model of fear conditioning suggests that it is mediated through modules involving the amygdala (AMY), hippocampus (HIP), and frontal lobe (FL). We now test the hypothesis that habituation and acquisition stages of a fear conditioning protocol are characterized by different event-related causal interactions (ERCs) within and between these modules. The protocol used the painful cutaneous laser as the unconditioned stimulus and ERC was estimated by analysis of local field potentials recorded through electrodes implanted for investigation of epilepsy. During the prestimulus interval of the habituation stage FL>AMY ERC interactions were common. For comparison, in the poststimulus interval of the habituation stage, only a subdivision of the FL (dorsolateral prefrontal cortex, dlPFC) still exerted the FL>AMY ERC interaction (dlFC>AMY). For a further comparison, during the poststimulus interval of the acquisition stage, the dlPFC>AMY interaction persisted and an AMY>FL interaction appeared. In addition to these ERC interactions between modules, the results also show ERC interactions within modules. During the poststimulus interval, HIP>HIP ERC interactions were more common during acquisition, and deep hippocampal contacts exerted causal interactions on superficial contacts, possibly explained by connectivity between the perihippocampal gyrus and the HIP. During the prestimulus interval of the habituation stage, AMY>AMY ERC interactions were commonly found, while interactions between the deep and superficial AMY (indirect pathway) were independent of intervals and stages. These results suggest that the network subserving fear includes distributed or widespread modules, some of which are themselves "local networks." ERC interactions between and within modules can be either static or change dynamically across intervals or stages of fear conditioning. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Neuronal activity patterns in the mediodorsal thalamus and related cognitive circuits are modulated by metabotropic glutamate receptors

PubMed Central

Copeland, C.S.; Neale, S.A.; Salt, T.E.

2015-01-01

The mediodorsal thalamus (MD) likely plays an important role in cognition as it receives abundant afferent connections from the amygdala and prefrontal cortex (PFC). Indeed, disturbed activity within the MD is thought to precipitate cognitive deficits associated with schizophrenia. As compounds acting at the Group II metabotropic glutamate (mGlu) receptors (subtypes mGlu2/mGlu3) have efficacy in animal models of schizophrenia, we investigated whether a Group II agonist and an mGlu2 positive allosteric modulator (PAM) could modulate MD activity. Extracellular single-unit recordings were made in vivo from MD neurones in anaesthetised rats. Responses were elicited by electrical stimulation of the PFC and/or amygdala, with Group II compounds locally applied as required. The Group II agonist reduced inhibition evoked in the MD: an effect manifested as an increase in short-latency responses, and a decrease in long-latency burst-firing. This disinhibitory action of the Group II receptors in the MD represents a mechanism of potential therapeutic importance as increased inhibition in the MD has been associated with cognitive deficit-onset. Furthermore, as co-application of the mGlu2 PAM did not potentiate the Group II agonist effects in the MD, we suggest that the Group II disinhibitory effect is majority-mediated via mGlu3. This heterogeneity in Group II receptor thalamic physiology bears consequence, as compounds active exclusively at the mGlu2 subtype are unlikely to perturb maladapted MD firing patterns associated with cognitive deficits, with activity at mGlu3 receptors possibly more appropriate. Indeed, polymorphisms in the mGlu3, but not the mGlu2, gene have been detected in patients with schizophrenia. PMID:25576798

The international society for developmental psychobiology Sackler symposium: early adversity and the maturation of emotion circuits--a cross-species analysis.

PubMed

Callaghan, Bridget L; Sullivan, Regina M; Howell, Brittany; Tottenham, Nim

2014-12-01

Early-life caregiving shapes the architecture and function of the developing brain. The fact that the infant-caregiver relationship is critically important for infant functioning across all altricial species, and that the anatomical circuits supporting emotional functioning are highly preserved across different species, suggests that the results of studies examining the role of early adversity and emotional functioning should be translatable across species. Here we present findings from four different research laboratories, using three different species, which have converged on a similar finding: adversity accelerates the developmental trajectory of amygdala-prefrontal cortex (PFC) development and modifies emotional behaviors. First, a rodent model of attachment learning associated with adversity is presented showing precocial disruption of attachment learning and emergence of heightened fear learning and emotionality. Second, a model of infant-mother separation is presented in which early adversity is shown to accelerate the developmental emergence of adult-like fear retention and extinction. Third, a model of early life adversity in Rhesus monkeys is presented in which a naturally occurring variation in maternal-care (abuse) is shown to alter the functioning of emotion circuits. Finally, a human model of maternal deprivation is presented in which children born into orphanages and then adopted abroad exhibit aberrant development of emotion circuits. The convergence of these cross-species studies on early life adversity suggests that adversity targets the amygdala and PFC and has immediate impact on infant behavior with the caregiver, and emotional reactions to the world. These results provide insight into mechanisms responsible for caregiver induced mental health trajectory alterations. © 2014 Wiley Periodicals, Inc.

Prenatal ethanol exposure modifies locomotor activity and induces selective changes in Met-enk expression in adolescent rats.

PubMed

Abate, P; Reyes-Guzmán, A C; Hernández-Fonseca, K; Méndez, M

2017-04-01

Several studies suggest that prenatal ethanol exposure (PEE) facilitates ethanol intake. Opioid peptides play a main role in ethanol reinforcement during infancy and adulthood. However, PEE effects upon motor responsiveness elicited by an ethanol challenge and the participation of opioids in these actions remain to be understood. This work assessed the susceptibility of adolescent rats to prenatal and/or postnatal ethanol exposure in terms of behavioral responses, as well as alcohol effects on Met-enk expression in brain areas related to drug reinforcement. Motor parameters (horizontal locomotion, rearings and stereotyped behaviors) in pre- and postnatally ethanol-challenged adolescents were evaluated. Pregnant rats received ethanol (2g/kg) or water during gestational days 17-20. Adolescents at postnatal day 30 (PD30) were tested in a three-trial activity paradigm (habituation, vehicle and drug sessions). Met-enk content was quantitated by radioimmunoassay in several regions: ventral tegmental area [VTA], nucleus accumbens [NAcc], prefrontal cortex [PFC], substantia nigra [SN], caudate-putamen [CP], amygdala, hypothalamus and hippocampus. PEE significantly reduced rearing responses. Ethanol challenge at PD30 decreased horizontal locomotion and showed a tendency to reduce rearings and stereotyped behaviors. PEE increased Met-enk content in the PFC, CP, hypothalamus and hippocampus, but did not alter peptide levels in the amygdala, VTA and NAcc. These findings suggest that PEE selectively modifies behavioral parameters at PD30 and induces specific changes in Met-enk content in regions of the mesocortical and nigrostriatal pathways, the hypothalamus and hippocampus. Prenatal and postnatal ethanol actions on motor activity in adolescents could involve activation of specific neural enkephalinergic pathways. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training.

PubMed

Zelena, Dóra; Mikics, Éva; Balázsfi, Diána; Varga, János; Klausz, Barbara; Urbán, Eszter; Sipos, Eszter; Biró, László; Miskolczi, Christina; Kovács, Krisztina; Ferenczi, Szilamér; Haller, József

2016-06-01

Calcium-permeable (GluA2 subunit-free) AMPA receptors (CP-AMPAR) play prominent roles in fear extinction; however, no blockers of these receptors were studied in tests relevant to extinction learning so far. The CP-AMPAR antagonist IEM-1460 was administered once before extinction trainings, which were started either 1 or 28 days after fear conditioning (FC). We used a mild extinction protocol that durably decreased but did not abolish conditioned fear. The messenger RNA (mRNA) expression of GluA1 and GluA2 subunits were investigated at both time points in the ventromedial prefrontal cortex (vmPFC) and amygdala. IEM-1460 transiently facilitated extinction 1 day after conditioning, but learned fear spontaneously recovered 4 weeks later. When the extinction protocol was applied 28 days after training, IEM-1460 enhanced extinction memory, moreover abolished conditioned fear for at least a month. The expression of GluA1 and GluA2 mRNAs was increased at both time points in the vmPFC. In the basolateral and central amygdala, the GluA1/GluA2 mRNA ratio increased, suggesting a shift towards the preponderance of GluA1 over GluA2 expression. AMPAR blockade lastingly enhanced the extinction of remote but not recent fear memories. Time-dependent changes in AMPA receptor subunit mRNA expression may explain the differential effects of CP-AMPAR blockade on recent and remote conditioned fear, further supporting the notion that the mechanisms maintaining learned fear change over time. Our findings suggest clinical implications for CP-AMPAR blockers, particularly for acquired anxieties (e.g., post-traumatic stress disorder) which have a slow onset and are durable.

Testosterone Administration Related Differences in Brain Activation during the Ultimatum Game

PubMed Central

Kopsida, Eleni; Berrebi, Jonathan; Petrovic, Predrag; Ingvar, Martin

2016-01-01

A plethora of studies on the Ultimatum Game have shown that responders forfeit the rule of profit maximization and punish unfair proposers, by rejecting their offers. This behavior has been linked to increased amygdala, insula, and dorsolateral prefrontal cortex activation. Studies have suggested a potential role of testosterone in the Ultimatum Game albeit with inconsistent findings. In the present study, we sought to further investigate the role of amygdala and testosterone in the Ultimatum Game, by conducting a double-blinded, single-administration study. Sixty milligram of Tostrex was administered to male and female healthy volunteers, 3 h prior to undergoing an fMRI session, during which they played a standard version of the Ultimatum Game. The behavioral analysis revealed a statistical trend, as participants in the testosterone group tended to accept a greater number of unfair offers than participants in the placebo group, irrespectively of gender. In terms of fMRI results, for the main contrast unfair>fair offers, the testosterone group displayed a greater activation in the right dlPFC compared to the placebo group. Increased testosterone levels were related to greater caudate activity. Our findings suggest a complex role of testosterone in social behavior and decision-making. PMID:26973448

The Responsive Amygdala: Treatment-induced Alterations in Functional Connectivity in Pediatric Complex Regional Pain Syndrome

PubMed Central

Simons, LE; Pielech, M; Erpelding, N; Linnman, C; Moulton, E; Sava, S; Lebel, A; Serrano, P; Sethna, N; Berde, C; Becerra, L; Borsook, D

2014-01-01

The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age-gender matched controls before and after intensive physical-biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared to controls, with differences predominantly in the left amygdala in the pre-treated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy controls from Time 1 to Time 2 (treatment effects); (3) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain-related fear scores and (4) decreases in pain-related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity following an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response. PMID:24861582

Functional Connectivity of the Amygdala Is Disrupted in Preschool-Aged Children With Autism Spectrum Disorder.

PubMed

Shen, Mark D; Li, Deana D; Keown, Christopher L; Lee, Aaron; Johnson, Ryan T; Angkustsiri, Kathleen; Rogers, Sally J; Müller, Ralph-Axel; Amaral, David G; Nordahl, Christine Wu

2016-09-01

The objective of this study was to determine whether functional connectivity of the amygdala is altered in preschool-age children with autism spectrum disorder (ASD) and to assess the clinical relevance of observed alterations in amygdala connectivity. A resting-state functional connectivity magnetic resonance imaging study of the amygdala (and a parallel study of primary visual cortex) was conducted in 72 boys (mean age 3.5 years; n = 43 with ASD; n = 29 age-matched controls). The ASD group showed significantly weaker connectivity between the amygdala and several brain regions involved in social communication and repetitive behaviors, including bilateral medial prefrontal cortex, temporal lobes, and striatum (p < .05, corrected). Weaker connectivity between the amygdala and frontal and temporal lobes was significantly correlated with increased autism severity in the ASD group (p < .05). In a parallel analysis examining the functional connectivity of primary visual cortex, the ASD group showed significantly weaker connectivity between visual cortex and sensorimotor regions (p < .05, corrected). Weaker connectivity between visual cortex and sensorimotor regions was not correlated with core autism symptoms, but instead was correlated with increased sensory hypersensitivity in the visual/auditory domain (p < .05). These findings indicate that preschool-age children with ASD have disrupted functional connectivity between the amygdala and regions of the brain important for social communication and language, which might be clinically relevant because weaker connectivity was associated with increased autism severity. Moreover, although amygdala connectivity was associated with behavioral domains that are diagnostic of ASD, altered connectivity of primary visual cortex was related to sensory hypersensitivity. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Initial and sustained brain responses to threat anticipation in blood-injection-injury phobia.

PubMed

Brinkmann, Leonie; Poller, Hendrik; Herrmann, Martin J; Miltner, Wolfgang; Straube, Thomas

2017-01-01

Blood-injection-injury (BII) phobia differs from other subtypes of specific phobia in that it is associated with elevated disgust-sensitivity as well as specific autonomic and brain responses during processing of phobia-relevant stimuli. To what extent these features play a role already during threat anticipation is unclear. In the current fMRI experiment, 16 female BII phobics and 16 female healthy controls anticipated the presentation of phobia-specific and neutral pictures. On the behavioral level, anxiety dominated the anticipatory period in BII phobics relative to controls, while both anxiety and disgust were elevated during picture presentation. By applying two different models for the analysis of brain responses to anticipation of phobia-specific versus neutral stimuli, we found initial and sustained increases of activation in anterior cingulate cortex (ACC), insula, lateral and medial prefrontal cortex (PFC), thalamus and visual areas, as well as initial activation in the amygdala for BII phobics as compared to healthy controls. These results suggest that BII phobia is characterized by activation of a typical neural defense network during threat anticipation, with anxiety as the predominant emotion.

Reduction of N-acetylaspartate in the medial prefrontal cortex correlated with symptom severity in obsessive-compulsive disorder: meta-analyses of 1H-MRS studies

PubMed Central

Aoki, Yuta; Aoki, Ai; Suwa, Hiroshi

2012-01-01

Structural and functional neuroimaging findings suggest that disturbance of the cortico–striato–thalamo–cortical (CSTC) circuits may underlie obsessive-compulsive disorder (OCD). However, some studies with 1H-magnetic resonance spectroscopy (1H-MRS) reported altered level of N-acetylaspartate (NAA), they yielded inconsistency in direction and location of abnormality within CSTC circuits. We conducted a comprehensive literature search and a meta-analysis of 1H-MRS studies in OCD. Seventeen met the inclusion criteria for a meta-analysis. Data were separated by frontal cortex region: medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex, orbitofrontal cortex, basal ganglia and thalamus. The mean and s.d. of the NAA measure were calculated for each region. A random effects model integrating 16 separate datasets with 225 OCD patients and 233 healthy comparison subjects demonstrated that OCD patients exhibit decreased NAA levels in the frontal cortex (P=0.025), but no significant changes in the basal ganglia (P=0.770) or thalamus (P=0.466). Sensitivity analysis in an anatomically specified subgroup consisting of datasets examining the mPFC demonstrated marginally significant reduction of NAA (P=0.061). Meta-regression revealed that NAA reduction in the mPFC was positively correlated with symptom severity measured by Yale–Brown Obsessive Compulsive Scale (P=0.011). The specific reduction of NAA in the mPFC and significant relationship between neurochemical alteration in the mPFC and symptom severity indicate that the mPFC is one of the brain regions that directly related to abnormal behavior in the pathophysiology of OCD. The current meta-analysis indicates that cortices and sub-cortices contribute in different ways to the etiology of OCD. PMID:22892718

NMDA Receptor-Dependent Processes in the Medial Prefrontal Cortex Are Important for Acquisition and the Early Stage of Consolidation during Trace, but Not Delay Eyeblink Conditioning

ERIC Educational Resources Information Center

Takehara-Nishiuchi, Kaori; Kawahara, Shigenori; Kirino, Yutaka

2005-01-01

Permanent lesions in the medial prefrontal cortex (mPFC) affect acquisition of conditioned responses (CRs) during trace eyeblink conditioning and retention of remotely acquired CRs. To clarify further roles of the mPFC in this type of learning, we investigated the participation of the mPFC in mnemonic processes both during and after daily…

Distant influences of amygdala lesion on visual cortical activation during emotional face processing.

PubMed

Vuilleumier, Patrik; Richardson, Mark P; Armony, Jorge L; Driver, Jon; Dolan, Raymond J

2004-11-01

Emotional visual stimuli evoke enhanced responses in the visual cortex. To test whether this reflects modulatory influences from the amygdala on sensory processing, we used event-related functional magnetic resonance imaging (fMRI) in human patients with medial temporal lobe sclerosis. Twenty-six patients with lesions in the amygdala, the hippocampus or both, plus 13 matched healthy controls, were shown pictures of fearful or neutral faces in task-releant or task-irrelevant positions on the display. All subjects showed increased fusiform cortex activation when the faces were in task-relevant positions. Both healthy individuals and those with hippocampal damage showed increased activation in the fusiform and occipital cortex when they were shown fearful faces, but this was not the case for individuals with damage to the amygdala, even though visual areas were structurally intact. The distant influence of the amygdala was also evidenced by the parametric relationship between amygdala damage and the level of emotional activation in the fusiform cortex. Our data show that combining the fMRI and lesion approaches can help reveal the source of functional modulatory influences between distant but interconnected brain regions.

Aberrant Neural Connectivity during Emotional Processing Associated with Posttraumatic Stress

PubMed Central

Sadeh, Naomi; Spielberg, Jeffrey M.; Warren, Stacie L.; Miller, Gregory A.; Heller, Wendy

2014-01-01

Given the complexity of the brain, characterizing relations among distributed brain regions is likely essential to describing the neural instantiation of posttraumatic stress symptoms. This study examined patterns of functional connectivity among key brain regions implicated in the pathophysiology of posttraumatic stress disorder (PTSD) in 35 trauma-exposed adults using an emotion-word Stroop task. PTSD symptom severity (particularly hyperarousal symptoms) moderated amygdala-mPFC coupling during the processing of unpleasant words, and this moderation correlated positively with reported real-world impairment and amygdala reactivity. Reexperiencing severity moderated hippocampus-insula coupling during pleasant and unpleasant words. Results provide evidence that PTSD symptoms differentially moderate functional coupling during emotional interference and underscore the importance of examining network connectivity in research on PTSD. They suggest that hyperarousal is associated with negative mPFC-amygdala coupling and that reexperiencing is associated with altered insula-hippocampus function, patterns of connectivity that may represent separable indicators of dysfunctional inhibitory control during affective processing. PMID:25419500

Aberrant Neural Connectivity during Emotional Processing Associated with Posttraumatic Stress.

PubMed

Sadeh, Naomi; Spielberg, Jeffrey M; Warren, Stacie L; Miller, Gregory A; Heller, Wendy

2014-11-01

Given the complexity of the brain, characterizing relations among distributed brain regions is likely essential to describing the neural instantiation of posttraumatic stress symptoms. This study examined patterns of functional connectivity among key brain regions implicated in the pathophysiology of posttraumatic stress disorder (PTSD) in 35 trauma-exposed adults using an emotion-word Stroop task. PTSD symptom severity (particularly hyperarousal symptoms) moderated amygdala-mPFC coupling during the processing of unpleasant words, and this moderation correlated positively with reported real-world impairment and amygdala reactivity. Reexperiencing severity moderated hippocampus-insula coupling during pleasant and unpleasant words. Results provide evidence that PTSD symptoms differentially moderate functional coupling during emotional interference and underscore the importance of examining network connectivity in research on PTSD. They suggest that hyperarousal is associated with negative mPFC-amygdala coupling and that reexperiencing is associated with altered insula-hippocampus function, patterns of connectivity that may represent separable indicators of dysfunctional inhibitory control during affective processing.

Prolonged maternal separation disturbs the serotonergic system during early brain development.

PubMed

Ohta, Ken-Ichi; Miki, Takanori; Warita, Katsuhiko; Suzuki, Shingo; Kusaka, Takashi; Yakura, Tomiko; Liu, Jun-Qian; Tamai, Motoki; Takeuchi, Yoshiki

2014-04-01

Early life stress interrupts brain development through the disturbance of various neurotransmitter and neurotrophic factor activities, but the details remain unclear. In the current study, we focused on the serotonergic system, which plays a critical role in brain development, and examined the time-dependent influence of prolonged maternal separation on male Sprague-Dawley rats. The rats were separated from their dams for 3h twice-daily during postnatal days (PDs) 2-20. The influence of prolonged maternal separation was analyzed on PDs 7, 14, 21, and 28 using HPLC to assess concentrations of serotonin and 5-hydroxyindoleacetic acid and using real-time RT-PCR to measure mRNA expression of the serotonin 1A and 2A receptors in various brain regions. HPLC revealed imbalance between serotonin and 5-hydroxyindoleacetic acid in midbrain raphe nuclei, the amygdala, the hippocampus, and the medial prefrontal cortex (mPFC) on PDs 7 and 14. Furthermore, real-time RT-PCR showed attenuation of mRNA expression of the serotonin 1A receptor in the hippocampus and the mPFC and of the serotonin 2A receptor only in the mPFC on PDs 7 and 14. The observed alterations returned to control levels after maternal separation ended. These findings suggest that the early life stress of prolonged maternal separation disturbs the serotonergic system during a crucial period of brain development, which might in part be responsible for emotional abnormalities later in life. Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.

Reciprocal activation/inactivation of ERK in the amygdala and frontal cortex is correlated with the degree of novelty of an open-field environment.

PubMed

Sanguedo, Frederico Velasco; Dias, Caio Vitor Bueno; Dias, Flavia Regina Cruz; Samuels, Richard Ian; Carey, Robert J; Carrera, Marinete Pinheiro

2016-03-01

Phosphorylated extracellular signal-regulated kinase (ERK) has been used to identify brain areas activated by exogenous stimuli including psychostimulant drugs. Assess the role of the amygdala in emotional responses. Experimental manipulations were performed in which environmental familiarity was the variable. To provide the maximal degree of familiarity, ERK was measured after removal from the home cage and re-placement back into the same cage. To maximize exposure to an unfamiliar environment, ERK was measured following placement into a novel open field. To assess whether familiarity was the critical variable in the ERK response to the novel open field, ERK was also measured after either four or eight placements into the same environment. ERK quantification was carried out in the amygdala, frontal cortex, and the nucleus accumbens. After home cage re-placement, ERK activation was found in the frontal cortex and nucleus accumbens but was absent in the amygdala. Following placement in a novel environment, ERK activation was more prominent in the amygdala than the frontal cortex or nucleus accumbens. In contrast, with habituation to the novel environment, ERK phosphors declined markedly in the amygdala but increased in the frontal cortex and nucleus accumbens to the level observed following home cage re-placement. The differential responsiveness of the amygdala versus the frontal cortex and the nucleus accumbens to a novel versus a habituated environment is consistent with a reciprocal interaction between these neural systems and points to their important role in the mediation of behavioral activation to novelty and behavioral inactivation with habituation.

Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility

PubMed Central

Murray, Andrew J.; Woloszynowska-Fraser, Marta U.; Ansel-Bollepalli, Laura; Cole, Katy L. H.; Foggetti, Angelica; Crouch, Barry; Riedel, Gernot; Wulff, Peer

2015-01-01

Dysfunction of parvalbumin (PV)-positive GABAergic interneurons (PVIs) within the prefrontal cortex (PFC) has been implicated in schizophrenia pathology. It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction. To identify how PVIs contribute to PFC-dependent behaviors we inactivated PVIs in the PFC in mice using region- and cell-type-selective expression of tetanus toxin light chain (TeLC) and compared the functional consequences of this manipulation with non-cell-type-selective perturbations of the same circuitry. By sampling for behavioral alterations that map onto distinct symptom categories in schizophrenia, we show that dysfunction of PVI signaling in the PFC specifically produces deficits in the cognitive domain, but does not give rise to PFC-dependent correlates of negative or positive symptoms. Our results suggest that distinct aspects of the complex symptomatology of PFC dysfunction in schizophrenia can be attributed to specific prefrontal circuit elements. PMID:26608841

The prefrontal cortex: a target for antipsychotic drugs.

PubMed

Artigas, F

2010-01-01

At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT(2) receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors.

Context Memory Decline in Middle Aged Adults is Related to Changes in Prefrontal Cortex Function

PubMed Central

Kwon, Diana; Maillet, David; Pasvanis, Stamatoula; Ankudowich, Elizabeth; Grady, Cheryl L.; Rajah, M. Natasha

2016-01-01

The ability to encode and retrieve spatial and temporal contextual details of episodic memories (context memory) begins to decline at midlife. In the current study, event-related fMRI was used to investigate the neural correlates of context memory decline in healthy middle aged adults (MA) compared with young adults (YA). Participants were scanned while performing easy and hard versions of spatial and temporal context memory tasks. Scans were obtained at encoding and retrieval. Significant reductions in context memory retrieval accuracy were observed in MA, compared with YA. The fMRI results revealed that overall, both groups exhibited similar patterns of brain activity in parahippocampal cortex, ventral occipito-temporal regions and prefrontal cortex (PFC) during encoding. In contrast, at retrieval, there were group differences in ventral occipito-temporal and PFC activity, due to these regions being more activated in MA, compared with YA. Furthermore, only in YA, increased encoding activity in ventrolateral PFC, and increased retrieval activity in occipital cortex, predicted increased retrieval accuracy. In MA, increased retrieval activity in anterior PFC predicted increased retrieval accuracy. These results suggest that there are changes in PFC contributions to context memory at midlife. PMID:25882039

Changes in prefrontal and amygdala activity during olanzapine treatment in schizophrenia.

PubMed

Blasi, Giuseppe; Popolizio, Teresa; Taurisano, Paolo; Caforio, Grazia; Romano, Raffaella; Di Giorgio, Annabella; Sambataro, Fabio; Rubino, Valeria; Latorre, Valeria; Lo Bianco, Luciana; Fazio, Leonardo; Nardini, Marcello; Weinberger, Daniel R; Bertolino, Alessandro

2009-07-15

Earlier imaging studies in schizophrenia have reported abnormal amygdala and prefrontal cortex activity during emotion processing. We investigated with functional magnetic resonance imaging (fMRI) during emotion processing changes in activity of the amygdala and of prefrontal cortex in patients with schizophrenia during 8 weeks of olanzapine treatment. Twelve previously drug-free/naive patients with schizophrenia were treated with olanzapine for 8 weeks and underwent two fMRI scans after 4 and 8 weeks of treatment during implicit and explicit emotional processing. Twelve healthy subjects were also scanned twice to control for potential repetition effects. Results showed a diagnosis by time interaction in left amygdala and a diagnosis by time by task interaction in right ventrolateral prefrontal cortex. In particular, activity in left amygdala was greater in patients than in controls at the first scan during both explicit and implicit processing, while it was lower in patients at the second relative to the first scan. Furthermore, during implicit processing, right ventrolateral prefrontal cortex activity was lower in patients than controls at the first scan, while it was greater in patients at the second relative to the first scan. These results suggest that longitudinal treatment with olanzapine may be associated with specific changes in activity of the amygdala and prefrontal cortex during emotional processing in schizophrenia.

Prefrontal cortical-specific differences in behavior and synaptic plasticity between adolescent and adult mice.

PubMed

Konstantoudaki, Xanthippi; Chalkiadaki, Kleanthi; Vasileiou, Elisabeth; Kalemaki, Katerina; Karagogeos, Domna; Sidiropoulou, Kyriaki

2018-03-01

Adolescence is a highly vulnerable period for the emergence of major neuropsychological disorders and is characterized by decreased cognitive control and increased risk-taking behavior and novelty-seeking. The prefrontal cortex (PFC) is involved in the cognitive control of impulsive and risky behavior. Although the PFC is known to reach maturation later than other cortical areas, little information is available regarding the functional changes from adolescence to adulthood in PFC, particularly compared with other primary cortical areas. This study aims to understand the development of PFC-mediated, compared with non-PFC-mediated, cognitive functions. Toward this aim, we performed cognitive behavioral tasks in adolescent and adult mice and subsequently investigated synaptic plasticity in two different cortical areas. Our results showed that adolescent mice exhibit impaired performance in PFC-dependent cognitive tasks compared with adult mice, whereas their performance in non-PFC-dependent tasks is similar to that of adults. Furthermore, adolescent mice exhibited decreased long-term potentiation (LTP) within upper-layer synapses of the PFC but not the barrel cortex. Blocking GABA A receptor function significantly augments LTP in both the adolescent and adult PFC. No change in intrinsic excitability of PFC pyramidal neurons was observed between adolescent and adult mice. Finally, increased expression of the NR2A subunit of the N-methyl-d-aspartate receptors is found only in the adult PFC, a change that could underlie the emergence of LTP. In conclusion, our results demonstrate physiological and behavioral changes during adolescence that are specific to the PFC and could underlie the reduced cognitive control in adolescents. NEW & NOTEWORTHY This study reports that adolescent mice exhibit impaired performance in cognitive functions dependent on the prefrontal cortex but not in cognitive functions dependent on other cortical regions. The current results propose reduced synaptic plasticity in the upper layers of the prefrontal cortex as a cellular correlate of this weakened cognitive function. This decreased synaptic plasticity is due to reduced N-methyl-d-aspartate receptor expression but not due to dampened intrinsic excitability or enhanced GABAergic signaling during adolescence.

Monitoring of prefrontal cortex activation during verbal n-back task with 24-channel functional NIRS imager

NASA Astrophysics Data System (ADS)

Li, Chengjun; Gong, Hui; Gan, Zhuo; Luo, Qingming

2005-01-01

Human prefrontal cortex (PFC) helps mediate working memory (WM), a system that is used for temporary storage and manipulation of information and is involved with many higher-level cognitive functions. Here, we report a functional near-infrared spectroscopy (NIRS) study on the PFC activation caused by verbal WM task. For investigating the effect of memory load on brain activation, we adopted the "n-back" task in which subjects must decide for each present letter whether it matches the letter presented n items back in sequence. 27 subjects (ages 18-24, 13 females) participated in the work. Concentration changes in oxy-Hb (HbO2), deoxy-Hb (Hb), and total-Hb (HbT) in the subjects" prefrontal cortex were monitored by a 24-channel functional NIRS imager. The cortical activations and deactivations were found in left ventrolateral PFC and bilateral dorsolateral PFC. As memory load increased, subjects showed poorer behavioral performance as well as monotonically increasing magnitudes of the activations and deactivations in PFC.

Brain abnormalities in high-risk violent offenders and their association with psychopathic traits and criminal recidivism.

PubMed

Leutgeb, V; Leitner, M; Wabnegger, A; Klug, D; Scharmüller, W; Zussner, T; Schienle, A

2015-11-12

Measures of psychopathy have been proved to be valuable for risk assessment in violent criminals. However, the neuronal basis of psychopathy and its contribution to the prediction of criminal recidivism is still poorly understood. We compared structural imaging data from 40 male high-risk violent offenders and 37 non-delinquent healthy controls via voxel-based morphometry. Psychopathic traits and risk of violence recidivism were correlated with gray matter volume (GMV) of regions of interest previously shown relevant for criminal behavior. Relative to controls, criminals showed less GMV in the prefrontal cortex (PFC) and more GMV in cerebellar regions and basal ganglia structures. Within criminals, we found a negative correlation between prefrontal GMV and psychopathy. Additionally, there was a positive correlation between cerebellar GMV and psychopathy as well as risk of recidivism for violence. Moreover, GMVs of the basal ganglia and supplementary motor area (SMA) were positively correlated with anti-sociality. GMV of the amygdala was negatively correlated with dynamic risk for violence recidivism. In contrast, GMV of (para)limbic areas (orbitofrontal cortex, insula) was positively correlated with anti-sociality and risk of violence recidivism. The current investigation revealed that in violent offenders deviations in GMV of the PFC as well as areas involved in the motor component of impulse control (cerebellum, basal ganglia, SMA) are differentially related to psychopathic traits and the risk of violence recidivism. The results might be valuable for improving existing risk assessment tools. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Limbic-Auditory Interactions of Tinnitus: An Evaluation Using Diffusion Tensor Imaging.

PubMed

Gunbey, H P; Gunbey, E; Aslan, K; Bulut, T; Unal, A; Incesu, L

2017-06-01

Tinnitus is defined as an imaginary subjective perception in the absence of an external sound. Convergent evidence proposes that tinnitus perception includes auditory, attentional and emotional components. The aim of this study was to investigate the thalamic, auditory and limbic interactions associated with tinnitus-related distress by Diffusion Tensor Imaging (DTI). A total of 36 tinnitus patients, 20 healthy controls underwent an audiological examination, as well as a magnetic resonance imaging protocol including structural and DTI sequences. All participants completed the Tinnitus Handicap Inventory (THI) and Visual Analog Scales (VAS) related with tinnitus. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained for the auditory cortex (AC), inferior colliculus (IC), lateral lemniscus (LL), medial geniculate body (MGB), thalamic reticular nucleus (TRN), amygdala (AMG), hippocampus (HIP), parahippocampus (PHIP) and prefrontal cortex (PFC). In tinnitus patients the FA values of IC, MGB, TRN, AMG, HIP decreased and the ADC values of IC, MGB, TRN, AMG, PHIP increased significantly. The contralateral IC-LL and bilateral MGB FA values correlated negatively with hearing loss. A negative relation was found between the AMG-HIP FA values and THI and VAS scores. Bilateral ADC values of PHIP and PFC significantly correlated with the attention deficiency-VAS scores. In conclusion, this is the first DTI study to investigate the grey matter structures related to tinnitus perception and the significant correlation of FA and ADC with clinical parameters suggests that DTI can provide helpful information for tinnitus. Magnifying the microstructures in DTI can help evaluate the three faces of tinnitus nature: hearing, emotion and attention.

Anxiety Evokes Hypofrontality and Disrupts Rule-Relevant Encoding by Dorsomedial Prefrontal Cortex Neurons.

PubMed

Park, Junchol; Wood, Jesse; Bondi, Corina; Del Arco, Alberto; Moghaddam, Bita

2016-03-16

Anxiety is a debilitating symptom of most psychiatric disorders, including major depression, post-traumatic stress disorder, schizophrenia, and addiction. A detrimental aspect of anxiety is disruption of prefrontal cortex (PFC)-mediated executive functions, such as flexible decision making. Here we sought to understand how anxiety modulates PFC neuronal encoding of flexible shifting between behavioral strategies. We used a clinically substantiated anxiogenic treatment to induce sustained anxiety in rats and recorded from dorsomedial PFC (dmPFC) and orbitofrontal cortex (OFC) neurons while they were freely moving in a home cage and while they performed a PFC-dependent task that required flexible switches between rules in two distinct perceptual dimensions. Anxiety elicited a sustained background "hypofrontality" in dmPFC and OFC by reducing the firing rate of spontaneously active neuronal subpopulations. During task performance, the impact of anxiety was subtle, but, consistent with human data, behavior was selectively impaired when previously correct conditions were presented as conflicting choices. This impairment was associated with reduced recruitment of dmPFC neurons that selectively represented task rules at the time of action. OFC rule representation was not affected by anxiety. These data indicate that a neural substrate of the decision-making deficits in anxiety is diminished dmPFC neuronal encoding of task rules during conflict-related actions. Given the translational relevance of the model used here, the data provide a neuronal encoding mechanism for how anxiety biases decision making when the choice involves overcoming a conflict. They also demonstrate that PFC encoding of actions, as opposed to cues or outcome, is especially vulnerable to anxiety. A debilitating aspect of anxiety is its impact on decision making and flexible control of behavior. These cognitive constructs depend on proper functioning of the prefrontal cortex (PFC). Understanding how anxiety affects PFC encoding of cognitive events is of great clinical and evolutionary significance. Using a clinically valid experimental model, we find that, under anxiety, decision making may be skewed by salient and conflicting environmental stimuli at the expense of flexible top-down guided choices. We also find that anxiety suppresses spontaneous activity of PFC neurons, and weakens encoding of task rules by dorsomedial PFC neurons. These data provide a neuronal encoding scheme for how anxiety disengages PFC during decision making. Copyright © 2016 the authors 0270-6474/16/363322-14$15.00/0.

Transcranial Direct Current Stimulation over the Medial Prefrontal Cortex and Left Primary Motor Cortex (mPFC-lPMC) Affects Subjective Beauty but Not Ugliness

PubMed Central

Nakamura, Koyo; Kawabata, Hideaki

2015-01-01

Neuroaesthetics has been searching for the neural bases of the subjective experience of beauty. It has been demonstrated that neural activities in the medial prefrontal cortex (mPFC) and the left primary motor cortex (lPMC) correlate with the subjective experience of beauty. Although beauty and ugliness seem to be semantically and conceptually opposite, it is still unknown whether these two evaluations represent extreme opposites in unitary or bivariate dimensions. In this study, we applied transcranial direct current stimulation (tDCS) to examine whether non-invasive brain stimulation modulates two types of esthetic evaluation; evaluating beauty and ugliness. Participants rated the subjective beauty and ugliness of abstract paintings before and after the application of tDCS. Application of cathodal tDCS over the mPFC with anode electrode over the lPMC, which induced temporal inhibition of neural excitability of the mPFC, led to a decrease in beauty ratings but not ugliness ratings. There were no changes in ratings of both beauty and ugliness when applying anodal tDCS or sham stimulation over the mPFC. Results from our experiment indicate that the mPFC and the lPMC have a causal role in generating the subjective experience of beauty, with beauty and ugliness evaluations constituting two distinct dimensions. PMID:26696865

Deconstructing white matter connectivity of human amygdala nuclei with thalamus and cortex subdivisions in vivo.

PubMed

Abivardi, Aslan; Bach, Dominik R

2017-08-01

Structural alterations in long-range amygdala connections are proposed to crucially underlie several neuropsychiatric disorders. While progress has been made in elucidating the function of these connections, our understanding of their structure in humans remains sparse and non-systematic. Harnessing diffusion-weighted imaging and probabilistic tractography in humans, we investigate connections between two main amygdala nucleus groups, thalamic nuclei, and cortex. We first parcellated amygdala into deep (basolateral) and superficial (centrocortical) nucleus groups, and thalamus into six subregions, using previously established protocols based on connectivity. Cortex was parcellated based on T1-weighted images. We found substantial amygdala connections to thalamus, with different patterns for the two amygdala nuclei. Crucially, we describe direct subcortical connections between amygdala and paraventricular thalamus. Different from rodents but similar to non-human primates, these are more pronounced for basolateral than centrocortical amygdala. Substantial white-matter connectivity between amygdala and visual pulvinar is also more pronounced for basolateral amygdala. Furthermore, we establish detailed connectivity profiles for basolateral and centrocortical amygdala to cortical regions. These exhibit cascadic connections with sensory cortices as suggested previously based on tracer methods in non-human animals. We propose that the quantitative connectivity profiles provided here may guide future work on normal and pathological function of human amygdala. Hum Brain Mapp 38:3927-3940, 2017. © 2017 Wiley Periodicals, Inc. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Deconstructing white matter connectivity of human amygdala nuclei with thalamus and cortex subdivisions in vivo

PubMed Central

2017-01-01

Abstract Structural alterations in long‐range amygdala connections are proposed to crucially underlie several neuropsychiatric disorders. While progress has been made in elucidating the function of these connections, our understanding of their structure in humans remains sparse and non‐systematic. Harnessing diffusion‐weighted imaging and probabilistic tractography in humans, we investigate connections between two main amygdala nucleus groups, thalamic nuclei, and cortex. We first parcellated amygdala into deep (basolateral) and superficial (centrocortical) nucleus groups, and thalamus into six subregions, using previously established protocols based on connectivity. Cortex was parcellated based on T1‐weighted images. We found substantial amygdala connections to thalamus, with different patterns for the two amygdala nuclei. Crucially, we describe direct subcortical connections between amygdala and paraventricular thalamus. Different from rodents but similar to non‐human primates, these are more pronounced for basolateral than centrocortical amygdala. Substantial white‐matter connectivity between amygdala and visual pulvinar is also more pronounced for basolateral amygdala. Furthermore, we establish detailed connectivity profiles for basolateral and centrocortical amygdala to cortical regions. These exhibit cascadic connections with sensory cortices as suggested previously based on tracer methods in non‐human animals. We propose that the quantitative connectivity profiles provided here may guide future work on normal and pathological function of human amygdala. Hum Brain Mapp 38:3927–3940, 2017. © 2017 Wiley Periodicals, Inc. PMID:28512761

Category-dependent and category-independent goal-value codes in human ventromedial prefrontal cortex

PubMed Central

McNamee, Daniel; Rangel, Antonio; O’Doherty, John P

2013-01-01

To choose between manifestly distinct options, it is suggested that the brain assigns values to goals using a common currency. Although previous studies have reported activity in ventromedial prefrontal cortex (vmPFC) correlating with the value of different goal stimuli, it remains unclear whether such goal-value representations are independent of the associated stimulus categorization, as required by a common currency. Using multivoxel pattern analyses on functional magnetic resonance imaging (fMRI) data, we found a region of medial prefrontal cortex to contain a distributed goal-value code that is independent of stimulus category. More ventrally in the vmPFC, we found spatially distinct areas of the medial orbitofrontal cortex to contain unique category-dependent distributed value codes for food and consumer items. These results implicate the medial prefrontal cortex in the implementation of a common currency and suggest a ventral versus dorsal topographical organization of value signals in the vmPFC. PMID:23416449

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.

Association of medial prefrontal cortex connectivity with consciousness level and its outcome in patients with acquired brain injury.

PubMed

Liu, Xiaoyan; Li, Jingqi; Gao, Jian; Zhou, Zhen; Meng, Fanxia; Pan, Gang; Luo, Benyan

2017-08-01

Medial prefrontal cortex (mPFC) is usually known for participating in virtually all self related processing. However, few have investigated the role of mPFC in modulating conscious awareness. This study aimed to depict the relationship between the mPFC connectivity and the severity and outcome of the disorders of consciousness (DOC) among patients with acquired brain injury. Thirty-four patients with DOC (17 in a minimally conscious state and 17 in an unresponsive wakefulness syndrome/vegetative state) and 11 healthy controls were recruited, underwent clinical assessment and resting-state functional MRI scan, and were further followed up to evaluate recovery outcome using the Glasgow Outcome Scale. The mPFC connectivity was then analyzed, by comparing DOC patients to healthy controls at baseline, and by comparing "recovered consciousness" and "non-recovered consciousness" patients at follow-up, as identified by graph theory. As a result, enhanced mPFC connectivity against weakened posteromedial cortex connectivity was observed in a minimally conscious state, not in an unresponsive wakefulness syndrome/vegetative state. Besides, increased mPFC connectivity was significantly associated with consciousness recovery. In conclusion, the mPFC connectivity could possibly serve as a mark to track the severity and outcome of DOC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mindful attention to breath regulates emotions via increased amygdala-prefrontal cortex connectivity.

PubMed

Doll, Anselm; Hölzel, Britta K; Mulej Bratec, Satja; Boucard, Christine C; Xie, Xiyao; Wohlschläger, Afra M; Sorg, Christian

2016-07-01

Mindfulness practice is beneficial for emotion regulation; however, the neural mechanisms underlying this effect are poorly understood. The current study focuses on effects of attention-to-breath (ATB) as a basic mindfulness practice on aversive emotions at behavioral and brain levels. A key finding across different emotion regulation strategies is the modulation of amygdala and prefrontal activity. It is unclear how ATB relevant brain areas in the prefrontal cortex integrate with amygdala activation during emotional stimulation. We proposed that, during emotional stimulation, ATB down-regulates activation in the amygdala and increases its integration with prefrontal regions. To address this hypothesis, 26 healthy controls were trained in mindfulness-based attention-to-breath meditation for two weeks and then stimulated with aversive pictures during both attention-to-breath and passive viewing while undergoing fMRI. Data were controlled for breathing frequency. Results indicate that (1) ATB was effective in regulating aversive emotions. (2) Left dorso-medial prefrontal cortex was associated with ATB in general. (3) A fronto-parietal network was additionally recruited during emotional stimulation. (4) ATB down regulated amygdala activation and increased amygdala-prefrontal integration, with such increased integration being associated with mindfulness ability. Results suggest amygdala-dorsal prefrontal cortex integration as a potential neural pathway of emotion regulation by mindfulness practice. Copyright © 2016 Elsevier Inc. All rights reserved.

A key role of the prefrontal cortex in the maintenance of chronic tinnitus: An fMRI study using a Stroop task.

PubMed

Araneda, Rodrigo; Renier, Laurent; Dricot, Laurence; Decat, Monique; Ebner-Karestinos, Daniela; Deggouj, Naïma; De Volder, Anne G

2018-01-01

Since we recently showed in behavioural tasks that the top-down cognitive control was specifically altered in tinnitus sufferers, here we wanted to establish the link between this impaired executive function and brain alterations in the frontal cortex in tinnitus patients. Using functional magnetic resonance imaging (fMRI), we monitored the brain activity changes in sixteen tinnitus patients (TP) and their control subjects (CS) while they were performing a spatial Stroop task, both in audition and vision. We observed that TP differed from CS in their functional recruitment of the dorsolateral prefrontal cortex (dlPFC, BA46), the cingulate gyrus and the ventromedial prefrontal cortex (vmPFC, BA10). This recruitment was higher during interference conditions in tinnitus participants than in controls, whatever the sensory modality. Furthermore, the brain activity level in the right dlPFC and vmPFC correlated with the performance in the Stroop task in TP. Due to the direct link between poor executive functions and prefrontal cortex alterations in TP, we postulate that a lack of inhibitory modulation following an impaired top-down cognitive control may maintain tinnitus by hampering habituation mechanisms. This deficit in executive functions caused by prefrontal cortex alterations would be a key-factor in the generation and persistence of tinnitus.

Prefrontal Cortex Contributions to Episodic Retrieval Monitoring and Evaluation

ERIC Educational Resources Information Center

Cruse, Damian; Wilding, Edward L.

2009-01-01

Although the prefrontal cortex (PFC) plays roles in episodic memory judgments, the specific processes it supports are not understood fully. Event-related potential (ERP) studies of episodic retrieval have revealed an electrophysiological modulation--the right-frontal ERP old/new effect--which is thought to reflect activity in PFC. The functional…

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

PubMed Central

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-01-01

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg−1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1  μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning. PMID:26371762

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning.

PubMed

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-09-15

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg(-1)) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.

Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014-2017).

PubMed

Helpman, Liat; Zhu, Xi; Suarez-Jimenez, Benjamin; Lazarov, Amit; Monk, Catherine; Neria, Yuval

2017-11-08

Sex differences in the epidemiology and clinical presentation of trauma-related psychopathology have long been documented. Multiple underlying mechanisms have been examined, both psychosocial and biological. Among the most promising biological mechanisms are neural substrates of trauma-related psychopathology that have been uncovered in recent years. Neuroimaging studies of sex-related heterogeneity published over the past 3 years (2014-2017) demonstrate an interaction between sex and type, timing, and load of trauma exposure. These studies suggest that, for males, early trauma exposure may involve a loss of gray matter in the limbic system, including the prefrontal cortex (PFC), amygdala, and hippocampus, and an over-activity and increased connectivity of salience hubs, and particularly dorsal anterior cingulate cortex (dACC). For females, however, early trauma exposure may involve overactive and possibly an enlarged amygdala, as well as decreased connectivity of salience hubs such as the dACC. Underlying mechanisms may include interaction with several endocrine systems and result in differential neural response to naturally occurring and added endocrine ligands, as well as sex-specific genetic and epigenetic risk and resilience factors. This complex interaction between multiple biological systems may be associated with sex-specific behavioral patterns, in turn associated with trauma-related psychopathology. While substantial number of published studies present preliminary evidence for neural mechanisms of sex-specific posttraumatic responses, there is a paucity of research directly designed to examine sex as a biological factor in trauma-related psychopathology. Specific foci for future studies aiming to bridge current gaps in the literature are discussed.

Reduced amygdala-orbitofrontal connectivity during moral judgments in youths with disruptive behavior disorders and psychopathic traits

PubMed Central

Marsh, Abigail A.; Finger, Elizabeth C.; Fowler, Katherine A.; Jurkowitz, Ilana T.N.; Schechter, Julia C.; Yu, Henry H.; Pine, Daniel S.; Blair, R. J. R.

2011-01-01

We used functional magnetic resonance imaging (fMRI) to investigate dysfunction in the amygdala and orbitofrontal cortex in adolescents with disruptive behavior disorders and psychopathic traits during a moral judgment task. Fourteen adolescents with psychopathic traits and 14 healthy controls were assessed using fMRI while they categorized illegal and legal behaviors in a moral judgment implicit association task. fMRI data were then analyzed using random-effects analysis of variance and functional connectivity. Youths with psychopathic traits showed reduced amygdala activity when making judgments about legal actions and reduced functional connectivity between the amygdala and orbitofrontal cortex during task performance. These results suggest that psychopathic traits are associated with amygdala and orbitofrontal cortex dysfunction. This dysfunction may relate to previous findings of disrupted moral judgment in this population. PMID:22047730

Reference frames for spatial frequency in face representation differ in the temporal visual cortex and amygdala.

PubMed

Inagaki, Mikio; Fujita, Ichiro

2011-07-13

Social communication in nonhuman primates and humans is strongly affected by facial information from other individuals. Many cortical and subcortical brain areas are known to be involved in processing facial information. However, how the neural representation of faces differs across different brain areas remains unclear. Here, we demonstrate that the reference frame for spatial frequency (SF) tuning of face-responsive neurons differs in the temporal visual cortex and amygdala in monkeys. Consistent with psychophysical properties for face recognition, temporal cortex neurons were tuned to image-based SFs (cycles/image) and showed viewing distance-invariant representation of face patterns. On the other hand, many amygdala neurons were influenced by retina-based SFs (cycles/degree), a characteristic that is useful for social distance computation. The two brain areas also differed in the luminance contrast sensitivity of face-responsive neurons; amygdala neurons sharply reduced their responses to low luminance contrast images, while temporal cortex neurons maintained the level of their responses. From these results, we conclude that different types of visual processing in the temporal visual cortex and the amygdala contribute to the construction of the neural representations of faces.

The amygdala and ventromedial prefrontal cortex in morality and psychopathy.

PubMed

Blair, R J R

2007-09-01

Recent work has implicated the amygdala and ventromedial prefrontal cortex in morality and, when dysfunctional, psychopathy. This model proposes that the amygdala, through stimulus-reinforcement learning, enables the association of actions that harm others with the aversive reinforcement of the victims' distress. Consequent information on reinforcement expectancy, fed forward to the ventromedial prefrontal cortex, can guide the healthy individual away from moral transgressions. In psychopathy, dysfunction in these structures means that care-based moral reasoning is compromised and the risk that antisocial behavior is used instrumentally to achieve goals is increased.

Task Division within the Prefrontal Cortex: Distinct Neuron Populations Selectively Control Different Aspects of Aggressive Behavior via the Hypothalamus.

PubMed

Biro, Laszlo; Sipos, Eszter; Bruzsik, Biborka; Farkas, Imre; Zelena, Dora; Balazsfi, Diana; Toth, Mate; Haller, Jozsef

2018-04-25

An important question in behavioral neurobiology is how particular neuron populations and pathways mediate the overall roles of brain structures. Here we investigated this issue by studying the medial prefrontal cortex (mPFC), an established locus of inhibitory control of aggression. We established in male rats that dominantly distinct mPFC neuron populations project to and produce dense fiber networks with glutamate release sites in the mediobasal hypothalamus (MBH) and lateral hypothalamus (LH; i.e., two executory centers of species-specific and violent bites, respectively). Optogenetic stimulation of mPFC terminals in MBH distinctively increased bite counts in resident/intruder conflicts, whereas the stimulation of similar terminals in LH specifically resulted in violent bites. No other behaviors were affected by stimulations. These findings show that the mPFC controls aggressiveness by behaviorally dedicated neuron populations and pathways, the roles of which may be opposite to those observed in experiments where the role of the whole mPFC (or of its major parts) has been investigated. Overall, our findings suggest that the mPFC organizes into working units that fulfill specific aspects of its wide-ranging roles. SIGNIFICANCE STATEMENT Aggression control is associated with many cognitive and emotional aspects processed by the prefrontal cortex (PFC). However, how the prefrontal cortex influences quantitative and qualitative aspects of aggressive behavior remains unclear. We demonstrated that dominantly distinct PFC neuron populations project to the mediobasal hypothalamus (MBH) and the lateral hypothalamus (LH; i.e., two executory centers of species-specific and violent bites, respectively). Stimulation of mPFC fibers in MBH distinctively increased bite counts during fighting, whereas stimulation of similar terminals in LH specifically resulted in violent bites. Overall, our results suggest a direct prefrontal control over the hypothalamus, which is involved in the modulation of quantitative and qualitative aspects of aggressive behavior through distinct prefrontohypothalamic projections. Copyright © 2018 the authors 0270-6474/18/384065-11$15.00/0.

Double dissociation of value computations in orbitofrontal and anterior cingulate neurons

PubMed Central

Kennerley, Steven W.; Behrens, Timothy E. J.; Wallis, Jonathan D.

2011-01-01

Damage to prefrontal cortex (PFC) impairs decision-making, but the underlying value computations that might cause such impairments remain unclear. Here we report that value computations are doubly dissociable within PFC neurons. While many PFC neurons encoded chosen value, they used opponent encoding schemes such that averaging the neuronal population eliminated value coding. However, a special population of neurons in anterior cingulate cortex (ACC) - but not orbitofrontal cortex (OFC) - multiplex chosen value across decision parameters using a unified encoding scheme, and encoded reward prediction errors. In contrast, neurons in OFC - but not ACC - encoded chosen value relative to the recent history of choice values. Together, these results suggest complementary valuation processes across PFC areas: OFC neurons dynamically evaluate current choices relative to recent choice values, while ACC neurons encode choice predictions and prediction errors using a common valuation currency reflecting the integration of multiple decision parameters. PMID:22037498

Medial prefrontal cortex as an action-outcome predictor.

PubMed

Alexander, William H; Brown, Joshua W

2011-09-18

The medial prefrontal cortex (mPFC) and especially anterior cingulate cortex is central to higher cognitive function and many clinical disorders, yet its basic function remains in dispute. Various competing theories of mPFC have treated effects of errors, conflict, error likelihood, volatility and reward, using findings from neuroimaging and neurophysiology in humans and monkeys. No single theory has been able to reconcile and account for the variety of findings. Here we show that a simple model based on standard learning rules can simulate and unify an unprecedented range of known effects in mPFC. The model reinterprets many known effects and suggests a new view of mPFC, as a region concerned with learning and predicting the likely outcomes of actions, whether good or bad. Cognitive control at the neural level is then seen as a result of evaluating the probable and actual outcomes of one's actions. © 2011 Nature America, Inc. All rights reserved.

Medial prefrontal cortex as an action-outcome predictor

PubMed Central

Alexander, William H.; Brown, Joshua W.

2011-01-01

The medial prefrontal cortex (mPFC) and especially anterior cingulate cortex (ACC) is central to higher cognitive function and numerous clinical disorders, yet its basic function remains in dispute. Various competing theories of mPFC have treated effects of errors, conflict, error likelihood, volatility, and reward, based on findings from neuroimaging and neurophysiology in humans and monkeys. To date, no single theory has been able to reconcile and account for the variety of findings. Here we show that a simple model based on standard learning rules can simulate and unify an unprecedented range of known effects in mPFC. The model reinterprets many known effects and suggests a new view of mPFC, as a region concerned with learning and predicting the likely outcomes of actions, whether good or bad. Cognitive control at the neural level is then seen as a result of evaluating the probable and actual outcomes of one's actions. PMID:21926982

Control of Intermale Aggression by Medial Prefrontal Cortex Activation in the Mouse

PubMed Central

Takahashi, Aki; Nagayasu, Kazuki; Nishitani, Naoya; Kaneko, Shuji; Koide, Tsuyoshi

2014-01-01

Aggressive behavior is widely observed throughout the animal kingdom because of its adaptiveness for social animals. However, when aggressive behavior exceeds the species-typical level, it is no longer adaptive, so there should be a mechanism to control excessive aggression to keep it within the adaptive range. Using optogenetics, we demonstrate that activation of excitatory neurons in the medial prefrontal cortex (mPFC), but not the orbitofrontal cortex (OFC), inhibits inter-male aggression in mice. At the same time, optogenetic silencing of mPFC neurons causes an escalation of aggressive behavior both quantitatively and qualitatively. Activation of the mPFC suppresses aggressive bursts and reduces the intensity of aggressive behavior, but does not change the duration of the aggressive bursts. Our findings suggest that mPFC activity has an inhibitory role in the initiation and execution, but not the termination, of aggressive behavior, and maintains such behavior within the adaptive range. PMID:24740241

Relationships Between Gum-Chewing and Stress.

PubMed

Konno, Michiyo; Takeda, Tomotaka; Kawakami, Yoshiaki; Suzuki, Yoshihiro; Kawano, Yoshiaki; Nakajima, Kazunori; Ozawa, Takamitsu; Ishigami, Keiichi; Takemura, Naohiro; Sakatani, Kaoru

2016-01-01

Studies have shown that chewing is thought to affect stress modification in humans. Also, studies in animals have demonstrated that active chewing of a wooden stick during immobilization stress ameliorates the stress-impaired synaptic plasticity and prevents stress-induced noradrenaline release in the amygdala. On the other hand, studies have suggested that the right prefrontal cortex (PFC) dominates the regulation of the stress response system, including the hypothalamic-pituitary-adrenal (HPA) axis. The International Affective Digitized Sounds-2 (IADS) is widely used in the study of emotions and neuropsychological research. Therefore, in this study, the effects of gum-chewing on physiological and psychological (including PFC activity measured by NIRS) responses to a negative stimulus selected from the IADS were measured and analyzed. The study design was approved by the Ethics Committee of Tokyo Dental College (No. 436). We studied 11 normal adults using: cerebral blood oxygenation in the right medial PFC by multi-channel NIRS; alpha wave intensity by EEG; autonomic nervous function by heart rate; and emotional conditions by the State-Trait Anxiety Inventory (STAI) test and the 100-mm visual analogue scale (VAS). Auditory stimuli selected were fewer than 3.00 in Pleasure value. Sounds were recorded in 3 s and reproduced at random using software. Every task session was designed in a block manner; seven rests: Brown Noise (30 s) and six task blocks: auditory stimuli or auditory stimuli with gum-chewing (30 s). During the test, the participants' eyes were closed. Paired Student's t-test was used for the comparison (P<0.05). Gum-chewing showed a significantly greater activation in the PFC, alpha wave appearance rate and HR. Gum-chewing also showed a significantly higher VAS score and a smaller STAI level indicating 'pleasant'. Gum-chewing affected physiological and psychological responses including PFC activity. This PFC activation change might influence the HPA axis and ANS activities. In summary, within the limitations of this study, the findings suggest that gum-chewing reduced stress-related responses. Gum-chewing might have a possible effect on stress coping.

Differential involvement of the basolateral amygdala and orbitofrontal cortex in the formation of sensory-specific associations in conditioned flavor preference and magazine approach paradigms.

PubMed

Scarlet, Janina; Delamater, Andrew R; Campese, Vincent; Fein, Matthew; Wheeler, Daniel S

2012-06-01

Four experiments examined the roles of the basolateral amygdala and orbitofrontal cortex in the formation of sensory-specific associations in conditioned flavor preference and conditioned magazine approach paradigms using unconditioned stimulus (US) devaluation and selective Pavlovian-instrumental transfer procedures in Long Evans rats. Experiment 1 found that pre-training amygdala and orbitofrontal cortex lesions had no detectable effect on the formation or flexible use of sensory-specific flavor-nutrient associations in a US devaluation task, where flavor cues were paired either simultaneously or sequentially with nutrient rewards in water-deprived subjects. In Experiment 2, pre-training amygdala and orbitofrontal cortex lesions both attenuated outcome-specific Pavlovian-instrumental transfer. Experiment 3 indicated that amygdala lesions have no effect on the formation of sensory-specific flavor-nutrient associations in a US devaluation task in food-deprived subjects. Finally, Experiment 4 demonstrated that the outcomes used in Experiment 3 were sufficiently motivationally significant to support conditioned flavor preference. These findings suggest that, although both orbitofrontal cortex and amygdala lesions attenuate the acquisition of sensory-specific associations in magazine approach conditioning, neither lesion reduces the ability to appropriately respond to a flavor cue that was paired with a devalued outcome. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

PubMed Central

Walker, Adam G.; Wenthur, Cody J.; Xiang, Zixiu; Rook, Jerri M.; Emmitte, Kyle A.; Niswender, Colleen M.; Lindsley, Craig W.; Conn, P. Jeffrey

2015-01-01

Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu3 may be useful in alleviating prefrontal impairments associated with several CNS disorders. PMID:25583490

Generalisation benefits of output gating in a model of prefrontal cortex

NASA Astrophysics Data System (ADS)

Kriete, Trent; Noelle, David C.

2011-06-01

The prefrontal cortex (PFC) plays a central role in flexible cognitive control, including the suppression of habitual responding in favour of situation-appropriate behaviours that can be quite novel. PFC provides a kind of working memory, maintaining the rules, goals, and/or actions that are to control behaviour in the current context. For flexible control, these PFC representations must be sufficiently componential to support systematic generalisation to novel situations. The anatomical structure of PFC can be seen as implementing a componential 'slot-filler' structure, with different components encoded over isolated pools of neurons. Previous PFC models have highlighted the importance of a dynamic gating mechanism to selectively update individual 'slot' contents. In this article, we present simulation results that suggest that systematic generalisation also requires an 'output gating' mechanism that limits the influence of PFC on more posterior brain areas to reflect a small number of representational components at any one time.

Sex-related differences in amygdala functional connectivity during resting conditions.

PubMed

Kilpatrick, L A; Zald, D H; Pardo, J V; Cahill, L F

2006-04-01

Recent neuroimaging studies have established a sex-related hemispheric lateralization of amygdala involvement in memory for emotionally arousing material. Here, we examine the possibility that sex-related differences in amygdala involvement in memory for emotional material develop from differential patterns of amygdala functional connectivity evident in the resting brain. Seed voxel partial least square analyses of regional cerebral blood flow data revealed significant sex-related differences in amygdala functional connectivity during resting conditions. The right amygdala was associated with greater functional connectivity in men than in women. In contrast, the left amygdala was associated with greater functional connectivity in women than in men. Furthermore, the regions displaying stronger functional connectivity with the right amygdala in males (sensorimotor cortex, striatum, pulvinar) differed from those displaying stronger functional connectivity with the left amygdala in females (subgenual cortex, hypothalamus). These differences in functional connectivity at rest may link to sex-related differences in medical and psychiatric disorders.

Authoritarianism, religious fundamentalism, and the human prefrontal cortex

PubMed Central

Asp, Erik; Ramchandran, Kanchna; Tranel, Daniel

2012-01-01

Objective The psychological processes of doubting and skepticism have recently become topics of neuroscientific investigation. In this context, we developed the False Tagging Theory, a neurobiological model of the belief and doubt process, which proposes that the prefrontal cortex is critical for normative doubt regarding properly comprehended cognitive representations. Here, we put our theory to an empirical test, hypothesizing that patients with prefrontal cortex damage would have a doubt deficit that would manifest as higher authoritarianism and religious fundamentalism. Method Ten patients with bilateral damage to the ventromedial prefrontal cortex (vmPFC), ten patients with damage to areas outside the vmPFC, and sixteen medical comparison patients, who experienced life-threatening (but non-neurological) medical events, completed a series of scales measuring authoritarianism, religious fundamentalism, and specific religious beliefs. Results VMPFC patients reported significantly higher authoritarianism and religious fundamentalism than the other groups. The degrees of authoritarianism and religious fundamentalism in the vmPFC group were significantly higher than normative values, as well; by contrast, the comparison groups did not differ from normative values. Moreover, vmPFC patients reported increased specific religious beliefs after brain injury. Conclusions The findings support the False Tagging Theory, and suggest that the vmPFC is critical for psychological doubt and resistance to authoritarian persuasion. PMID:22612576

Exposure to a mildly aversive early life experience leads to prefrontal cortex deficits in the rat.

PubMed

Stamatakis, Antonios; Manatos, Vasileios; Kalpachidou, Theodora; Stylianopoulou, Fotini

2016-11-01

Aversive early life experiences in humans have been shown to result in deficits in the function of the prefrontal cortex (PFC). In an effort to elucidate possible neurobiological mechanisms involved, we investigated in rats, the effects of a mildly aversive early experience on PFC structure and function. The early experience involved exposure of rat pups during postnatal days (PND) 10-13 to a T-maze in which they search for their mother, but upon finding her are prohibited contact with her, thus being denied the expected reward (DER). We found that the DER experience resulted in adulthood in impaired PFC function, as assessed by two PFC-dependent behavioral tests [attention set-shifting task (ASST) and fear extinction]. In the ASST, DER animals showed deficits specifically in the intra-dimensional reversal shifts and a lower activation-as determined by c-Fos immunohistochemistry-of the medial orbital cortex (MO), a PFC subregion involved in this aspect of the task. Furthermore, the DER experience resulted in decreased glutamatergic neuron and dendritic spine density in the MO and infralimbic cortex (IL) in the adult brain. The decreased neuronal density was detected as early as PND12 and was accompanied by increased micro- and astroglia-density in the MO/IL.

Context Memory Decline in Middle Aged Adults is Related to Changes in Prefrontal Cortex Function.

PubMed

Kwon, Diana; Maillet, David; Pasvanis, Stamatoula; Ankudowich, Elizabeth; Grady, Cheryl L; Rajah, M Natasha

2016-06-01

The ability to encode and retrieve spatial and temporal contextual details of episodic memories (context memory) begins to decline at midlife. In the current study, event-related fMRI was used to investigate the neural correlates of context memory decline in healthy middle aged adults (MA) compared with young adults (YA). Participants were scanned while performing easy and hard versions of spatial and temporal context memory tasks. Scans were obtained at encoding and retrieval. Significant reductions in context memory retrieval accuracy were observed in MA, compared with YA. The fMRI results revealed that overall, both groups exhibited similar patterns of brain activity in parahippocampal cortex, ventral occipito-temporal regions and prefrontal cortex (PFC) during encoding. In contrast, at retrieval, there were group differences in ventral occipito-temporal and PFC activity, due to these regions being more activated in MA, compared with YA. Furthermore, only in YA, increased encoding activity in ventrolateral PFC, and increased retrieval activity in occipital cortex, predicted increased retrieval accuracy. In MA, increased retrieval activity in anterior PFC predicted increased retrieval accuracy. These results suggest that there are changes in PFC contributions to context memory at midlife. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The Mediodorsal Thalamus Drives Feedforward Inhibition in the Anterior Cingulate Cortex via Parvalbumin Interneurons

PubMed Central

Delevich, Kristen; Tucciarone, Jason; Huang, Z. Josh

2015-01-01

Although the medial prefrontal cortex (mPFC) is classically defined by its reciprocal connections with the mediodorsal thalamic nucleus (MD), the nature of information transfer between MD and mPFC is poorly understood. In sensory thalamocortical pathways, thalamic recruitment of feedforward inhibition mediated by fast-spiking, putative parvalbumin-expressing (PV) interneurons is a key feature that enables cortical neurons to represent sensory stimuli with high temporal fidelity. Whether a similar circuit mechanism is in place for the projection from the MD (a higher-order thalamic nucleus that does not receive direct input from the periphery) to the mPFC is unknown. Here we show in mice that inputs from the MD drive disynaptic feedforward inhibition in the dorsal anterior cingulate cortex (dACC) subregion of the mPFC. In particular, we demonstrate that axons arising from MD neurons directly synapse onto and excite PV interneurons that in turn mediate feedforward inhibition of pyramidal neurons in layer 3 of the dACC. This feedforward inhibition in the dACC limits the time window during which pyramidal neurons integrate excitatory synaptic inputs and fire action potentials, but in a manner that allows for greater flexibility than in sensory cortex. These findings provide a foundation for understanding the role of MD-PFC circuit function in cognition. PMID:25855185

The role of medial prefrontal cortex in memory and decision making.

PubMed

Euston, David R; Gruber, Aaron J; McNaughton, Bruce L

2012-12-20

Some have claimed that the medial prefrontal cortex (mPFC) mediates decision making. Others suggest mPFC is selectively involved in the retrieval of remote long-term memory. Yet others suggests mPFC supports memory and consolidation on time scales ranging from seconds to days. How can all these roles be reconciled? We propose that the function of the mPFC is to learn associations between context, locations, events, and corresponding adaptive responses, particularly emotional responses. Thus, the ubiquitous involvement of mPFC in both memory and decision making may be due to the fact that almost all such tasks entail the ability to recall the best action or emotional response to specific events in a particular place and time. An interaction between multiple memory systems may explain the changing importance of mPFC to different types of memories over time. In particular, mPFC likely relies on the hippocampus to support rapid learning and memory consolidation. Copyright © 2012 Elsevier Inc. All rights reserved.

dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.

PubMed

Manitt, C; Eng, C; Pokinko, M; Ryan, R T; Torres-Berrío, A; Lopez, J P; Yogendran, S V; Daubaras, M J J; Grant, A; Schmidt, E R E; Tronche, F; Krimpenfort, P; Cooper, H M; Pasterkamp, R J; Kolb, B; Turecki, G; Wong, T P; Nestler, E J; Giros, B; Flores, C

2013-12-17

Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.

Specializations for reward-guided decision-making in the primate ventral prefrontal cortex.

PubMed

Murray, Elisabeth A; Rudebeck, Peter H

2018-05-23

The estimated values of choices, and therefore decision-making based on those values, are influenced by both the chance that the chosen items or goods can be obtained (availability) and their current worth (desirability) as well as by the ability to link the estimated values to choices (a process sometimes called credit assignment). In primates, the prefrontal cortex (PFC) has been thought to contribute to each of these processes; however, causal relationships between particular subdivisions of the PFC and specific functions have been difficult to establish. Recent lesion-based research studies have defined the roles of two different parts of the primate PFC - the orbitofrontal cortex (OFC) and the ventral lateral frontal cortex (VLFC) - and their subdivisions in evaluating each of these factors and in mediating credit assignment during reward-based decision-making.

Development of Rostral Prefrontal Cortex and Cognitive and Behavioural Disorders

ERIC Educational Resources Information Center

Dumontheil, Iroise; Burgess, Paul W.; Blakemore, Sarah-Jayne

2008-01-01

Information on the development and functions of rostral prefrontal cortex (PFC), or Brodmann area 10, has been gathered from different fields, from anatomical development to functional neuroimaging in adults, and put forward in relation to three particular cognitive and behavioural disorders. Rostral PFC is larger and has a lower cell density in…

Separable Neural Mechanisms Contribute to Feedback Processing in a Rule-Learning Task

ERIC Educational Resources Information Center

Zanolie, K.; Van Leijenhorst, L.; Rombouts, S. A. R. B.; Crone, E. A.

2008-01-01

To adjust performance appropriately to environmental demands, it is important to monitor ongoing action and process performance feedback for possible errors. In this study, we used fMRI to test whether medial prefrontal cortex (PFC)/anterior cingulate cortex (ACC) and dorsolateral (DL) PFC have different roles in feedback processing. Twenty adults…

Lateral, Not Medial, Prefrontal Cortex Contributes to Punishment and Aversive Instrumental Learning

ERIC Educational Resources Information Center

Jean-Richard-dit-Bressel , Philip; McNally, Gavan P.

2016-01-01

Aversive outcomes punish behaviors that cause their occurrence. The prefrontal cortex (PFC) has been implicated in punishment learning and behavior, although the exact roles for different PFC regions in instrumental aversive learning and decision-making remain poorly understood. Here, we assessed the role of the orbitofrontal (OFC), rostral…

Induction of hyperphagia and carbohydrate intake by mu-opioid receptor stimulation in circumscribed regions of frontal cortex

PubMed Central

Mena, Jesus D.; Sadeghian, Ken; Baldo, Brian A.

2011-01-01

Frontal cortical regions are activated by food-associated stimuli, and this activation appears to be dysregulated in individuals with eating disorders. Nevertheless, frontal control of basic unconditioned feeding responses remains poorly understood. Here we show that hyperphagia can be driven by μ-opioid receptor stimulation in restricted regions of ventral medial prefrontal cortex (vmPFC) and orbitofrontal cortex. In both ad libitum-fed and food-restricted male Sprague-Dawley rats, bilateral infusions of the μ-opioid agonist, DAMGO, markedly increased intake of standard rat chow. When given a choice between palatable fat- versus carbohydrate enriched test diets, intra-vmPFC DAMGO infusions selectively increased carbohydrate intake, even in rats with a baseline fat preference. Rats also exhibited motor hyperactivity characterized by rapid switching between brief bouts of investigatory and ingestive behaviors. Intra-vmPFC DAMGO affected neither water intake nor non-specific oral behavior. Similar DAMGO infusions into neighboring areas of lateral orbital or anterior motor cortex had minimal effects on feeding. Neither stimulation of vmPFC-localized delta-opioid, kappa-opioid, dopaminergic, serotonergic, or noradrenergic receptors, nor antagonism of D1, 5HT1A, or alpha- or beta-adrenoceptors, reproduced the profile of DAMGO effects. Muscimol-mediated inactivation of the vmPFC, and intra-vmPFC stimulation of κ-opioid receptors or blockade of 5HT2A receptors, suppressed motor activity and increased feeding bout duration-a profile opposite to that seen with DAMGO. Hence, μ-opioid-induced hyperphagia and carbohydrate intake can be elicited with remarkable pharmacological and behavioral specificity from discrete subterritories of the frontal cortex. These findings may have implications for understanding affect-driven feeding and loss of restraint in eating disorders. PMID:21368037

Induction of hyperphagia and carbohydrate intake by μ-opioid receptor stimulation in circumscribed regions of frontal cortex.

PubMed

Mena, Jesus D; Sadeghian, Ken; Baldo, Brian A

2011-03-02

Frontal cortical regions are activated by food-associated stimuli, and this activation appears to be dysregulated in individuals with eating disorders. Nevertheless, frontal control of basic unconditioned feeding responses remains poorly understood. Here we show that hyperphagia can be driven by μ-opioid receptor stimulation in restricted regions of ventral medial prefrontal cortex (vmPFC) and orbitofrontal cortex. In both ad libitum-fed and food-restricted male Sprague Dawley rats, bilateral infusions of the μ-opioid agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) markedly increased intake of standard rat chow. When given a choice between palatable fat-enriched versus carbohydrate-enriched test diets, intra-vmPFC DAMGO infusions selectively increased carbohydrate intake, even in rats with a baseline fat preference. Rats also exhibited motor hyperactivity characterized by rapid switching between brief bouts of investigatory and ingestive behaviors. Intra-vmPFC DAMGO affected neither water intake nor nonspecific oral behavior. Similar DAMGO infusions into neighboring areas of lateral orbital or anterior motor cortex had minimal effects on feeding. Neither stimulation of vmPFC-localized δ-opioid, κ-opioid, dopaminergic, serotonergic, or noradrenergic receptors, nor antagonism of D1, 5HT1A, or α- or β-adrenoceptors, reproduced the profile of DAMGO effects. Muscimol-mediated inactivation of the vmPFC, and intra-vmPFC stimulation of κ-opioid receptors or blockade of 5-HT2A (5-hydroxytryptamine receptor 2A) receptors, suppressed motor activity and increased feeding bout duration-a profile opposite to that seen with DAMGO. Hence, μ-opioid-induced hyperphagia and carbohydrate intake can be elicited with remarkable pharmacological and behavioral specificity from discrete subterritories of the frontal cortex. These findings may have implications for understanding affect-driven feeding and loss of restraint in eating disorders.

Amygdala Contributions to Stimulus-Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning.

PubMed

Rudebeck, Peter H; Ripple, Joshua A; Mitz, Andrew R; Averbeck, Bruno B; Murray, Elisabeth A

2017-02-22

Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC. SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus-reward associations. MFC also showed increased encoding of the instrumental responses that monkeys made on each trial. Behaviorally, changes in neural activity were accompanied by slower stimulus-reward learning. The findings suggest that interactions among amygdala, OFC, and MFC contribute to learning about stimuli that predict rewards. Copyright © 2017 the authors 0270-6474/17/372186-17$15.00/0.

Amygdala Contributions to Stimulus–Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning

PubMed Central

Averbeck, Bruno B.

2017-01-01

Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus–reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus–reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus–reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus–reward associations rapidly by shaping encoding within OFC and MFC. SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus–reward associations. MFC also showed increased encoding of the instrumental responses that monkeys made on each trial. Behaviorally, changes in neural activity were accompanied by slower stimulus–reward learning. The findings suggest that interactions among amygdala, OFC, and MFC contribute to learning about stimuli that predict rewards. PMID:28123082

The direct pathway from the brainstem reticular formation to the cerebral cortex in the ascending reticular activating system: A diffusion tensor imaging study.

PubMed

Jang, Sung Ho; Kwon, Hyeok Gyu

2015-10-08

Precise evaluation of the ascending reticular activating system (ARAS) is important for diagnosis, prediction of prognosis, and management of patients with disorders of impaired consciousness. In the current study, we attempted to reconstruct the direct neural pathway between the brainstem reticular formation (RF) and the cerebral cortex in normal subjects, using diffusion tensor imaging (DTI). Forty-one healthy subjects were recruited for this study. DTIs were performed using a sensitivity-encoding head coil at 1.5Tesla with FMRIB Software Library. For connectivity of the brainstem RF, we used two regions of interest (ROIs) for the brainstem RF (seed ROI) and the thalamus and hypothalamus (exclusion ROI). Connectivity was defined as the incidence of connection between the brainstem RF and target brain regions at the threshold of 5 and 50 streamlines. Regarding the thresholds of 5 and 50, the brainstem RF showed high connectivity to the lateral prefrontal cortex (lPFC, 67.1% and 20.7%) and ventromedial prefrontal cortex (vmPFC, 50.0% and 18.3%), respectively. In contrast, the brainstem RF showed low connectivity to the primary motor cortex (31.7% and 3.7%), premotor cortex (24.4% and 3.7%), primary somatosensory cortex (23.2% and 2.4%), orbitofrontal cortex (17.1% and 7.3%), and posterior parietal cortex (12.2% and 0%), respectively. The brainstem RF was mainly connected to the prefrontal cortex, particularly lPFC and vmPFC. We believe that the methodology and results of this study would be useful to clinicians involved in the care of patients with impaired consciousness and researchers in studies of the ARAS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Distributed value representation in the medial prefrontal cortex during intertemporal choices.

PubMed

Wang, Qiang; Luo, Shan; Monterosso, John; Zhang, Jintao; Fang, Xiaoyi; Dong, Qi; Xue, Gui

2014-05-28

The ability to resist current temptations in favor of long-term benefits is a critical human capacity. Despite the extensive studies on the neural mechanisms of intertemporal choices, how the subjective value of immediate and delayed rewards is represented and compared in the brain remains to be elucidated. The present fMRI study addressed this question by simultaneously and independently manipulating the magnitude of immediate and delayed rewards in an intertemporal decision task, combined with univariate analysis and multiple voxel pattern analysis. We found that activities in the posterior portion of the dorsal medial prefrontal cortex (DmPFC) were modulated by the value of immediate options, whereas activities in the adjacent anterior DmPFC were modulated by the subjective value of delayed options. Brain signal change in the ventral mPFC was positively correlated with the "relative value" (the absolute difference of subjective value between two intertemporal alternatives). In contrast, the dorsal anterior cingulate cortex activity was negatively correlated with the relative value. These results suggest that immediate and delayed rewards are separately represented in the dorsal mPFC and compared in the ventral mPFC to guide decisions. The functional dissociation of posterior and anterior DmPFC in representing immediate and delayed reward is consistent with the general structural and functional architecture of the prefrontal cortex and may provide a neural basis for human's unique capacity to delayed gratification. Copyright © 2014 the authors 0270-6474/14/347522-09$15.00/0.

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala.

PubMed

Ihara, Fumiaki; Nishimura, Maki; Muroi, Yoshikage; Mahmoud, Motamed Elsayed; Yokoyama, Naoaki; Nagamune, Kisaburo; Nishikawa, Yoshifumi

2016-10-01

Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Early memory formation disrupted by atypical PKC inhibitor ZIP in the medial prefrontal cortex but not hippocampus

PubMed Central

Evuarherhe, Obaro; Barker, Gareth R. I.; Savalli, Giorgia; Warburton, Elizabeth C.; Brown, Malcolm W.

2014-01-01

Atypical isoforms of protein kinase C (aPKCs; particularly protein kinase M zeta: PKMζ) have been hypothesised to be necessary and sufficient for the maintenance of long-term potentiation (LTP) and long term memory by maintaining postsynaptic AMPA receptors via the GluR2 subunit. A myristoylated PKMζ pseudosubstrate peptide (ZIP) blocks PKMζ activity. We examined the actions of ZIP in medial prefrontal cortex (mPFC) and hippocampus in associative recognition memory in rats during early memory formation and memory maintenance. ZIP infusion in either hippocampus or mPFC impaired memory maintenance. However, early memory formation was impaired by ZIP in mPFC but not hippocampus; and blocking GluR2-dependent removal of AMPA receptors did not affect this impairment caused by ZIP in the mPFC. The findings indicate: (i) a difference in the actions of ZIP in hippocampus and medial prefrontal cortex, and (ii) a GluR2-independent target of ZIP (possibly PKCλ) in the mPFC during early memory formation. PMID:24729442

From rule to response: neuronal processes in the premotor and prefrontal cortex.

PubMed

Wallis, Jonathan D; Miller, Earl K

2003-09-01

The ability to use abstract rules or principles allows behavior to generalize from specific circumstances (e.g., rules learned in a specific restaurant can subsequently be applied to any dining experience). Neurons in the prefrontal cortex (PFC) encode such rules. However, to guide behavior, rules must be linked to motor responses. We investigated the neuronal mechanisms underlying this process by recording from the PFC and the premotor cortex (PMC) of monkeys trained to use two abstract rules: "same" or "different." The monkeys had to either hold or release a lever, depending on whether two successively presented pictures were the same or different, and depending on which rule was in effect. The abstract rules were represented in both regions, although they were more prevalent and were encoded earlier and more strongly in the PMC. There was a perceptual bias in the PFC, relative to the PMC, with more PFC neurons encoding the presented pictures. In contrast, neurons encoding the behavioral response were more prevalent in the PMC, and the selectivity was stronger and appeared earlier in the PMC than in the PFC.

Dimensional change card sort performance associated with age-related differences in functional connectivity of lateral prefrontal cortex.

PubMed

Ezekiel, Fredrick; Bosma, Rachael; Morton, J Bruce

2013-07-01

The Dimensional Change Card Sort (DCCS) is a standard procedure for assessing executive functioning early in development. In the task, participants switch from sorting cards one way (e.g., by color) to sorting them a different way (e.g., by shape). Traditional accounts associate age-related changes in DCCS performance with circumscribed changes in lateral prefrontal cortex (lPFC) functioning, but evidence of age-related differences in the modulation of lPFC activity by switching is mixed. The current study therefore tested for possible age-related differences in functional connectivity of lPFC with regions that comprise a larger cognitive control network. Functional magnetic resonance imaging (fMRI) data collected from children and adults performing the DCCS were analyzed by means of independent components analysis (ICA). The analysis revealed several important age-related differences in functional connectivity of lPFC. In particular, lPFC was more strongly connected with the anterior cingulate, inferior parietal cortex, and the ventral tegmental area in adults than in children. Theoretical implications are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

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.

Social Isolation During the Critical Period Reduces Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Cell in Mouse Prefrontal Cortex.

PubMed

Yamamuro, Kazuhiko; Yoshino, Hiroki; Ogawa, Yoichi; Makinodan, Manabu; Toritsuka, Michihiro; Yamashita, Masayuki; Corfas, Gabriel; Kishimoto, Toshifumi

2018-03-01

Juvenile social experience is crucial for the functional development of forebrain regions, especially the prefrontal cortex (PFC). We previously reported that social isolation for 2 weeks after weaning induces prefrontal cortex dysfunction and hypomyelination. However, the effect of social isolation on physiological properties of PFC neuronal circuit remained unknown. Since hypomyelination due to isolation is prominent in deep-layer of medial PFC (mPFC), we focused on 2 types of Layer-5 pyramidal cells in the mPFC: prominent h-current (PH) cells and nonprominent h-current (non-PH) cells. We found that a 2-week social isolation after weaning leads to a specific deterioration in action potential properties and reduction in excitatory synaptic inputs in PH cells. The effects of social isolation on PH cells, which involve reduction in functional glutamatergic synapses and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate charge ratio, are specific to the 2 weeks after weaning and to the mPFC. We conclude that juvenile social experience plays crucial roles in the functional development in a subtype of Layer-5 pyramidal cells in the mPFC. Since these neurons project to subcortical structures, a deficit in social experience during the critical period may result in immature neural circuitry between mPFC and subcortical targets. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

From Anxious to Reckless: A Control Systems Approach Unifies Prefrontal-Limbic Regulation Across the Spectrum of Threat Detection.

PubMed

Mujica-Parodi, Lilianne R; Cha, Jiook; Gao, Jonathan

2017-01-01

Here we provide an integrative review of basic control circuits, and introduce techniques by which their regulation can be quantitatively measured using human neuroimaging. We illustrate the utility of the control systems approach using four human neuroimaging threat detection studies ( N = 226), to which we applied circuit-wide analyses in order to identify the key mechanism underlying individual variation. In so doing, we build upon the canonical prefrontal-limbic control system to integrate circuit-wide influence from the inferior frontal gyrus (IFG). These were incorporated into a computational control systems model constrained by neuroanatomy and designed to replicate our experimental data. In this model, the IFG acts as an informational set point, gating signals between the primary prefrontal-limbic negative feedback loop and its cortical information-gathering loop. Along the cortical route, if the sensory cortex provides sufficient information to make a threat assessment, the signal passes to the ventromedial prefrontal cortex (vmPFC), whose threat-detection threshold subsequently modulates amygdala outputs. However, if signal outputs from the sensory cortex do not provide sufficient information during the first pass, the signal loops back to the sensory cortex, with each cycle providing increasingly fine-grained processing of sensory data. Simulations replicate IFG (chaotic) dynamics experimentally observed at both ends at the threat-detection spectrum. As such, they identify distinct types of IFG disconnection from the circuit, with associated clinical outcomes. If IFG thresholds are too high, the IFG and sensory cortex cycle for too long; in the meantime the coarse-grained (excitatory) pathway will dominate, biasing ambiguous stimuli as false positives. On the other hand, if cortical IFG thresholds are too low, the inhibitory pathway will suppress the amygdala without cycling back to the sensory cortex for much-needed fine-grained sensory cortical data, biasing ambiguous stimuli as false negatives. Thus, the control systems model provides a consistent mechanism for IFG regulation, capable of producing results consistent with our data for the full spectrum of threat-detection: from fearful to optimal to reckless. More generally, it illustrates how quantitative characterization of circuit dynamics can be used to unify a fundamental dimension across psychiatric affective symptoms, with implications for populations that range from anxiety disorders to addiction.

Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders

PubMed Central

Bukalo, Olena; Pinard, Courtney R; Holmes, Andrew

2014-01-01

The burden of anxiety disorders is growing, but the efficacy of available anxiolytic treatments remains inadequate. Cognitive behavioural therapy for anxiety disorders focuses on identifying and modifying maladaptive patterns of thinking and behaving, and has a testable analogue in rodents in the form of fear extinction. A large preclinical literature has amassed in recent years describing the neural and molecular basis of fear extinction in rodents. In this review, we discuss how this work is being harnessed to foster translational research on anxiety disorders and facilitate the search for new anxiolytic treatments. We begin by summarizing the anatomical and functional connectivity of a medial prefrontal cortex (mPFC)–amygdala circuit that subserves fear extinction, including new insights from optogenetics. We then cover some of the approaches that have been taken to model impaired fear extinction and associated impairments with mPFC–amygdala dysfunction. The principal goal of the review is to evaluate evidence that various neurotransmitter and neuromodulator systems mediate fear extinction by modulating the mPFC–amygdala circuitry. To that end, we describe studies that have tested how fear extinction is impaired or facilitated by pharmacological manipulations of dopamine, noradrenaline, 5-HT, GABA, glutamate, neuropeptides, endocannabinoids and various other systems, which either directly target the mPFC–amygdala circuit, or produce behavioural effects that are coincident with functional changes in the circuit. We conclude that there are good grounds to be optimistic that the progress in defining the molecular substrates of mPFC–amygdala circuit function can be effectively leveraged to identify plausible candidates for extinction-promoting therapies for anxiety disorders. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20 PMID:24835117

Greater Working Memory Load Results in Greater Medial Temporal Activity at Retrieval

PubMed Central

Quiroz, Yakeel T.; Hasselmo, Michael E.; Stern, Chantal E.

2009-01-01

Most functional magnetic resonance imaging (fMRI) studies examining working memory (WM) load have focused on the prefrontal cortex (PFC) and have demonstrated increased prefrontal activity with increased load. Here we examined WM load effects in the medial temporal lobe (MTL) using an fMRI Sternberg task with novel complex visual scenes. Trials consisted of 3 sequential events: 1) sample presentation (encoding), 2) delay period (maintenance), and 3) probe period (retrieval). During sample encoding, subjects saw either 2 or 4 pictures consecutively. During retrieval, subjects indicated whether the probe picture matched one of the sample pictures. Results revealed that activity in the left anterior hippocampal formation, bilateral retrosplenial area, and left amygdala was greater at retrieval for trials with larger memory load, whereas activity in the PFC was greater at encoding for trials with larger memory load. There was no load effect during the delay. When encoding, maintenance, and retrieval periods were compared with fixation, activity was present in the hippocampal body/tail and fusiform gyrus bilaterally during encoding and retrieval, but not maintenance. Bilateral dorsolateral prefrontal activity was present during maintenance, but not during encoding or retrieval. The results support models of WM predicting that activity in the MTL should be modulated by WM load. PMID:19224975

Reduced amygdala-orbitofrontal connectivity during moral judgments in youths with disruptive behavior disorders and psychopathic traits.

PubMed

Marsh, Abigail A; Finger, Elizabeth C; Fowler, Katherine A; Jurkowitz, Ilana T N; Schechter, Julia C; Yu, Henry H; Pine, Daniel S; Blair, R J R

2011-12-30

We used functional magnetic resonance imaging (fMRI) to investigate dysfunction in the amygdala and orbitofrontal cortex in adolescents with disruptive behavior disorders and psychopathic traits during a moral judgment task. Fourteen adolescents with psychopathic traits and 14 healthy controls were assessed using fMRI while they categorized illegal and legal behaviors in a moral judgment implicit association task. fMRI data were then analyzed using random-effects analysis of variance and functional connectivity. Youths with psychopathic traits showed reduced amygdala activity when making judgments about legal actions and reduced functional connectivity between the amygdala and orbitofrontal cortex during task performance. These results suggest that psychopathic traits are associated with amygdala and orbitofrontal cortex dysfunction. This dysfunction may relate to previous findings of disrupted moral judgment in this population. 2011 Elsevier Ireland Ltd. All rights reserved.

Amygdala Functional Connectivity is Reduced After the Cold Pressor Task

PubMed Central

Clewett, David; Schoeke, Andrej; Mather, Mara

2013-01-01

The amygdala forms a crucial link between central pain and stress systems. There is much evidence that psychological stress affects amygdala activity, but it is less clear how painful stressors influence subsequent amygdala functional connectivity. In the present study, we used pulsed arterial spin labeling (PASL) to investigate differences in healthy male adults’ resting-state amygdala functional connectivity following a cold pressor versus control task, with the stressor and control conditions conducted on different days. During the period of peak cortisol response to acute stress (approximately fifteen to thirty minutes after stressor onset), participants were asked to rest for six minutes with their eyes closed during a PASL scanning sequence. The cold pressor task led to reduced resting-state functional connectivity between the amygdalae and orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (VMPFC), which occurred irrespective of cortisol release. The stressor also induced greater inverse connectivity between the left amygdala and dorsal anterior cingulate cortex (dACC), a brain region implicated in the down-regulation of amygdala responsivity. Furthermore, the degree of post-stressor left amygdala decoupling with the lateral OFC varied according to self-reported pain intensity during the cold pressor task. These findings indicate that the cold pressor task alters amygdala interactions with prefrontal and ACC regions 15–30 minutes after the stressor, and that these altered functional connectivity patterns are related to pain perception rather than cortisol feedback. PMID:23645370

Childhood Poverty Predicts Adult Amygdala and Frontal Activity and Connectivity in Response to Emotional Faces.

PubMed

Javanbakht, Arash; King, Anthony P; Evans, Gary W; Swain, James E; Angstadt, Michael; Phan, K Luan; Liberzon, Israel

2015-01-01

Childhood poverty negatively impacts physical and mental health in adulthood. Altered brain development in response to social and environmental factors associated with poverty likely contributes to this effect, engendering maladaptive patterns of social attribution and/or elevated physiological stress. In this fMRI study, we examined the association between childhood poverty and neural processing of social signals (i.e., emotional faces) in adulthood. Fifty-two subjects from a longitudinal prospective study recruited as children, participated in a brain imaging study at 23-25 years of age using the Emotional Faces Assessment Task. Childhood poverty, independent of concurrent adult income, was associated with higher amygdala and medial prefrontal cortical (mPFC) responses to threat vs. happy faces. Also, childhood poverty was associated with decreased functional connectivity between left amygdala and mPFC. This study is unique, because it prospectively links childhood poverty to emotional processing during adulthood, suggesting a candidate neural mechanism for negative social-emotional bias. Adults who grew up poor appear to be more sensitive to social threat cues and less sensitive to positive social cues.

Dorsal medial prefrontal cortex contributes to conditioned taste aversion memory consolidation and retrieval.

PubMed

Gonzalez, Maria Carolina; Villar, Maria Eugenia; Igaz, Lionel M; Viola, Haydée; Medina, Jorge H

2015-12-01

The medial prefrontal cortex (mPFC) is known for its role in decision making and memory processing, including the participation in the formation of extinction memories. However, little is known regarding its contribution to aversive memory consolidation. Here we demonstrate that neural activity and protein synthesis are required in the dorsal mPFC for memory formation of a conditioned taste aversion (CTA) task and that this region is involved in the retrieval of recent and remote long-term CTA memory. In addition, both NMDA receptor and CaMKII activity in dorsal mPFC are needed for CTA memory consolidation, highlighting the complexity of mPFC functions. Copyright © 2015 Elsevier Inc. All rights reserved.

Dynamic Neuroplasticity after Human Prefrontal Cortex Damage

PubMed Central

Voytek, Bradley; Davis, Matar; Yago, Elena; Barceló, Francisco; Vogel, Edward K.; Knight, Robert T.

2010-01-01

Summary Memory and attention deficits are common after prefrontal cortex (PFC) damage, yet people generally recover some function over time. Recovery is thought to be dependent upon undamaged brain regions but the temporal dynamics underlying cognitive recovery are poorly understood. Here we provide evidence that the intact PFC compensates for damage in the lesioned PFC on a trial-by-trial basis dependent on cognitive load. The extent of this rapid functional compensation is indexed by transient increases in electrophysiological measures of attention and memory in the intact PFC, detectable within a second after stimulus presentation and only when the lesioned hemisphere is challenged. These observations provide evidence supporting a dynamic and flexible model of compensatory neural plasticity. PMID:21040843

Role of medial prefrontal cortex Narp in the extinction of morphine conditioned place preference.

PubMed

Blouin, Ashley M; Han, Sungho; Pearce, Anne M; Cheng, Kailun; Lee, Jongah J; Johnson, Alexander W; Wang, Chuansong; During, Matthew J; Holland, Peter C; Shaham, Yavin; Baraban, Jay M; Reti, Irving M

2013-01-15

Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus (AAV) expressing wild-type (WT) Narp into the mPFC of Narp KO mice rescued the extinction and the injection of AAV expressing a dominant negative form of Narp (NarpN) into the mPFC of WT mice impaired the extinction of morphine CPP. These findings suggest that Narp in the mPFC mediates the extinction of morphine CPP.

Sex differences in amygdala activation during the perception of facial affect.

PubMed

Killgore, W D; Yurgelun-Todd, D A

2001-08-08

The cognitive and affective systems of the cerebral cortex are often more lateralized in males than females, but it is unclear whether these differences extend to subcortical systems. We used fMRI to examine sex differences in lateralized amygdala activity during happy and fearful face perception. Amygdala activation differed for men and women depending on the valence of the expression. Overall, males were more lateralized than females, but the direction differed between valence conditions. Happy faces produced greater right than left amygdala activation for males but not females. Both sexes showed greater left amygdala activation for fearful faces. These findings suggest that the lateralization of affective function may extend beyond the cortex to subcortical regions such as the amygdala.

Dissociation and Convergence of the Dorsal and Ventral Visual Streams in the Human Prefrontal Cortex

PubMed Central

Takahashi, Emi; Ohki, Kenichi; Kim, Dae-Shik

2012-01-01

Visual information is largely processed through two pathways in the primate brain: an object pathway from the primary visual cortex to the temporal cortex (ventral stream) and a spatial pathway to the parietal cortex (dorsal stream). Whether and to what extent dissociation exists in the human prefrontal cortex (PFC) has long been debated. We examined anatomical connections from functionally defined areas in the temporal and parietal cortices to the PFC, using noninvasive functional and diffusion-weighted magnetic resonance imaging. The right inferior frontal gyrus (IFG) received converging input from both streams, while the right superior frontal gyrus received input only from the dorsal stream. Interstream functional connectivity to the IFG was dynamically recruited only when both object and spatial information were processed. These results suggest that the human PFC receives dissociated and converging visual pathways, and that the right IFG region serves as an integrator of the two types of information. PMID:23063444

Acute stress evokes sexually dimorphic, stressor-specific patterns of neural activation across multiple limbic brain regions in adult rats.

PubMed

Sood, Ankit; Chaudhari, Karina; Vaidya, Vidita A

2018-03-01

Stress enhances the risk for psychiatric disorders such as anxiety and depression. Stress responses vary across sex and may underlie the heightened vulnerability to psychopathology in females. Here, we examined the influence of acute immobilization stress (AIS) and a two-day short-term forced swim stress (FS) on neural activation in multiple cortical and subcortical brain regions, implicated as targets of stress and in the regulation of neuroendocrine stress responses, in male and female rats using Fos as a neural activity marker. AIS evoked a sex-dependent pattern of neural activation within the cingulate and infralimbic subdivisions of the medial prefrontal cortex (mPFC), lateral septum (LS), habenula, and hippocampal subfields. The degree of neural activation in the mPFC, LS, and habenula was higher in males. Female rats exhibited reduced Fos positive cell numbers in the dentate gyrus hippocampal subfield, an effect not observed in males. We addressed whether the sexually dimorphic neural activation pattern noted following AIS was also observed with the short-term stress of FS. In the paraventricular nucleus of the hypothalamus and the amygdala, FS similar to AIS resulted in robust increases in neural activation in both sexes. The pattern of neural activation evoked by FS was distinct across sexes, with a heightened neural activation noted in the prelimbic mPFC subdivision and hippocampal subfields in females and differed from the pattern noted with AIS. This indicates that the sex differences in neural activation patterns observed within stress-responsive brain regions are dependent on the nature of stressor experience.

Neural Correlates of Opposing Effects of Emotional Distraction on Working Memory and Episodic Memory: An Event-Related fMRI Investigation

PubMed Central

Dolcos, Florin; Iordan, Alexandru D.; Kragel, James; Stokes, Jared; Campbell, Ryan; McCarthy, Gregory; Cabeza, Roberto

2013-01-01

A fundamental question in the emotional memory literature is why emotion enhances memory in some conditions but disrupts memory in other conditions. For example, separate studies have shown that emotional stimuli tend to be better remembered in long-term episodic memory (EM), whereas emotional distracters tend to impair working memory (WM) maintenance. The first goal of this study was to directly compare the neural correlates of EM enhancement (EME) and WM impairing (WMI) effects, and the second goal was to explore individual differences in these mechanisms. During event-related functional magnetic resonance imaging (fMRI), participants maintained faces in WM while being distracted by emotional or neutral pictures presented during the delay period. EM for the distracting pictures was tested after scanning and was used to identify successful encoding activity for the picture distracters. The first goal yielded two findings: (1) emotional pictures that disrupted face WM but enhanced subsequent EM were associated with increased amygdala (AMY) and hippocampal activity (ventral system) coupled with reduced dorsolateral PFC (dlPFC) activity (dorsal system); (2) trials in which emotion enhanced EM without disrupting WM were associated with increased ventrolateral PFC activity. The ventral-dorsal switch can explain EME and WMI, while the ventrolateral PFC effect suggests a coping mechanism. The second goal yielded two additional findings: (3) participants who were more susceptible to WMI showed greater amygdala increases and PFC reductions; (4) AMY activity increased and dlPFC activity decreased with measures of attentional impulsivity. Taken together, these results clarify the mechanisms linking the enhancing and impairing effects of emotion on memory, and provide insights into the role of individual differences in the impact of emotional distraction. PMID:23761770

Electrolytic Lesions of the Medial Prefrontal Cortex Do Not Interfere with Long-Term Memory of Extinction of Conditioned Fear

ERIC Educational Resources Information Center

Garcia, Rene; Chang, Chun-hui; Maren, Stephen

2006-01-01

Lesion studies indicate that rats without the medial prefrontal cortex (mPFC) have difficulty recalling fear extinction acquired the previous day. Several electrophysiological studies have also supported this observation by demonstrating that extinction-related increases in neuronal activity in the mPFC participate in expression of fear…

Persistent Prelimbic Cortex Activity Contributes to Enhanced Learned Fear Expression in Females

ERIC Educational Resources Information Center

Fenton, Georgina E.; Pollard, Amelia K.; Halliday, David M.; Mason, Rob; Bredy, Timothy W.; Stevenson, Carl W.

2014-01-01

Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but…

The Ventromedial Prefrontal Cortex in a Model of Traumatic Stress: Fear Inhibition or Contextual Processing?

ERIC Educational Resources Information Center

Pennington, Zachary T.; Anderson, Austin S.; Fanselow, Michael S.

2017-01-01

The ventromedial prefrontal cortex (vmPFC) has consistently appeared altered in post-traumatic stress disorder (PTSD). Although the vmPFC is thought to support the extinction of learned fear responses, several findings support a broader role for this structure in the regulation of fear. To further characterize the relationship between vmPFC…

The Medial Prefrontal Cortex Is Critical for Memory Retrieval and Resolving Interference

ERIC Educational Resources Information Center

Peters, Gregory J.; David, Christopher N.; Marcus, Madison D.; Smith, David M.

2013-01-01

The prefrontal cortex (PFC) is known to be critically involved in strategy switching, attentional set shifting, and inhibition of prepotent responses. A central feature of this kind of behavioral flexibility is the ability to resolve conflicting response tendencies, suggesting a general role of the PFC in resolving interference. If so, the PFC…

Prefrontal Cortex and Hippocampus Subserve Different Components of Working Memory in Rats

ERIC Educational Resources Information Center

Yoon, Taejib; Okada, Jeffrey; Jung, Min W.; Kim, Jeansok J.

2008-01-01

Both the medial prefrontal cortex (mPFC) and hippocampus are implicated in working memory tasks in rodents. Specifically, it has been hypothesized that the mPFC is primarily engaged in the temporary storage and processing of information lasting from a subsecond to several seconds, while the hippocampal function becomes more critical as the working…

Zinc release in the lateral nucleus of the amygdala by stimulation of the entorhinal cortex.

PubMed

Takeda, Atsushi; Imano, Sachie; Itoh, Hiromasa; Oku, Naoto

2006-11-06

Zinc release in the lateral nucleus of the amygdala was examined using rat brain slices. The lateral and basolateral nuclei in the amygdala were evidently stained by Timm's sulfide-silver staining method. When the amygdala including both the nuclei was stimulated with 100 mM KCl by means of in vivo microdialysis, extracellular zinc concentration was increased significantly. Zinc release in the lateral nucleus of the amygdala innervated by the entorhinal cortex was next examined in brain slices double-stained with zinc and calcium indicators. Extracellular zinc signal (ZnAF-2) in the lateral nucleus was increased with intracellular calcium signal (calcium orange) during delivery of tetanic stimuli to the entorhinal cortex. Both the increases were completely inhibited by addition of 1 micro M tetrodotoxin, a sodium channel blocker. Furthermore, calcium signal in the lateral nucleus during delivery of tetanic stimuli to the entorhinal cortex was increased in the presence of 10 micro M CNQX, an AMPA/KA receptor antagonist, and this increase was facilitated by addition of 1 mM CaEDTA, a membrane-impermeable zinc chelator. The present study suggested that zinc is released in the lateral nucleus of the amygdala by depolarization of the entorhinal neurons. In the lateral nucleus, zinc released may suppress the increase in presynaptic calcium signal.

Effects of transcranial direct current stimulation of the motor cortex on prefrontal cortex activation during a neuromuscular fatigue task: an fNIRS study.

PubMed

Muthalib, Makii; Kan, Benjamin; Nosaka, Kazunori; Perrey, Stephane

2013-01-01

This study investigated whether manipulation of motor cortex excitability by transcranial direct current stimulation (tDCS) modulates neuromuscular fatigue and functional near-infrared spectroscopy (fNIRS)-derived prefrontal cortex (PFC) activation. Fifteen healthy men (27.7 ± 8.4 years) underwent anodal (2 mA, 10 min) and sham (2 mA, first 30 s only) tDCS delivered to the scalp over the right motor cortex. Subjects initially performed a baseline sustained submaximal (30 % maximal voluntary isometric contraction, MVC) isometric contraction task (SSIT) of the left elbow flexors until task failure, which was followed 50 min later by either an anodal or sham treatment condition, then a subsequent posttreatment SSIT. Endurance time (ET), torque integral (TI), and fNIRS-derived contralateral PFC oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin concentration changes were determined at task failure. Results indicated that during the baseline and posttreatment SSIT, there were no significant differences in TI and ET, and increases in fNIRS-derived PFC activation at task failure were observed similarly regardless of the tDCS conditions. This suggests that the PFC neuronal activation to maintain muscle force production was not modulated by anodal tDCS.

Cortical inhibition within motor and frontal regions in alcohol dependence post-detoxification: A pilot TMS-EEG study.

PubMed

Naim-Feil, Jodie; Bradshaw, John L; Rogasch, Nigel C; Daskalakis, Zafiris J; Sheppard, Dianne M; Lubman, Dan I; Fitzgerald, Paul B

2016-10-01

Preclinical studies suggest that cortical alterations within the prefrontal cortex (PFC) are critical to the pathophysiology of alcohol dependence. Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows direct assessment of cortical excitability and inhibition within the PFC of human subjects. We report the first application of TMS-EEG to measure these indices within the PFC of alcohol-dependent (ALD) patients post-detoxification. Cortical inhibition was assessed in 12 ALD patients and 14 healthy controls through single and paired-pulse TMS paradigms. Long-interval cortical inhibition indexed cortical inhibition in the PFC. In the motor cortex (MC), short- interval intracortical inhibition and cortical silent period determined inhibition, while intracortical facilitation measured facilitation, resting and active motor threshold indexed cortical excitability. ALD patients demonstrated altered cortical inhibition across the bilateral frontal cortices relative to controls. There was evidence of altered cortical excitability in ALD patients; however, no significant differences in MC inhibition. Our study provides first direct evidence of reduced cortical inhibition in the PFC of ALD patients post-detoxification. Altered cortical excitability in the MC may reflect hyper-excitability within the cortex associated with chronic alcohol consumption. These findings provide initial neurophysiological evidence of disrupted cortical excitability within the PFC of ALD patients.

[Comparative study of effects of cortical nucleus of amygdala and pyriform cortex on activity of bulbar respiratory neurons in cats].

PubMed

Nersesian, L B; Eganova, V S; Pogosian, N L; Avetisian, I N

2011-01-01

Comparative microelectrophysiological study of character and peculiarities of effects of the cortical nucleus of amygdala and of the periamygdalar area of pyriform cortex on impulse activity was performed on the same single functionally identified respiratory medullar neurons. A high reactivity of bulbar respiratory neurons on stimulation is established in both studied limbic structures. There is established the qualitatively different character of their response reactions at stimulation of the cortical amygdala nucleus and the periamygdalar cortex. The cortical amygdala nucleus has been shown to produce on the activity of medullar respiratory neurons both facilitating and inhibitory action with predominance of the activating one (without topographical orderliness). The effect of periamygdalar cortex at stimulation of various parts was characterized by topographic differentiation. The suppressing reactions of neurons in the majority of cases were recorded at stimulation of the rostral area of periamygdalar cortex, whereas the excitatory reactions--at stimulation of its caudal part. Functional organization of respiratory control of the studied limbic system structures is discussed.

Biological and cognitive underpinnings of religious fundamentalism.

PubMed

Zhong, Wanting; Cristofori, Irene; Bulbulia, Joseph; Krueger, Frank; Grafman, Jordan

2017-06-01

Beliefs profoundly affect people's lives, but their cognitive and neural pathways are poorly understood. Although previous research has identified the ventromedial prefrontal cortex (vmPFC) as critical to representing religious beliefs, the means by which vmPFC enables religious belief is uncertain. We hypothesized that the vmPFC represents diverse religious beliefs and that a vmPFC lesion would be associated with religious fundamentalism, or the narrowing of religious beliefs. To test this prediction, we assessed religious adherence with a widely-used religious fundamentalism scale in a large sample of 119 patients with penetrating traumatic brain injury (pTBI). If the vmPFC is crucial to modulating diverse personal religious beliefs, we predicted that pTBI patients with lesions to the vmPFC would exhibit greater fundamentalism, and that this would be modulated by cognitive flexibility and trait openness. Instead, we found that participants with dorsolateral prefrontal cortex (dlPFC) lesions have fundamentalist beliefs similar to patients with vmPFC lesions and that the effect of a dlPFC lesion on fundamentalism was significantly mediated by decreased cognitive flexibility and openness. These findings indicate that cognitive flexibility and openness are necessary for flexible and adaptive religious commitment, and that such diversity of religious thought is dependent on dlPFC functionality. Copyright © 2017 Elsevier Ltd. All rights reserved.

Biological and cognitive underpinnings of religious fundamentalism

PubMed Central

Zhong, Wanting; Cristofori, Irene; Bulbulia, Joseph; Krueger, Frank; Grafman, Jordan

2017-01-01

Beliefs profoundly affect people's lives, but their cognitive and neural pathways are poorly understood. Although previous research has identified the ventromedial prefrontal cortex (vmPFC) as critical to representing religious beliefs, the means by which vmPFC enables religious belief is uncertain. We hypothesized that the vmPFC represents diverse religious beliefs and that a vmPFC lesion would be associated with religious fundamentalism, or the narrowing ofreligious beliefs. To test this prediction, we assessed religious adherence with a widely-used religious fundamentalism scale in a large sample of 119 patients with penetrating traumatic brain injury (pTBI). If the vmPFC is crucial to modulating diverse personal religious beliefs, we predicted that pTBI patients with lesions to the vmPFC would exhibit greater fundamentalism, and that this would be modulated by cognitive flexibility and trait openness. Instead, we found that participants with dorsolateral prefrontal cortex (dlPFC) lesions have fundamentalist beliefs similar to patients with vmPFC lesions and that the effect of a dlPFC lesion on fundamentalism was significantly mediated by decreased cognitive flexibility and openness. These findings indicate that cognitive flexibility and openness are necessary for flexible and adaptive religious commitment, and that such diversity of religious thought is dependent on dlPFC functionality. PMID:28392301

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

PubMed Central

Yang, Yang; Paspalas, Constantinos D.; Jin, Lu E.; Picciotto, Marina R.; Arnsten, Amy F. T.; Wang, Min

2013-01-01

The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510–1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477–485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore α7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade of α7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110–1114]. We additionally show that α7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to α7-nAChR would profoundly disrupt cognitive experience in patients with schizophrenia. PMID:23818597

Transient alcohol craving suppression by rTMS of dorsal anterior cingulate: an fMRI and LORETA EEG study.

PubMed

De Ridder, Dirk; Vanneste, Sven; Kovacs, Silvia; Sunaert, Stefan; Dom, Geert

2011-05-27

It has recently become clear that alcohol addiction might be related to a brain dysfunction, in which a genetic background and environmental factors shape brain mechanisms involved with alcohol consumption. Craving, a major component determining relapses in alcohol abuse has been linked to abnormal activity in the orbitofrontal cortex, dorsal anterior cingulated cortex (dACC) and amygdala. We report the results of a patient who underwent rTMS targeting the dACC using a double cone coil in an attempt to suppress very severe intractable alcohol craving. Functional imaging studies consisting of fMRI and resting state EEG were performed before rTMS, after successful rTMS and after unsuccessful rTMS with relapse. Craving was associated with EEG beta activity and connectivity between the dACC and PCC in the patient in comparison to a healthy population, which disappeared after successful rTMS. Cue induced worsening of craving pre-rTMS activated the ACC-vmPFC and PCC on fMRI, as well as the nucleus accumbens area, and lateral frontoparietal areas. The nucleus accumbens, ACC-vmPFC and PCC activation disappeared on fMRI following successful rTMS. Relapse was associated with recurrence of ACC and PCC EEG activity, but in gamma band, in comparison to a healthy population. On fMRI nucleus accumbens, ACC and PCC activation returned to the initial activation pattern. A pathophysiological approach is described to suppress alcohol craving temporarily by rTMS directed at the anterior cingulate. Linking functional imaging changes to craving intensity suggests this approach warrants further exploration. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

Academic stress and personality interact to increase the neural response to high-calorie food cues.

PubMed

Neseliler, Selin; Tannenbaum, Beth; Zacchia, Maria; Larcher, Kevin; Coulter, Kirsty; Lamarche, Marie; Marliss, Errol B; Pruessner, Jens; Dagher, Alain

2017-09-01

Psychosocial stress is associated with an increased intake of palatable foods and weight gain in stress-reactive individuals. Personality traits have been shown to predict stress-reactivity. However, it is not known if personality traits influence brain activity in regions implicated in appetite control during psychosocial stress. The current study assessed whether Gray's Behavioural Inhibition System (BIS) scale, a measure of stress-reactivity, was related to the activity of brain regions implicated in appetite control during a stressful period. Twenty-two undergraduate students participated in a functional magnetic resonance imaging (fMRI) experiment once during a non-exam period and once during final exams in a counter-balanced order. In the scanner, they viewed food and scenery pictures. In the exam compared with the non-exam condition, BIS scores related to increased perceived stress and correlated with increased blood-oxygen-level dependent (BOLD) response to high-calorie food images in regions implicated in food reward and subjective value, such as the ventromedial prefrontal cortex, (vmPFC) and the amygdala. BIS scores negatively related to the functional connectivity between the vmPFC and the dorsolateral prefrontal cortex. The results demonstrate that the BIS trait influences stress reactivity. This is observed both as an increased activity in brain regions implicated in computing the value of food cues and decreased connectivity of these regions to prefrontal regions implicated in self-control. This suggests that the effects of real life stress on appetitive brain function and self-control is modulated by a personality trait. This may help to explain why stressful periods can lead to overeating in vulnerable individuals. Copyright © 2017 Elsevier Ltd. All rights reserved.

Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses.

PubMed

Mareckova, Klara; Holsen, Laura M; Admon, Roee; Makris, Nikos; Seidman, Larry; Buka, Stephen; Whitfield-Gabrieli, Susan; Goldstein, Jill M

2016-11-01

Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n = 99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen-level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO - R OFC, R AMYG - R OFC, and R AMYG - R HIPP. Overall, our findings demonstrated sex-dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex-dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733-3744, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

‘Imagined guilt’ vs ‘recollected guilt’: implications for fMRI

PubMed Central

Mclatchie, Neil; Giner-Sorolla, Roger; Derbyshire, Stuart W. G.

2016-01-01

Abstract Guilt is thought to maintain social harmony by motivating reparation. This study compared two methodologies commonly used to identify the neural correlates of guilt. The first, imagined guilt, requires participants to read hypothetical scenarios and then imagine themselves as the protagonist. The second, recollected guilt, requires participants to reflect on times they personally experienced guilt. In the fMRI scanner, participants were presented with guilt/neutral memories and guilt/neutral hypothetical scenarios. Contrasts confirmed a priori predictions that guilt memories, relative to guilt scenarios, were associated with significantly greater activity in regions associated with affect [anterior cingulate cortex (ACC), Caudate, Insula, orbital frontal cortex (OFC)] and social cognition [temporal pole (TP), precuneus). Similarly, results indicated that guilt memories, relative to neutral memories, were also associated with greater activity in affective (ACC, amygdala, Insula, OFC) and social cognition (mPFC, TP, precuneus, temporo-parietal junction) regions. There were no significant differences between guilt hypothetical scenarios and neutral hypothetical scenarios in either affective or social cognition regions. The importance of distinguishing between different guilt inductions inside the scanner is discussed. We offer explanations of our results and discuss ideas for future research. PMID:26746179

'Imagined guilt' vs 'recollected guilt': implications for fMRI.

PubMed

Mclatchie, Neil; Giner-Sorolla, Roger; Derbyshire, Stuart W G

2016-05-01

Guilt is thought to maintain social harmony by motivating reparation. This study compared two methodologies commonly used to identify the neural correlates of guilt. The first, imagined guilt, requires participants to read hypothetical scenarios and then imagine themselves as the protagonist. The second, recollected guilt, requires participants to reflect on times they personally experienced guilt. In the fMRI scanner, participants were presented with guilt/neutral memories and guilt/neutral hypothetical scenarios. Contrasts confirmed a priori predictions that guilt memories, relative to guilt scenarios, were associated with significantly greater activity in regions associated with affect [anterior cingulate cortex (ACC), Caudate, Insula, orbital frontal cortex (OFC)] and social cognition [temporal pole (TP), precuneus). Similarly, results indicated that guilt memories, relative to neutral memories, were also associated with greater activity in affective (ACC, amygdala, Insula, OFC) and social cognition (mPFC, TP, precuneus, temporo-parietal junction) regions. There were no significant differences between guilt hypothetical scenarios and neutral hypothetical scenarios in either affective or social cognition regions. The importance of distinguishing between different guilt inductions inside the scanner is discussed. We offer explanations of our results and discuss ideas for future research. © The Author (2016). Published by Oxford University Press.

Sex differences in extinction recall in posttraumatic stress disorder: A pilot fMRI study

PubMed Central

Shvil, Erel; Sullivan, Gregory M.; Schafer, Scott; Markowitz, John C.; Campeas, Miriam; Wager, Tor D.; Milad, Mohammed R.; Neria, Yuval

2014-01-01

Recent research has found that individuals with posttraumatic stress disorder (PTSD) exhibit an impaired memory of fear extinction compounded by deficient functional activation of key nodes of the fear network including the amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC). Research has shown these regions are sexually dimorphic and activate differentially in healthy men and women during fear learning tasks. To explore biological markers of sex differences following exposure to psychological trauma, we used a fear learning and extinction paradigm together with functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) to assess 31 individuals with PTSD (18 women; 13 men) and 25 matched trauma-exposed healthy control subjects (13 women; 12 men). Whereas no sex differences appeared within the trauma-exposed healthy control group, both psychophysiological and neural activation patterns within the PTSD group indicated deficient recall of extinction memory among men and not among women. Men with PTSD exhibited increased activation in the left rostral dACC during extinction recall compared with women with PTSD. These findings highlight the importance of tracking sex differences in fear extinction when characterizing the underlying neurobiological mechanisms of PTSD psychopathology. PMID:24560771

Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking.

PubMed

Augur, Isabel F; Wyckoff, Andrew R; Aston-Jones, Gary; Kalivas, Peter W; Peters, Jamie

2016-09-28

The ventromedial prefrontal cortex (vmPFC) has been shown to negatively regulate cocaine-seeking behavior, but the precise conditions by which vmPFC activity can be exploited to reduce cocaine relapse are currently unknown. We used viral-mediated gene transfer of designer receptors (DREADDs) to activate vmPFC neurons and examine the consequences on cocaine seeking in a rat self-administration model of relapse. Activation of vmPFC neurons with the Gq-DREADD reduced reinstatement of cocaine seeking elicited by cocaine-associated cues, but not by cocaine itself. We used a retro-DREADD approach to confine the Gq-DREADD to vmPFC neurons that project to the medial nucleus accumbens shell, confirming that these neurons are responsible for the decreased cue-induced reinstatement of cocaine seeking. The effects of vmPFC activation on cue-induced reinstatement depended on prior extinction training, consistent with the reported role of this structure in extinction memory. These data help define the conditions under which chemogenetic activation of extinction neural circuits can be exploited to reduce relapse triggered by reminder cues. The ventromedial prefrontal cortex (vmPFC) projection to the nucleus accumbens shell is important for extinction of cocaine seeking, but its anatomical proximity to the relapse-promoting projection from the dorsomedial prefrontal cortex to the nucleus accumbens core makes it difficult to selectively enhance neuronal activity in one pathway or the other using traditional pharmacotherapy (e.g., systemically administered drugs). Viral-mediated gene delivery of an activating Gq-DREADD to vmPFC and/or vmPFC projections to the nucleus accumbens shell allows the chemogenetic exploitation of this extinction neural circuit to reduce cocaine seeking and was particularly effective against relapse triggered by cocaine reminder cues. Copyright © 2016 the authors 0270-6474/16/3610174-07$15.00/0.

Differential Functional Connectivity Alterations of Two Subdivisions within the Right dlPFC in Parkinson's Disease

PubMed Central

Caspers, Julian; Mathys, Christian; Hoffstaedter, Felix; Südmeyer, Martin; Cieslik, Edna C.; Rubbert, Christian; Hartmann, Christian J.; Eickhoff, Claudia R.; Reetz, Kathrin; Grefkes, Christian; Michely, Jochen; Turowski, Bernd; Schnitzler, Alfons; Eickhoff, Simon B.

2017-01-01

Patients suffering from Parkinson's disease (PD) often show impairments in executive function (EF) like decision-making and action control. The right dorsolateral prefrontal cortex (dlPFC) has been strongly implicated in EF in healthy subjects and has repeatedly been reported to show alterations related to EF impairment in PD. Recently, two key regions for cognitive action control have been identified within the right dlPFC by co-activation based parcellation. While the posterior region is engaged in rather basal EF like stimulus integration and working memory, the anterior region has a more abstract, supervisory function. To investigate whether these functionally distinct subdivisions of right dlPFC are differentially affected in PD, we analyzed resting-state functional connectivity (FC) in 39 PD patients and 44 age- and gender-matched healthy controls. Patients were examined both after at least 12 h withdrawal of dopaminergic drugs (OFF) and under their regular dopaminergic medication (ON). We found that only the posterior right dlPFC subdivision shows FC alterations in PD, while the anterior part remains unaffected. PD-related decreased FC with posterior right dlPFC was found in the bilateral medial posterior parietal cortex (mPPC) and left dorsal premotor region (PMd) in the OFF state. In the medical ON, FC with left PMd normalized, while decoupling with bilateral mPPC remained. Furthermore, we observed increased FC between posterior right dlPFC and the bilateral dorsomedial prefrontal cortex (dmPFC) in PD in the ON state. Our findings point to differential disturbances of right dlPFC connectivity in PD, which relate to its hierarchical organization of EF processing by stronger affecting the functionally basal posterior aspect than the hierarchically higher anterior part. PMID:28611616

Juvenile social experience and differential age-related changes in the dendritic morphologies of subareas of the prefrontal cortex in rats.

PubMed

Himmler, Brett T; Mychasiuk, Richelle; Nakahashi, Ayuno; Himmler, Stephanie M; Pellis, Sergio M; Kolb, Bryan

2018-04-01

Juvenile social interactions have been shown to influence the dendritic complexity of neurons in the prefrontal cortex (PFC). In particular, social play induces pruning of the cells in the medial prefrontal cortex (mPFC), whereas interacting with multiple partners, whether those interactions involve play or not, increases the complexity of cells in the orbital frontal cortex (OFC). Previous studies suggest that these changes differ in their stability during adulthood. In the present study, rats were reared in groups of either four (quads) or two (pairs) and the brains of the rats from each rearing condition were then harvested at 60 days (i.e., shortly after sexual maturity) and 100 days (i.e., fully adult). The rats housed with multiple partners had more complex neurons of the OFC at 60 days and this complexity declined to a comparable level to that of pair housed rats by 100 days. In contrast, the play-induced changes of the mPFC remained similar at both ages. These findings suggest that the changes in the PFC induced by different social experiences in the juvenile period differ in how long they are maintained in adulthood. Differences in the functions regulated by the OFC and the mPFC are considered with regard to these differences in the stability of juvenile-induced neural changes. © 2017 Wiley Periodicals, Inc.

Afferent and Efferent Connections of the Cortex-Amygdala Transition Zone in Mice

PubMed Central

Cádiz-Moretti, Bernardita; Abellán-Álvaro, María; Pardo-Bellver, Cecília; Martínez-García, Fernando; Lanuza, Enrique

2016-01-01

The transitional zone between the ventral part of the piriform cortex and the anterior cortical nucleus of the amygdala, named the cortex-amygdala transition zone (CxA), shows two differential features that allow its identification as a particular structure. First, it receives dense cholinergic and dopaminergic innervations as compared to the adjacent piriform cortex and amygdala, and second, it receives projections from the main and accessory olfactory bulbs. In this work we have studied the pattern of afferent and efferent projections of the CxA, which are mainly unknown, by using the retrograde tracer Fluorogold and the anterograde tracer biotinylated dextranamine. The results show that the CxA receives a relatively restricted set of intratelencephalic connections, originated mainly by the olfactory system and basal forebrain, with minor afferents from the amygdala. The only relevant extratelencephalic afference originates in the ventral tegmental area (VTA). The efferent projections of the CxA reciprocate the inputs from the piriform cortex and olfactory amygdala. In addition, the CxA projects densely to the basolateral amygdaloid nucleus and the olfactory tubercle. The extratelencephalic projections of the CxA are very scarce, and target mainly hypothalamic structures. The pattern of connections of the CxA suggests that it is indeed a transitional area between the piriform cortex and the cortical amygdala. Double labeling with choline acetyltransferase indicates that the afferent projection from the basal forebrain is the origin of its distinctive cholinergic innervation, and double labeling with dopamine transporter shows that the projection from the VTA is the source of dopaminergic innervation. These connectivity and neurochemical features, together with the fact that it receives vomeronasal in addition to olfactory information, suggest that the CxA may be involved in processing olfactory information endowed with relevant biological meaning, such as odors related to reproductive or defensive behaviors. PMID:28066196

Afferent and Efferent Connections of the Cortex-Amygdala Transition Zone in Mice.

PubMed

Cádiz-Moretti, Bernardita; Abellán-Álvaro, María; Pardo-Bellver, Cecília; Martínez-García, Fernando; Lanuza, Enrique

2016-01-01

The transitional zone between the ventral part of the piriform cortex and the anterior cortical nucleus of the amygdala, named the cortex-amygdala transition zone (CxA), shows two differential features that allow its identification as a particular structure. First, it receives dense cholinergic and dopaminergic innervations as compared to the adjacent piriform cortex and amygdala, and second, it receives projections from the main and accessory olfactory bulbs. In this work we have studied the pattern of afferent and efferent projections of the CxA, which are mainly unknown, by using the retrograde tracer Fluorogold and the anterograde tracer biotinylated dextranamine. The results show that the CxA receives a relatively restricted set of intratelencephalic connections, originated mainly by the olfactory system and basal forebrain, with minor afferents from the amygdala. The only relevant extratelencephalic afference originates in the ventral tegmental area (VTA). The efferent projections of the CxA reciprocate the inputs from the piriform cortex and olfactory amygdala. In addition, the CxA projects densely to the basolateral amygdaloid nucleus and the olfactory tubercle. The extratelencephalic projections of the CxA are very scarce, and target mainly hypothalamic structures. The pattern of connections of the CxA suggests that it is indeed a transitional area between the piriform cortex and the cortical amygdala. Double labeling with choline acetyltransferase indicates that the afferent projection from the basal forebrain is the origin of its distinctive cholinergic innervation, and double labeling with dopamine transporter shows that the projection from the VTA is the source of dopaminergic innervation. These connectivity and neurochemical features, together with the fact that it receives vomeronasal in addition to olfactory information, suggest that the CxA may be involved in processing olfactory information endowed with relevant biological meaning, such as odors related to reproductive or defensive behaviors.

Selection, integration, and conflict monitoring; assessing the nature and generality of prefrontal cognitive control mechanisms.

PubMed

Badre, David; Wagner, Anthony D

2004-02-05

Prefrontal cortex (PFC) supports flexible behavior by mediating cognitive control, though the elemental forms of control supported by PFC remain a central debate. Dorsolateral PFC (DLPFC) is thought to guide response selection under conditions of response conflict or, alternatively, may refresh recently active representations within working memory. Lateral frontopolar cortex (FPC) may also adjudicate response conflict, though others propose that FPC supports higher order control processes such as subgoaling and integration. Anterior cingulate cortex (ACC) is hypothesized to upregulate response selection by detecting response conflict; it remains unclear whether ACC functions generalize beyond monitoring response conflict. The present fMRI experiment directly tested these competing theories regarding the functional roles of DLPFC, FPC, and ACC. Results reveal dissociable control processes in PFC, with mid-DLPFC selectively mediating resolution of response conflict and FPC further mediating subgoaling/integration. ACC demonstrated a broad sensitivity to control demands, suggesting a generalized role in modulating cognitive control.

Dynamic representation of partially occluded objects in primate prefrontal and visual cortex

PubMed Central

Choi, Hannah; Shea-Brown, Eric

2017-01-01

Successful recognition of partially occluded objects is presumed to involve dynamic interactions between brain areas responsible for vision and cognition, but neurophysiological evidence for the involvement of feedback signals is lacking. Here, we demonstrate that neurons in the ventrolateral prefrontal cortex (vlPFC) of monkeys performing a shape discrimination task respond more strongly to occluded than unoccluded stimuli. In contrast, neurons in visual area V4 respond more strongly to unoccluded stimuli. Analyses of V4 response dynamics reveal that many neurons exhibit two transient response peaks, the second of which emerges after vlPFC response onset and displays stronger selectivity for occluded shapes. We replicate these findings using a model of V4/vlPFC interactions in which occlusion-sensitive vlPFC neurons feed back to shape-selective V4 neurons, thereby enhancing V4 responses and selectivity to occluded shapes. These results reveal how signals from frontal and visual cortex could interact to facilitate object recognition under occlusion. PMID:28925354

The role of prefrontal cortex in psychopathy

PubMed Central

Koenigs, Michael

2014-01-01

Psychopathy is a personality disorder characterized by remorseless and impulsive antisocial behavior. Given the significant societal costs of the recidivistic criminal activity associated with the disorder, there is a pressing need for more effective treatment strategies, and hence, a better understanding of the psychobiological mechanisms underlying the disorder. The prefrontal cortex (PFC) is likely to play an important role in psychopathy. In particular, the ventromedial and anterior cingulate sectors of PFC are theorized to mediate a number of social and affective decision-making functions that appear to be disrupted in psychopathy. This article provides a critical summary of human neuroimaging data implicating prefrontal dysfunction in psychopathy. A growing body of evidence associates psychopathy with structural and functional abnormalities in ventromedial PFC and anterior cingulate cortex. Although this burgeoning field still faces a number of methodological challenges and outstanding questions that will need to be resolved by future studies, the research to date has established a link between psychopathy and PFC. PMID:22752782

Chemogenetic inhibition of the medial prefrontal cortex reverses the effects of REM sleep loss on sucrose consumption

PubMed Central

McEown, Kristopher; Takata, Yohko; Cherasse, Yoan; Nagata, Nanae; Aritake, Kosuke; Lazarus, Michael

2016-01-01

Rapid eye movement (REM) sleep loss is associated with increased consumption of weight-promoting foods. The prefrontal cortex (PFC) is thought to mediate reward anticipation. However, the precise role of the PFC in mediating reward responses to highly palatable foods (HPF) after REM sleep deprivation is unclear. We selectively reduced REM sleep in mice over a 25–48 hr period and chemogenetically inhibited the medial PFC (mPFC) by using an altered glutamate-gated and ivermectin-gated chloride channel that facilitated neuronal inhibition through hyperpolarizing infected neurons. HPF consumption was measured while the mPFC was inactivated and REM sleep loss was induced. We found that REM sleep loss increased HPF consumption compared to control animals. However, mPFC inactivation reversed the effect of REM sleep loss on sucrose consumption without affecting fat consumption. Our findings provide, for the first time, a causal link between REM sleep, mPFC function and HPF consumption. DOI: http://dx.doi.org/10.7554/eLife.20269.001 PMID:27919319

5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex.

PubMed

Morici, Juan Facundo; Miranda, Magdalena; Gallo, Francisco Tomás; Zanoni, Belén; Bekinschtein, Pedro; Weisstaub, Noelia V

2018-05-02

Context-dependent memories may guide adaptive behavior relaying in previous experience while updating stored information through reconsolidation. Retrieval can be triggered by partial and shared cues. When the cue is presented, the most relevant memory should be updated. In a contextual version of the object recognition task, we examined the effect of medial PFC (mPFC) serotonin 2a receptor (5-HT2aR) blockade during retrieval in reconsolidation of competing objects memories. We found that mPFC 5-HT2aR controls retrieval and reconsolidation of object memories in the perirhinal cortex (PRH), but not in the dorsal hippocampus in rats. Also, reconsolidation of objects memories in PRH required a functional interaction between the ventral hippocampus and the mPFC. Our results indicate that in the presence of conflicting information at retrieval, mPFC 5-HT2aR may facilitate top-down context-guided control over PRH to control the behavioral response and object memory reconsolidation. © 2018, Morici et al.

Directional hippocampal-prefrontal interactions during working memory.

PubMed

Liu, Tiaotiao; Bai, Wenwen; Xia, Mi; Tian, Xin

2018-02-15

Working memory refers to a system that is essential for performing complex cognitive tasks such as reasoning, comprehension and learning. Evidence shows that hippocampus (HPC) and prefrontal cortex (PFC) play important roles in working memory. The HPC-PFC interaction via theta-band oscillatory synchronization is critical for successful execution of working memory. However, whether one brain region is leading or lagging relative to another is still unclear. Therefore, in the present study, we simultaneously recorded local field potentials (LFPs) from rat ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) and while the rats performed a Y-maze working memory task. We then applied instantaneous amplitudes cross-correlation method to calculate the time lag between PFC and vHPC to explore the functional dynamics of the HPC-PFC interaction. Our results showed a strong lead from vHPC to mPFC preceded an animal's correct choice during the working memory task. These findings suggest the vHPC-leading interaction contributes to the successful execution of working memory. Copyright © 2017. Published by Elsevier B.V.

Rostro-caudal and dorso-ventral gradients in medial and lateral prefrontal cortex during cognitive control of affective and cognitive interference.

PubMed

Rahm, Christoffer; Liberg, Benny; Wiberg-Kristoffersen, Maria; Aspelin, Peter; Msghina, Mussie

2013-04-01

Characterizing the anatomical substrates of major brain functions such as cognition and emotion is of utmost importance to the ongoing efforts of understanding the nature of psychiatric ailments and their potential treatment. The aim of our study was to investigate how the brain handles affective and cognitive interferences on cognitive processes. Functional magnetic resonance imaging investigation was performed on healthy individuals, comparing the brain oxygenation level dependent activation patterns during affective and cognitive counting Stroop tasks. The affective Stroop task activated rostral parts of medial prefrontal cortex (PFC) and rostral and ventral parts of lateral PFC, while cognitive Stroop activated caudal parts of medial PFC and caudal and dorsal parts of lateral PFC. Our findings suggest that the brain may handle affective and cognitive interference on cognitive processes differentially, with affective interference preferentially activating rostral and ventral PFC networks and cognitive interference activating caudal and dorsal PFC networks. © 2013 The Authors. Scandinavian Journal of Psychology © 2013 The Scandinavian Psychological Associations.

5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex

PubMed Central

Morici, Juan Facundo; Miranda, Magdalena; Gallo, Francisco Tomás; Zanoni, Belén; Bekinschtein, Pedro

2018-01-01

Context-dependent memories may guide adaptive behavior relaying in previous experience while updating stored information through reconsolidation. Retrieval can be triggered by partial and shared cues. When the cue is presented, the most relevant memory should be updated. In a contextual version of the object recognition task, we examined the effect of medial PFC (mPFC) serotonin 2a receptor (5-HT2aR) blockade during retrieval in reconsolidation of competing objects memories. We found that mPFC 5-HT2aR controls retrieval and reconsolidation of object memories in the perirhinal cortex (PRH), but not in the dorsal hippocampus in rats. Also, reconsolidation of objects memories in PRH required a functional interaction between the ventral hippocampus and the mPFC. Our results indicate that in the presence of conflicting information at retrieval, mPFC 5-HT2aR may facilitate top-down context-guided control over PRH to control the behavioral response and object memory reconsolidation. PMID:29717980

Dorsomedial Prefrontal Cortex Contribution to Behavioral and Nucleus Accumbens Neuronal Responses to Incentive Cues

PubMed Central

Ishikawa, Akinori; Ambroggi, Frederic; Nicola, Saleem M.; Fields, Howard L.

2008-01-01

Cue-elicited phasic changes in firing of nucleus accumbens (NAc) neurons can facilitate reward-seeking behavior. Here, we test the hypothesis that the medial prefrontal cortex (mPFC), which sends a dense glutamatergic projection to the NAc core, contributes to NAc neuronal firing responses to reward-predictive cues. Rats trained to perform an operant response to a cue for sucrose were implanted with recording electrodes in the core of the NAc and microinjection cannulas in the dorsal mPFC (dmPFC). The cue-evoked firing of NAc neurons was reduced by bilateral injection of GABAA and GABAB agonists into the dmPFC concomitant with loss of behavioral responding to the cue. In addition, unilateral dmPFC inactivation reduced ipsilateral cue excitations and contralateral cue inhibitions. These findings indicate that cue-evoked excitations and inhibitions of NAc core neurons depend on dmPFC projections to the NAc and that these phasic changes contribute to the behavioral response to reward-predictive cues. PMID:18463262

Fronto-Limbic Functioning in Children and Adolescents with and without Autism

ERIC Educational Resources Information Center

Loveland, Katherine A.; Bachevalier, Jocelyne; Pearson, Deborah A.; Lane, David M.

2008-01-01

We used neuropsychological tasks to investigate integrity of brain circuits linking orbitofrontal cortex and amygdala (orbitofrontal-amygdala), and dorsolateral prefrontal cortex and hippocampus (dorsolateral prefrontal-hippocampus), in 138 individuals aged 7-18 years, with and without autism. We predicted that performance on…

Dissecting contributions of prefrontal cortex and fusiform face area to face working memory.

PubMed

Druzgal, T Jason; D'Esposito, Mark

2003-08-15

Interactions between prefrontal cortex (PFC) and stimulus-specific visual cortical association areas are hypothesized to mediate visual working memory in behaving monkeys. To clarify the roles for homologous regions in humans, event-related fMRI was used to assess neural activity in PFC and fusiform face area (FFA) of subjects performing a delay-recognition task for faces. In both PFC and FFA, activity increased parametrically with memory load during encoding and maintenance of face stimuli, despite quantitative differences in the magnitude of activation. Moreover, timing differences in PFC and FFA activation during memory encoding and retrieval implied a context dependence in the flow of neural information. These results support existing neurophysiological models of visual working memory developed in the nonhuman primate.

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

PubMed Central

Banks, Paul James; Burroughs, Amelia Caroline; Barker, Gareth Robert Isaac; Brown, Jon Thomas; Warburton, Elizabeth Clea; Bashir, Zafar Iqbal

2015-01-01

Functional connectivity between the hippocampus and prefrontal cortex (PFC) is essential for associative recognition memory and working memory. Disruption of hippocampal–PFC synchrony occurs in schizophrenia, which is characterized by hypofunction of NMDA receptor (NMDAR)-mediated transmission. We demonstrate that activity of dopamine D2-like receptors (D2Rs) leads selectively to long-term depression (LTD) of hippocampal–PFC NMDAR-mediated synaptic transmission. We show that dopamine-dependent LTD of NMDAR-mediated transmission profoundly disrupts normal synaptic transmission between hippocampus and PFC. These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia. PMID:26286993

Medial Prefrontal Cortex Activity When Thinking About Others Depends on Their Age

PubMed Central

Ebner, Natalie C.; Gluth, Sebastian; Johnson, Matthew R.; Raye, Carol L.; Mitchell, Karen J.; Johnson, Marcia K.

2011-01-01

This functional magnetic resonance imaging (fMRI) study examined medial prefrontal cortex (mPFC) activity as young and older participants rated an unknown young and older person, and themselves, on personality characteristics. For both young and older participants, there was greater activation in ventral mPFC (anterior cingulate) when they made judgments about own-age than other-age individuals. Additionally, across target age and participant age, there was greater activity in a more anterior region of ventral mPFC (largely medial frontal gyrus, anterior cingulate) when participants rated others than when they rated themselves. We discuss potential interpretations of these findings in the context of previous results suggesting functional specificity of subregions of ventral mPFC. PMID:21432722

Hippocampal Train Stimulation Modulates Recall of Fear Extinction Independently of Prefrontal Cortex Synaptic Plasticity and Lesions

ERIC Educational Resources Information Center

Garcia, Rene; Farinelli, Melissa; Deschaux, Olivier; Hugues, Sandrine; Thevenet, Aurelie

2006-01-01

It has been shown that long-term potentiation (LTP) develops in the connection between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) and between the hippocampus (HPC) and the mPFC following fear extinction, and correlates with extinction retention. However, recent lesion studies have shown that combined lesions of the MD…

Variation in orbitofrontal cortex volume: relation to sex, emotion regulation and affect.

PubMed

Welborn, B Locke; Papademetris, Xenophon; Reis, Deidre L; Rajeevan, Nallakkandi; Bloise, Suzanne M; Gray, Jeremy R

2009-12-01

Sex differences in brain structure have been examined extensively but are not completely understood, especially in relation to possible functional correlates. Our two aims in this study were to investigate sex differences in brain structure, and to investigate a possible relation between orbitofrontal cortex subregions and affective individual differences. We used tensor-based morphometry to estimate local brain volume from MPRAGE images in 117 healthy right-handed adults (58 female), age 18-40 years. We entered estimates of local brain volume as the dependent variable in a GLM, controlling for age, intelligence and whole-brain volume. Men had larger left planum temporale. Women had larger ventromedial prefrontal cortex (vmPFC), right lateral orbitofrontal (rlOFC), cerebellum, and bilateral basal ganglia and nearby white matter. vmPFC but not rlOFC volume covaried with self-reported emotion regulation strategies (reappraisal, suppression), expressivity of positive emotions (but not of negative), strength of emotional impulses, and cognitive but not somatic anxiety. vmPFC volume statistically mediated sex differences in emotion suppression. The results confirm prior reports of sex differences in orbitofrontal cortex structure, and are the first to show that normal variation in vmPFC volume is systematically related to emotion regulation and affective individual differences.

Functional heterogeneity of conflict, error, task-switching, and unexpectedness effects within medial prefrontal cortex.

PubMed

Nee, Derek Evan; Kastner, Sabine; Brown, Joshua W

2011-01-01

The last decade has seen considerable discussion regarding a theoretical account of medial prefrontal cortex (mPFC) function with particular focus on the anterior cingulate cortex. The proposed theories have included conflict detection, error likelihood prediction, volatility monitoring, and several distinct theories of error detection. Arguments for and against particular theories often treat mPFC as functionally homogeneous, or at least nearly so, despite some evidence for distinct functional subregions. Here we used functional magnetic resonance imaging (fMRI) to simultaneously contrast multiple effects of error, conflict, and task-switching that have been individually construed in support of various theories. We found overlapping yet functionally distinct subregions of mPFC, with activations related to dominant error, conflict, and task-switching effects successively found along a rostral-ventral to caudal-dorsal gradient within medial prefrontal cortex. Activations in the rostral cingulate zone (RCZ) were strongly correlated with the unexpectedness of outcomes suggesting a role in outcome prediction and preparing control systems to deal with anticipated outcomes. The results as a whole support a resolution of some ongoing debates in that distinct theories may each pertain to corresponding distinct yet overlapping subregions of mPFC. Copyright © 2010 Elsevier Inc. All rights reserved.

Neural correlates of preparatory and regulatory control over positive and negative emotion.

PubMed

Seo, Dongju; Olman, Cheryl A; Haut, Kristen M; Sinha, Rajita; MacDonald, Angus W; Patrick, Christopher J

2014-04-01

This study used functional magnetic resonance imaging to investigate brain activation during preparatory and regulatory control while participants (N = 24) were instructed either to simply view or decrease their emotional response to, pleasant, neutral or unpleasant pictures. A main effect of emotional valence on brain activity was found in the right precentral gyrus, with greater activation during positive than negative emotion regulation. A main effect of regulation phase was evident in the bilateral anterior prefrontal cortex (PFC), precuneus, posterior cingulate cortex, right putamen and temporal and occipital lobes, with greater activity in these regions during preparatory than regulatory control. A valence X regulation interaction was evident in regions of ventromedial PFC and anterior cingulate cortex, reflecting greater activation while regulating negative than positive emotion, but only during active emotion regulation (not preparation). Conjunction analyses revealed common brain regions involved in differing types of emotion regulation including selected areas of left lateral PFC, inferior parietal lobe, temporal lobe, right cerebellum and bilateral dorsomedial PFC. The right lateral PFC was additionally activated during the modulation of both positive and negative valence. Findings demonstrate significant modulation of brain activity during both preparation for, and active regulation of positive and negative emotional states.

No evidence for enhancements to visual working memory with transcranial direct current stimulation to prefrontal or posterior parietal cortices.

PubMed

Robison, Matthew K; McGuirk, William P; Unsworth, Nash

2017-08-01

The present study examined the relative contributions of the prefrontal cortex (PFC) and posterior parietal cortex (PPC) to visual working memory. Evidence from a number of different techniques has led to the theory that the PFC controls access to working memory (i.e., filtering), determining which information is encoded and maintained for later use whereas the parietal cortex determines how much information is held at 1 given time, regardless of relevance (i.e., capacity; McNab & Klingberg, 2008; Vogel, McCollough, & Machizawa, 2005). To test this theory, we delivered transcranial DC stimulation (tDCS) to the right PFC and right PPC and measured visual working memory capacity and filtering abilities both during and immediately following stimulation. We observed no evidence that tDCS to either the PFC or PPC significantly improved visual working memory. Although the present results did not allow us to make firm theoretical conclusions about the roles of the PFC and PPC in working memory, the results add to the growing body of literature surrounding tDCS and its associated behavioral and neurophysiological effects. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

The Change of Intra-cerebral CST Location during Childhood and Adolescence; Diffusion Tensor Tractography Study.

PubMed

Kwon, Yong M; Kwon, Hyeok G; Rose, Jessica; Son, Su M

2016-01-01

Objectives: Corticospinal tract (CST) is the most important tract in motor control. However, there was no study about the change of CST location with aging. In this study, using diffusion tensor tractography (DTT), we attempted to investigate the change of CST location at cortex, corona radiata (CR) and posterior limb of internal capsule (IC) level with aging in typically developing children. Methods: We recruited 76 healthy pediatric subjects (range; 0-19 years). According to the result of DTT, the location of CST at cortex level was classified as follows; prefrontal cortex (PFC), PFC with Premotor cortex (PMC), PMC, PMC with primary motor cortex (M1), M1, M1 with Primary sensory cortex (S1). Anterior-posterior location (%) of CSTs at CR and IC level was also assessed. Results: DTT results about CSTs of 152 hemispheres from 76 subjects were obtained. The most common location of CST projection was M1 area (58.6%) including PMC with M1 (25.7%), M1 (17.8%), and M1 with S1 (15.1%). The mean age of the projection of CST showed considerably younger at anterior cortex than posterior; (PFC; 4.12 years, PFC with PMC; 6.41 years, PMC; 6.72 years, PMC with M1; 9.75 years, M1; 9.85 years, M1 with S1; 12.99 years, S1; 13.75 years). Spearman correlation showed positive correlation between age and the location of CST from anterior to posterior brain cortex ( r = 0.368). Conclusion: We demonstrated that the location of CST projection is different with aging. The result of this study can provide the scientific insight to the maturation study in human brain.

Thiopental sodium reduces glutamate extracellular levels in rat intact prefrontal cortex.

PubMed

Liu, Hongliang; Yao, Shanglong

2005-12-01

To investigate the effect of thiopental sodium on glutamate extracellular levels in the prefrontal cortex (PFC) of rats, a microdialysis probe was inserted into the PFC, the perfusate was collected every 10 min throughout the experiment with thiopental sodium ip or perfused into the PFC locally. The concentrations of glutamate in the perfusate were determined by reversed-phase high performance liquid chromatography. Thiopental sodium 30 mg kg(-1) ip significantly decreased glutamate levels in the perfusate after 10, 20, 30, and 40 min; glutamate levels in the perfusate were also decreased from 10 to 90 min after thiopental sodium 50 mg kg(-1) ip. Thiopental sodium with concentrations of 30, 100, or 300 microM perfused into the PFC also decreased glutamate levels in the perfusate significantly. The results suggest that thiopental sodium decreases glutamate extracellular levels in rat intact PFC.

Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex.

PubMed

Muschamp, John W; Regina, Meredith J; Hull, Elaine M; Winter, Jerrold C; Rabin, Richard A

2004-10-08

The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT(2A) antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT(2A/C) agonist [-]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 microM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was observed. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.

Theta–gamma coordination between anterior cingulate and prefrontal cortex indexes correct attention shifts

PubMed Central

Voloh, Benjamin; Valiante, Taufik A.; Everling, Stefan; Womelsdorf, Thilo

2015-01-01

Anterior cingulate and lateral prefrontal cortex (ACC/PFC) are believed to coordinate activity to flexibly prioritize the processing of goal-relevant over irrelevant information. This between-area coordination may be realized by common low-frequency excitability changes synchronizing segregated high-frequency activations. We tested this coordination hypothesis by recording in macaque ACC/PFC during the covert utilization of attention cues. We found robust increases of 5–10 Hz (theta) to 35–55 Hz (gamma) phase–amplitude correlation between ACC and PFC during successful attention shifts but not before errors. Cortical sites providing theta phases (i) showed a prominent cue-induced phase reset, (ii) were more likely in ACC than PFC, and (iii) hosted neurons with burst firing events that synchronized to distant gamma activity. These findings suggest that interareal theta–gamma correlations could follow mechanistically from a cue-triggered reactivation of rule memory that synchronizes theta across ACC/PFC. PMID:26100868

Maternal prefrontal cortex activation by newborn infant odors.

PubMed

Nishitani, Shota; Kuwamoto, Saori; Takahira, Asuka; Miyamura, Tsunetake; Shinohara, Kazuyuki

2014-03-01

Mothers are attracted by infant cues of a variety of different modalities. To clarify the possible neural mechanisms underlying maternal attraction to infant odor cues, we used near-infrared spectroscopy to examine prefrontal cortex (PFC) activity during odor detection tasks in which 19 mothers and 19 nulliparous females (nonmothers) were presented with infant or adult male odors. They were instructed to make a judgment about whether they smelled an odor during each task. We estimated the PFC activity by measuring the relative oxyhemoglobin (oxyHb) concentrations. The results showed that while detecting the infant odors, bilateral PFC activities were increased in mothers but not in nonmothers. In contrast, adult male odors activated the PFC similarly in mothers and nonmothers. These findings suggest that maternal activation of the PFC in response to infant odors explains a part of the neural mechanisms for maternal attraction to infant odors.

Molecular Modulation of Prefrontal Cortex: Rational Development of Treatments for Psychiatric Disorders

PubMed Central

Gamo, Nao J.; Arnsten, Amy F.T.

2011-01-01

Dysfunction of the prefrontal cortex (PFC) is a central feature of many psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia and bipolar disorder. Thus, understanding molecular influences on PFC function through basic research in animals is essential to rational drug development. In this review, we discuss the molecular signaling events initiated by norepinephrine and dopamine that strengthen working memory function mediated by the dorsolateral PFC under optimal conditions, and weaken working memory function during uncontrollable stress. We also discuss how these intracellular mechanisms can be compromised in psychiatric disorders, and how novel treatments based on these findings may restore a molecular environment conducive to PFC regulation of behavior, thought and emotion. Examples of successful translation from animals to humans include guanfacine for the treatment of ADHD and related PFC disorders, and prazosin for the treatment of PTSD. PMID:21480691

Depression alters maternal extended amygdala response and functional connectivity during distress signals in attachment relationship

PubMed Central

Ho, S. Shaun; Swain, James E.

2017-01-01

Maternal attachment-related parenting behaviors require mothers to regulate self-related and child-related distress. Emotion regulation is, in turn, influenced by maternal mood and personal developmental history. In the current study we examined how depressive mood may alter maternal limbic system function and functional connectivity underlying defensive and hedonic motivations. Twenty nine mothers were recruited to undergo a baby-cry task during a functional magnetic resonance imaging (fMRI) scan. Based on self-reported depression symptoms and clinical interview, the participants were grouped as healthy controls (n = 15) and currently depressed (n = 14). In the baby-cry task, 30s-long auditory stimuli of baby-cry sounds were presented to simulate four conditions: generic baby-cry (Just-Listen), baby-cry as if it were their own child’s cry (Your-Baby), baby-cry as if it were themselves (Self), and matched control sounds (Noise). Depressed mothers, as compared to healthy controls, showed greater Self versus Just-Listen responses in left extended amygdala and decreased functional coupling between this left extended amygdala as the seed and nucleus accumbens (NAc) in self-oriented (Self versus Just-Listen) and child-oriented (Your-Baby versus Just-Listen) distress signals. Moreover, the extended amygdala’s differential functional connectivity with dorsomedial prefrontal cortex (dmPFC) during the Your-Baby versus Self was increased for depressed mothers and decreased for healthy controls. Thus, depression may affect mothers by increasing baby-cry threat responses and dysregulating associations between threat and heathy child-oriented parenting motivations. These results are discussed in the context of attachment and self-psychology. PMID:28263829

Direct comparison of prefrontal cortex regions engaged by working and long-term memory tasks.

PubMed

Braver, T S; Barch, D M; Kelley, W M; Buckner, R L; Cohen, N J; Miezin, F M; Snyder, A Z; Ollinger, J M; Akbudak, E; Conturo, T E; Petersen, S E

2001-07-01

Neuroimaging studies have suggested the involvement of ventrolateral, dorsolateral, and frontopolar prefrontal cortex (PFC) regions in both working (WM) and long-term memory (LTM). The current study used functional magnetic resonance imaging (fMRI) to directly compare whether these PFC regions show selective activation associated with one memory domain. In a within-subjects design, subjects performed the n-back WM task (two-back condition) as well as LTM encoding (intentional memorization) and retrieval (yes-no recognition) tasks. Additionally, each task was performed with two different types of stimulus materials (familiar words, unfamiliar faces) in order to determine the influence of material-type vs task-type. A bilateral region of dorsolateral PFC (DL-PFC; BA 46/9) was found to be selectively activated during the two-back condition, consistent with a hypothesized role for this region in active maintenance and/or manipulation of information in WM. Left frontopolar PFC (FP-PFC) was also found to be selectively engaged during the two-back. Although FP-PFC activity has been previously associated with retrieval from LTM, no frontopolar regions were found to be selectively engaged by retrieval. Finally, lateralized ventrolateral PFC (VL-PFC) regions were found to be selectively engaged by material-type, but uninfluenced by task-type. These results highlight the importance of examining PFC activity across multiple memory domains, both for functionally differentiating PFC regions (e.g., task-selectivity vs material-selectivity in DL-PFC and VL-PFC) and for testing the applicability of memory domain-specific theories (e.g., FP-PFC in LTM retrieval).

Morphological alterations in the prefrontal cortex and the amygdala in unsuccessful psychopaths.

PubMed

Yang, Yaling; Raine, Adrian; Colletti, Patrick; Toga, Arthur W; Narr, Katherine L

2010-08-01

Although deficits in several cortical and subcortical structures have been found in psychopaths, it remains unclear whether the neuropathology differs between subgroups of psychopaths (i.e., unsuccessful and successful). Using both traditional and novel image analyses methods, this study aims to reveal gross and subtle morphological changes in the prefrontal cortex and the amygdala in unsuccessful and successful psychopaths. Volumetric segmentation, cortical pattern matching, and surface-based mesh modeling methods were used to examine prefrontal and amygdala structures in 16 unsuccessful psychopaths, 10 successful psychopaths, and 27 controls. Significant reduced gray matter volume and cortical thickness/surface shape in the middle frontal, orbitofrontal cortex and the amygdala were found in unsuccessful psychopaths but not successful psychopaths, compared with controls. This study provides the first evidence of greater prefrontal and amygdala structural deficits in unsuccessful psychopaths, which may predispose them to poor behavioral control and impaired decision-making, thus making them more prone to convictions. Copyright 2010 APA, all rights reserved

Ventromedial prefrontal cortex encodes emotional value.

PubMed

Winecoff, Amy; Clithero, John A; Carter, R McKell; Bergman, Sara R; Wang, Lihong; Huettel, Scott A

2013-07-03

The ventromedial prefrontal cortex (vmPFC) plays a critical role in processing appetitive stimuli. Recent investigations have shown that reward value signals in the vmPFC can be altered by emotion regulation processes; however, to what extent the processing of positive emotion relies on neural regions implicated in reward processing is unclear. Here, we investigated the effects of emotion regulation on the valuation of emotionally evocative images. Two independent experimental samples of human participants performed a cognitive reappraisal task while undergoing fMRI. The experience of positive emotions activated the vmPFC, whereas the regulation of positive emotions led to relative decreases in vmPFC activation. During the experience of positive emotions, vmPFC activation tracked participants' own subjective ratings of the valence of stimuli. Furthermore, vmPFC activation also tracked normative valence ratings of the stimuli when participants were asked to experience their emotions, but not when asked to regulate them. A separate analysis of the predictive power of vmPFC on behavior indicated that even after accounting for normative stimulus ratings and condition, increased signal in the vmPFC was associated with more positive valence ratings. These results suggest that the vmPFC encodes a domain-general value signal that tracks the value of not only external rewards, but also emotional stimuli.

Working Memory and Decision-Making in a Frontoparietal Circuit Model

PubMed Central

2017-01-01

Working memory (WM) and decision-making (DM) are fundamental cognitive functions involving a distributed interacting network of brain areas, with the posterior parietal cortex (PPC) and prefrontal cortex (PFC) at the core. However, the shared and distinct roles of these areas and the nature of their coordination in cognitive function remain poorly understood. Biophysically based computational models of cortical circuits have provided insights into the mechanisms supporting these functions, yet they have primarily focused on the local microcircuit level, raising questions about the principles for distributed cognitive computation in multiregional networks. To examine these issues, we developed a distributed circuit model of two reciprocally interacting modules representing PPC and PFC circuits. The circuit architecture includes hierarchical differences in local recurrent structure and implements reciprocal long-range projections. This parsimonious model captures a range of behavioral and neuronal features of frontoparietal circuits across multiple WM and DM paradigms. In the context of WM, both areas exhibit persistent activity, but, in response to intervening distractors, PPC transiently encodes distractors while PFC filters distractors and supports WM robustness. With regard to DM, the PPC module generates graded representations of accumulated evidence supporting target selection, while the PFC module generates more categorical responses related to action or choice. These findings suggest computational principles for distributed, hierarchical processing in cortex during cognitive function and provide a framework for extension to multiregional models. SIGNIFICANCE STATEMENT Working memory and decision-making are fundamental “building blocks” of cognition, and deficits in these functions are associated with neuropsychiatric disorders such as schizophrenia. These cognitive functions engage distributed networks with prefrontal cortex (PFC) and posterior parietal cortex (PPC) at the core. It is not clear, however, what the contributions of PPC and PFC are in light of the computations that subserve working memory and decision-making. We constructed a biophysical model of a reciprocally connected frontoparietal circuit that revealed shared and distinct functions for the PFC and PPC across working memory and decision-making tasks. Our parsimonious model connects circuit-level properties to cognitive functions and suggests novel design principles beyond those of local circuits for cognitive processing in multiregional brain networks. PMID:29114071

Working Memory and Decision-Making in a Frontoparietal Circuit Model.

PubMed

Murray, John D; Jaramillo, Jorge; Wang, Xiao-Jing

2017-12-13

Working memory (WM) and decision-making (DM) are fundamental cognitive functions involving a distributed interacting network of brain areas, with the posterior parietal cortex (PPC) and prefrontal cortex (PFC) at the core. However, the shared and distinct roles of these areas and the nature of their coordination in cognitive function remain poorly understood. Biophysically based computational models of cortical circuits have provided insights into the mechanisms supporting these functions, yet they have primarily focused on the local microcircuit level, raising questions about the principles for distributed cognitive computation in multiregional networks. To examine these issues, we developed a distributed circuit model of two reciprocally interacting modules representing PPC and PFC circuits. The circuit architecture includes hierarchical differences in local recurrent structure and implements reciprocal long-range projections. This parsimonious model captures a range of behavioral and neuronal features of frontoparietal circuits across multiple WM and DM paradigms. In the context of WM, both areas exhibit persistent activity, but, in response to intervening distractors, PPC transiently encodes distractors while PFC filters distractors and supports WM robustness. With regard to DM, the PPC module generates graded representations of accumulated evidence supporting target selection, while the PFC module generates more categorical responses related to action or choice. These findings suggest computational principles for distributed, hierarchical processing in cortex during cognitive function and provide a framework for extension to multiregional models. SIGNIFICANCE STATEMENT Working memory and decision-making are fundamental "building blocks" of cognition, and deficits in these functions are associated with neuropsychiatric disorders such as schizophrenia. These cognitive functions engage distributed networks with prefrontal cortex (PFC) and posterior parietal cortex (PPC) at the core. It is not clear, however, what the contributions of PPC and PFC are in light of the computations that subserve working memory and decision-making. We constructed a biophysical model of a reciprocally connected frontoparietal circuit that revealed shared and distinct functions for the PFC and PPC across working memory and decision-making tasks. Our parsimonious model connects circuit-level properties to cognitive functions and suggests novel design principles beyond those of local circuits for cognitive processing in multiregional brain networks. Copyright © 2017 the authors 0270-6474/17/3712167-20$15.00/0.

Amygdala-prefrontal cortical functional connectivity during implicit emotion processing differentiates youth with bipolar spectrum from youth with externalizing disorders.

PubMed

Hafeman, Danella; Bebko, Genna; Bertocci, Michele A; Fournier, Jay C; Chase, Henry W; Bonar, Lisa; Perlman, Susan B; Travis, Michael; Gill, Mary Kay; Diwadkar, Vaibhav A; Sunshine, Jeffrey L; Holland, Scott K; Kowatch, Robert A; Birmaher, Boris; Axelson, David; Horwitz, Sarah M; Arnold, L Eugene; Fristad, Mary A; Frazier, Thomas W; Youngstrom, Eric A; Findling, Robert L; Phillips, Mary L

2017-01-15

Both bipolar spectrum disorders (BPSD) and attention deficit hyperactivity disorder (ADHD) present with emotion-regulation deficits, but require different clinical management. We examined how the neurobiological underpinnings of emotion regulation might differentiate youth with BPSD versus ADHD (and healthy controls, HCs), specifically assessing functional connectivity (FxC) of amygdala-prefrontal circuitry during an implicit emotion processing task. We scanned a subset of the Longitudinal Assessment of Manic Symptoms (LAMS) sample, a clinically recruited cohort with elevated behavioral and emotional dysregulation, and age/sex-ratio matched HCs. Our sample consisted of 22 youth with BPSD, 30 youth with ADHD/no BPSD, and 26 HCs. We used generalized psychophysiological interaction (gPPI) to calculate group differences to emerging emotional faces vs. morphing shapes in FxC between bilateral amygdala and ventral prefrontal cortex/anterior cingulate cortex. FxC between amygdala and left ventrolateral prefrontal cortex (VLPFC) in response to emotions vs. shapes differed by group (p=.05): while BPSD showed positive FxC (emotions>shapes), HC and ADHD showed inverse FxC (emotions

Reduced expression of conditioned fear in the R6/2 mouse model of Huntington’s disease is related to abnormal activity in prelimbic cortex

PubMed Central

Walker, Adam G.; Ummel, Jason R.; Rebec, George V.

2011-01-01

Prefrontal cortex (PFC) dysfunction is common in patients with Huntington’s disease (HD), a dominantly inherited neurological disorder, and has been linked to cognitive disruption. We previously reported alterations in neuronal firing patterns recorded from PFC of the R6/2 mouse model of HD. To determine if PFC dysfunction results in behavioral impairments, we evaluated performance of wild-type (WT) and R6/2 mice in a fear conditioning and extinction behavioral task. Fear conditioning and extinction retrieval were similar in both genotypes, but R6/2s exhibited less fear during extinction by freezing less than WTs. A fear reinstatement test after extinction retrieval indicated that faster extinction was not due to poor memory for conditioning. During initial extinction and extinction retrieval training, neuronal activity was recorded from prelimbic (PL) cortex, a subregion of PFC known to be important for fear expression. In WTs, a large number of neurons were activated by the conditioned stimulus during initial extinction and this activation was significantly impaired in R6/2s. Notably, there was no genotype difference in PFC activity during extinction retrieval. Thus, altered extinction is likely a result of reduced fear expression due to impairments in PL activation. Collectively, our results suggest that PFC dysfunction may play a key role in R6/2 cognitive impairments. PMID:21515374

Role of medial prefrontal cortex serotonin 2A receptors in the control of retrieval of recognition memory in rats.

PubMed

Bekinschtein, Pedro; Renner, Maria Constanza; Gonzalez, Maria Carolina; Weisstaub, Noelia

2013-10-02

Often, retrieval cues are not uniquely related to one specific memory, which could lead to memory interference. Controlling interference is particularly important during episodic memory retrieval or when remembering specific events in a spatiotemporal context. Despite a clear involvement of prefrontal cortex (PFC) in episodic memory in human studies, information regarding the mechanisms and neurotransmitter systems in PFC involved in memory is scarce. Although the serotoninergic system has been linked to PFC functionality and modulation, its role in memory processing is poorly understood. We hypothesized that the serotoninergic system in PFC, in particular the 5-HT2A receptor (5-HT2AR) could have a role in the control of memory retrieval. In this work we used different versions of the object recognition task in rats to study the role of the serotoninergic modulation in the medial PFC (mPFC) in memory retrieval. We found that blockade of 5-HT2AR in mPFC affects retrieval of an object in context memory in a spontaneous novelty preference task, while sparing single-item recognition memory. We also determined that 5-HT2ARs in mPFC are required for hippocampal-mPFC interaction during retrieval of this type of memory, suggesting that the mPFC controls the expression of memory traces stored in the hippocampus biasing retrieval to the most relevant one.

Abnormal Amygdala and Prefrontal Cortex Activation to Facial Expressions in Pediatric Bipolar Disorder

ERIC Educational Resources Information Center

Garrett, Amy S.; Reiss, Allan L.; Howe, Meghan E.; Kelley, Ryan G.; Singh, Manpreet K.; Adleman, Nancy E.; Karchemskiy, Asya; Chang, Kiki D.

2012-01-01

Objective: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late…

Extinction of Conditioned Taste Aversion Depends on Functional Protein Synthesis but Not on NMDA Receptor Activation in the Ventromedial Prefrontal Cortex

ERIC Educational Resources Information Center

Akirav, Irit; Khatsrinov, Vicktoria; Vouimba, Rose-Marie; Merhav, Maayan; Ferreira, Guillaume; Rosenblum, Kobi; Maroun, Mouna

2006-01-01

We investigated the role of the ventromedial prefrontal cortex (vmPFC) in extinction of conditioned taste aversion (CTA) by microinfusing a protein synthesis inhibitor or N-methyl-d-asparate (NMDA) receptors antagonist into the vmPFC immediately following a non-reinforced extinction session. We found that the protein synthesis blocker anisomycin,…

Trace and Contextual Fear Conditioning Require Neural Activity and NMDA Receptor-Dependent Transmission in the Medial Prefrontal Cortex

ERIC Educational Resources Information Center

Gilmartin, Marieke R.; Helmstetter, Fred J.

2010-01-01

The contribution of the medial prefrontal cortex (mPFC) to the formation of memory is a subject of considerable recent interest. Notably, the mechanisms supporting memory acquisition in this structure are poorly understood. The mPFC has been implicated in the acquisition of trace fear conditioning, a task that requires the association of a…

The medial prefrontal cortex-lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition.

PubMed

Chao, Owen Y; Huston, Joseph P; Li, Jay-Shake; Wang, An-Li; de Souza Silva, Maria A

2016-05-01

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item-associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic-like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic-like (what-where-when) and object-recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic-like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic-like and associative object-recognition memory. © 2015 Wiley Periodicals, Inc.

The effects of gestational stress and Selective Serotonin reuptake inhibitor antidepressant treatment on structural plasticity in the postpartum brain--A translational model for postpartum depression.

PubMed

Haim, Achikam; Albin-Brooks, Christopher; Sherer, Morgan; Mills, Emily; Leuner, Benedetta

2016-01-01

This article is part of a Special Issue "Parental Care". Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Although the neural basis of PPD remains unknown, previous research in rats has shown that gestational stress, a risk factor for PPD, induces depressive-like behavior during the postpartum period. Moreover, the effect of gestational stress on postpartum mood is accompanied by structural modifications within the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC)-limbic regions that have been linked to PPD. Mothers diagnosed with PPD are often prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant medications and yet little is known about their effects in models of PPD. Thus, here we investigated whether postpartum administration of Citalopram, an SSRI commonly used to treat PPD, would ameliorate the behavioral and morphological consequences of gestational stress. In addition, we examined the effects of gestational stress and postpartum administration of Citalopram on structural plasticity within the basolateral amygdala (BLA) which together with the mPFC and NAc forms a circuit that is sensitive to stress and is involved in mood regulation. Our results show that postpartum rats treated with Citalopram do not exhibit gestational stress-induced depressive-like behavior in the forced swim test. In addition, Citalopram was effective in reversing gestational stress-induced structural alterations in the postpartum NAc shell and mPFC. We also found that gestational stress increased spine density within the postpartum BLA, an effect which was not reversed by Citalopram treatment. Overall, these data highlight the usefulness of gestational stress as a valid and informative translational model for PPD. Furthermore, they suggest that structural alterations in the mPFC-NAc pathway may underlie stress-induced depressive-like behavior during the postpartum period and provide much needed information on how SSRIs may act in the maternal brain to treat PPD. Copyright © 2015 Elsevier Inc. All rights reserved.

The effects of gestational stress and SSRI antidepressant treatment on structural plasticity in the postpartum brain - a translational model for postpartum depression

PubMed Central

Haim, Achikam; Albin-Brooks, Christopher; Sherer, Morgan; Mills, Emily; Leuner, Benedetta

2015-01-01

Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Although the neural basis of PPD remains unknown previous research in rats has shown that gestational stress, a risk factor for PPD, induces depressive-like behavior during the postpartum period. Moreover, the effect of gestational stress on postpartum mood is accompanied by structural modifications within the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC) – limbic regions that have been linked to PPD. Mothers diagnosed with PPD are often prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant medications and yet little is known about their effects in models of PPD. Thus, here we investigated whether postpartum administration of Citalopram, an SSRI commonly used to treat PPD, would ameliorate the behavioral and morphological consequences of gestational stress. In addition, we examined the effects of gestational stress and postpartum administration of Citalopram on structural plasticity within the basolateral amygdala (BLA) which together with the mPFC and NAc forms a circuit that is sensitive to stress and is involved in mood regulation. Our results show that postpartum rats treated with Citalopram do not exhibit gestational stress-induced depressive-like behavior in the forced swim test. In addition, Citalopram was effective in reversing gestational stress-induced structural alterations in the postpartum NAc shell and mPFC. We also found that gestational stress increased spine density within the postpartum BLA, an effect which was not reversed by Citalopram treatment. Overall, these data highlight the usefulness of gestational stress as a valid and informative translational model for PPD. Furthermore, they suggest that structural alterations in the mPFC-NAc pathway may underlie stress-induced depressive-like behavior during the postpartum period and provide much needed information on how SSRIs may act in the maternal brain to treat PPD. PMID:25997412

Ethanol Mediated Inhibition of Synaptic Vesicle Recycling at Amygdala Glutamate Synapses Is Dependent upon Munc13-2

PubMed Central

Gioia, Dominic A.; Alexander, Nancy; McCool, Brian A.

2017-01-01

Chronic exposure to alcohol produces adaptations within the basolateral amygdala (BLA) that are associated with the development of anxiety-like behaviors during withdrawal. In part, these adaptations are mediated by plasticity in glutamatergic synapses occurring through an AMPA receptor mediated form of post-synaptic facilitation in addition to a unique form of presynaptic facilitation. In comparison to the post-synaptic compartment, relatively less is understood about the mechanisms involved in the acute and chronic effects of ethanol in the presynaptic terminal. Previous research has demonstrated that glutamatergic terminals in the mouse BLA are sensitive to ethanol mediated inhibition of synaptic vesicle recycling in a strain-dependent fashion. Importantly, the strain-dependent differences in presynaptic ethanol sensitivity are in accordance with known strain-dependent differences in ethanol/anxiety interactions. In the present study, we have used a short-hairpin RNA to knockdown the expression of the presynaptic Munc13-2 protein in C57BL/6J mice, whose BLA glutamate terminals are normally ethanol-insensitive. We injected this shRNA, or a scrambled control virus, into the medial prefrontal cortex (mPFC) which sends dense projections to the BLA. Accordingly, this knockdown strategy reduces the expression of the Munc13-2 isoform in mPFC terminals within the BLA and alters presynaptic terminal function in C57BL/6J mice in a manner that phenocopies DBA/2J glutamate terminals which are normally ethanol-sensitive. Here, we provide evidence that manipulation of this single protein, Munc13-2, renders C57BL/6J terminals sensitive to ethanol mediated inhibition of synaptic vesicle recycling and post-tetanic potentiation. Furthermore, we found that this ethanol inhibition was dose dependent. Considering the important role of Munc13 proteins in synaptic plasticity, this study potentially identifies a molecular mechanism regulating the acute presynaptic effects of ethanol to the long lasting adaptations in the BLA that occur during chronic ethanol exposure. PMID:28785200

Modulating Emotional Experience Using Electrical Stimulation of the Medial-Prefrontal Cortex: A Preliminary tDCS-fMRI Study.

PubMed

Abend, Rany; Sar-El, Roy; Gonen, Tal; Jalon, Itamar; Vaisvaser, Sharon; Bar-Haim, Yair; Hendler, Talma

2018-05-09

Implicit regulation of emotions involves medial-prefrontal cortex (mPFC) regions exerting regulatory control over limbic structures. Diminished regulation relates to aberrant mPFC functionality and psychopathology. Establishing means of modulating mPFC functionality could benefit research on emotion and its dysregulation. Here, we tested the capacity of transcranial direct current stimulation (tDCS) targeting mPFC to modulate subjective emotional states by facilitating implicit emotion regulation. Stimulation was applied concurrently with functional magnetic resonance imaging to validate its neurobehavioral effect. Sixteen participants were each scanned twice, counterbalancing active and sham tDCS application, while undergoing negative mood induction (clips featuring negative vs. neutral contents). Effects of stimulation on emotional experience were assessed using subjective and neural measures. Subjectively, active stimulation led to significant reduction in reported intensity of experienced emotions to negatively valenced (p = 0.005) clips but not to neutral clips (p > 0.99). Active stimulation further mitigated a rise in stress levels from pre- to post-induction (sham: p = 0.004; active: p = 0.15). Neurally, stimulation increased activation in mPFC regions associated with implicit emotion regulation (ventromedial-prefrontal cortex; subgenual anterior-cingulate cortex, sgACC), and in ventral striatum, a core limbic structure (all ps < 0.05). Stimulation also altered functional connectivity (assessed using whole-brain psycho-physiological interaction) between these regions, and with additional limbic regions. Stimulation-induced sgACC activation correlated with reported emotion intensity and depressive symptoms (rs > 0.64, ps < 0.018), suggesting individual differences in stimulation responsivity. Results of this study indicate the potential capacity of tDCS to facilitate brain activation in mPFC regions underlying implicit regulation of emotion and accordingly modulate subjective emotional experiences. © 2018 International Neuromodulation Society.

Ventral medial prefrontal cortex (vmPFC) as a target of the dorsolateral prefrontal modulation by transcranial direct current stimulation (tDCS) in drug addiction.

PubMed

Nakamura-Palacios, Ester Miyuki; Lopes, Isabela Bittencourt Coutinho; Souza, Rodolpho Albuquerque; Klauss, Jaisa; Batista, Edson Kruger; Conti, Catarine Lima; Moscon, Janine Andrade; de Souza, Rodrigo Stênio Moll

2016-10-01

Here, we report some electrophysiologic and imaging effects of the transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (dlPFC) in drug addiction, notably in alcohol and crack-cocaine dependence. The low resolution electromagnetic tomography (LORETA) analysis obtained through event-related potentials (ERPs) under drug-related cues, more specifically in its P3 segment (300-500 ms) in both, alcoholics and crack-cocaine users, showed that the ventral medial prefrontal cortex (vmPFC) was the brain area with the largest change towards increasing activation under drug-related cues in those subjects that kept abstinence during and after the treatment with bilateral tDCS (2 mA, 35 cm(2), cathodal left and anodal right) over dlPFC, applied repetitively (five daily sessions). In an additional study in crack-cocaine, which showed craving decreases after repetitive bilateral tDCS, we examined data originating from diffusion tensor imaging (DTI), and we found increased DTI parameters in the left connection between vmPFC and nucleus accumbens (NAcc), such as the number of voxels, fractional anisotropy (FA) and apparent diffusion coefficient (ADC), in tDCS-treated crack-cocaine users when compared to the sham-tDCS group. This increasing of DTI parameters was significantly correlated with craving decreasing after the repetitive tDCS. The vmPFC relates to the control of drug seeking, possibly by extinguishing this behavior. In our studies, the bilateral dlPFC tDCS reduced relapses and craving to the drug use, and increased the vmPFC activation under drug cues, which may be of a great importance in the control of drug use in drug addiction.

Adaptive Encoding of Outcome Prediction by Prefrontal Cortex Ensembles Supports Behavioral Flexibility.

PubMed

Del Arco, Alberto; Park, Junchol; Wood, Jesse; Kim, Yunbok; Moghaddam, Bita

2017-08-30

The prefrontal cortex (PFC) is thought to play a critical role in behavioral flexibility by monitoring action-outcome contingencies. How PFC ensembles represent shifts in behavior in response to changes in these contingencies remains unclear. We recorded single-unit activity and local field potentials in the dorsomedial PFC (dmPFC) of male rats during a set-shifting task that required them to update their behavior, among competing options, in response to changes in action-outcome contingencies. As behavior was updated, a subset of PFC ensembles encoded the current trial outcome before the outcome was presented. This novel outcome-prediction encoding was absent in a control task, in which actions were rewarded pseudorandomly, indicating that PFC neurons are not merely providing an expectancy signal. In both control and set-shifting tasks, dmPFC neurons displayed postoutcome discrimination activity, indicating that these neurons also monitor whether a behavior is successful in generating rewards. Gamma-power oscillatory activity increased before the outcome in both tasks but did not differentiate between expected outcomes, suggesting that this measure is not related to set-shifting behavior but reflects expectation of an outcome after action execution. These results demonstrate that PFC neurons support flexible rule-based action selection by predicting outcomes that follow a particular action. SIGNIFICANCE STATEMENT Tracking action-outcome contingencies and modifying behavior when those contingencies change is critical to behavioral flexibility. We find that ensembles of dorsomedial prefrontal cortex neurons differentiate between expected outcomes when action-outcome contingencies change. This predictive mode of signaling may be used to promote a new response strategy at the service of behavioral flexibility. Copyright © 2017 the authors 0270-6474/17/378363-11$15.00/0.

Increased prefrontal cortex neurogranin enhances plasticity and extinction learning.

PubMed

Zhong, Ling; Brown, Joshua; Kramer, Audra; Kaleka, Kanwardeep; Petersen, Amber; Krueger, Jamie N; Florence, Matthew; Muelbl, Matthew J; Battle, Michelle; Murphy, Geoffrey G; Olsen, Christopher M; Gerges, Nashaat Z

2015-05-13

Increasing plasticity in neurons of the prefrontal cortex (PFC) has been proposed as a possible therapeutic tool to enhance extinction, a process that is impaired in post-traumatic stress disorder, schizophrenia, and addiction. To test this hypothesis, we generated transgenic mice that overexpress neurogranin (a calmodulin-binding protein that facilitates long-term potentiation) in the PFC. Neurogranin overexpression in the PFC enhanced long-term potentiation and increased the rates of extinction learning of both fear conditioning and sucrose self-administration. Our results indicate that elevated neurogranin function within the PFC can enhance local plasticity and increase the rate of extinction learning across different behavioral tasks. Thus, neurogranin can provide a molecular link between enhanced plasticity and enhanced extinction. Copyright © 2015 the authors 0270-6474/15/357503-06$15.00/0.

Age-Dependent Relationships between Prefrontal Cortex Activation and Processing Efficiency

PubMed Central

Motes, Michael A.; Biswal, Bharat B.; Rypma, Bart

2012-01-01

fMRI was used in the present study to examine the neural basis for age-related differences in processing efficiency, particularly targeting prefrontal cortex (PFC). During scanning, older and younger participants completed a processing efficiency task in which they determined on each trial whether a symbol-number pair appeared in a simultaneously presented array of nine symbol-number pairs. Estimates of task-related BOLD signal-change were obtained for each participant. These estimates were then correlated with the participants’ performance on the task. For younger participants, BOLD signal-change within PFC decreased with better performance, but for older participants, BOLD signal-change within PFC increased with better performance. The results support the hypothesis that the availability and use of PFC resources mediates age-related changes in processing efficiency. PMID:22792129

Age-Dependent Relationships between Prefrontal Cortex Activation and Processing Efficiency.

PubMed

Motes, Michael A; Biswal, Bharat B; Rypma, Bart

2011-01-01

fMRI was used in the present study to examine the neural basis for age-related differences in processing efficiency, particularly targeting prefrontal cortex (PFC). During scanning, older and younger participants completed a processing efficiency task in which they determined on each trial whether a symbol-number pair appeared in a simultaneously presented array of nine symbol-number pairs. Estimates of task-related BOLD signal-change were obtained for each participant. These estimates were then correlated with the participants' performance on the task. For younger participants, BOLD signal-change within PFC decreased with better performance, but for older participants, BOLD signal-change within PFC increased with better performance. The results support the hypothesis that the availability and use of PFC resources mediates age-related changes in processing efficiency.

Induction of c-Fos immunoreactivity in the amygdala of mice expressing anxiety-like behavior after local perfusion of veratrine in the prelimbic medial prefrontal cortex.

PubMed

Yamada, Misa; Saitoh, Akiyoshi; Ohashi, Masanori; Suzuki, Satoshi; Oka, Jun-Ichiro; Yamada, Mitsuhiko

2015-08-01

Local perfusion of the sodium channel activator veratrine in mouse prelimbic medial prefrontal cortex (PL) induced c-Fos immunoreactivity in the sub-regions of amygdala. Co-perfusion of the NMDA receptor antagonist MK-801 diminished the c-Fos expression. Significant correlations were observed between c-Fos immunoreactivity and behavioral measures in the open-field test. The PL stimulation activates a neural network projecting to the amygdala via NMDA receptor-mediated glutamatergic neurotransmission. Anxiety-like behavior induced after the PL stimulation may be partly mediated through the activation of amygdala.

Amygdala-cingulate intrinsic connectivity is associated with degree of social inhibition

PubMed Central

Blackford, Jennifer Urbano; Clauss, Jacqueline A.; Avery, Suzanne N.; Cowan, Ronald L.; Benningfield, Margaret M.; VanDerKlok, Ross M.

2014-01-01

The tendency to approach or avoid novel people is a fundamental human behavior and is a core dimension of social anxiety. Resting state fMRI was used to test for an association between social inhibition and intrinsic connectivity in 40 young adults ranging from low to high in social inhibition. Higher levels of social inhibition were associated with specific patterns of reduced amygdala-cingulate cortex connectivity. Connectivity was reduced between the superficial amygdala and the rostral cingulate cortex and between the centromedial amygdala and the dorsal anterior cingulate cortex. Social inhibition also modulated connectivity in several well-established intrinsic networks; higher social inhibition correlated with reduced connectivity with default mode and dorsal attention networks and enhanced connectivity in salience and executive control networks. These findings provide important preliminary evidence that social inhibition reflects differences in the underlying intrinsic connectivity of the brain in the absence of social stimuli or stressors. PMID:24534162

Lesions of the medial prefrontal cortex cause maladaptive sexual behavior in male rats.

PubMed

Davis, Jon F; Loos, Maarten; Di Sebastiano, Andrea R; Brown, Jennifer L; Lehman, Michael N; Coolen, Lique M

2010-06-15

An inability to inhibit behaviors once they become maladaptive is a component of several psychiatric illnesses, and the medial prefrontal cortex (mPFC) was identified as a potential mediator of behavioral inhibition. The current study tested if the mPFC is involved in inhibition of sexual behavior when associated with aversive outcomes. Using male rats, effects of lesions of the infralimbic and prelimbic areas of the mPFC on expression of sexual behavior and ability to inhibit mating were tested using a paradigm of copulation-contingent aversion. Medial prefrontal cortex lesions did not alter expression of sexual behavior. In contrast, mPFC lesions completely blocked the acquisition of sex-aversion conditioning and lesioned animals continued to mate, in contrast to the robust behavioral inhibition toward copulation in mPFC intact male animals, resulting in only 22% of intact male animals continuing to mate. However, rats with mPFC lesions were capable of forming a conditioned place preference to sexual reward and conditioned place aversion for lithium chloride, suggesting that these lesions did not alter associative learning or sensitivity for lithium chloride. The current study indicates that animals with mPFC lesions are likely capable of forming the associations with aversive outcomes of their behavior but lack the ability to suppress seeking of sexual reward in the face of aversive consequences. These data may contribute to a better understanding of a common pathology underlying impulse control disorders, as compulsive sexual behavior has a high prevalence of comorbidity with psychiatric disorders and Parkinson's disease.

Ventromedial Prefrontal Cortex Is Critical for Helping Others Who Are Suffering.

PubMed

Beadle, Janelle N; Paradiso, Sergio; Tranel, Daniel

2018-01-01

Neurological patients with damage to the ventromedial prefrontal cortex (vmPFC) are reported to display reduced empathy toward others in their daily lives in clinical case studies. However, the empathic behavior of patients with damage to the vmPFC has not been measured experimentally in response to an empathy-eliciting event. This is important because characterizing the degree to which patients with damage to the vmPFC have lower empathic behavior will allow for the development of targeted interventions to improve patients' social skills and in turn will help family members to better understand their impairments so they can provide appropriate supports. For the first time, we induced empathy using an ecologically-valid empathy induction in neurological patients with damage to the vmPFC and measured their empathic emotional responses and behavior in real time. Eight neurological patients with focal damage to the vmPFC were compared to demographically-matched brain-damaged and healthy comparison participants. Patients with damage to the vmPFC gave less money in the empathy condition to a person who was suffering (a confederate) than comparison participants. This provides the first direct experimental evidence that the vmPFC is critical for empathic behavior toward individuals who are suffering.

G proteins in rat prefrontal cortex (PFC) are differentially activated as a function of oxygen status and PFC region.

PubMed

Hambrecht, V S; Vlisides, P E; Row, B W; Gozal, D; Baghdoyan, H A; Lydic, R

2009-03-01

This study tested the hypothesis that activation of guanine nucleotide binding (G) proteins in rat prefrontal cortex (PFC) is altered by hypoxia. G protein activation by the cholinergic agonist carbachol and the opioid agonist DAMGO was quantified using [(35)S]GTPgammaS autoradiography. G protein activation was expressed as nCi/g tissue in the PFC of 18 rats exposed for 14 consecutive days to sustained hypoxia (10% O(2)), intermittent hypoxia (10% and 21% O(2) alternating every 90 s), or room air (21% O(2)). Relative to basal levels of G protein activation, carbachol and DAMGO increased G protein activation by approximately 70% across all oxygen concentrations. Compared to the room air condition, sustained hypoxia caused a significant increase in G protein activation in frontal association (FrA) region of the PFC. Region-specific comparisons revealed that intermittent and sustained hypoxia caused greater DAMGO-stimulated G protein activation in the FrA than in the pre-limbic (PrL). The data show for the first time that hypoxia increased G protein activation in PFC. The results suggest the potential for hypoxia-induced enhancements in G protein activation to alter PFC function.

Sevoflurane Induces Coherent Slow-Delta Oscillations in Rats.

PubMed

Guidera, Jennifer A; Taylor, Norman E; Lee, Justin T; Vlasov, Ksenia Y; Pei, JunZhu; Stephen, Emily P; Mayo, J Patrick; Brown, Emery N; Solt, Ken

2017-01-01

Although general anesthetics are routinely administered to surgical patients to induce loss of consciousness, the mechanisms underlying anesthetic-induced unconsciousness are not fully understood. In rats, we characterized changes in the extradural EEG and intracranial local field potentials (LFPs) within the prefrontal cortex (PFC), parietal cortex (PC), and central thalamus (CT) in response to progressively higher doses of the inhaled anesthetic sevoflurane. During induction with a low dose of sevoflurane, beta/low gamma (12-40 Hz) power increased in the frontal EEG and PFC, PC and CT LFPs, and PFC-CT and PFC-PFC LFP beta/low gamma coherence increased. Loss of movement (LOM) coincided with an abrupt decrease in beta/low gamma PFC-CT LFP coherence. Following LOM, cortically coherent slow-delta (0.1-4 Hz) oscillations were observed in the frontal EEG and PFC, PC and CT LFPs. At higher doses of sevoflurane sufficient to induce loss of the righting reflex, coherent slow-delta oscillations were dominant in the frontal EEG and PFC, PC and CT LFPs. Dynamics similar to those observed during induction were observed as animals emerged from sevoflurane anesthesia. We conclude that the rat is a useful animal model for sevoflurane-induced EEG oscillations in humans, and that coherent slow-delta oscillations are a correlate of sevoflurane-induced behavioral arrest and loss of righting in rats.

Depression of Excitatory Synapses onto Parvalbumin Interneurons in the Medial Prefrontal Cortex in Susceptibility to Stress

PubMed Central

Delevich, Kristen

2015-01-01

In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. PMID:25698754

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

PubMed Central

Honório Junior, José Eduardo Ribeiro; Vasconcelos, Germana Silva; Rodrigues, Francisca Taciana Sousa; Sena Filho, José Guedes; Barbosa-Filho, José Maria; Aguiar, Carlos Clayton Torres; Leal, Luzia Kalyne Almeida Moreira; Soares, Pedro Marcos Gomes; Woods, David John; Fonteles, Marta Maria de França; Vasconcelos, Silvânia Maria Mendes

2012-01-01

This work was designed to study MCT effect in histopathological analysis of hippocampus (HC) and parahippocampal cortex (PHC) and in oxidative stress (OS) parameters in brain areas such as hippocampus (HC), prefrontal cortex (PFC), and striatum (ST). Swiss mice (25–30 g) were administered a single i.p. dose of MCT (5, 50, or 100 mg/kg) or 4% Tween 80 in saline (control group). After 30 minutes, the animals were sacrificed by decapitation and the brain areas (HC, PHC, PFC, or ST) were removed for histopathological analysis or dissected and homogenized for measurement of OS parameters (lipid peroxidation, nitrite, and catalase) by spectrophotometry. Histological evaluation of brain structures of rats treated with MCT (50 and 100 mg/kg) revealed lesions in the hippocampus and parahippocampal cortex compared to control. Lipid peroxidation was evident in all brain areas after administration of MCT. Nitrite/nitrate content decreased in all doses administered in HC, PFC, and ST. Catalase activity was increased in the MCT group only in HC. In conclusion, monocrotaline caused cell lesions in the hippocampus and parahippocampal cortex regions and produced oxidative stress in the HC, PFC, and ST in mice. These findings may contribute to the neurological effects associated with this compound. PMID:23251721

Neuronal activity-regulated pentraxin expressed in medial prefrontal cortex neurons is not necessary for extinction of heroin self-administration.

PubMed

Blouin, Ashley M; Stern, Anna L; Han, Sungho; Theberge, Florence R; Wang, Chuansong; During, Matthew J; Baraban, Jay M; Reti, Irving M

2013-08-01

The medial prefrontal cortex (mPFC) plays a key role in extinction learning. Previously, we found that expression of a neuronal activity-regulated pentraxin (Narp) dominant-negative construct in the mPFC of mice blocked extinction of morphine-conditioned place preference. To further investigate the role of mPFC Narp in the extinction of drug seeking, we tested whether mPFC Narp is necessary for the extinction of heroin self-administration in rats. Specifically, we injected an adeno-associated viral vector expressing a dominant-negative form of Narp (NarpN) into the infralimbic region of the mPFC of rats and compared lever presses during extinction to those of rats injected with a control virus. In contrast to our previous study, we found that injection of NarpN did not affect extinction of heroin self-administration. Our findings suggest that mPFC Narp is necessary for extinction of opiate seeking in the Pavlovian-conditioned place preference paradigm but not in the operant paradigm of drug self-administration.

Chronic Gestational Stress Leads to Depressive-Like Behavior and Compromises Medial Prefrontal Cortex Structure and Function during the Postpartum Period

PubMed Central

Leuner, Benedetta; Fredericks, Peter J.; Nealer, Connor; Albin-Brooks, Christopher

2014-01-01

Postpartum depression, which affects approximately 15% of new mothers, is associated with impaired mother-infant interactions and deficits in cognitive function. Exposure to stress during pregnancy is a major risk factor for postpartum depression. However, little is known about the neural consequences of gestational stress. The medial prefrontal cortex (mPFC) is a brain region that has been linked to stress, cognition, maternal care, and mood disorders including postpartum depression. Here we examined the effects of chronic gestational stress on mPFC function and whether these effects might be linked to structural modifications in the mPFC. We found that in postpartum rats, chronic gestational stress resulted in maternal care deficits, increased depressive-like behavior, and impaired performance on an attentional set shifting task that relies on the mPFC. Furthermore, exposure to chronic stress during pregnancy reduced dendritic spine density on mPFC pyramidal neurons and altered spine morphology. Taken together, these findings suggest that pregnancy stress may contribute to postpartum mental illness and its associated symptoms by compromising structural plasticity in the mPFC. PMID:24594708

Cocaine. Selective regional effects on central monoamines.

PubMed

Hadfield, M G

1995-01-01

Cocaine HCl (0, 10, or 50 mg/kg) was injected into adult male ICR mice ip. Thirty minutes later, the brains were removed, and nine regions were isolated: olfactory bulbs, olfactory tubercles, prefrontal cortex, septum, striatum, amygdala, hypothalamus, hippocampus, and thalamus. Using high-performance liquid chromatography, concentrations of norepinephrine, dopamine, serotonin, and their major metabolites and the metabolite/neurotransmitter ratios were determined as an indicator of utilization. Serotonergic systems responded most dramatically. 5HIAA/5-HT decreases were seen in all the brain regions, except the septum, hippocampus, and olfactory bulbs. In most instances, the alterations were dose-dependent. The most profound changes were seen in the amygdala, prefrontal cortex, hypothalamus, and thalamus. For noradrenergic systems, significant responses were seen only in the amygdala, prefrontal cortex, and hypothalamus, but then only at the lower dose. The dopaminergic responses were more complex and not always dose-dependent. The DOPAC/DA ratio was decreased only in the amygdala and striatum at the lower dose, and the olfactory tubercles at the higher dose. It was increased in the septum. The HVA/DA ratios were decreased in the amygdala, prefrontal cortex, and hypothalamus, but only at the lower dose (like MHPG/NE). The 3MT/DA ratio was decreased in the thalamus at the lower dose and in the olfactory tubercles at the higher dose, whereas it was increased in the prefrontal cortex at the lower dose. The HVA and DOPAC routes of degradation were both utilized only by the amygdala. Thus, cocaine produced its most comprehensive effects in this nucleus, as well as the greatest absolute percentage changes for all three of the monoamine systems studied.

Ventromedial prefrontal cortex, adding value to autobiographical memories

PubMed Central

Lin, Wen-Jing; Horner, Aidan J.; Burgess, Neil

2016-01-01

The medial prefrontal cortex (mPFC) has been consistently implicated in autobiographical memory recall and decision making. Its function in decision making tasks is believed to relate to value representation, but its function in autobiographical memory recall is not yet clear. We hypothesised that the mPFC represents the subjective value of elements during autobiographical memory retrieval. Using functional magnetic resonance imaging during an autobiographical memory recall task, we found that the blood oxygen level dependent (BOLD) signal in ventromedial prefrontal cortex (vmPFC) was parametrically modulated by the affective values of items in participants’ memories when they were recalling and evaluating these items. An unrelated modulation by the participant’s familiarity with the items was also observed. During retrieval of the event, the BOLD signal in the same region was modulated by the personal significance and emotional intensity of the memory, which was correlated with the values of the items within them. These results support the idea that vmPFC processes self-relevant information, and suggest that it is involved in representing the personal emotional values of the elements comprising autobiographical memories. PMID:27338616

Ventromedial prefrontal cortex, adding value to autobiographical memories.

PubMed

Lin, Wen-Jing; Horner, Aidan J; Burgess, Neil

2016-06-24

The medial prefrontal cortex (mPFC) has been consistently implicated in autobiographical memory recall and decision making. Its function in decision making tasks is believed to relate to value representation, but its function in autobiographical memory recall is not yet clear. We hypothesised that the mPFC represents the subjective value of elements during autobiographical memory retrieval. Using functional magnetic resonance imaging during an autobiographical memory recall task, we found that the blood oxygen level dependent (BOLD) signal in ventromedial prefrontal cortex (vmPFC) was parametrically modulated by the affective values of items in participants' memories when they were recalling and evaluating these items. An unrelated modulation by the participant's familiarity with the items was also observed. During retrieval of the event, the BOLD signal in the same region was modulated by the personal significance and emotional intensity of the memory, which was correlated with the values of the items within them. These results support the idea that vmPFC processes self-relevant information, and suggest that it is involved in representing the personal emotional values of the elements comprising autobiographical memories.

Pyramidal Cells in Prefrontal Cortex of Primates: Marked Differences in Neuronal Structure Among Species

PubMed Central

Elston, Guy N.; Benavides-Piccione, Ruth; Elston, Alejandra; Manger, Paul R.; DeFelipe, Javier

2010-01-01

The most ubiquitous neuron in the cerebral cortex, the pyramidal cell, is characterized by markedly different dendritic structure among different cortical areas. The complex pyramidal cell phenotype in granular prefrontal cortex (gPFC) of higher primates endows specific biophysical properties and patterns of connectivity, which differ from those in other cortical regions. However, within the gPFC, data have been sampled from only a select few cortical areas. The gPFC of species such as human and macaque monkey includes more than 10 cortical areas. It remains unknown as to what degree pyramidal cell structure may vary among these cortical areas. Here we undertook a survey of pyramidal cells in the dorsolateral, medial, and orbital gPFC of cercopithecid primates. We found marked heterogeneity in pyramidal cell structure within and between these regions. Moreover, trends for gradients in neuronal complexity varied among species. As the structure of neurons determines their computational abilities, memory storage capacity and connectivity, we propose that these specializations in the pyramidal cell phenotype are an important determinant of species-specific executive cortical functions in primates. PMID:21347276