Coelho, Luzia Flavia; Barbosa, Deise Lima Fernandes; Rizzutti, Sueli; Muszkat, Mauro; Bueno, Orlando Francisco Amodeo; Miranda, Monica Carolina
Medication has proved highly efficacious as a means of alleviating general symptoms of attention-deficit hyperactivity disorder (ADHD). However, many patients remain functionally impaired by inappropriate behavior. The present study analyzed the use of cognitive behavioral therapy (CBT) with the Token-Economy (TE) technique to alleviate problem behavior for 25 participants with ADHD, all children (19 boys, mean age 10.11) on long-term methylphenidate medication, who were given 20 CBT sessions with 10 weeks of TE introduced as of session 5. Their ten most acute problem behaviors were selected and written records kept. On weekdays, parents recorded each inappropriate behavior and provided a suitable model for their actions. At weekly sessions, problem behaviors were counted and incident-free participants rewarded with a token. To analyze improvement (less frequent problem behavior), a list of 11 behavioral categories was rated: inattention, impulsivity, hyperactivity, disorganization, disobeying rules and routines, poor self-care, verbal/physical aggression, low frustration tolerance, compulsive behavior, antisocial behavior, lacking in initiative and distraction. Two CBT specialists categorized behaviors and an ADHD specialist ruled on discrepancies. Statistical analyses used were Generalized Estimating Equations with Poisson distribution and autoregressive order correlation structure. In the course of the sessions, problematic behaviors decreased significantly in seven categories: impulsiveness, hyperactivity, disorganization, disobeying rules and routine, poor self-care, low frustration tolerance, compulsive behaviors, and antisocial behaviors. Caregiver attitudes to children’s inappropriate behavior were discussed and reshaped. As functional improvement was observed on applying TE for 10 weeks, this type of intervention may be useful as an auxiliary strategy combined with medication. PMID:26635642
Coelho, Luzia Flavia; Barbosa, Deise Lima Fernandes; Rizzutti, Sueli; Muszkat, Mauro; Bueno, Orlando Francisco Amodeo; Miranda, Monica Carolina
Medication has proved highly efficacious as a means of alleviating general symptoms of attention-deficit hyperactivity disorder (ADHD). However, many patients remain functionally impaired by inappropriate behavior. The present study analyzed the use of cognitive behavioral therapy (CBT) with the Token-Economy (TE) technique to alleviate problem behavior for 25 participants with ADHD, all children (19 boys, mean age 10.11) on long-term methylphenidate medication, who were given 20 CBT sessions with 10 weeks of TE introduced as of session 5. Their ten most acute problem behaviors were selected and written records kept. On weekdays, parents recorded each inappropriate behavior and provided a suitable model for their actions. At weekly sessions, problem behaviors were counted and incident-free participants rewarded with a token. To analyze improvement (less frequent problem behavior), a list of 11 behavioral categories was rated: inattention, impulsivity, hyperactivity, disorganization, disobeying rules and routines, poor self-care, verbal/physical aggression, low frustration tolerance, compulsive behavior, antisocial behavior, lacking in initiative and distraction. Two CBT specialists categorized behaviors and an ADHD specialist ruled on discrepancies. Statistical analyses used were Generalized Estimating Equations with Poisson distribution and autoregressive order correlation structure. In the course of the sessions, problematic behaviors decreased significantly in seven categories: impulsiveness, hyperactivity, disorganization, disobeying rules and routine, poor self-care, low frustration tolerance, compulsive behaviors, and antisocial behaviors. Caregiver attitudes to children's inappropriate behavior were discussed and reshaped. As functional improvement was observed on applying TE for 10 weeks, this type of intervention may be useful as an auxiliary strategy combined with medication.
Zhou, Xiao Yan; Zhang, Fang; Ying, Chang Jiang; Chen, Jing; Chen, Ling; Dong, Jing; Shi, Yue; Tang, Mang; Hu, Xiao Tong; Pan, Zhi Hua; Xu, Na Na; Zheng, Kui Yang; Tang, Ren Xian; Song, Yuan Jian
Diabetes mellitus often results in a number of complications involving impaired brain function, including cognitive deficits and depression. However, the potential mechanisms for diabetes-related cognitive deficits and depression are not fully understood. Neurons in the hippocampal, cortical and amygdala functional regions are more susceptible to damage during hyperglycemia. Neuroprotection in the brain can rescue cognitive deficits and depression induced by hyperglycemia. This study investigated the potential mechanisms underlying diabetes-related congnitive deficits and depression, determined whether the inflammatory factor inducible nitric oxide synthase (iNOS) and the nitric oxide (NO)/soluble guanylyl cyclases (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway, play key roles in cognitive deficits and depression associated. In the present study, diabetic animal models were induced by streptozotocin (STZ, 150mg/kg) in mice, and aminoguanidine (AG), a selective inhibitor of iNOS, was given by intraperitoneal injection for 10 weeks. Blood glucose, activities of NOS and the levels of NO in serum and brain regions were measured. The spatial memory was detected using the Morris water maze test, depressive behavior was evaluated by the tail suspension test (TST), forced swimming test (FST), closed field test (CFT) and open field test (OFT). We also detected neuronal survival and cleaved caspase-3 positive ratios in three brain regions and the levels of iNOS, sGC, cGMP and PKG in hippocampus and frontal cortex. Data indicated that diabetic mice exerted impairments in spatial memory, decreased locomotor activity and increased immobile time in diabetic mice. In addition, diabetic mice had significantly decreased surviving neuronal density and showed signs of obvious neuronal injury in the hippocampus, frontal cortex and amygdala. iNOS overexpression and its associated signaling pathway NO/sGC/cGMP/PKG in the hippocampus and frontal cortex were
Wang, Wei-Wei; Han, Jian-Hong; Wang, Lin; Bao, Tian-Hao
Objective(s): Scutellarin, a flavonoid extracted from the medicinal herb Erigeron breviscapus Hand-Mazz, protects neurons from damage and inhibits glial activation. Here we examined whether scutellarin may also protect neurons from hypoxia-induced damage. Materials and Methods: Mice were exposed to hypoxia for 7 days and then administered scutellarin (50 mg/kg/d) or vehicle for 30 days Cognitive impairment in the two groups was assessed using the Morris water maze test, cell proliferation in the hippocampus was compared using 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry, and hippocampal levels of nestin and neuronal class III β-tubulin (Tuj-1) were measured using Western blotting. These results were validated in vitro by treating cultured neural stem cells (NSCs) with scutellarin (30 μM). Results: Treating mice with scutellarin shortened escape times and increased the number of platform crossings, it increased the number of BrdU-positive proliferating cells in the hippocampus, and it up-regulated expression of nestin and Tuj-1. Treating NSC cultures with scutellarin increased the number of proliferating cells and the proportion of cells differentiating into neurons instead of astrocytes. The increase in NSC proliferation was associated with phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, while neuronal differentiation was associated with altered expression of differentiation-related genes. Conclusion: Scutellarin may alleviate cognitive impairment in a mouse model of hypoxia by promo-ting proliferation and neuronal differentiation of NSCs. PMID:28392899
Glicksohn, J; Cohen, Y
It has recently been reported that students performed relatively better on cognitive tasks after listening to music. Conceivably, music might reduce the level of arousal in subjects who are tense, thereby improving their performance. A test case would be schizophrenic subjects, noted for poor performance on tasks demanding attention, who have been characterized as suffering from hyperarousal, which mediates these attentional deficits. We investigated whether cognitive task performance could be facilitated by music in schizophrenics and report a beneficial effect.
Rychkova, O V; Gurevich, G L
To study the association between neurocognitive deficit and impairment of social cognition in schizophrenia, we assessed 30 patients and 30 healthy people (controls) using clinical, psychometric and psychological tests. Based on the results obtained in the study, authors could single out a specific block of impairment which was not associated with perceptive and gnostic deficits. The data confirmed the significant contribution of deficit neurodynamic and regulatory parameters in the impairment of social cognition in schizophrenia.
Hoff, Anne L; Svetina, Christine; Maurizio, Andrea M; Crow, Timothy J; Spokes, Kate; DeLisi, Lynn E
Susceptibility to schizophrenia is considered familial, but the mechanism for transmission has not been found. Since widespread cognitive deficits have been found in patients with schizophrenia, several of these have been proposed as candidate familial endophenotypes that may or may not be predictive of who develops the illness. The current study examines these candidates in individuals from 32 families with at least 2 members having the diagnosis of chronic schizophrenia and normal comparison subjects using an extensive neuropsychological battery. Consistent with previous literature, family members with schizophrenia were significantly impaired on all measures compared with controls. Well relatives demonstrated significantly worse performance on a measure of verbal learning, delayed visual recall, perceptual-motor, and pure motor speed. Expressive and receptive language, but not other functions, were highly correlated within both concordant for schizophrenia and discordant sibling pairs, suggesting that they are familial vulnerability endophenotypes, but not predictive of whom becomes ill. On the other hand, some measures of perceptual-motor, pure motor speed, and frontal/executive functioning were significantly correlated in concordant, but not discordant pairs. These latter correlations suggest that some cognitive measures may be genetically related to the illness.
Archer, Trevor; Kostrzewa, Richard M
The heterogeneous, chronic, and proliferating aspect of attention deficit hyperactivity disorder (ADHD) and comorbidities covers heritability, cognitive, emotional, motor, and everyday behavioral domains that place individuals presenting the condition at some considerable disadvantage. Disruption of "typical developmental trajectories" in the manifestation of gene-environment interactive predispositions implies that ADHD children and adolescents may continue to perform at defective levels as adults with regard to academic achievement, occupational enterprises, and interpersonal relationships, despite the promise of pharmacotherapeutic treatments. Physical exercise provides a plethora of beneficial effects against stress, anxiety, depression, negative affect and behavior, poor impulse control, and compulsive behavior concomitant with improved executive functioning, working memory and positive affect, as well as improved conditions for relatives and care-givers. Brain-derived neurotrophic factor, an essential element in normal brain development that promotes health-associated behaviors and quality-of-life, though reduced in ADHD, is increased markedly by the intervention of regular physical exercise. Functional, regional, and biomarker deficits, as well as hypothalamic-pituitary-adrenal disruptions, have been improved through regular and carefully applied exercise programs. In view of the complications involving ADHD with co-morbidities, such as obesity, the influence of regular physical exercise has not been found negligible. Physical exercise bestows a propensity for eventual manifestation of "redifferentiated" developmental trajectories that may equip ADHD adults with a prognosis that is more adaptive functionally, independent of the applications of other therapeutic agents and treatments.
Reports empirical findings indicating that autistic children have a basic cognitive deficit that is not a secondary consequence of social withdrawal. The precise nature of the deficit is discussed, as are studies of autistic children's general intelligence, language abnormalities, and social impairments. (RH)
Zuo, Zejie; Qi, Fangfang; Yang, Junhua; Wang, Xiao; Wu, Yingying; Wen, Yaru; Yuan, Qunfang; Zou, Juntao; Guo, Kaihua; Yao, Zhi Bin
The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aβ1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aβ1-15 group, but did not reduce the β-amyloid (Aβ) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3(+) regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aβ1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aβ1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aβ1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.
Gadow, Kenneth D.
Research on the effects of stimulant drugs on attention and cognitive deficits in children with hyperactivity is reviewed. Topics covered include: attention and impulsivity, paired associate learning, school achievement, and drug induced attention and cognitive deficits. (CL)
Sacks-Zimmerman, Amanda; Liberta, Taylor
Cognitive deficits have been widely observed in patients with primary brain tumors consequent to diagnosis and treatment. Given the early onset and the relatively long survival rate of patients, it seems pertinent to study and refine the techniques used to treat these deficits. The purpose of this article is to discuss cognitive deficits that follow neurosurgical treatment for low-grade gliomas as well as to outline a neuropsychological intervention to treat these deficits, specifically working memory and attention. Cognitive remediation therapy is a neuropsychological intervention that aims to enhance attention, working memory, and executive functioning, thereby diminishing the impact of these deficits on daily functioning. Computerized cognitive remediation training programs facilitate access to treatment through providing online participation. The authors include preliminary results of three participants who have completed the computerized training program as part of an ongoing study that is investigating the efficacy of this program in patients who have undergone treatment for low-grade gliomas. The results so far suggest some improvement in working memory and attention from baseline scores. It is the hope of the present authors to highlight the importance of this treatment in the continuity of care of brain tumor survivors. PMID:26623205
Algarabel, Salvador; Fuentes, Manuel; Escudero, Joaquín; Pitarque, Alfonso; Peset, Vicente; Mazón, José-Francisco; Meléndez, Juan-Carlos
There is no agreement on the pattern of recognition memory deficits characteristic of patients diagnosed with mild cognitive impairment (MCI). Whereas lower performance in recollection is the hallmark of MCI, there is a strong controversy about possible deficits in familiarity estimates when using recognition memory tasks. The aim of this research is to shed light on the pattern of responding in recollection and familiarity in MCI. Five groups of participants were tested. The main participant samples were those formed by two MCI groups differing in age and an Alzheimer's disease group (AD), which were compared with two control groups. Whereas one of the control groups served to assess the performance of the MCI and AD people, the other one, composed of young healthy participants, served the purpose of evaluating the adequacy of the experimental tasks used in the evaluation of the different components of recognition memory. We used an associative recognition task as a direct index of recollection and a choice task on a pair of stimuli, one of which was perceptually similar to those studied in the associative recognition phase, as an index of familiarity. Our results indicate that recollection decreases with age and neurological status, and familiarity remains stable in the elderly control sample but it is deficient in MCI. This research shows that a unique encoding situation generated deficits in recollective and familiarity mechanisms in mild cognitive impaired individuals, providing evidence for the existence of deficits in both retrieval processes in recognition memory in a MCI stage.
Ravindran, O. S.; Rani, Mrudula P.; Priya, G.
Background and Objectives: Children infected with HIV are at risk for significant neurological and neuropsychological problems. This study is aimed at identifying cognitive deficits in HIV-infected children and to compare them with equal number of normal controls. Materials and Methods: Twenty children with HIV infection who are currently on antiretroviral therapy were recruited. They were assessed for their intelligence using Malin's Intelligence Scale for Indian Children and also evaluated for their cognitive abilities with a comprehensive neuropsychological battery. They were matched with equal number of normal controls. Results: HIV-infected children have shown substantial impairments in the domains of attention, language, verbal learning and memory, visuomotor functions, fine motor performance, and executive functions. Conclusion: HIV-infected children have average intelligence, but they performed poorly on several neuropsychological measures. PMID:25035547
Arnsten, Amy F T; Girgis, Ragy R; Gray, David L; Mailman, Richard B
Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D1 receptors (D1R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1 agonists, e.g., the first full D1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D1 agonists with better pharmacokinetics, functionally selective D1 ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice.
McGrath, Lauren M.; Pennington, Bruce F.; Shanahan, Michelle A.; Santerre-Lemmon, Laura E.; Barnard, Holly D.; Willcutt, Erik G.; DeFries, John C.; Olson, Richard K.
Background: This study tests a multiple cognitive deficit model of reading disability (RD), attention-deficit/hyperactivity disorder (ADHD), and their comorbidity. Methods: A structural equation model (SEM) of multiple cognitive risk factors and symptom outcome variables was constructed. The model included phonological awareness as a unique…
Xue, Wei-Zhen; Yang, Qian-Qian; Chen, Yiwen; Zou, Rong-Xin; Xing, Dong; Xu, Yi; Liu, Yong-Sheng
Lead (Pb) exposure, in particular during early postnatal life, increases susceptibility to cognitive dysfunction and neurodegenerative outcomes. The detrimental effect of Pb exposure is basically due to an increasing ROS production which overcomes the antioxidant systems and finally leads to cognitive dysfunction. Kiwifruit is rich in the antioxidants like vitamin C and polyphenols. This study aims to investigate the effects and mechanism of kiwifruit to alleviate learning and memory deficits induced by Pb exposure. Sprague-Dawley (SD) rat pups acquired Pb indirectly through their mothers during lactation period and after postnatal day 21 (PND21) directly acquired Pb by themselves. Five kinds of kiwifruits were collected in this study and the amounts of vitamin C and polyphenols in them were measured and the antioxidation effects were determined. Among them, Qinmei kiwifruit (Qm) showed the strongest antioxidation effects in vitro. In vivo, Qm significantly repaired Pb-induced learning and memory deficits and dendritic spine loss. In addition, Pb compromised the enzymatic activity and transcriptional levels of SOD and GSH-Px and decreased the microglial activation, which, to some extent, could be reversed by Qm kiwifruit administration. The results suggest that kiwifruit could alleviate Pb-induced cognitive deficits possibly through antioxidative stress and microglia inactivation. Consequently, kiwifruit could be potentially regarded as the functional food favorable in the prevention and treatment of Pb intoxication. PMID:28386309
Zeier, Joshua D; Baskin-Sommers, Arielle R; Hiatt Racer, Kristina D; Newman, Joseph P
Antisociality has been linked to a variety of executive functioning deficits, including poor cognitive control. Surprisingly, cognitive control deficits are rarely found in psychopathic individuals, despite their notoriously severe and persistent antisocial behavior. In fact, primary (low-anxious) psychopathic individuals display superior performance on cognitive control-type tasks under certain circumstances. To clarify these seemingly contradictory findings, we administered a response competition (i.e., flanker) task to incarcerated offenders, who were assessed for Antisocial Personality Disorder (APD) symptoms and psychopathy. As hypothesized, APD related to poorer accuracy, especially on incongruent trials. Contrary to expectation, however, the same pattern of results was found in psychopathy. Additional analyses indicated that these effects of APD and psychopathy were associated with overlapping variance. The findings suggest that psychopathy and APD symptoms are both associated with deficits in cognitive control, and that this deficit relates to general antisociality as opposed to a specific antisocial syndrome.
Englund, Julia A.; Decker, Scott L.; Allen, Ryan A.; Roberts, Alycia M.
Cognitive deficits in working memory (WM) are characteristic features of Attention-Deficit/Hyperactivity Disorder (ADHD) and autism. However, few studies have investigated cognitive deficits using a wide range of cognitive measures. We compared children with ADHD ("n" = 49) and autism ("n" = 33) with a demographically matched…
Loe, Irene M.; Feldman, Heidi M.; Yasui, Enami; Luna, Beatriz
The evaluation of the cognitive control in children with attention-deficit hyperactivity disorder through the use of oculomotor tests reveal that this group showed susceptibility to peripheral distractors and deficits in response inhibition. All subjects were found to have intact sensorimotor function and working memory.
Bose, Anushree; Agarwal, Sri Mahavir; Kalmady, Sunil V.; Venkatasubramanian, Ganesan
Hippocampal deficits are an established feature of schizophrenia and are complementary with recent evidences of marked allocentric processing deficits being reported in this disorder. By “Cognitive mapping” we intend to refer to the concepts from the seminal works of O’Keefe and Nadel (1978) that led to the development of cognitive map theory of hippocampal function. In this review, we summarize emerging evidences and issues that indicate that “Cognitive mapping deficits” form one of the important cognitive aberrations in schizophrenia. The importance has been placed upon hippocampally mediated allocentric processing deficits and their role in pathology of schizophrenia, for spatial/representational cognitive deficits and positive symptoms in particular. It is modestly summarized that emerging evidences point toward a web of spatial and cognitive representation errors concurrent with pronounced hippocampal dysfunction. In general, it can be stated that there are clear and consistent evidences that favor the cognitive mapping theory in explaining certain deficits of schizophrenia and for drawing out a possible and promising endophenotype/biomarkers. Further research in this regard demands attention. PMID:24701005
Lesh, Tyler A; Niendam, Tara A; Minzenberg, Michael J; Carter, Cameron S
Although schizophrenia is an illness that has been historically characterized by the presence of positive symptomatology, decades of research highlight the importance of cognitive deficits in this disorder. This review proposes that the theoretical model of cognitive control, which is based on contemporary cognitive neuroscience, provides a unifying theory for the cognitive and neural abnormalities underlying higher cognitive dysfunction in schizophrenia. To support this model, we outline converging evidence from multiple modalities (eg, structural and functional neuroimaging, pharmacological data, and animal models) and samples (eg, clinical high risk, genetic high risk, first episode, and chronic subjects) to emphasize how dysfunction in cognitive control mechanisms supported by the prefrontal cortex contribute to the pathophysiology of higher cognitive deficits in schizophrenia. Our model provides a theoretical link between cellular abnormalities (eg, reductions in dentritic spines, interneuronal dysfunction), functional disturbances in local circuit function (eg, gamma abnormalities), altered inter-regional cortical connectivity, a range of higher cognitive deficits, and symptom presentation (eg, disorganization) in the disorder. Finally, we discuss recent advances in the neuropharmacology of cognition and how they can inform a targeted approach to the development of effective therapies for this disabling aspect of schizophrenia. PMID:20844478
Cumming, Toby B; Marshall, Randolph S; Lazar, Ronald M
Cognitive impairment after stroke is common and can cause disability with major impacts on quality of life and independence. There are also indirect effects of cognitive impairment on functional recovery after stroke through reduced participation in rehabilitation and poor adherence to treatment guidelines. In this article, we attempt to establish the following: ● whether there is a distinct profile of cognitive impairment after stroke; ● whether the type of cognitive deficit can be associated with the features of stroke-related damage; and ● whether interventions can improve poststroke cognitive performance. There is not a consistent profile of cognitive deficits in stroke, though slowed information processing and executive dysfunction tend to predominate. Our understanding of structure-function relationships has been advanced using imaging techniques such as lesion mapping and will be further enhanced through better characterization of damage to functional networks and identification of subtle white matter abnormalities. Effective cognitive rehabilitation approaches have been reported for focal cortical deficits such as neglect and aphasia, but treatments for more diffusely represented cognitive impairment remain elusive. In the future, the hope is that different techniques that have been shown to promote neural plasticity (e.g., exercise, brain stimulation, and pharmacological agents) can be applied to improve the cognitive function of stroke survivors.
Keshavan, Matcheri S.; Kulkarni, Shreedhar; Bhojraj, Tejas; Francis, Alan; Diwadkar, Vaibhav; Montrose, Debra M.; Seidman, Larry J.; Sweeney, John
Neurocognitive deficits in schizophrenia (SZ) are thought to be stable trait markers that predate the illness and manifest in relatives of patients. Adolescence is the age of maximum vulnerability to the onset of SZ and may be an opportune “window” to observe neurocognitive impairments close to but prior to the onset of psychosis. We reviewed the extant studies assessing neurocognitive deficits in young relatives at high risk (HR) for SZ and their relation to brain structural alterations. We also provide some additional data pertaining to the relation of these deficits to psychopathology and brain structural alterations from the Pittsburgh Risk Evaluation Program (PREP). Cognitive deficits are noted in the HR population, which are more severe in first-degree relatives compared to second-degree relatives and primarily involve psychomotor speed, memory, attention, reasoning, and social-cognition. Reduced general intelligence is also noted, although its relationship to these specific domains is underexplored. Premorbid cognitive deficits may be related to brain structural and functional abnormalities, underlining the neurobiological basis of this illness. Cognitive impairments might predict later emergence of psychopathology in at-risk subjects and may be targets of early remediation and preventive strategies. Although evidence for neurocognitive deficits in young relatives abounds, further studies on their structural underpinnings and on their candidate status as endophenotypes are needed. PMID:20300465
Etkin, Amit; Gyurak, Anett; O'Hara, Ruth
Deficits in brain networks that support cognitive regulatory functions are prevalent in many psychiatric disorders. Findings across neuropsychology and neuroimaging point to broad-based impairments that cross traditional diagnostic boundaries. These dysfunctions are largely separate from the classical symptoms of the disorders, and manifest in regulatory problems in both traditional cognitive and emotional domains. As such, they relate to the capacity of patients to engage effectively in their daily lives and activity, often persist even in the face of symptomatically effective treatment, and are poorly targeted by current treatments. Advances in cognitive neuroscience now allow us to ground an understanding of these cognitive regulatory deficits in the function and interaction of key brain networks. This emerging neurobiological understanding furthermore points to several promising routes for novel neuroscience-informed treatments targeted more specifically at improving cognitive function in a range of psychiatric disorders.
Blake, Emily; Gannon, Theresa
This literature review examines the differences between sex offenders and nonoffenders with regard to social perception skills, cognitive distortions, and empathy skills in order to investigate sex offenders' cognition. The literature on cognitive distortions is discussed, with reference to the confusion surrounding its definition, and the debate between cognitive distortions as offense-supportive beliefs or justifications is examined. In terms of social perception, particular reference is made to sex offenders' misinterpretations of women's social cues and the source of this deficit. The authors discuss possibilities for this deficit, including offense-supportive beliefs that are driven by underlying implicit theories or schemata held by offenders. The concept of empathy and its relation to both social perception skills and cognitive distortions is discussed, and the integration of these factors is represented in a new model.
Jennekens-Schinkel, A; Sanders, E A
Three female patients (ages 32, 37 and 27 years) developed progressive deficits of cognition in stages of multiple sclerosis in which physical disability ratings were low. Neuropsychological examination revealed severe cognitive impairments in the first two patients. Cognitive functioning was essentially intact in the third patient, although her work pace was significantly slowed. CT scanning of the brain showed cortical atrophy as well as white matter lesions in patients 1 and 2, and multiple lesions and oedema of predominantly white matter in patient 3. The differences of cognitive dysfunction between the third and the first two patients may be related to involvement of different anatomical structures. Images PMID:3806111
Ramalingayya, Grandhi Venkata; Nampoothiri, Madhavan; Nayak, Pawan G.; Kishore, Anoop; Shenoy, Rekha R.; Mallikarjuna Rao, Chamallamudi; Nandakumar, Krishnadas
Background: Cognitive decline or dementia is a debilitating problem of neurological disorders such as Alzheimer's and Parkinson's disease, including special conditions like chemobrain. Dietary flavonoids proved to be efficacious in delaying the incidence of neurodegenerative diseases. Two such flavonoids, naringin (NAR) and rutin (RUT) were reported to have neuroprotective potential with beneficial effects on spatial and emotional memories in particular. However, the efficacy of these flavonoids is poorly understood on episodic memory, which comprises an important form of autobiographical memory. Objective: This study objective is to evaluate NAR and RUT to reverse time-delay-induced long-term and scopolamine-induced short-term episodic memory deficits in Wistar rats. Materials and Methods: We have evaluated both short-term and long-term episodic memory forms using novel object recognition task. Open field paradigm was used to assess locomotor activity for any confounding influence on memory assessment. Donepezil was used as positive control and was effective in both models at 1 mg/kg, i.p. Results: Animals treated with NAR and RUT at 50 and 100 mg/kg, p.o. spent significantly more time exploring novel object compared to familiar one, whereas control animals spent almost equal time with both objects in choice trial. NAR and RUT dose-dependently increased recognition and discriminative indices in time-induced long-term as well as scopolamine-induced short-term episodic memory deficit models without interfering with the locomotor activity. Conclusion: We conclude that, NAR and RUT averted both short- and long-term episodic memory deficits in Wistar rats, which may be potential interventions for neurodegenerative diseases as well as chemobrain condition. SUMMARY Incidence of Alzheimer's disease is increasing globally and the current therapy is only symptomatic. Curative treatment is a major lacuna. NAR and RUT are natural flavonoids proven for their pleiotropic
Silva, Katiane L.; Guimaraes-da-Silva, Paula O.; Grevet, Eugenio H.; Victor, Marcelo M.; Salgado, Carlos A. I.; Vitola, Eduardo S.; Mota, Nina R.; Fischer, Aline G.; Contini, Veronica; Picon, Felipe A.; Karam, Rafael G.; Belmonte-de-Abreu, Paulo; Rohde, Luis A.; Bau, Claiton H. D.
Objective: This study addresses if deficits in cognitive, attention, and inhibitory control performance in adults with ADHD are better explained by the disorder itself or by comorbid conditions. Method Adult patients with ADHD ("n" = 352) and controls ("n" = 94) were evaluated in the ADHD program of a tertiary hospital. The…
Jackson, Daren C.; Sandoval-Garcia, Carolina; Rocque, Brandon G.; Wilbrand, Stephanie M.; Mitchell, Carol C.; Hermann, Bruce P.; Dempsey, Robert J.
The role played by vessel disease in stroke-related cognition dysfunction is unclear. We assessed the impact of significant atherosclerotic disease on cognition—even in patients asymptomatic for stroke. We hypothesized that patients would perform poorly relative to controls, but that symptomatic/asymptomatic status (history of stroke/transient ischemic attack) would have no effect. Fifty-two carotid endarterectomy candidates with >60% carotid stenosis and 17 controls underwent a 60-min neuropsychological test protocol. Symptomatic and asymptomatic patients showed deficits in executive function, delayed verbal recall, and general knowledge. Patients symptomatic for stroke also performed worse on tests of language and motor/visuomotor ability. Symptomatic and asymptomatic patients differed in working memory and language task performance. Although all patients showed deficits in executive function and memory, only symptomatic patients showed additional deficits in language and motor function. Cognitive abnormalities in patients viewed as “asymptomatic” for stroke underscore the need for early identification and treatment. PMID:26663810
with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1...Approved for public release; distribution unlimited In rats, dietary supplementation with the amino acid tyrosine (TYR) prevented depletion of central...that cold exposure degrades cognitive performance and supplementation with TYR alleviates working memory decrements, even with a reduced core
Capogrosso, Marco; Milekovic, Tomislav; Borton, David; Wagner, Fabien; Moraud, Eduardo Martin; Mignardot, Jean-Baptiste; Buse, Nicolas; Gandar, Jerome; Barraud, Quentin; Xing, David; Rey, Elodie; Duis, Simone; Jianzhong, Yang; Ko, Wai Kin D; Li, Qin; Detemple, Peter; Denison, Tim; Micera, Silvestro; Bezard, Erwan; Bloch, Jocelyne; Courtine, Grégoire
Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for
Popp, Pauline; Wulff, Melanie; Finke, Kathrin; Rühl, Maxine; Brandt, Thomas; Dieterich, Marianne
Behavioral studies in rodents and humans have demonstrated deficits of spatial memory and orientation in bilateral vestibular failure (BVF). Our aim was to explore the functional consequences of chronic vestibular failure on different cognitive domains including spatial as well as non-spatial cognitive abilities. Sixteen patients with a unilateral vestibular failure (UVF), 18 patients with a BVF, and 17 healthy controls (HC) participated in the study. To assess the cognitive domains of short-term memory, executive function, processing speed and visuospatial abilities the following tests were used: Theory of Visual Attention (TVA), TAP Alertness and Visual Scanning, the Stroop Color-Word, and the Corsi Block Tapping Test. The cognitive scores were correlated with the degree of vestibular dysfunction and the duration of the disease, respectively. Groups did not differ significantly in age, sex, or handedness. BVF patients were significantly impaired in all of the examined cognitive domains but not in all tests of the particular domain, whereas UVF patients exhibited significant impairments in their visuospatial abilities and in one of the two processing speed tasks when compared independently with HC. The degree of vestibular dysfunction significantly correlated with some of the cognitive scores. Neither the side of the lesion nor the duration of disease influenced cognitive performance. The results demonstrate that vestibular failure can lead to cognitive impairments beyond the spatial navigation deficits described earlier. These cognitive impairments are more significant in BVF patients, suggesting that the input from one labyrinth which is distributed into bilateral vestibular circuits is sufficient to maintain most of the cognitive functions. These results raise the question whether BVF patients may profit from specific cognitive training in addition to physiotherapy.
Trauner, Doris A.; Spilkin, Amy M.; Williams, Jennifer; Babchuck, Lynne
Objectives Infantile nephropathic cystinosis is associated with a specific cognitive deficit in visual spatial processing in older children and adults. The cause of this deficit is unknown. This study was designed to determine whether the cognitive deficit is present in young children with cystinosis, suggesting an early effect of the genetic disorder on brain development. Study design Young children (n=25; ages 3− 8 years) with cystinosis, and 25 matched controls, underwent cognitive testing including tests of intelligence, visual perceptual, visual spatial, and visual motor functions. Results Children with cystinosis performed significantly more poorly on tests of visual spatial and visual motor function than did controls. Visual perceptual abilities were equivalent in the two groups. Conclusion The fact that the same pattern of visual spatial deficit is present in very young children with cystinosis as has previously been demonstrated in older children and adults suggests that there may be an influence of the cystinosis gene on brain development, rather than an adverse effect of prolonged cystine accumulation in the brain during childhood. PMID:17643777
King, M K; Jope, R S
Fragile X syndrome (FXS) is caused by suppressed expression of fragile X mental retardation protein (FMRP), which results in intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity, seizures and autistic-like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with lithium has been reported to ameliorate locomotor hyperactivity, prevent hypersensitivity to audiogenic seizures, improve passive avoidance behavior and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is cognitive impairment, we tested if lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to lithium differed in adolescent and adult mice and tested if therapeutic effects persisted after discontinuation of lithium administration. Fmr1 KO mice displayed impaired cognition in the novel object detection task, temporal ordering for objects task and coordinate and categorical spatial processing tasks. Chronic lithium treatment of adolescent (from 4 to 8 weeks of age) and adult (from 8 to 12 weeks of age) mice abolished cognitive impairments in all four cognitive tasks. Cognitive deficits returned after lithium treatment was discontinued for 4 weeks. These results show that Fmr1 KO mice exhibit severe impairments in these cognitive tasks, that lithium is equally effective in normalizing cognition in these tasks whether it is administered to young or adult mice and that lithium administration must be continued for the cognitive improvements to be sustained. These findings provide further evidence that lithium administration may be beneficial for individuals with FXS.
Gottwald, B; Wilde, B; Mihajlovic, Z; Mehdorn, H
Objectives: Anatomical evidence and lesion studies, as well as functional magnetic resonance imaging (fMRI) studies, indicate that the cerebellum contributes to higher cognitive functions. Cerebellar posterior lateral regions seem to be relevant for cognition, while vermal lesions seem to be associated with changes in affect. However, the results remain controversial. Deficits of patients are sometimes still attributed to motor impairment. Methods: We present data from a detailed neuropsychological examination of 21 patients with cerebellar lesions due to tumour or haematoma, and 21 controls matched for age, sex, and years of education. Results: Patients showed deficits in executive function, and in attentional processes such as working memory and divided attention. Further analysis revealed that patients with right-sided lesions were in general more impaired than those with left-sided lesions. Conclusions: Those hypotheses that suggest that lesions of the right cerebellar hemisphere lead to verbal deficits, while those of the left lead to non-verbal deficits, have in part been confirmed. The generally greater impairment of those patients with a right-sided lesion has been interpreted as resulting from the connection of the right cerebellum to the left cerebral hemisphere, which is dominant for language functions and crucial for right hand movements. Motor impairment was correlated with less than half of the cognitive measures, with no stronger tendency for correlation with cognitive tests that require motor responses discernible. The results are discussed on the basis of an assumption that the cerebellum has a predicting and preparing function, indicating that cerebellar lesions lead to a "dysmetria of thought." PMID:15489381
Boukrina, Olga; Barrett, A. M.; Alexander, Edward J.; Yao, Bing; Graves, William W.
According to cognitive models of reading, words are processed by interacting orthographic (spelling), phonological (sound), and semantic (meaning) information. Despite extensive study of the neural basis of reading in healthy participants, little group data exist on patients with reading deficits from focal brain damage pointing to critical neural systems for reading. Here, we report on one such study. We have performed neuropsychological testing and magnetic resonance imaging on 11 patients with left-hemisphere stroke (<=5 weeks post-stroke). Patients completed tasks assessing cognitive components of reading such as semantics (matching picture or word choices to a target based on meaning), phonology (matching word choices to a target based on rhyming), and orthography (a two-alternative forced choice of the most plausible non-word). They also read aloud pseudowords and words with high or low levels of usage frequency, imageability, and spelling-sound consistency. As predicted by the cognitive model, when averaged across patients, the influence of semantics was most salient for low-frequency, low-consistency words, when phonological decoding is especially difficult. Qualitative subtraction analyses revealed lesion sites specific to phonological processing. These areas were consistent with those shown previously to activate for phonology in healthy participants, including supramarginal, posterior superior temporal, middle temporal, inferior frontal gyri, and underlying white matter. Notable divergence between this analysis and previous functional imaging is the association of lesions in the mid-fusiform gyrus and anterior temporal lobe with phonological reading deficits. This study represents progress toward identifying brain lesion-deficit relationships in the cognitive components of reading. Such correspondences are expected to help not only better understand the neural mechanisms of reading, but may also help tailor reading therapy to individual neurocognitive
Boukrina, Olga; Barrett, A M; Alexander, Edward J; Yao, Bing; Graves, William W
According to cognitive models of reading, words are processed by interacting orthographic (spelling), phonological (sound), and semantic (meaning) information. Despite extensive study of the neural basis of reading in healthy participants, little group data exist on patients with reading deficits from focal brain damage pointing to critical neural systems for reading. Here, we report on one such study. We have performed neuropsychological testing and magnetic resonance imaging on 11 patients with left-hemisphere stroke (<=5 weeks post-stroke). Patients completed tasks assessing cognitive components of reading such as semantics (matching picture or word choices to a target based on meaning), phonology (matching word choices to a target based on rhyming), and orthography (a two-alternative forced choice of the most plausible non-word). They also read aloud pseudowords and words with high or low levels of usage frequency, imageability, and spelling-sound consistency. As predicted by the cognitive model, when averaged across patients, the influence of semantics was most salient for low-frequency, low-consistency words, when phonological decoding is especially difficult. Qualitative subtraction analyses revealed lesion sites specific to phonological processing. These areas were consistent with those shown previously to activate for phonology in healthy participants, including supramarginal, posterior superior temporal, middle temporal, inferior frontal gyri, and underlying white matter. Notable divergence between this analysis and previous functional imaging is the association of lesions in the mid-fusiform gyrus and anterior temporal lobe with phonological reading deficits. This study represents progress toward identifying brain lesion-deficit relationships in the cognitive components of reading. Such correspondences are expected to help not only better understand the neural mechanisms of reading, but may also help tailor reading therapy to individual neurocognitive
Xie, Tao; Wang, Wei-ping; Jia, Li-jing; Mao, Zhuo-feng; Qu, Zhen-zhen; Luan, Shao-qun; Kan, Min-chen
Maternal seizure has adverse effects on brain histology as well as on learning and memory ability in progeny. An enriched environment (EE) is known to promote structural changes in the brain and improve cognitive and motor deficits following a variety of brain injuries. Whether EE treatment in early postnatal periods could restore cognitive impairment induced by prenatal maternal seizure is unknown. Adult female Sprague-Dawley rats were randomly separated into two groups and were injected intraperitoneally either saline or pentylenetetrazol (PTZ) for 30 days. Then the fully kindled rats and control animals were allowed to mate. PTZ administration was continued until delivery, while the control group received saline at the same time. After weaning at postnatal day 22, one-half of the male offspring in the control and in the prenatal maternal group were given the environmental enrichment treatment through all the experiments until they were tested. Morris water maze testing was performed at 8 weeks of age. Western blot and synaptic ultrastructure analysis were then performed. We found that EE treatment reversed spatial learning deficits induced by prenatal maternal seizure. An EE also reversed the changes in synaptic ultrastructure following prenatal maternal seizure. In addition, prenatal maternal seizure significantly decreased phosphorylation states of cAMP response element binding (CREB) in the hippocampus, whereas EE reversed this reduced expression. These findings suggest that EE treatment on early postnatal periods could be a potential therapy for improving cognitive deficits induced by prenatal maternal seizure.
Woo, Young Sup; Rosenblat, Joshua D.; Kakar, Ron; Bahk, Won-Myong; McIntyre, Roger S.
Cognitive deficits in major depressive disorder (MDD) patients have been described in numerous studies. However, few reports have aimed to describe cognitive deficits in the remitted state of MDD and the mediational effect of cognitive deficits on occupational outcome. The aim of the current review is to synthesize the literature on the mediating and moderating effects of specific domains of cognition on occupational impairment among people with remitted MDD. In addition, predictors of cognitive deficits found to be vocationally important will be examined. Upon examination of the extant literature, attention, executive function and verbal memory are areas of consistent impairment in remitted MDD patients. Cognitive domains shown to have considerable impact on vocational functioning include deficits in memory, attention, learning and executive function. Factors that adversely affect cognitive function related to occupational accommodation include higher age, late age at onset, residual depressive symptoms, history of melancholic/psychotic depression, and physical/psychiatric comorbidity, whereas higher levels of education showed a protective effect against cognitive deficit. Cognitive deficits are a principal mediator of occupational impairment in remitted MDD patients. Therapeutic interventions specifically targeting cognitive deficits in MDD are needed, even in the remitted state, to improve functional recovery, especially in patients who have a higher risk of cognitive deficit. PMID:26792035
Webster, W G
Previous research has indicated that men who stutter transcribe rapidly presented sequences of letters more slowly and less accurately than nonstutterer controls. Experiment 1 demonstrated that the transcription deficit is not limited to task conditions that demand concurrent monitoring and responding. This was evidenced by comparable deficits on a successive response condition that required subjects to write letters after the presentation was complete. The results of Experiment 2 indicated that the deficit is not due to a difficulty by stutterers in parsing streams of stimulus information internally. Their performance did not differentially improve when letters were grouped with brief pauses, nor with experience in transcribing preparsed letter sequences. This experiment also demonstrated that the phenomenon is generalizable to women. In related testing, stutterers were slower than controls in writing internally generated sequences of letters, those of the alphabet forwards and backwards, but not in writing the same two letters, A and B, repetitively nor in the cognitively more demanding task of writing numbers backwards by three's. These results parallel those obtained with finger tapping of same versus unique sequences by stutterers and were interpreted as being consistent with the idea that while stutterers are not generally slower motorically than nonstutterers, they experience difficulty when required to organize and carry out tasks with new multiple response transitions. The two experiments have replicated and extended, under different conditions, the earlier findings of a letter sequence transcription deficit in stutterers, but the nature of the interference still remains to be clarified.
Vaidya, Chandan J.; Stollstorff, Melanie
Cognitive neuroscience studies of Attention Deficit Hyperactivity Disorder (ADHD) suggest multiple loci of pathology with respect to both cognitive domains and neural circuitry. Cognitive deficits extend beyond executive functioning to include spatial, temporal, and lower-level "nonexecutive" functions. Atypical functional anatomy extends beyond…
Morimoto, Sarah Shizuko; Alexopoulos, George S.
Synopsis The purpose of this article is to identify the cognitive deficits commonly associated with geriatric depression, and describe their clinical significance. We then summarize the complex relationship between geriatric depression and dementia and discuss possible shared mechanisms. Last, we present evidence regarding whether the cognitive deficits in depression may be mitigated with medication or with computerized cognitive remediation. PMID:24229654
O'Reilly, Kally C; Kao, Hsin-Yi; Lee, Heekyung; Fenton, André A
Despite substantial effort and immense need, the treatment options for major neuropsychiatric illnesses like schizophrenia are limited and largely ineffective at improving the most debilitating cognitive symptoms that are central to mental illness. These symptoms include cognitive control deficits, the inability to selectively use information that is currently relevant and ignore what is currently irrelevant. Contemporary attempts to accelerate progress are in part founded on an effort to reconceptualize neuropsychiatric illness as a disorder of neural development. This neuro-developmental framework emphasizes abnormal neural circuits on the one hand, and on the other, it suggests there are therapeutic opportunities to exploit the developmental processes of excitatory neuron pruning, inhibitory neuron proliferation, elaboration of myelination, and other circuit refinements that extend through adolescence and into early adulthood. We have crafted a preclinical research program aimed at cognition failures that may be relevant to mental illness. By working with a variety of neurodevelopmental rodent models, we strive to identify a common pathophysiology that underlies cognitive control failure as well as a common strategy for improving cognition in the face of neural circuit abnormalities. Here we review our work to characterize cognitive control deficits in rats with a neonatal ventral hippocampus lesion and rats that were exposed to Methylazoxymethanol acetate (MAM) in utero. We review our findings as they pertain to early developmental processes, including neurogenesis, as well as the power of cognitive experience to refine neural circuit function within the mature and maturing brain's cognitive circuitry.
Martinez-Coria, Hilda; Yeung, Stephen T; Ager, Rahasson R; Rodriguez-Ortiz, Carlos J; Baglietto-Vargas, David; LaFerla, Frank M
Alzheimer's disease is a neurodegenerative disease associated with progressive memory and cognitive decline. Previous studies have identified the benefits of cognitive enrichment on reducing disease pathology. Additionally, epidemiological and clinical data suggest that repeated exercise, and cognitive and social enrichment, can improve and/or delay the cognitive deficiencies associated with aging and neurodegenerative diseases. In the present study, 3xTg-AD mice were exposed to a rigorous training routine beginning at 3 months of age, which consisted of repeated training in the Morris water maze spatial recognition task every 3 months, ending at 18 months of age. At the conclusion of the final Morris water maze training session, animals subsequently underwent testing in another hippocampus-dependent spatial task, the Barnes maze task, and on the more cortical-dependent novel object recognition memory task. Our data show that periodic cognitive enrichment throughout aging, via multiple learning episodes in the Morris water maze task, can improve the memory performance of aged 3xTg-AD mice in a separate spatial recognition task, and in a preference memory task, when compared to naïve aged matched 3xTg-AD mice. Furthermore, we observed that the cognitive enrichment properties of Morris water maze exposer, was detectable in repeatedly trained animals as early as 6 months of age. These findings suggest early repeated cognitive enrichment can mitigate the diverse cognitive deficits observed in Alzheimer's disease.
McPhee, Grace M; Downey, Luke A; Noble, Anthony; Stough, Con
As the elderly population grows the impact of age associated cognitive decline as well as neurodegenerative diseases such as Alzheimer's disease and dementia will increase. Ageing is associated with consistent impairments in cognitive processes (e.g., processing speed, memory, executive function and learning) important for work, well-being, life satisfaction and overall participation in society. Recently, there has been increased effort to conduct research examining methods to improve cognitive function in older citizens. Cognitive training has been shown to improve performance in some cognitive domains; including memory, processing speed, executive function and attention in older adults. These cognitive changes are thought to be related to improvements in brain connectivity and neural circuitry. Bacopa monnieri has also been shown to improve specific domains of cognition, sensitive to age associated cognitive decline (particularly processing speed and memory). These Bacopa monnieri dependent improvements may be due to the increase in specific neuro-molecular mechanisms implicated in the enhancement of neural connections in the brain (i.e. synaptogenesis). In particular, a number of animal studies have shown Bacopa monnieri consumption upregulates calcium dependent kinases in the synapse and post-synaptic cell, crucial for strengthening and growing connections between neurons. These effects have been shown to occur in areas important for cognitive processes, such as the hippocampus. As Bacopa monnieri has shown neuro-molecular mechanisms that encourage synaptogenesis, while cognitive training enhances brain connectivity, Bacopa monnieri supplementation could theoretically enhance and strengthen synaptic changes acquired through cognitive training. Therefore, the current paper hypothesises that the combination of these two interventions could improve cognitive outcomes, over and above the effects of administrating these interventions independently, as an effective
Zhu, Lingpeng; Chen, Tong; Chang, Xiayun; Zhou, Rui; Luo, Fen; Liu, Jingyan; Zhang, Kai; Wang, Yue; Yang, Ying; Long, Hongyan; Liu, Yu; Yan, Tianhua; Ma, Chunhua
The prevalence of cognitive impairment in rheumatoid arthritis (RA) patients was increasingly serious nowadays. The purpose of the current study was to explore whether salidroside (Sal) could alleviate arthritis-induced cognition deficits and examine the relationship between the impairment and Rho/ROCK/NF-κB pathway. Collagen-induced arthritis (CIA) was established by the injection of chicken type II collagen (CII), complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA). Arthritic lesions of CIA rats were assessed by arthritis index score, swelling of paws and histological analysis. Cognitive deficits symptoms of CIA rats were monitored through Morris water maze test. The contents of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) in hippocampus and serum were significantly reduced with salidroside (20 mg/kg, 40 mg/kg) treatment compared with those in the CIA group. In parallel, we demonstrated that the expressions of RhoA, ROCK1, ROCK2, p-NF-κBp65, p-IκBα, p-IKKα and p-IKKβ were enhanced accompanying the investigation arthritis-induced cognition deficits, which were remarkably down-regulated by salidroside and confirmed by the results obtained from western blot and immunohistochemistry. LC-MS/MS results ascertained that Sal could enter into the blood and brain tissues to exhibit the protective effect on arthritis-induced cognitive dysfunction. Therefore, it was assumed that Sal might be a potential therapeutic candidate to treat arthritis-induced brain cognition deficits through the regulation of Rho/ROCK/NF-κB signaling.
Ho, Connie Suk-Han; Chan, David Wai-Ock; Leung, Patrick W. L.; Lee, Suk-Han; Tsang, Suk-Man
Most past research findings suggest that phonological deficit is unique to developmental dyslexia insofar as alphabetic languages are concerned. The present study investigated the existence of any similar unique reading-related cognitive deficits associated with developmental dyslexia in a nonalphabetic script, Chinese. The pattern of comorbidity…
Huang, Lihong; Li, Gang; Feng, Xiaofang; Wang, Luojun
To investigate the effect of PPARγ agonist 15d-PGJ2 treatment on the microglia activation and neurological deficit of ischemia reperfusion in diabetic rat model, adult Sprague-Dawley rats were sacrificed for the research. The rats were randomly categorized into four groups: (1) sham-operated group; (2) standard ischemia group; (3) diabetic ischemia group; (4) diabetic ischemia group with diabetes and treated with 15d-PGJ2. Compared to the sham-operated group, all the ischemic groups have significantly severer neurological deficits, more TNF-α and IL-1 expression, increased labeling of apoptotic cells, increased CD68 positive staining of brain lesion, and increased volume of infarct and cerebral edema in both 24 hours and 7 days after reperfusion. Interestingly, reduced neurological deficits, decreased TNF-α and IL-1 expression, less apoptotic cells and CD68 positive staining, and alleviated infarct and cerebral edema volume were observed when 15d-PGJ2 was intraperitoneally injected after reperfusion in diabetic ischemia group, suggesting its neuroprotective role in regulating microglia activation, which may have a therapeutic application in the future. PMID:26844229
Roseman, Alexander S; McGregor, Claire; Thornton, Janice E
Clinical studies have suggested that estrogens may affect the symptoms of schizophrenia. The novel object recognition task (NORT) in female rats treated with sub-chronic phencyclidine (PCP) was used as an animal model of the cognitive deficits in schizophrenia. The current studies investigated whether chronic estradiol (E) could alleviate sub-chronic PCP-induced cognitive deficits in the NORT. Adult Sprague-Dawley rats were ovariectomized (ovx) and treated with either sub-chronic PCP (2 mg/kg bidaily i.p. for seven days), or with 0.9% saline and their object recognition memory was tested with the NORT using an acquisition trial, 1 min inter-trial interval, and retention trial. Sub-chronic PCP administration did not reliably affect behavior in the acquisition trial but significantly impaired object recognition in the retention trial for 1-2 and 27-29 weeks. Ovx females spent significantly (p<0.05) more time exploring the novel compared to the familiar object, whereas PCP-treated ovx females did not. This effect of PCP was attenuated by long-lasting E capsules implanted prior to PCP treatment. PCP-treated females implanted with E again spent significantly more time exploring the novel compared to the familiar object (p<0.01). When ovx rats were treated with sub-chronic PCP and a long-lasting E capsule was implanted either before or after PCP treatment, estradiol alleviated the PCP-induced deficits when administered in either regimen (p=0.01 and p=0.047 respectively). These data suggest that further exploration of estradiol as a possible therapeutic compound to treat the cognitive deficits of schizophrenia is warranted.
We evaluated the interaction effects of a kaolin-based particle film and water deficit on leaf and berry surface temperature, light reflectance, gas exchange characteristics, berry composition and yield of Malbec vines under field conditions over three growing seasons to test the hypothesis that the...
Frank, Jennifer Sandson; Vance, David E; Triebel, Kristen L; Meneses, Karen M
Adjuvant treatments, specifically chemotherapy and hormonal therapy, have dramatically increased breast cancer survival, resulting in increased attention to the residual effects of treatment. Breast cancer survivors (BCS) frequently report that cognitive deficits are a particular source of distress, interfering with many aspects of quality of life. The literature on neuropsychological performance measures in BCS supports the reality of subtle cognitive deficits after both chemotherapy and hormonal therapy. This premise is supported by recent imaging studies, which reveal anatomical changes after chemotherapy as well as changes in patterns of neural activation while performing cognitive tasks. This review suggests that, even when performance on neuropsychological performance measures is within normal limits, BCS may be using increased cognitive resources in the face of reduced cognitive reserve. Potential interventions for cognitive deficits after adjuvant therapy include prescriptions for healthy living, pharmacotherapy, complementary therapy, and cognitive remediation therapy directed toward specific cognitive deficits or a combination of several strategies.
Szczodry, Olga; van der Staay, Franz Josef; Arndt, Saskia S
To enable the development of effective treatments for dementias such as Alzheimer's disease (AD), it is important to establish valid animal models of cognitive impairments. Scopolamine is widely used to induce cognitive deficits in animal models of AD, but also causes non-cognitive side effects. We assessed whether biperiden, a selective antagonist of M1 muscarinic receptors, which are predominantly expressed in brain areas involved in cognitive processes, causes cognitive deficits without inducing peripheral side-effects. Two different doses of biperiden (3 or 10mgkg(-1)) on the acquisition of a spatial cone field task were assessed in male Lister Hooded rats. This task measures, among others, spatial working (WM) - and reference memory (RM) simultaneously. Biperiden did not impair learning of the task. The animals reached asymptotic levels for all variables except reference memory and the number of rewards collected. However, the 10mgkg(-1) dose decreased the tendency of rats to use searching strategies to solve the task and made them slower to start searching and completing the task. In conclusion, though no effects on WM and RM performance were seen, the present study cannot conclude that biperiden acts as a more selective cognition impairer than scopolamine in other rats strains and/or other doses than those tested.
Jangra, Ashok; Kwatra, Mohit; Singh, Tavleen; Pant, Rajat; Kushwah, Pawan; Ahmed, Sahabuddin; Dwivedi, Durgesh; Saroha, Babita; Lahkar, Mangala
Cisplatin is a chemotherapeutic agent used in the treatment of malignant tumors. A major clinical limitation of cisplatin is its potential toxic effects, including neurotoxicity. Edaravone, a potent free radical scavenger, has been reported to have the neuroprotective effect against neurological deficits. The aim of the present study was to determine the neuroprotective effect of edaravone against cisplatin-induced behavioral and biochemical anomalies in male Wistar rats. Our results showed that cisplatin (5mg/kg/week, i.p.) administration for seven weeks caused marked cognitive deficits and motor incoordination in rats. This was accompanied by oxido-nitrosative stress, neuroinflammation, NF-κB activation and down-regulation of Nrf2/HO-1 gene expression level in the hippocampus. Edaravone (10mg/kg/week, i.p.) treatment for seven weeks inhibited the aforementioned neurobehavioral and neurochemical deficits. Furthermore, edaravone was found to up-regulate the gene expression level of Nrf2/HO-1 and prevented the cisplatin-induced NF-κB activation. These findings demonstrated that oxido-nitrosative stress and inflammatory signaling mediators play a key role in the development of cisplatin-induced neurobehavioral deficits which were prevented by edaravone treatment.
Chan, Won Shing Raymond; Hung, Se Fong; Liu, Suet Nga; Lee, Cheuk Kiu Kathy
The cognitive profiles of children with Developmental Reading Disorder (RD) and Attention-Deficit/Hyperactivity Disorders (ADHD) have been extensively studied in alphabetic language communities. Deficits in phonological processing and rapid naming have been implicated as core features of RD although whether the latter is a deficit specific to RD…
He, Xiao-Li; Wang, Yue-Hua; Bi, Ming-Gang; Du, Guan-Hua
Chronic cerebral hypoperfusion, induced by permanent occlusion of bilateral common carotid arteries (2VO), is related to neurological disorders and contributes to cognitive decline. Chrysin (5,7-dihydroxyflavone) is an important member of the flavonoid family. The aim of this study is to investigate the effects of chrysin on cognitive deficits and brain damage in this rat 2VO model. At 52days after ligation, the escape latency in Morris water maze was significantly increased in rats subjected to 2VO, the neuronal damage was also increased accompanied by a large proliferation in glial fibrillary acidic protein (GFAP) immunoreactivity with marked white matter lesions, and neuronal cell apoptosis, all of which were significantly alleviated by long treatment of chrysin (30mg/kg). Biochemical examinations revealed that chrysin decreased lipid peroxide, reduced the increased activities of superoxide dismutase, and attenuated the decreased activities of glutathione peroxidase in 2VO rats. The results suggest that chrysin may have therapeutic potential for the treatment of neurodegeneration and dementia caused by decreased cerebral blood flow, which is most likely related, at least in part, to its anti-inflammatory and antioxidant properties.
Murray, Laura L.
Purpose: This study was designed to further elucidate the relationship between cognition and aphasia, with a focus on attention. It was hypothesized that individuals with aphasia would display variable deficit patterns on tests of attention and other cognitive functions and that their attention deficits, particularly those of complex attention…
de Zeeuw, Patrick; Weusten, Juliette; van Dijk, Sarai; van Belle, Janna; Durston, Sarah
Recent neurobiological models of ADHD suggest that deficits in different neurobiological pathways may independently lead to symptoms of this disorder. At least three independent pathways may be involved: a dorsal frontostriatal pathway involved in cognitive control, a ventral frontostriatal pathway involved in reward processing and a frontocerebellar pathway related to temporal processing. Importantly, we and others have suggested that disruptions in these three pathways should lead to separable deficits at the cognitive level. Furthermore, if these truly represent separate biological pathways to ADHD, these cognitive deficits should segregate between individuals with ADHD. The present study tests these hypotheses in a sample of children, adolescents and young adults with ADHD and controls. 149 Subjects participated in a short computerized battery assessing cognitive control, timing and reward sensitivity. We used Principal Component Analysis to find independent components underlying the variance in the data. The segregation of deficits between individuals was tested using Loglinear Analysis. We found four components, three of which were predicted by the model: Cognitive control, reward sensitivity and timing. Furthermore, 80% of subjects with ADHD that had a deficit were deficient on only one component. Loglinear Analysis statistically confirmed the independent segregation of deficits between individuals. We therefore conclude that cognitive control, timing and reward sensitivity were separable at a cognitive level and that deficits on these components segregated between individuals with ADHD. These results support a neurobiological framework of separate biological pathways to ADHD with separable cognitive deficits.
Rivera-Flores, Gladys Wilma
Introduction: Children with attention deficit with hyperactivity disorder (ADHD) have an impulsive, rigid and field-dependent cognitive style. This study examines whether self-instructional cognitive training reduces impulsive cognitive style in children diagnosed with this disorder. Method: The subjects were 10 children between the ages of 6 and…
Zhang, Yang; Gu, Fenghua; Chen, Jia; Dong, Wenxin
Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, regulates the expression of brain-derived neurotrophic factor (BDNF) in the brain, and mediates mood. Antidepressants alleviate stress and up-regulate BDNF gene expression. In this study, we investigated the effect of chronic unpredictable mild stress (CUMS) and the different kinds of antidepressant treatments on the HPA axis and the BDNF expression in the rat brain. Adult Wistar male rats were exposed to a six-week CUMS procedure and received different antidepressant treatments including venlafaxine, mirtazapine, and fluoxetine. Immunohistochemistry and real-time PCR were used to measure BDNF expression levels in the rat brain, and ELISAs were used to investigate the plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels. CUMS significantly decreased the BDNF protein level in the DG, CA1, and CA3 of the hippocampus and increased plasma CORT level. Chronic antidepressant treatments all significantly increased BDNF protein levels in the hippocampus and the pre-frontal cortex. In addition, venlafaxine and mirtazapine inhibited the increase of plasma CORT level. These results suggested that an increase in the BDNF level in the brain could be a pivotal mechanism of various antidepressants to exert their therapeutic effects.
Ethridge, Lauren E; Soilleux, Melanie; Nakonezny, Paul A; Reilly, James L; Hill, S Kristian; Keefe, Richard S E; Gershon, Elliot S; Pearlson, Godfrey D; Tamminga, Carol A; Keshavan, Matcheri S; Sweeney, John A
Difficulty inhibiting context-inappropriate behavior is a common deficit in psychotic disorders. The diagnostic specificity of this impairment, its familiality, and its degree of independence from the generalized cognitive deficit associated with psychotic disorders remain to be clarified. Schizophrenia, schizoaffective and bipolar patients with history of psychosis (n=523), their available first-degree biological relatives (n=656), and healthy participants (n=223) from the multi-site B-SNIP study completed a manual Stop Signal task. A nonlinear mixed model was used to fit logistic curves to success rates on Stop trials as a function of parametrically varied Stop Signal Delay. While schizophrenia patients had greater generalized cognitive deficit than bipolar patients, their deficits were similar on the Stop Signal task. Further, only bipolar patients showed impaired inhibitory control relative to healthy individuals after controlling for generalized cognitive deficit. Deficits accounted for by the generalized deficit were seen in relatives of schizophrenia and schizoaffective patients, but not in relatives of bipolar patients. In clinically stable patients with psychotic bipolar disorder, impaired inhibitory behavioral control was a specific cognitive impairment, distinct from the generalized neuropsychological impairment associated with psychotic disorders. Thus, in bipolar disorder with psychosis, a deficit in inhibitory control may contribute to risk for impulsive behavior. Because the deficit was not familial in bipolar families and showed a lack of independence from the generalized cognitive deficit in schizophrenia spectrum disorders, it appears to be a trait related to illness processes rather than one tracking familial risk factors.
Shbat, Modar Safir; Tuzlukov, Vyacheslav
The most commonly used spectrum sensing techniques in cognitive radio (CR) networks, such as the energy detector (ED), matched filter (MF), and others, suffer from the noise uncertainty and signal-to-noise ratio (SNR) wall phenomenon. These detectors cannot achieve the required signal detection performance regardless of the sensing time. In this paper, we explore a signal processing scheme, namely, the generalized detector (GD) constructed based on the generalized approach to signal processing (GASP) in noise, in spectrum sensing of CR network based on antenna array with the purpose to alleviate the SNR wall problem and improve the signal detection robustness under the low SNR. The simulation results confirm our theoretical issues and effectiveness of GD implementation in CR networks based on antenna array. PMID:26151216
Watson, Arden K.
Communication apprehension (CA) affects from 15% to 20% of the college population, indicating inherent problems of negative cognitive appraisal, conditioned anxiety, or skills deficits. Use of an individualized approach to the alleviation of CA has been shown to increase students' class interaction and to improve their verbal skills. During an…
Mansbach, William E; Mace, Ryan A; Clark, Kristen M
Background/Study Context: Whereas computer-assisted cognitive rehabilitation (CR) programs show promise as tools for improving cognition in certain populations, there is not a consensus regarding their efficacy. This study focuses on restorative CR, a treatment designed to improve cognitive functioning affected by progressive brain changes due to disease or aging, through computer-assisted cognitive exercises. The purpose of this study was to investigate the efficacy of a computer-assisted restorative CR intervention for improving cognitive functioning in older rehabilitation patients with relatively mild cognitive deficits.
Maier, Larissa J; Wunderli, Michael D; Vonmoos, Matthias; Römmelt, Andreas T; Baumgartner, Markus R; Seifritz, Erich; Schaub, Michael P; Quednow, Boris B
The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naïve controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits.
Maier, Larissa J.; Wunderli, Michael D.; Vonmoos, Matthias; Römmelt, Andreas T.; Baumgartner, Markus R.; Seifritz, Erich
The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naïve controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits. PMID:26107846
Hermens, Daniel F; Soei, Eleonore X C; Clarke, Simon D; Kohn, Michael R; Gordon, Evian; Williams, Leanne M
Quantitative electroencephalography has contributed significantly to elucidating the neurobiologic mechanisms of attention-deficit hyperactivity disorder. The most consistent and robust electroencephalographic disturbance in attention-deficit hyperactivity disorder has been abnormally increased theta band during resting conditions. Separate research using attention-demanding tests has elucidated cognitive disturbances that differentiate attention-deficit hyperactivity disorder. This study attempts to integrate electroencephalographic and neuropsychological indices to determine whether cognitive performance is specifically related to increased theta. Theta activity was recorded during a resting condition for 46 children/adolescents with attention-deficit hyperactivity disorder and their sex- and age-matched control subjects. Accuracy and reaction time during an auditory oddball and a visual continuous performance test were then recorded. Compared with control subjects, the attention-deficit hyperactivity disorder group manifested significantly increased (primarily left) frontal theta. Furthermore, the attention-deficit hyperactivity disorder group scored significantly delayed reaction time and decreased accuracy in both tasks. Correlation analysis revealed a significant relationship between frontal (primarily left) theta and oddball accuracy for the attention-deficit hyperactivity disorder group compared with a significant relationship between posterior (primarily right) theta and reaction time in the continuous performance test for the control group. These results indicate that spatial neurophysiologic deficits in attention-deficit hyperactivity disorder may be related to disturbances in signal detection. This observation has important implications for the role of trait-like biologic deficits in attention-deficit hyperactivity disorder predicting performance in information processing.
Hui, Li; Han, Mei; Du, Xiang Dong; Zhang, Bao Hua; He, Shu Chang; Shao, Tian Nan; Yin, Guang Zhong
Cognitive deficits have been regarded as one of the most significant clinical symptoms of depressive disorder. Accumulating evidence has shown that apolipoprotein B (ApoB) levels, which are responsible for inducing neurodegeneration, may be involved in cognitive deficits. This study examines cognitive deficits, and the correlation of serum ApoB levels with cognitive deficits of depressive disorder. 90 depressive patients and 90 healthy controls with matched age and gender were recruited. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum ApoB levels in depressive patients were measured by immunoturbidimetric method. Our results showed that depressive patients had lower scores of cognition including RBANS total score and subscales of language and delayed memory (all, p < 0.001) than healthy controls after controlling for the variables. The differences in cognitive functions also passed Bonferroni corrections. Serum ApoB levels were negatively correlated with delayed memory score in depressive patients (r = −0.30, p = 0.01). Furthermore, stepwise multivariate regression analysis indicated that serum ApoB levels independently contributed to delayed memory in depressive patients (t = −2.68, p = 0.01). Our findings support that serum ApoB levels may be involved in delayed memory decline in depressive patients. Depressive patients also experience greater cognitive deficits, especially in delayed memory and language than healthy controls. PMID:28054633
Richman, Lynn C.
The study examined patterns of cognitive ability in 57 cleft lip and palate children (ages 7 to 9) with verbal deficit, but without general intellectual retardation to evaluate whether the verbal disability displayed by these children was related primarily to a specific verbal expression deficit or a more general symbolic mediation problem.…
Skagerlund, Kenny; Träff, Ulf
This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with…
Shi, Yu; Zhang, Yi; Yao, Hejin; Wu, Jiawen; Sun, Hao; Gong, Haijun
The beneficial effects of silicon on plant growth and development under drought have been widely reported. However, little information is available on the effects of silicon on seed germination under drought. In this work, the effects of exogenous silicon (0.5 mM) on the seed germination and tolerance performance of tomato (Solanum lycopersicum L.) bud seedlings under water deficit stress simulated by 10% (w/v) polyethylene glycol (PEG-6000) were investigated in four cultivars ('Jinpengchaoguan', 'Zhongza No.9', 'Houpi L402' and 'Oubao318'). The results showed that the seed germination percentage was notably decreased in the four cultivars under water stress, and it was significantly improved by added silicon. Compared with the non-silicon treatment, silicon addition increased the activities of superoxide dismutase (SOD) and catalase (CAT), and decreased the production of superoxide anion (O2·) and hydrogen peroxide (H2O2) in the radicles of bud seedlings under water stress. Addition of silicon decreased the total phenol concentrations in radicles under water stress, which might contribute to the decrease of peroxidase (POD) activity, as observed in the in vivo and in vitro experiments. The decrease of POD activity might contribute to a less accumulation of hydroxyl radical (·OH) under water stress. Silicon addition also decreased the concentrations of malondialdehyde (MDA) in the radicles under stress, indicating decreased lipid peroxidation. These results suggest that exogenous silicon could improve seed germination and alleviate oxidative stress to bud seedling of tomato by enhancing antioxidant defense. The positive effects of silicon observed in a silicon-excluder also suggest the active involvement of silicon in biochemical processes in plants.
Denis, Isabelle; Guay, Marie-Claude; Foldes-Busque, Guillaume; BenAmor, Leila
Twenty-five percent of children with ADHD also have an anxiety disorder (AD). As per Quay and in light of Barkley's model, anxiety may have a protective effect on cognitive deficits and behaviors associated with ADHD. This study aimed to evaluate the effect of treating AD on cognitive deficits and behaviors associated with ADHD in children with both disorders. Twenty-four children with ADHD and AD were divided into two groups: treatment for AD, and wait list. Participants were assessed at pre-treatment, post-treatment, and 6-month follow-up with the ADIS-C, the CBCL, and neuropsychological measures. The results revealed a significant improvement in automatic response inhibition and flexibility, and a decrease in inattention/hyperactivity behaviors following the treatment for AD. No significant differences were observed in motor response inhibition, working memory, or attention deficits. The results do not seem to support Quay's hypothesis: treating AD did not exacerbate cognitive deficits and behaviors associated with ADHD in our sample.
Magen, Iddo; Fleming, Sheila M.; Zhu, Chunni; Garcia, Eddie C.; Cardiff, Katherine M.; Dinh, Diana; De La Rosa, Krystal; Sanchez, Maria; Torres, Eileen Ruth; Masliah, Eliezer; Jentsch, J. David; Chesselet, Marie-Françoise
Early cognitive deficits are increasingly recognized in patients with Parkinson's disease (PD), and represent an unmet need for the treatment of PD. These early deficits have been difficult to model in mice, and their mechanisms are poorly understood. α-Synuclein is linked to both familial and sporadic forms of PD, and is believed to accumulate in brains of patients with PD before cell loss. Mice expressing human wild-type a-synuclein under the Thy1 promoter (Thy1-aSyn mice) exhibit broad overexpression of α-synuclein throughout the brain and dynamic alterations in dopamine release several months before striatal dopamine loss. We now show that these mice exhibit deficits in cholinergic systems involved in cognition, and cognitive deficits in domains affected in early PD. Together with an increase in extracellular dopamine and a decrease in cortical acetylcholine at 4–6 months of age, Thy1-aSyn mice made fewer spontaneous alternations in the Y-maze and showed deficits in tests of novel object recognition (NOR), object–place recognition, and operant reversal learning, as compared with age-matched wild-type littermates. These data indicate that cognitive impairments that resemble early PD manifestations are reproduced by α-synuclein overexpression in a murine genetic model of PD. With high power to detect drug effects, these anomalies provide a novel platform for testing improved treatments for these pervasive cognitive deficits. PMID:22356593
Mackenzie, Catherine; Green, Jan
Background: Multiple sclerosis is a disabling neurological disease with varied symptoms, including dysarthria and cognitive and linguistic impairments. Association between dysarthria and cognitive-linguistic deficit has not been explored in clinical multiple sclerosis studies. Aims: In patients with chronic progressive multiple sclerosis, the…
Gong, Liang; Yin, Yingying; He, Cancan; Ye, Qing; Bai, Feng; Yuan, Yonggui; Zhang, Haisan; Lv, Luxian; Zhang, Hongxing; Xie, Chunming; Zhang, Zhijun
Neuroimaging studies have demonstrated that major depressive disorder (MDD) patients show blunted activity responses to reward-related tasks. However, whether abnormal reward circuits affect cognition and depression in MDD patients remains unclear. Seventy-five drug-naive MDD patients and 42 cognitively normal (CN) subjects underwent a resting-state functional magnetic resonance imaging scan. The bilateral nucleus accumbens (NAc) were selected as seeds to construct reward circuits across all subjects. A multivariate linear regression analysis was employed to investigate the neural substrates of cognitive function and depression severity on the reward circuits in MDD patients. The common pathway underlying cognitive deficits and depression was identified with conjunction analysis. Compared with CN subjects, MDD patients showed decreased reward network connectivity that was primarily located in the prefrontal-striatal regions. Importantly, distinct and common neural pathways underlying cognition and depression were identified, implying the independent and synergistic effects of cognitive deficits and depression severity on reward circuits. This study demonstrated that disrupted topological organization within reward circuits was significantly associated with cognitive deficits and depression severity in MDD patients. These findings suggest that in addition to antidepressant treatment, normalized reward circuits should be a focus and a target for improving depression and cognitive deficits in MDD patients.
Todd, Richard D.; Rasmussen, Erik R.; Wood, Catherine; Levy, Florence; Hay, David A.
Objective: To determine the impact of including sluggish cognitive tempo items on the factor and latent class structure of attention-deficit/hyperactivity disorder (ADHD) subtypes in boys and girls. Method: Parent report of two sluggish cognitive tempo items on a population-based sample of 1,430 female twins and 1,414 male twins were analyzed…
Prades, Roger; Munarriz-Cuezva, Eva; Urigüen, Leyre; Gil-Pisa, Itziar; Gómez, Lídia; Mendieta, Laura; Royo, Soledad; Giralt, Ernest; Tarragó, Teresa; Meana, J Javier
Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia.
Winblad, Stefan; Lindberg, Christopher; Hansen, Stefan
Background This study was designed to investigate cognitive abilities and their correlations with CTG repeat expansion size in classical Myotonic dystrophy type 1 (DM1), given that earlier studies have indicated cognitive deficits, possibly correlating with blood CTG repeats expansion size. Methods A measurement of CTG repeat expansion in lymphocytes and an extensive neuropsychological examination was made in 47 patients (25 women and 22 men). Individual results in the examination were compared with normative data. Results A substantial proportion of patients with DM1 (> 40%) scored worse in comparison to normative collectives on tests measuring executive, arithmetic, attention, speed and visuospatial abilities. We found significant correlations between longer CTG repeat expansion size and lower results on most tests associated with these abilities. Furthermore, the association between executive (frontal) deficits and DM1 were strengthened when considering both test results and correlations with CTG repeat expansion size in lymphocytes. Conclusion This study showed deficits in several cognitive abilities when patients with DM1 are compared to normative collectives. Some of the neuropsychological tests associated with these abilities are correlated to CTG repeat expansion size in blood. These data highlight the importance of considering cognitive deficits when seeing patients with classical DM1 in clinical practice, but also the utility of using blood CTG repeat expansion size as a broad predictor of finding cognitive deficit in DM1. PMID:16696870
Waterhouse, Uta; Roper, Vic E.; Brennan, Katharine A.
ABSTRACT Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI). PMID:27483346
Valdois, Sylviane; Bosse, Marie-Line; Tainturier, Marie-Josèphe
There is strong converging evidence suggesting that developmental dyslexia stems from a phonological processing deficit. However, this hypothesis has been challenged by the widely admitted heterogeneity of the dyslexic population, and by several reports of dyslexic individuals with no apparent phonological deficit. In this paper, we discuss the hypothesis that a phonological deficit may not be the only core deficit in developmental dyslexia and critically examine several alternative proposals. To establish that a given cognitive deficit is causally related to dyslexia, at least two conditions need to be fulfilled. First, the hypothesized deficit needs to be associated with developmental dyslexia independently of additional phonological deficits. Second, the hypothesized deficit must predict reading ability, on both empirical and theoretical grounds. While most current hypotheses fail to fulfil these criteria, we argue that the visual attentional deficit hypothesis does. Recent studies providing evidence for the independence of phonological and visual attentional deficits in developmental dyslexia are reviewed together with empirical data showing that phonological and visual attentional processing skills contribute independently to reading performance. A theoretical model of reading is outlined in support of a causal link between a visual attentional disorder and a failure in reading acquisition.
Rosenfeld, Andrew J.; Lieberman, Jeffrey A.; Jarskog, L. Fredrik
Until recently, the social cognitive impairment in schizophrenia has been underappreciated and remains essentially untreated. Deficits in emotional processing, social perception and knowledge, theory of mind, and attributional bias may contribute to functional social cognitive impairments in schizophrenia. The amygdala has been implicated as a key component of social cognitive circuitry in both animal and human studies. In addition, structural and functional studies of schizophrenia reproducibly demonstrate abnormalities in the amygdala and dopaminergic signaling. Finally, the neurohormone oxytocin plays an important role in multiple social behaviors in several mammals, including humans. We propose a model of social cognitive dysfunction in schizophrenia and discuss its therapeutic implications. The model comprises abnormalities in oxytocinergic and dopaminergic signaling in the amygdala that result in impaired emotional salience processing with consequent social cognitive deficits. PMID:20308198
Krysta, Krzysztof; Bratek, Agnieszka; Zawada, Karolina; Stepańczak, Radosław
Obstructive sleep apnea (OSA) can negatively affect the patient's physical and psychological functioning, as well as their quality of life. A major consequence of OSA is impaired cognitive functioning. Indeed, several studies have shown that OSA mainly leads to deficits in executive functions, attention, and memory. As OSA can present in all age groups, these associated cognitive deficits have been observed in adults, as well as in children and adolescents. However, these cognitive deficits may have a different clinical picture in young patients compared to adults. In this review, we analyze the most affected cognitive domains in adults and children/adolescents with OSA, as evaluated by neuropsychological and neuroimaging studies. We found that deficits in working memory, attention, or executive functions cognitive domains are found in both adults and children with OSA. However, children with OSA also show changes in behavior and phonological processing necessary for proper development. Moreover, we examine the possible OSA treatments in children and adults that can have a positive influence on cognition, and therefore, improve patients' general functioning and quality of life.
Cognitive impairment is a prominent feature in a range of different movement disorders. Children with Alternating Hemiplegia of Childhood are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older. Heterozygous mutations of the ATP1A3 gene, encoding the Na+,K+-ATPase α3 subunit, have been identified as the primary cause of Alternating Hemiplegia. Heterozygous Myshkin mice have an amino acid change (I810N) in Na+,K+-ATPase α3 that is also found in Alternating Hemiplegia. To investigate whether Myshkin mice exhibit learning and memory deficits resembling the cognitive impairments of patients with Alternating Hemiplegia, we subjected them to a range of behavioral tests that interrogate various cognitive domains. Myshkin mice showed impairments in spatial memory, spatial habituation, locomotor habituation, object recognition, social recognition, and trace fear conditioning, as well as in the visible platform version of the Morris water maze. Increasing the duration of training ameliorated the deficit in social recognition but not in spatial habituation. The deficits of Myshkin mice in all of the learning and memory tests used are consistent with the cognitive impairment of the vast majority of AHC patients. These mice could thus help advance our understanding of the underlying neural mechanisms influencing cognitive impairment in patients with ATP1A3-related disorders. PMID:26501181
Kirshenbaum, Greer S; Dachtler, James; Roder, John C; Clapcote, Steven J
Cognitive impairment is a prominent feature in a range of different movement disorders. Children with Alternating Hemiplegia of Childhood are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older. Heterozygous mutations of the ATP1A3 gene, encoding the Na+,K+-ATPase α3 subunit, have been identified as the primary cause of Alternating Hemiplegia. Heterozygous Myshkin mice have an amino acid change (I810N) in Na+,K+-ATPase α3 that is also found in Alternating Hemiplegia. To investigate whether Myshkin mice exhibit learning and memory deficits resembling the cognitive impairments of patients with Alternating Hemiplegia, we subjected them to a range of behavioral tests that interrogate various cognitive domains. Myshkin mice showed impairments in spatial memory, spatial habituation, locomotor habituation, object recognition, social recognition, and trace fear conditioning, as well as in the visible platform version of the Morris water maze. Increasing the duration of training ameliorated the deficit in social recognition but not in spatial habituation. The deficits of Myshkin mice in all of the learning and memory tests used are consistent with the cognitive impairment of the vast majority of AHC patients. These mice could thus help advance our understanding of the underlying neural mechanisms influencing cognitive impairment in patients with ATP1A3-related disorders.
Simon, Tony J.; Bearden, Carrie E.; Mc-Ginn, Donna McDonald; Zackai, Elaine
This article presents some of the earliest evidence of visuospatial and numerical cognitive deficits in children with the chromosome 22q11.2 deletion syndrome; a common but ill-understood genetic disorder resulting in medical complications, cognitive impairment, and brain morphologic changes. Relative to a group of typically developing controls, deleted children performed more poorly on tests of visual attentional orienting, visual enumeration and relative numerical magnitude judgment. Results showed that performance deficits in children with the deletion could not be explained by a global deficit in psychomotor speed. Instead, our findings are supportive of the hypothesis that visuospatial and numerical deficits in children with the chromosome 22q11.2 deletion are due, at least in part, to posterior parietal dysfunction. PMID:15714897
van Duijvenbode, Neomi; Didden, Robert; VanDerNagel, Joanne El; Korzilius, Hubert Plm; Engels, Rutger Cme
We examined cognitive deficits in problematic drinkers with and without mild to borderline intellectual disability (MBID). Problematic drinkers were expected to show a significantly lower estimated performance IQ (PIQ), but not a lower estimated verbal IQ (VIQ), compared to light drinkers. Participants ( N = 474) were divided into four groups based on IQ and severity of alcohol use-related problems. IQ was estimated using (a short form of) the Wechsler Adult Intelligence Scale third edition. Severity of alcohol use-related problems was assessed using the Alcohol Use Disorder Identification Test. Overall, there were no significant differences between light and problematic drinkers on estimated VIQ. Within the group without MBID, estimated PIQ was significantly lower. Estimated PIQ was not lower in problematic drinkers with MBID compared to light drinkers with MBID. The results are indicative of cognitive deficits in problematic drinkers without MBID. Screening for cognitive deficits with additional instruments is advised.
Orchard, Tonya S; Gaudier-Diaz, Monica M; Weinhold, Kellie R; Courtney DeVries, A
Cancer treatments such as chemotherapy have been an important part of extending survival in women diagnosed with breast cancer. However, chemotherapy can cause potentially toxic side effects in the brain that impair memory, verbal fluency, and processing speed in up to 30% of women treated. Women report that post-chemotherapy cognitive deficits negatively impact quality of life and may last up to ten years after treatment. Mechanisms underlying these cognitive impairments are not fully understood, but emerging evidence suggests that chemotherapy induces structural changes in the brain, produces neuroinflammation, and reduces adult hippocampal neurogenesis. Dietary approaches that modify inflammation and neurogenesis are promising strategies for reducing chemotherapy-induced cognitive deficits in breast cancer survivors. In this review, we describe the cognitive and neuronal side effects associated with commonly used chemotherapy treatments for breast cancer, and we focus on the often opposing actions of omega-3 fatty acids and added sugars on cognitive function, neuroinflammation, and adult hippocampal neurogenesis. Omega-3 fatty acids administered concurrently with doxorubicin chemotherapy have been shown to prevent depressive-like behaviors and reduce neuroinflammation, oxidative stress, and neural apoptosis in rodent models. In contrast, diets high in added sugars may interact with n-3 FAs to diminish their anti-inflammatory activity or act independently to increase neuroinflammation, reduce adult hippocampal neurogenesis, and promote cognitive deficits. We propose that a diet rich in long-chain, marine-derived omega-3 fatty acids and low in added sugars may be an ideal pattern for preventing or alleviating neuroinflammation and oxidative stress, thereby protecting neurons from the toxic effects of chemotherapy. Research testing this hypothesis could lead to the identification of modifiable dietary choices to reduce the long-term impact of chemotherapy on the
Wu, Dong-mei; Lu, Jun; Zhang, Yan-qiu; Zheng, Yuan-lin; Hu, Bin; Cheng, Wei; Zhang, Zi-feng; Li, Meng-qiu
Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitive deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.
Raine, Adrian; Yaralian, Pauline S; Reynolds, Chandra; Venables, Peter H; Mednick, Sarnoff A
Previous studies have repeatedly shown verbal intelligence deficits in adolescent antisocial individuals, but it is not known whether these deficits are in place prior to kindergarten or, alternatively, whether they are acquired throughout childhood. This study assesses whether cognitive deficits occur as early as age 3 years and whether they are specific to persistently antisocial individuals. Verbal and spatial abilities were assessed at ages 3 and 11 years in 330 male and female children, while antisocial behavior was assessed at ages 8 and 17 years. Persistently antisocial individuals (N = 47) had spatial deficits in the absence of verbal deficits at age 3 years compared to comparisons (N = 133), and also spatial and verbal deficits at age 11 years. Age 3 spatial deficits were independent of social adversity, early hyperactivity, poor test motivation, poor test comprehension, and social discomfort during testing, and they were found in females as well as males. Findings suggest that early spatial deficits contribute to persistent antisocial behavior whereas verbal deficits are developmentally acquired. An early-starter model is proposed whereby early spatial impairments interfere with early bonding and attachment, reflect disrupted right hemisphere affect regulation and expression, and predispose to later persistent antisocial behavior.
Kerns, Kimberley A.; Don, Audrey; Mateer, Catherine A.; Streissguth, Ann P.
Sixteen nonretarded young adults with fetal alcohol syndrome were divided into two groups, one with average to above average IQ and one with borderline to low average IQ. Subjects in both groups manifested clear deficits on neuropsychological measures sensitive to complex attention, verbal learning, and executive function at a frequency and…
Wu, Jing; Li, Huihui; Sun, Xiaoru; Zhang, Hui; Hao, Shuangying; Ji, Muhuo; Yang, Jianjun; Li, Kuanyu
Isoflurane possesses neurotoxicity and can induce cognitive deficits, particularly in aging mammals. Mitochondrial reactive oxygen species (mtROS) have been linked to the early pathogenesis of this disorder. However, the role of mtROS remains to be evaluated due to a lack of targeted method to treat mtROS. Here, we determined in aging mice the effects of the mitochondrion-targeted antioxidant SS-31, on cognitive deficits induced by isoflurane, a general inhalation anesthetic. We further investigated the possible mechanisms underlying the effects of SS-31 on hippocampal neuro-inflammation and apoptosis. The results showed that isoflurane induced hippocampus-dependent memory deficit, which was associated with mitochondrial dysfunction including reduced ATP contents, increased ROS levels, and mitochondrial swelling. Treatment with SS-31 significantly ameliorated isoflurane-induced cognitive deficits through the improvement of mitochondrial integrity and function. Mechanistically, SS-31 treatment suppressed pro-inflammatory responses by decreasing the levels of NF-κB, NLRP3, caspase 1, IL-1β, and TNF-α; and inhibited the apoptotic pathway by decreasing the Bax/Bcl-2 ratio, reducing the release of cytochrome C, and blocking the cleavage of caspase 3. Our results indicate that isoflurane-induced cognitive deficits may be attenuated by mitochondrion-targeted antioxidants, such as SS-31. Therefore, SS-31 may have therapeutic potentials in preventing injuries from oxidative stresses that contribute to anesthetic-induced neurotoxicity.
Smith, S E; Hodges, H; Sowinski, P; Man, C M; Leach, M J; Sinden, J D; Gray, J A; Meldrum, B S
4-Amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine (BW619C89) is a sodium channel antagonist which when administered parenterally reduces neurological deficit and infarct volume after middle cerebral artery occlusion in rats. We have investigated whether BW619C89 administered orally before middle cerebral artery occlusion is cerebroprotective when rats are assessed at one day after stroke, and whether cerebroprotection is long lasting and related to functional recovery. A cerebroprotective oral dose of BW619C89 (20 mg/kg) was used to determine whether reduction in infarct volume is long lasting and can be enhanced with continued therapy, and whether behavioural deficits occurring after middle cerebral artery occlusion such as disturbances in cognition and motor coordination are ameliorated by treatment with BW619C89. Rats received sham surgery or middle cerebral artery occlusion with a single treatment of BW619C89 (20 mg/kg) 1 h before middle cerebral artery occlusion, a double treatment group receiving 20 mg/kg BW619C89 1 h before and 10 mg/kg 5 h after middle cerebral artery occlusion, or continued treatment with BW619C89 for up to five days. Neurological deficit, assessed from days 1 to 21, and at 70 days after middle cerebral artery occlusion, was reduced to a similar extent in all three groups of rats treated with BW619C89, compared with vehicle-treated controls. At 70 days after middle cerebral artery occlusion, all groups performed at control level. Vehicle-treated rats were impaired in the Morris water maze and step-through passive avoidance paradigm five to eight weeks after middle cerebral artery occlusion, when neurological deficit was minimal. These deficits were partially alleviated, to a similar extent, by all of the three treatments with BW619C89. Total volumes of brain damage, assessed at 70 days after middle cerebral artery occlusion in Luxol Fast Blue- and Cresyl Violet-stained coronal sections, were reduced in all three groups
Bertrand, Josie-Anne; Bedetti, Christophe; Postuma, Ronald B; Monchi, Oury; Génier Marchand, Daphné; Jubault, Thomas; Gagnon, Jean-François
Color discrimination deficit is a common nonmotor manifestation of Parkinson's disease (PD). However, the pathophysiology of this dysfunction remains poorly understood. Although retinal structure changes found in PD have been suggested to cause color discrimination deficits, the impact of cognitive impairment and cortical alterations remains to be determined. We investigated the contribution of cognitive impairment to color discrimination deficits in PD and correlated them with cortical anomalies. Sixty-six PD patients without dementia and 20 healthy controls performed the Farnsworth-Munsell 100 hue test and underwent a comprehensive neuropsychological assessment for mild cognitive impairment diagnosis. In a subgroup of 26 PD patients, we also used high-definition neuroanatomical magnetic resonance imaging for cortical thickness and diffusion tensor analysis. PD patients with mild cognitive impairment performed poorly on the Farnsworth-Munsell 100 hue test compared with PD patients without mild cognitive impairment and controls. In PD patients, performance on the Farnsworth-Munsell 100 hue test was correlated with measures of visuospatial abilities and executive functions. Neuroimaging analysis revealed higher mean and radial diffusivity values in right posterior white-matter structures that correlated with poor performance on the Farnsworth-Munsell 100 hue test. No cortical thickness correlation reached significance. This study showed that cognitive impairment makes a major contribution to the color discrimination deficits reported in PD. Thus, performance on the Farnsworth-Munsell 100 hue test may reflect cognitive impairment more than color discrimination deficits in PD. Poor performance on the Farnsworth-Munsell 100 hue test was also associated with white-matter alterations in right posterior brain regions.
Fu, Yanyan; Liu, Hongzhi; Song, Chengjie; Zhang, Fang; Liu, Yi; Wu, Jian; Wen, Xiangru; Liang, Chen; Ma, Kai; Li, Lei; Zhang, Xunbao; Shao, Xiaoping; Sun, Yafeng; Du, Yang; Song, Yuanjian
Accumulating evidence reveals that lipopolysaccharide (LPS) can induce neuroinflammation, ultimately leading to cognitive deficits. Mangiferin, a natural glucoxilxanthone, is known to possess various biological activities. The present study aimed to investigate the effects of mangiferin on LPS-induced cognitive deficits and explore the underlying mechanisms. Brain injury was induced in mice via intraperitoneal LPS injection (1mg/kg) for five consecutive days. Mangiferin was orally pretreatmented (50mg/kg) for seven days and then treatmented (50mg/kg) for five days after LPS injection. The Morris water maze was used to detect changes in cognitive function. Immunohistochemical and immunoblotting were respectively performed to measure the expression of interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) in the hippocampus. The results showed that mangiferin can ameliorate cognitive deficits. Moreover, mangiferin decreased LPS-induced IL-6 production and increase HO-1 in the hippocampus. Taken together, these results suggest that mangiferin attenuates LPS-induced cognitive deficits, which may be potentially linked to modulating HO-1 in the hippocampus.
Canestrari, R; Godino, A
Problems related to psychometric measures of intelligence are discussed with regard to both the general characteristics and metric properties (validity, reliability and sensibility) of mental tests, and interindividual differences (cultural background, education, life contents and age-cohorts). Currently used standard intelligence tests explore the structure of intelligence only in part, so a distinction must be made between true actual intelligence, potential inheritance of intelligence, and psychometrical or scored intelligence. The correct use of intelligence testing, however, does provide some relevant and objective information regarding the evolution of cognitive structure during adulthood and in relationship to aging. Cognitive performance in the elderly follows a downward curve that is not explained as a result of aging on physiological responses (i.e., reaction time delay, signal-noise ratio in the CNS, degenerative loss of cortical cells, etc.). Biologically based theories of intelligence cannot explain the large individual differences in cognitive abilities observed in subjects who have very similar physical characteristics. Cognitive approaches to intelligence enable us to better understand the causal factors of the cognitive deficits in the elderly, and an interactive model permits us to fully integrate both the individual differences in cognitive abilities and the large consistency in performances. We compared the cognitive performances of two groups of elderly subjects, ranging in age from 65 to 97 years; we observed some statistically significant effects on cognitive deficit that could be explained as fully deriving from emotional and extra-cognitive responses to environmental changes.
Ghosh, Boyd C P; Calder, Andrew J; Peers, Polly V; Lawrence, Andrew D; Acosta-Cabronero, Julio; Pereira, João M; Hodges, John R; Rowe, James B
Although progressive supranuclear palsy is defined by its akinetic rigidity, vertical supranuclear gaze palsy and falls, cognitive impairments are an important determinant of patients' and carers' quality of life. Here, we investigate whether there is a broad deficit of modality-independent social cognition in progressive supranuclear palsy and explore the neural correlates for these. We recruited 23 patients with progressive supranuclear palsy (using clinical diagnostic criteria, nine with subsequent pathological confirmation) and 22 age- and education-matched controls. Participants performed an auditory (voice) emotion recognition test, and a visual and auditory theory of mind test. Twenty-two patients and 20 controls underwent structural magnetic resonance imaging to analyse neural correlates of social cognition deficits using voxel-based morphometry. Patients were impaired on the voice emotion recognition and theory of mind tests but not auditory and visual control conditions. Grey matter atrophy in patients correlated with both voice emotion recognition and theory of mind deficits in the right inferior frontal gyrus, a region associated with prosodic auditory emotion recognition. Theory of mind deficits also correlated with atrophy of the anterior rostral medial frontal cortex, a region associated with theory of mind in health. We conclude that patients with progressive supranuclear palsy have a multimodal deficit in social cognition. This deficit is due, in part, to progressive atrophy in a network of frontal cortical regions linked to the integration of socially relevant stimuli and interpretation of their social meaning. This impairment of social cognition is important to consider for those managing and caring for patients with progressive supranuclear palsy.
Kashala, Espérance; Elgen, Irene; Sommerfelt, Kristian; Tylleskär, Thorkild; Lundervold, Astri
The aims of the study were: (1) to describe the performance of African children with symptoms of attention-deficit hyperactivity disorder on selected neuropsychologic tests and compare it with performance among peers of the same age without symptoms; (2) to explore through a factor analysis if the selected tests cover the same functions as known from studies in Europe and North America. A nested case-control approach was used to select the two groups of children. The tests were selected to measure aspects of executive functions, attention and memory functions as well as motor skills. A total of 185 schoolchildren (28 cases and 157 control subjects) aged 85 to 119 months old were included. The findings indicate only minor difference between children with symptoms of attention-deficit hyperactivity disorder and control subjects in most of the tasks. However, children with symptoms of attention-deficit hyperactivity disorder performed more poorly on tests of motor skills and had more violations of rules on the planning task. The factor analysis indicated a three-factor model, confirming that the selected tests could be used as measures of executive/motor functions, attention, and memory functions. Similar findings have been reported among children in Europe and North America.
Beilharz, Jessica E; Maniam, Jayanthi; Morris, Margaret J
It is of vital importance to understand how the foods which are making us fat also act to impair cognition. In this review, we compare the effects of acute and chronic exposure to high-energy diets on cognition and examine the relative contributions of fat (saturated and polyunsaturated) and sugar to these deficits. Hippocampal-dependent memory appears to be particularly vulnerable to the effects of high-energy diets and these deficits can occur rapidly and prior to weight gain. More chronic diet exposure seems necessary however to impair other sorts of memory. Many potential mechanisms have been proposed to underlie diet-induced cognitive decline and we will focus on inflammation and the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Finally, given supplementation of diets with omega-3 and curcumin has been shown to have positive effects on cognitive function in healthy ageing humans and in disease states, we will discuss how these nutritional interventions may attenuate diet-induced cognitive decline. We hope this approach will provide important insights into the causes of diet-induced cognitive deficits, and inform the development of novel therapeutics to prevent or ameliorate such memory impairments.
Beilharz, Jessica E.; Maniam, Jayanthi; Morris, Margaret J.
It is of vital importance to understand how the foods which are making us fat also act to impair cognition. In this review, we compare the effects of acute and chronic exposure to high-energy diets on cognition and examine the relative contributions of fat (saturated and polyunsaturated) and sugar to these deficits. Hippocampal-dependent memory appears to be particularly vulnerable to the effects of high-energy diets and these deficits can occur rapidly and prior to weight gain. More chronic diet exposure seems necessary however to impair other sorts of memory. Many potential mechanisms have been proposed to underlie diet-induced cognitive decline and we will focus on inflammation and the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Finally, given supplementation of diets with omega-3 and curcumin has been shown to have positive effects on cognitive function in healthy ageing humans and in disease states, we will discuss how these nutritional interventions may attenuate diet-induced cognitive decline. We hope this approach will provide important insights into the causes of diet-induced cognitive deficits, and inform the development of novel therapeutics to prevent or ameliorate such memory impairments. PMID:26274972
Viscogliosi, Chantal; Belleville, Sylvie; Desrosiers, Johanne; Caron, Chantal D; Ska, Bernadette
Participation refers to the engagement of a person in daily activities and social roles. The goal of this study was to compare changes in older adults' participation over time following a stroke as a function of the presence of deficits in memory, visual perception, executive functions, visual attention or language. A total of 197 persons with stroke were assessed 3 weeks, 3 months and 6 months after discharge from an acute care hospital, rehabilitation unit or geriatric day hospital. The Assessment of Life Habits (ALH) was used to measure participation. Neuropsychological measures were used to assess the presence of a cognitive deficit in the domains of memory, visual perception, executive functions (inhibition), visual attention and language. Overall, results indicate that participation after a stroke improves over time after hospital discharge in spite of cognitive deficits. Changes in participation over time differed between unimpaired and impaired participants only for language and executive deficits in three domains: interpersonal relationships, community life and responsibilities. These results indicate that when returning to the community after a stroke, positive changes in participation over time are possible even with cognitive deficits.
Hart, Susan Crandall; DiPerna, James Clyde
This study aimed to examine whether having knowledge of student cognitive skill deficits changes teacher beliefs and responses in regard to classroom misbehavior. Teachers (N = 272) were randomly assigned to an experimental or control condition. Although teachers in both conditions read the same vignette describing a student's misbehavior, the…
Gupta, Rashmi; Kar, Bhoomika R.
We present a critical account of existing tools used to diagnose children with Attention Deficit Hyperactivity Disorder and to make a case for the assessment of cognitive impairments as a part of diagnostic system. Surveys have shown that clinicians rely almost entirely upon subjective reports or their own clinical judgment when arriving at…
Solari, Nicola; Bonito-Oliva, Alessandra; Fisone, Gilberto; Brambilla, Riccardo
Parkinson's disease (PD) has been, until recently, mainly defined by the presence of characteristic motor symptoms, such as rigidity, tremor, bradykinesia/akinesia, and postural instability. Accordingly, pharmacological and surgical treatments have so far addressed these motor disturbances, leaving nonmotor, cognitive deficits an unmet…
Wu, Jing; Zhang, Mingqiang; Hao, Shuangying; Jia, Ming; Ji, Muhuo; Qiu, Lili; Sun, Xiaoyan; Yang, Jianjun; Li, Kuanyu
Sepsis-associated encephalopathy (SAE) is associated with increased mortality, morbidity, and long-term cognitive impairments. Its pathophysiology remains to be determined and an effective pharmacologic treatment is lacking. The goal of this study was to investigate the effects of the mitochondria-targeted peptide SS-31 on mitochondrial function and cognitive deficits in SAE mice. C57BL/6 male mice were randomly divided into sham, sham + SS-31, cecal ligation and puncture (CLP), and CLP + SS-31 groups. Peptide SS-31 (5 mg/kg) was intraperitoneally administrated immediately after operation and afterwards once daily for six consecutive days. Surviving mice were subjected to behavioral tests and the hippocampus was collected for biochemical analysis 7 days after operation. The results showed that CLP resulted in high mortality rate and cognitive deficits, representative characteristics of SAE. A physiological mechanistic investigation revealed that mitochondrial function of hippocampus was severely impaired, coupled with reactive oxygen species (ROS) generation, triggering neuronal apoptosis and inflammation. Notably, administration of peptide SS-31 protected the integrity of mitochondria, reversed the mitochondrial dysfunction, inhibited the apoptosis resulting from the release of cytochrome c, diminished the response of inflammation, and ultimately reversed the behavior deficits in the SAE mice. In conclusion, our data demonstrate that daily treatment with mitochondria-targeted peptide SS-31 reduces mortality rate and ameliorates cognitive deficits, which is possibly through a mechanism of reversing mitochondrial dysfunction and partial inhibition of neuronal apoptosis and inflammation in the hippocampus of the SAE mice.
A random sample of 200 men and 200 women taken from the general population as well as subsamples of 31 male and 17 female excessive social drinkers were investigated with neuropsychological tests and computed tomography of the brain. Relatively high alcohol intake per drinking occasion did not give evidence of cognitive deficits or morphological cerebral changes. However, in males, mild cognitive deficits and morphological cerebral changes as a result of high recent alcohol intake, particularly during the 24-hr period prior to the investigation, were observed. When excluding acute effects of recent alcohol intake, mild cognitive deficits but not morphological cerebral changes that are apparently due to long-term excessive social drinking were observed in males. In females there was no association between the drinking variables and cognitive deficits or morphological cerebral changes, probably due to their less advanced drinking habits. It is suggested that future risk evaluations and estimations of safe alcohol intake should take into consideration the potential risk for brain damage due to excessive social drinking. However, it is premature to make any definite statements about safe alcohol intake and the risk for brain damage in social drinkers from the general population.
Skirbekk, Benedicte; Hansen, Berit Hjelde; Oerbeck, Beate; Kristensen, Hanne
The objective of the present study was to examine the relationship between sluggish cognitive tempo (SCT), subtypes of attention-deficit/hyperactivity disorder (ADHD), and anxiety disorders (AnxDs). One hundred and forty-one children (90 males, 51 females) aged 7-13 years were assigned to four groups, i.e., referred children with comorbid AnxDs…
McCauley, Elizabeth; And Others
The study attemped to link cognitive and social problems seen in girls with Turner syndrome by assessing the girls' ability to process affective cues. Seventeen 9- to 17-year-old girls diagnosed with Turner syndrome were compared to a matched control group on a task which required interpretation of affective intention from facial expression.…
Chen, Jason I; Hergert, Danielle C
The purpose of this essay is to explore the long-term impact of depression on cognitive functioning and to discuss possible treatment strategies that mental health and psychiatric nurses may employ in practice or pursue in research to improve patient outcomes. As psychiatric and mental health nurses play a valuable role in promoting recovery from depression, addressing cognitive difficulties associated with depression may be an important area for nursing practice. This essay will first introduce the rationale for evaluating cognitive deficits in remitted depression in regards to the impact on quality of life (QOL). This article is protected by copyright. All rights reserved.
Kesby, James P; Markou, Athina; Semenova, Svetlana
Methamphetamine abuse is common among individuals infected by human immunodeficiency virus (HIV). Neurocognitive outcomes tend to be worse in methamphetamine users with HIV. However, it is unclear whether discrete cognitive domains are susceptible to impairment after combined HIV infection and methamphetamine abuse. The expression of HIV/gp120 protein induces neuropathology in mice similar to HIV-induced pathology in humans. We investigated the separate and combined effects of methamphetamine exposure and gp120 expression on cognitive function in transgenic (gp120-tg) and control mice. The mice underwent an escalating methamphetamine binge regimen and were tested in novel object/location recognition, object-in-place recognition, and Barnes maze tests. gp120 expression disrupted performance in the object-in-place test (i.e. similar time spent with all objects, regardless of location), indicating deficits in associative recognition memory. gp120 expression also altered reversal learning in the Barnes maze, suggesting impairments in executive function. Methamphetamine exposure impaired spatial strategy in the Barnes maze, indicating deficits in spatial learning. Methamphetamine-exposed gp120-tg mice had the lowest spatial strategy scores in the final acquisition trials in the Barnes maze, suggesting greater deficits in spatial learning than all of the other groups. Although HIV infection involves interactions between multiple proteins and processes, in addition to gp120, our findings in gp120-tg mice suggest that humans with the dual insult of HIV infection and methamphetamine abuse may exhibit a broader spectrum of cognitive deficits than those with either factor alone. Depending on the cognitive domain, the combination of both insults may exacerbate deficits in cognitive performance compared with each individual insult.
Kesby, James P.; Markou, Athina; Semenova, Svetlana
Methamphetamine abuse is common among individuals infected by human immunodeficiency virus (HIV). Neurocognitive outcomes tend to be worse in methamphetamine users with HIV. However, it is unclear whether discrete cognitive domains are susceptible to impairment after combined HIV infection and methamphetamine abuse. The expression of HIV/gp120 protein induces neuropathology in mice similar to HIV-induced pathology in humans. We investigated the separate and combined effects of methamphetamine exposure and gp120 expression on cognitive function in transgenic (gp120-tg) and control mice. The mice underwent an escalating methamphetamine binge regimen and were tested in novel object/location recognition, object-in-place recognition, and Barnes maze tests. gp120 expression disrupted performance in the object-in-place test (i.e., similar time spent with all objects, regardless of location), indicating deficits in associative recognition memory. gp120 expression also altered reversal learning in the Barnes maze, suggesting impairments in executive function. Methamphetamine exposure impaired spatial strategy in the Barnes maze, indicating deficits in spatial learning. Methamphetamine-exposed gp120-tg mice had the lowest spatial strategy scores in the final acquisition trials in the Barnes maze, suggesting greater deficits in spatial learning than all of the other groups. Although HIV infection involves interactions between multiple proteins and processes, in addition to gp120, our findings in gp120-tg mice suggest that humans with the dual insult of HIV infection and methamphetamine abuse may exhibit a broader spectrum of cognitive deficits than those with either factor alone. Depending on the cognitive domain, the combination of both insults may exacerbate deficits in cognitive performance compared with each individual insult. PMID:25476577
Siepel, Françoise J; Brønnick, Kolbjørn S; Booij, Jan; Ravina, Bernard M; Lebedev, Alexander V; Pereira, Joana B; Grüner, Renate; Aarsland, Dag
Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug-naïve PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross-sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single-photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [(123) I]FP-CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age-moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD.
Davis, Andrew S; Trotter, Jeffrey S; Hertza, Jeremy; Bell, Christopher D; Dean, Raymond S
The purpose of this study was to examine the presence of finger agnosia in patients with Alzheimer's disease (AD) and to determine if level of finger agnosia was related to cognitive impairment. Finger agnosia is a sensitive measure of cerebral impairment and is associated with neurofunctional areas implicated in AD. Using a standardized and norm-referenced approach, results indicated that patients with AD evidenced significantly decreased performance on tests of bilateral finger agnosia compared with healthy age-matched controls. Finger agnosia was predictive of cognitive dysfunction on four of seven domains, including: Crystallized Language, Fluid Processing, Associative Learning, and Processing Speed. Results suggest that measures of finger agnosia, a short and simple test, may be useful in the early detection of AD.
Jung, Na-Yeon; Han, Cheol E; Kim, Hee Jin; Yoo, Sang Wook; Kim, Hee-Jong; Kim, Eun-Joo; Na, Duk L; Lockhart, Samuel N; Jagust, William J; Seong, Joon-Kyung; Seo, Sang Won
The white matter tract-specific correlates of neuropsychological deficits are not fully established in patients with subcortical vascular cognitive impairment (SVCI), where white matter tract damage may be a critical factor in cognitive impairment. The purpose of this study is to investigate the tract-specific correlates of neuropsychological deficits in SVCI patients using tract-specific statistical analysis (TSSA). We prospectively recruited 114 SVCI patients, and 55 age-, gender-, and education-matched individuals with normal cognition (NC). All participants underwent diffusion weighted imaging and neuropsychological testing. We classified tractography results into fourteen major fiber tracts and analyzed group comparison and correlation with cognitive impairments. Relative to NC subjects, SVCI patients showed decreased fractional anisotropy values in bilateral anterior-thalamic radiation, cingulum, superior-longitudinal fasciculus, uncinate fasciculus, corticospinal tract, and left inferior-longitudinal fasciculus. Focal disruptions in specific tracts were associated with specific cognitive impairments. Our findings suggest that disconnection of specific white matter tracts, especially those neighboring and providing connections between gray matter regions important to certain cognitive functions, may contribute to specific cognitive impairments in SVCI.
Shukitt-Hale, B.; Casadesus, G.; Cantuti-Castelvetri, I.; Rabin, B. M.; Joseph, J. A.
Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.
Shukitt-Hale, B.; Casadesus, G.; Cantuti-Castelvetri, I.; Rabin, B. M.; Joseph, J. A.
Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere. Published by Elsevier Science Ltd on behalf of COSPAR.
Miller, Amanda C.; Keenan, Janice M.; Betjemann, Rebecca S.; Willcutt, Erik; Pennington, Bruce F.; Olson, Richard K.
We examined reading comprehension in children with ADHD by assessing their ability to build a coherent mental representation that allows them to recall central and peripheral information. We compared children with ADHD (mean age 9.78) to word reading-matched controls (mean age 9.89) on their ability to retell a passage. We found that even though children with ADHD recalled more central than peripheral information, they showed their greatest deficit, relative to controls, on central information – a centrality deficit (Miller & Keenan, 2009). We explored the cognitive underpinnings of this deficit using regressions to compare how well cognitive factors (working memory, inhibition, processing speed, and IQ) predicted the ability to recall central information, after controlling for word reading ability, and whether these cognitive factors interacted with ADHD symptoms. Working memory accounted for the most unique variance. Although previous evidence for reading comprehension difficulties in children with ADHD have been mixed, this study suggests that even when word reading ability is controlled, children with ADHD have difficulty building a coherent mental representation, and this difficulty is likely related to deficits in working memory. PMID:23054132
Debes, Frodi; Weihe, Pal; Grandjean, Philippe
Prenatal exposure to mercury has been associated with adverse effects on child neurodevelopment. The present study aims to determine the extent to which methylmercury-associated cognitive deficits persist into adult age. In a Faroese birth cohort originally formed in 1986–1987 (N=1,022), prenatal methylmercury exposure was assessed in terms of the mercury concentration in cord blood and maternal hair. Clinical examinations of 847 cohort members at age 22 years were carried out in 2008–2009 using a panel of neuropsychological tests that reflected major functional domains. Subjects with neurological and psychiatric diagnoses were excluded from the data analysis, thus leaving 814 subjects. Multiple regression analysis included covariates previously identified for adjustment. Deficits in Boston Naming Test and other tests of verbal performance were significantly associated with the cord-blood mercury concentration. Deficits were also present in all other tests applied, although most were not statistically significant. Structural equation models were developed to ascertain the possible differences in vulnerability of specific functional domains and the overall association with general intelligence. In models for individual domains, all of them showed negative associations, with crystallized intelligence being highly significant. A hierarchical model for general intelligence based on all domains again showed a highly significant negative association with the exposure, with an approximate deficit that corresponds to about 2.2 IQ points at a 10-fold increased prenatal methylmercury exposure. Thus, although the cognitive deficits observed were smaller than at examinations at younger ages, maternal seafood diets were associated with adverse effects in this birth cohort at age 22 years. The deficits affected major domains of brain functions as well as general intelligence. Thus, prenatal exposure to this marine contaminant appears to cause permanent adverse effects on
Abram, Samantha V; Wisner, Krista M; Fox, Jaclyn M; Barch, Deanna M; Wang, Lei; Csernansky, John G; MacDonald, Angus W; Smith, Matthew J
Impaired cognitive empathy is a core social cognitive deficit in schizophrenia associated with negative symptoms and social functioning. Cognitive empathy and negative symptoms have also been linked to medial prefrontal and temporal brain networks. While shared behavioral and neural underpinnings are suspected for cognitive empathy and negative symptoms, research is needed to test these hypotheses. In two studies, we evaluated whether resting-state functional connectivity between data-driven networks, or components (referred to as, inter-component connectivity), predicted cognitive empathy and experiential and expressive negative symptoms in schizophrenia subjects. Study 1: We examined associations between cognitive empathy and medial prefrontal and temporal inter-component connectivity at rest using a group-matched schizophrenia and control sample. We then assessed whether inter-component connectivity metrics associated with cognitive empathy were also related to negative symptoms. Study 2: We sought to replicate the connectivity-symptom associations observed in Study 1 using an independent schizophrenia sample. Study 1 results revealed that while the groups did not differ in average inter-component connectivity, a medial-fronto-temporal metric and an orbito-fronto-temporal metric were related to cognitive empathy. Moreover, the medial-fronto-temporal metric was associated with experiential negative symptoms in both schizophrenia samples. These findings support recent models that link social cognition and negative symptoms in schizophrenia. Hum Brain Mapp 38:1111-1124, 2017. © 2016 Wiley Periodicals, Inc.
Pearson, Jennifer N.; Rowley, Shane; Liang, Li-Ping; White, Andrew M.; Day, Brian J.; Patel, Manisha
Cognitive dysfunction is an important comorbidity of temporal lobe epilepsy (TLE). However, no targeted therapies are available and the mechanisms underlying cognitive impairment, specifically deficits in learning and memory associated with TLE remain unknown. Oxidative stress is known to occur in the pathogenesis of TLE but its functional role remains to be determined. Here, we demonstrate that oxidative stress and resultant processes contribute to cognitive decline associated with epileptogenesis. Using a synthetic catalytic antioxidant, we show that pharmacological removal of reactive oxygen species (ROS) prevents 1) oxidative stress, 2) deficits in mitochondrial oxygen consumption rates, 3) hippocampal neuronal loss and 4) cognitive dysfunction without altering the intensity of the initial status epilepticus (SE) or epilepsy development in a rat model of SE-induced TLE. Moreover, the effects of the catalytic antioxidant on cognition persisted beyond the treatment period suggestive of disease-modification. The data implicate oxidative stress as a novel mechanism by which cognitive dysfunction can arise during epileptogenesis and suggest a potential disease-modifying therapeutic approach to target it. PMID:26184893
Timmann, Dagmar; Drepper, J; Maschke, M; Kolb, F P; Böring, D; Thilmann, A F; Diener, H C
There is a strong evidence that the cerebellum is involved in associative motor learning. The exact role of the cerebellum in motor learning, and whether it is involved in cognitive learning processes too, are still controversially discussed topics. A common problem of assessing cognitive capabilities of cerebellar patients is the existence of additional motor demands in all cognitive tests. Even if the patients are able to cope well with the motor requirements of the task, their performance could still involve compensating strategies which cost them more attentional resources than the normal controls. To investigate such interaction effects of cognitive and motor demands in cerebellar patients, we conducted a cognitive associative learning paradigm and varied systematically the motor demands and the cognitive requirements of the task. Nine patients with isolated cerebellar disease and nine matched healthy controls had to learn the association between pairs of color squares, presented centrally on a computer monitor together with a left or right answer button. In the simple motor condition, the answer button had to be pressed once and in the difficult condition three times. We measured the decision times and evaluated the correctly named associations after the test was completed. The cerebellar subjects showed a learning deficit, compared to the normal controls. However, this deficit was independent of the motor difficulty of the task. The cerebellum seems to contribute to motor-independent processes, which are generally involved in associative learning.
Lee, Kathy Y. S.; Crooke, Pamela J.; Lui, Aster L. Y.; Kan, Peggy P. K.; Mark, Yuen-mai; van Hasselt, Charles Andrew; Tong, Michael C. F.
The use of cognitive-based strategies for improving social communication behaviours for individuals who have solid language and cognition is an important question. This study investigated the outcome of teaching Social Thinking®, a framework based in social-cognition, to Chinese adolescents with social communication deficits. Thirty-nine students…
Mata, Ignacio F.; Leverenz, James B.; Weintraub, Daniel; Trojanowski, John Q.; Chen-Plotkin, Alice; Van Deerlin, Vivianna M.; Ritz, Beate; Rausch, Rebecca; Factor, Stewart A.; Wood-Siverio, Cathy; Quinn, Joseph F.; Chung, Kathryn A.; Peterson-Hiller, Amie L.; Goldman, Jennifer G.; Stebbins, Glenn T.; Bernard, Bryan; Espay, Alberto J.; Revilla, Fredy J.; Devoto, Johnna; Rosenthal, Liana S.; Dawson, Ted M.; Albert, Marilyn S.; Tsuang, Debby; Huston, Haley; Yearout, Dora; Hu, Shu-Ching; Cholerton, Brenna A.; Montine, Thomas J.; Edwards, Karen L.; Zabetian, Cyrus P.
Background Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Objectives/Methods We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at 8 sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised), working memory/executive function (Letter-Number Sequencing and Trail Making A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (Montreal Cognitive Assessment). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni corrections. Results Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio =5.1; p=9.7 × 10−6; E326K, odds ratio =6.4; p=5.7 × 10−7) and lower performance on Letter-Number Sequencing (mutations, corrected p[pc]=9.0 × 10−4; E326K, pc=0.036), Trail Making B-A (mutations, pc=0.018; E326K, pc=0.018), and Benton Judgment of Line Orientation (mutations, pc=0.0045; E326K, pc=0.0013). Conclusions Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits. PMID:26296077
Hirjak, Dusan; Wolf, Robert C; Remmele, Barbara; Seidl, Ulrich; Thomann, Anne K; Kubera, Katharina M; Schröder, Johannes; Maier-Hein, Klaus H; Thomann, Philipp A
Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi-structured interview (E-AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2-3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.
Ji, Mu-Huo; Jia, Min; Zhang, Ming-Qiang; Liu, Wen-Xue; Xie, Zhong-Cong; Wang, Zhong-Yun; Yang, Jian-Jun
Post-traumatic stress disorder (PTSD) is a psychiatric disease that has substantial health implications, including high rates of health morbidity and mortality, as well as increased health-related costs. Although many pharmacological agents have proven the effects on the development of PTSD, current pharmacotherapies typically only produce partial improvement of PTSD symptoms. Dexmedetomidine is a selective, short-acting α2-adrenoceptor agonist, which has anxiolytic, sedative, and analgesic effects. We therefore hypothesized that dexmedetomidine possesses the ability to prevent the development of PTSD and alleviate its symptoms. By using the rat model of PTSD induced by five electric foot shocks followed by three weekly exposures to situational reminders, we showed that the stressed rats displayed pronounced anxiety-like behaviors and cognitive impairments compared to the controls. Notably, repeated administration of 20μg/kg dexmedetomidine showed impaired fear conditioning memory, decreased anxiety-like behaviors, and improved spatial cognitive impairments compared to the vehicle-treated stressed rats. These data suggest that dexmedetomidine may exert preventive and protective effects against anxiety-like behaviors and cognitive impairments in the rats with PTSD after repeated administration.
Maschio, Marta; Dinapoli, Loredana; Fabi, Alessandra; Giannarelli, Diana; Cantelmi, Tonino
The aim of this pilot observational study was to evaluate effect of cognitive rehabilitation training (RehabTr) on cognitive performances in patients with brain tumor-related epilepsy (BTRE) and cognitive disturbances. Medical inclusion criteria: patients (M/F) ≥ 18 years ≤ 75 with symptomatic seizures due to primary brain tumors or brain metastases in stable treatment with antiepileptic drugs; previous surgical resection or biopsy; >70 Karnofsky Performance Status; stable oncological disease. Eligible patients recruited from 100 consecutive patients with BTRE at first visit to our Center from 2011 to 2012. All recruited patients were administered battery of neuropsychological tests exploring various cognitive domains. Patients considered to have a neuropsychological deficit were those with at least one test score for a given domain indicative of impairment. Thirty patients out of 100 showed cognitive deficits, and were offered participation in RehabTr, of which 16 accepted (5 low grade glioma, 4 high grade glioma, 2 glioblastoma, 2 meningioma and 3 metastases) and 14 declined for various reasons. The RehabTr consisted of one weekly individual session of 1 h, for a total of 10 weeks, carried out by a trained psychologist. The functions trained were: memory, attention, visuo-spatial functions, language and reasoning by means of Training NeuroPsicologico (TNP(®)) software. To evaluate the effect of the RehabTr, the same battery of tests was administered directly after cognitive rehabilitation (T1), and at six-month follow-up (T2). Statistical analysis with Student T test for paired data showed that short-term verbal memory, episodic memory, fluency and long term visuo-spatial memory improved immediately after the T1 and remained stable at T2. At final follow-up all patients showed an improvement in at least one domain that had been lower than normal at baseline. Our results demonstrated a positive effect of rehabilitative training at different times, and, for
Sharpley, Christopher F; Bitsika, Vicki; Christie, David R H
The incidence and contribution to total depression of the depressive symptoms of cognitive deficit and cognitive bias in prostate cancer (PCa) patients were compared from cohorts sampled during the first 2 years after diagnosis. Survey data were collected from 394 patients with PCa, including background information, treatments, and disease status, plus total scores of depression and scores for subscales of the depressive symptoms of cognitive bias and cognitive deficit via the Zung Self-Rating Depression Scale. The sample was divided into eight 3-monthly time-since-diagnosis cohorts and according to depression severity. Mean scores for the depressive symptoms of cognitive deficit were significantly higher than those for cognitive bias for the whole sample, but the contribution of cognitive bias to total depression was stronger than that for cognitive deficit. When divided according to overall depression severity, patients with clinically significant depression showed reversed patterns of association between the two subsets of cognitive symptoms of depression and total depression compared with those patients who reported less severe depression. Differences in the incidence and contribution of these two different aspects of the cognitive symptoms of depression for patients with more severe depression argue for consideration of them when assessing and diagnosing depression in patients with PCa. Treatment requirements are also different between the two types of cognitive symptoms of depression, and several suggestions for matching treatment to illness via a personalized medicine approach are discussed.
Levetiracetam is a homologue of piracetam with an a-ethyl side-chain substitution and it is a Food and Drug Administration (FDA) approved antiepileptic drug. Recently, several studies have found that levetiracetam was able to reduce seizure frequency in epileptic seizures patients without affecting their cognitive functions. In the present review, the effects of levetiracetam on cognitive improvement were summarized in epileptic seizures patients with or without Alzheimer's disease (AD), high-grade glioma (HGG) patients and amnestic mild cognitive impairment (aMCI) patients. In addition, levetiracetam was observed to improve the cognitive deficits in normal aged animals and the transgenic animal models with AD, suggesting that levetiracetam may be a better choice for the prevention or treatment of AD.
Koelkebeck, Katja; Uwatoko, Teruhisa; Tanaka, Jiro; Kret, Mariska Esther
Social cognitive skills are indispensable for successful communication with others. Substantial research has determined deficits in these abilities in patients with mental disorders. In neurobiological development and continuing into adulthood, cross-cultural differences in social cognition have been demonstrated. Moreover, symptomatic patterns in mental disorders may vary according to the cultural background of an individual. Cross-cultural studies can thus help in understanding underlying (biological) mechanisms and factors that influence behavior in health and disease. In addition, studies that apply novel paradigms assessing the impact of culture on cognition may benefit and advance neuroscience research. In this review, the authors give an overview of cross-cultural research in the field of social cognition in health and in mental disorders and provide an outlook on future research directions, taking a neuroscience perspective.
van Zwieten, Anita; Meyer, Johanna; Hermens, Daniel F.; Hickie, Ian B.; Hawes, David J.; Glozier, Nicholas; Naismith, Sharon L.; Scott, Elizabeth M.; Lee, Rico S. C.; Guastella, Adam J.
Antisocial behaviours and psychopathic traits place an individual at risk for criminality, mental illness, substance dependence, and psychosocial dysfunction. Social cognition deficits appear to be associated with psychopathic traits and are believed to contribute to interpersonal dysfunction. Most research investigating the relationship of these traits with social cognition has been conducted either in children or adult forensic settings. We investigated whether psychopathic traits were associated with social cognition in 91 young people presenting for mental healthcare (aged between 15 and 25 years). Participants completed symptom severity measures, neuropsychological tests, the Reading the Mind in the Eyes Test of social cognition (RMET), and the Antisocial Process Screening Device (APSD) to assess psychopathic personality traits. Correlation analyses showed poorer social cognition was associated with greater psychopathic traits (r = −.36, p = .01). Interestingly, social cognition performance predicted unique variance in concurrent psychopathic personality traits above gender, IQ sustained attention, and working memory performance. These findings suggest that social cognitive impairments are associated with psychopathic tendencies in young people presenting for community mental healthcare. Research is needed to establish the directionality of this relationship and to determine whether social cognition training is an effective treatment amongst young people with psychopathic tendencies. PMID:23861799
Masur, David; Shinnar, Shlomo; Cnaan, Avital; Shinnar, Ruth C.; Clark, Peggy; Wang, Jichuan; Weiss, Erica F.; Hirtz, Deborah G.
Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated childhood absence epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine. Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16–20 visit. Results: At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16–20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving ethosuximide (32%) or lamotrigine (24%) (p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment (p < 0.0001). Conclusions: Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted. Classification of evidence: This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than ethosuximide or lamotrigine in children with newly diagnosed CAE. PMID:24089388
McNamara, P; Durso, R; Brown, A; Lynch, A
Background: Counterfactuals are mental representations of alternatives to past events. Recent research has shown them to be important for other cognitive processes, such as planning, causal reasoning, problem solving, and decision making—all processes independently linked to the frontal lobes. Objective: To test the hypothesis that counterfactual thinking is impaired in some patients with Parkinson's disease and is linked to frontal dysfunction in these patients. Methods. Measures of counterfactual processing and frontal lobe functioning were administered to 24 persons with Parkinson's disease and 15 age matched healthy controls. Results. Patients with Parkinson's disease spontaneously generated significantly fewer counterfactuals than controls despite showing no differences from controls on a semantic fluency test; they also performed at chance levels on a counterfactual inference test, while age matched controls performed above chance levels on this test. Performance on both the counterfactual generation and inference tests correlated significantly with performance on two tests traditionally linked to frontal lobe functioning (Stroop colour–word interference and Tower of London planning tasks) and one test of pragmatic social communication skills. Conclusions: Counterfactual thinking is impaired in Parkinson's disease. This impairment may be related to frontal lobe dysfunction. PMID:12876235
He, Hao; Bustillo, Juan; Du, Yuhui; Yu, Qingbao; Jones, Thomas R.; Jiang, Tianzi; Calhoun, Vince D.; Sui, Jing
The cognitive deficits of schizophrenia are largely resistant to current treatment, and are thus a life-long burden to patients. The MATRICS consensus cognitive battery (MCCB) provides a reliable and valid assessment of cognition across a comprehensive set of cognitive domains for schizophrenia. In resting-state fMRI, functional connectivity associated with MCCB has not yet been examined. In this paper, the interrelationships between MCCB and the abnormalities seen in two types of functional measures from resting-state fMRI—fractional amplitude of low frequency fluctuations (fALFF) and functional network connectivity (FNC) maps were investigated in data from 47 schizophrenia patients and 50 age-matched healthy controls. First, the fALFF maps were generated and decomposed by independent component analysis (ICA), and then the component showing the highest correlation with MCCB composite scores was selected. Second, the whole brain was separated into functional networks by group ICA, and the FNC maps were calculated. The FNC strengths with most significant correlations with MCCB were displayed and spatially overlapped with the fALFF component of interest. It demonstrated increased cognitive performance associated with higher fALFF values (intensity of regional spontaneous brain activity) in prefrontal regions, inferior parietal lobe (IPL) but lower ALFF values in thalamus, striatum, and superior temporal gyrus (STG). Interestingly, the FNC showing significant correlations with MCCB were in well agreement with the activated regions with highest z-values in fALFF component. Our results support the view that functional deficits in distributed cortico-striato-thalamic circuits and inferior parietal lobe may account for several aspects of cognitive impairment in schizophrenia.
Delusional beliefs are characteristic of psychosis and, of the delusions, the paranoid delusion is the single most common type associated with psychosis. The many years of research focused on neurocognition in schizophrenia, using standardized neurocognitive tests, have failed to find conclusive cognitive deficits in relation to positive symptoms. However, UK-based psychological research has identified sociocognitive anomalies in relation to paranoid thinking in the form of theory of mind (ToM), causal reasoning and threat-related processing anomalies. Drawing from recent neuroscientific research on the default mode network, this paper asserts that the common theme running through the psychological tests that are sensitive to the cognitive impairment of paranoia is the need to cognitively project the self through time, referred to as mental time travel. Such an understanding of the cognitive roots of paranoid ideation provides a synthesis between psychological and biological accounts of psychosis while also retaining the powerful argument that understanding abnormal thinking must start with models of normal cognition. This is the core theme running through the cognitive psychological literature of psychiatric disorders that enables research from this area to inform psychological therapy.
Background This is an update of a previous meta-analysis published in 2005. Methods It includes the data published up to march 2010 for a total of 247 papers and 18,300 cases. Cognitive deficits are examined in 5 different domains: Memory functioning (128 studies), Global cognitive functioning (131 studies), Language (70 studies), Executive function (67 studies), Attention (76 studies). Only controlled studies were included: patients vs. normal subjects. Results Results evidence that in all domains and in all different analyses performed within each domain, patients show a significant reduction of cognitive efficiency with respect to normal subjects. The between studies heterogeneity is very high in almost all domains. There are various sources of this heterogeneity (age, sex, sample size, type of patients, and type of measurement) which contribute to the high degree of not-overlapping information offered by the single studies. Conclusions Our results, based on the current scientific evidence, confirm the previous findings that there is a generalized impairment of various cognitive functions in patients with schizophrenia when compared to normal cases. The modalities with which these results are obtained have not changed over the years and the more recent studies do not modify the high heterogeneity previously found between the studies. This reduces the methodological quality of the results. In order to improve the methodological quality of the studies performed in the field of cognitive deficits of patients with schizophrenia, various factors should be taken into account and better managed in designing future studies. PMID:22715980
Heflin, Lara H; Meyerowitz, Beth E; Hall, Per; Lichtenstein, Paul; Johansson, Boo; Pedersen, Nancy L; Gatz, Margaret
Previous studies have shown that cancer survivors frequently experience short-term cognitive deficits, but it is unknown how long these deficits last or whether they worsen over time. Using a co-twin control design, the cognitive function of 702 cancer survivors aged 65 years and older was compared with that of their cancer-free twins. Dementia rates were also compared in 486 of the twin pairs discordant for cancer. Cancer survivors overall, as well as individuals who had survived cancer for 5 or more years before cognitive testing, were more likely than their co-twins to have cognitive dysfunction (odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.36 to 3.24; P<.001; and OR = 2.71, 95% CI = 1.47 to 5.01; P<.001, respectively). Cancer survivors were also twice as likely to be diagnosed with dementia as their co-twins, but this odds ratio did not reach statistical significance (OR = 2.0, 95% CI = 0.86 to 4.67; P = .10). These results suggest that cancer patients are at increased risk for long-term cognitive dysfunction compared with individuals who have never had cancer, even after controlling for the influence of genetic factors and rearing environment.
Lu, Ping; Mamiya, Takayoshi; Lu, Lingling; Mouri, Akihiro; Niwa, Minae; Kim, Hyoung-Chun; Zou, Li-Bo; Nagai, Taku; Yamada, Kiyofumi; Ikejima, Takashi; Nabeshima, Toshitaka
Cognitive deficits are a core feature of patients with methamphetamine (METH) abuse. It has been reported that repeated METH treatment impairs long-term recognition memory in the novel object recognition test (NORT) in mice. Recent studies indicate that silibinin, a flavonoid derived from the herb milk thistle, has potent neuroprotective effects in cell cultures and several animal models of neurological diseases. However, its effect on the cognitive deficit induced by METH remains unclear. In the present study, we attempt to clarify the effect of silibinin on impairments of recognition memory caused by METH in mice. Mice were co-administered silibinin with METH for 7 days and then cognitive function was assessed by NORT after 7-day withdrawal. Tissue levels of dopamine and serotonin as well as their metabolites in the prefrontal cortex and hippocampus were measured 1 day after NORT. Silibinin dose-dependently ameliorated the impairment of recognition memory caused by METH treatment in mice. Silibinin significantly attenuated the decreases in the dopamine content of the prefrontal cortex and serotonin content of the hippocampus caused by METH treatment. We also found a correlation between the recognition values and dopamine and serotonin contents of the prefrontal cortex and hippocampus. The effect of silibinin on cognitive impairment may be associated with an amelioration of decreases in dopamine and serotonin levels in the prefrontal cortex and hippocampus, respectively. These results suggest that silibinin may be useful as a pharmacological tool to investigate the mechanisms of METH-induced cognitive impairments.
Sircar, R; Wu, L-C; Reddy, K; Sircar, D; Basak, A K
We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex.
Sircar, R; Wu, L-C; Reddy, K; Sircar, D; Basak, A.K
We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex. PMID:21886597
Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J
The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.
Arai, Sawako; Takuma, Kazuhiro; Mizoguchi, Hiroyuki; Ibi, Daisuke; Nagai, Taku; Kamei, Hiroyuki; Kim, Hyoung-Chun; Yamada, Kiyofumi
In this study, we investigated the effects of GABA(A) and GABA(B) receptor agonists on the methamphetamine-induced impairment of recognition memory in mice. Repeated treatment with methamphetamine at a dose of 1 mg/kg for 7 days induced an impairment of recognition memory. Baclofen, a GABA(B) receptor agonist, ameliorated the repeated methamphetamine-induced cognitive impairment, although gaboxadol, a GABA(A) receptor agonist, had no significant effect. GABA(B) receptors may constitute a putative new target in treating cognitive deficits in patients suffering from schizophrenia, as well as methamphetamine psychosis.
Shin, Yeon-Jeong; Joo, Yo-Han; Kim, Jong-Hoon
Background We investigated self-perceived cognitive deficits and their relationship with internalized stigma and quality of life in patients with schizophrenia in order to shed light on the clinical correlates of subjective cognitive deficits in schizophrenia. Methods Seventy outpatients with schizophrenia were evaluated. Patients’ self-perceived cognitive deficits, internalized stigma, and subjective quality of life were assessed using the Scale to Investigate Cognition in Schizophrenia (SSTICS), the Internalized Stigma of Mental Illness Scale (ISMI), and the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4), respectively. Correlation and regression analyses controlling for the severity of symptoms of schizophrenia were performed, and a mediation analysis was conducted to examine the hypothesis that internalized stigma mediates the relationship between self-perceived cognitive deficits and subjective quality of life. Results Pearson’s partial correlation analysis showed significant correlations among the SSTICS, ISMI, and SQLS-R4 scores (P<0.01). Multiple regression analysis showed that the SSTICS and ISMI scores significantly predicted the SQLS-R4 score (P<0.01). Mediation analysis revealed that the strength of the association between the SSTICS and SQLS-R4 scores decreased from β=0.74 (P<0.01) to β=0.56 (P<0.01), when the ISMI score was statistically controlled. The Sobel test revealed that this difference was significant (P<0.01), indicating that internalized stigma partially mediated the relationship between self-perceived cognitive deficits and quality of life. Conclusion The present study indicates that self-perceived cognitive deficits are significantly associated with internalized stigma and quality of life. Furthermore, internalized stigma was identified as a partial mediator of the relationship between self-perceived cognitive deficits and quality of life. These findings suggest that clinicians should be aware that patients with
University in City of New York New York, NY 10032-3725 REPORT DATE: April 2013 TYPE OF REPORT: Annual Report PREPARED FOR: U.S. Army Medical...this report are those of the author( s ) and should not be construed as an official Department of the Army position, policy or decision unless so...1-0142 Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil. 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S
Garcia, Vanessa Athaíde; Hirotsu, Camila; Matos, Gabriela; Alvarenga, Tathiana; Pires, Gabriel Natan; Kapczinski, Flávio; Schröder, Nadja; Tufik, Sergio; Andersen, Monica Levy
Animals exposed to an early adverse event may be more susceptible to a second source of stress later in life, and these stressors may have additive deleterious effects. Sleep deprivation is known to be a stressor, affecting multiple body functions such as the cognition. Modafinil enhances working memory and attention in healthy non-sleep deprived subjects and in animal models of sleep deprivation. The first aim of the present study was to investigate the effects of maternal separation (MS) combined with paradoxical sleep deprivation (PSD) in adulthood on recognition memory in rats. Second, we aimed to evaluate whether the administration of modafinil would be able to ameliorate memory deficits induced by MS and PSD. Wistar rat pups were initially distributed into MS and handling (H) groups, with their litters standardized in 4 females and 4 males. In adulthood, the male rats were submitted to PSD or control condition, being redistributed afterwards in modafinil- or vehicle-treatment immediately after the training session of object recognition task. PSD did not potentiate the cognitive deficit due to MS. However, modafinil was able to recover memory impairments associated to PSD and also to MS in the neonatal period. This study demonstrates for the first time that modafinil ameliorates cognitive deficits associated to MS and to PSD in adulthood, independent from MS in the neonatal period.
Horiuchi, Y; Kondo, M A; Okada, K; Takayanagi, Y; Tanaka, T; Ho, T; Varvaris, M; Tajinda, K; Hiyama, H; Ni, K; Colantuoni, C; Schretlen, D; Cascella, N G; Pevsner, J; Ishizuka, K; Sawa, A
Cognitive impairment is a key feature of schizophrenia (SZ) and determines functional outcome. Nonetheless, molecular signatures in neuronal tissues that associate with deficits are not well understood. We conducted nasal biopsy to obtain olfactory epithelium from patients with SZ and control subjects. The neural layers from the biopsied epithelium were enriched by laser-captured microdissection. We then performed an unbiased microarray expression study and implemented a systematic neuropsychological assessment on the same participants. The differentially regulated genes in SZ were further filtered based on correlation with neuropsychological traits. This strategy identified the SMAD 5 gene, and real-time quantitative PCR analysis also supports downregulation of the SMAD pathway in SZ. The SMAD pathway has been important in multiple tissues, including the role for neurodevelopment and bone formation. Here the involvement of the pathway in adult brain function is suggested. This exploratory study establishes a strategy to better identify neuronal molecular signatures that are potentially associated with mental illness and cognitive deficits. We propose that the SMAD pathway may be a novel target in addressing cognitive deficit of SZ in future studies. PMID:27727244
Li, Qiliang; Song, Wenqi; Tian, Ze; Wang, Peichang
Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Many "treated" patients continued to display various degrees of mental retardation and psychomotor delay, which could be caused by brain damage from elevated oxidative stress. Aminoguanidine (AG), a synthetic antioxidant, was tested in a MMA rat model for its potential therapeutic effects on memory impairment. The effects of AG on MMA-induced cognitive impairment in Wistar rats were evaluated with Morris Water Maze. The levels of nerve cell apoptosis and microglial activation were investigated to illustrate the mechanisms of the improvement of cognition with AG treatment in MMA rats. To further explore the mechanism of neuroprotection induced by AG, several biomarkers including free radicals and inflammatory cytokines in the hippocampus were quantified. The results showed that the rats treated with AG exhibited better neurological behavior performances than MMA model rats. The AG-treated rats had a decreased level of apoptosis of the hippocampal neurons, which could be the structural basis of the observed neural behavior protection. In addition, AG treatment significantly inhibited the activation of microglia. The AG-treated rats had decreased levels of IL-1β, IL-6, TNF-α, NO, malonaldehyde and iNOS activities in the hippocampus. The level of glutathione and superoxide dismutase activity in the hippocampus of the AG-treated rats increased significantly. In conclusion, AG could alleviate the MMA-induced cognitive impairment via down-regulating of oxidative stress and inflammatory reaction and provide a basis as a therapeutic potential against MMA-induced cognitive impairment.
Gormezano, Linda J; Rockwell, Robert F
Climate change is predicted to expand the ice-free season in western Hudson Bay and when it grows to 180 days, 28-48% of adult male polar bears are projected to starve unless nutritional deficits can be offset by foods consumed on land. We updated a dynamic energy budget model developed by Molnar et al. to allow influx of additional energy from novel terrestrial foods (lesser snow geese, eggs, caribou) that polar bears currently consume as part of a mixed diet while on land. We calculated the units of each prey, alone and in combination, needed to alleviate these lethal energy deficits under conditions of resting or limited movement (2 km d-1) prior to starvation. We further considered the total energy available from each sex and age class of each animal prey over the period they would overlap land-bound polar bears and calculated the maximum number of starving adult males that could be sustained on each food during the ice-free season. Our results suggest that the net energy from land-based food, after subtracting costs of limited movement to obtain it, could eliminate all projected nutritional deficits of starving adult male polar bears and likely other demographic groups as well. The hunting tactics employed, success rates as well as behavior and abundance of each prey will determine the realized energetic values for individual polar bears. Although climate change may cause a phenological mismatch between polar bears and their historical ice-based prey, it may simultaneously yield a new match with certain land-based foods. If polar bears can transition their foraging behavior to effectively exploit these resources, predictions for starvation-related mortality may be overestimated for western Hudson Bay. We also discuss potential complications with stable-carbon isotope studies to evaluate utilization of land-based foods by polar bears including metabolic effects of capture-related stress and consuming a mixed diet.
Gormezano, Linda J.; Rockwell, Robert F.
Climate change is predicted to expand the ice-free season in western Hudson Bay and when it grows to 180 days, 28–48% of adult male polar bears are projected to starve unless nutritional deficits can be offset by foods consumed on land. We updated a dynamic energy budget model developed by Molnar et al. to allow influx of additional energy from novel terrestrial foods (lesser snow geese, eggs, caribou) that polar bears currently consume as part of a mixed diet while on land. We calculated the units of each prey, alone and in combination, needed to alleviate these lethal energy deficits under conditions of resting or limited movement (2 km d-1) prior to starvation. We further considered the total energy available from each sex and age class of each animal prey over the period they would overlap land-bound polar bears and calculated the maximum number of starving adult males that could be sustained on each food during the ice-free season. Our results suggest that the net energy from land-based food, after subtracting costs of limited movement to obtain it, could eliminate all projected nutritional deficits of starving adult male polar bears and likely other demographic groups as well. The hunting tactics employed, success rates as well as behavior and abundance of each prey will determine the realized energetic values for individual polar bears. Although climate change may cause a phenological mismatch between polar bears and their historical ice-based prey, it may simultaneously yield a new match with certain land-based foods. If polar bears can transition their foraging behavior to effectively exploit these resources, predictions for starvation-related mortality may be overestimated for western Hudson Bay. We also discuss potential complications with stable-carbon isotope studies to evaluate utilization of land-based foods by polar bears including metabolic effects of capture-related stress and consuming a mixed diet. PMID:26061693
Whitson, Heather E.; Whitaker, Diane; Potter, Guy; McConnell, Eleanor; Tripp, Fay; Sanders, Linda L.; Muir, Kelly W.; Cohen, Harvey J.; Cousins, Scott W.
Objective To design and pilot test a low vision rehabilitation program for patients with macular disease and cognitive deficits. Methods The Memory or Reasoning Enhanced Low Vision Rehabilitation (MORE-LVR) program was created by a team representing optometry, occupational therapy, ophthalmology, neuropsychology, and geriatrics. Key components of MORE-LVR are: 1) repetitive training with a therapist twice weekly over a 6-week period, 2) simplified training experience addressing no more than three individualized goals in a minimally distracting environment, 3) involvement of an informal companion (friend or family member). Eligible patients were recruited from an LVR clinic; measures were compared before and after the 6 week program. Results Twelve non-demented patients (mean age 84.5 years, 75% female) who screened positive for cognitive deficits completed the MORE-LVR intervention. Participants demonstrated improved scores on the National Eye Institute’s Visual Function Questionnaire (VFQ-25) composite score (47.2±16.3 to 54.8±13.8, p=0.01) and near activities score (21.5±14.0 to 41.0±23.1, p=0.02), timed performance measures (writing a grocery list [p=0.03], filling in a crossword puzzle answer [p=0.003]), a score indicating satisfaction with independence (p=0.05), and logical memory (p=0.02). All patients and companions reported progress toward at least one individualized goal; >70% reported progress toward all three goals. Conclusions This pilot study demonstrates feasibility of an LVR program for macular disease patients with mild cognitive deficits. Participants demonstrated improvements in vision-related function and cognitive measures and expressed high satisfaction. Future work is needed to determine if MORE-LVR is superior to usual outpatient LVR for persons with co-existing visual and cognitive impairments. PMID:23619914
Wu, Tiffany; Hanson, Jesse E.; Alam, Nazia M.; Ngu, Hai; Lauffer, Benjamin E.; Lin, Han H.; Dominguez, Sara L.; Reeder, Jens; Tom, Jennifer; Steiner, Pascal; Foreman, Oded; Prusky, Glen T.
Abstract Age is the main risk factor for sporadic Alzheimer’s disease. Yet, cognitive decline in aged rodents has been less well studied, possibly due to concomitant changes in sensory or locomotor function that can complicate cognitive tests. We tested mice that were 3, 11, and 23 months old in cognitive, sensory, and motor measures, and postmortem measures of gliosis and neural activity (c-Fos). Hippocampal synaptic function was also examined. While age-related impairments were detectable in tests of spatial memory, greater age-dependent effects were observed in tests of associative learning [active avoidance (AA)]. Gross visual function was largely normal, but startle responses to acoustic stimuli decreased with increased age, possibly due to hearing impairments. Therefore, a novel AA variant in which light alone served as the conditioning stimuli was used. Age-related deficits were again observed. Mild changes in vision, as measured by optokinetic responses, were detected in 19- versus 4-month-old mice, but these were not correlated to AA performance. Thus, deficits in hearing or vision are unlikely to account for the observed deficits in cognitive measures. Increased gliosis was observed in the hippocampal formation at older ages. Age-related changes in neural function and plasticity were observed with decreased c-Fos in the dentate gyrus, and decreased synaptic strength and paired-pulse facilitation in CA1 slices. This work, which carefully outlines age-dependent impairments in cognitive and synaptic function, c-Fos activity, and gliosis during normal aging in the mouse, suggests robust translational measures that will facilitate further study of the biology of aging. PMID:26473169
Williams, Jonathan; Taylor, Eric
The underlying defects in ADHD (Attention Deficit/Hyperactivity Disorder) are not yet clear. The current paper tests three existing theories: State Regulation, Cognitive Deficit, and Temporal Difference (TD) learning. We present computational simulations of the Matching Familiar Figures Task and compare these with the experimental results reported by Sonuga- Barke (2002). The TD model contains four parameters: the learning rate, discounting for future rewards, brittleness (randomness) of behavior, and action bias. The results show that the basic TD model accounts well for control performance in trials of 5 sec, 10 sec, and 15 sec duration; but not for the deficits in ADHD performance at 5 sec and 15 sec. Extending the TD model to incorporate either a state regulation deficit, or working memory deficit and delay in starting trials, can provide a good account of both control and ADHD results, at all trial-lengths. We discuss the significance of the results for theories of ADHD and make suggestions for future experimentation. PMID:15303309
Schulz, Kurt P; Bédard, Anne-Claude V; Fan, Jin; Clerkin, Suzanne M; Dima, Danai; Newcorn, Jeffrey H; Halperin, Jeffrey M
Affect recognition deficits found in individuals with attention-deficit/hyperactivity disorder (ADHD) across the lifespan may bias the development of cognitive control processes implicated in the pathophysiology of the disorder. This study aimed to determine the mechanism through which facial expressions influence cognitive control in young adults diagnosed with ADHD in childhood. Fourteen probands with childhood ADHD and 14 comparison subjects with no history of ADHD were scanned with functional magnetic resonance imaging while performing a face emotion go/no-go task. Event-related analyses contrasted activation and functional connectivity for cognitive control collapsed over face valence and tested for variations in activation for response execution and inhibition as a function of face valence. Probands with childhood ADHD made fewer correct responses and inhibitions overall than comparison subjects, but demonstrated comparable effects of face emotion on response execution and inhibition. The two groups showed similar frontotemporal activation for cognitive control collapsed across face valence, but differed in the functional connectivity of the right dorsolateral prefrontal cortex, with fewer interactions with the subgenual cingulate cortex, inferior frontal gyrus, and putamen in probands than in comparison subjects. Further, valence-dependent activation for response execution was seen in the amygdala, ventral striatum, subgenual cingulate cortex, and orbitofrontal cortex in comparison subjects but not in probands. The findings point to functional anomalies in limbic networks for both the valence-dependent biasing of cognitive control and the valence-independent cognitive control of face emotion processing in probands with childhood ADHD. This limbic dysfunction could impact cognitive control in emotional contexts and may contribute to the social and emotional problems associated with ADHD.
Bellgrove, Mark A; Hawi, Ziarih; Gill, Michael; Robertson, Ian H
Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DbetaH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.
Kunitachi, Shinsui; Fujita, Yuko; Ishima, Tamaki; Kohno, Mami; Horio, Mao; Tanibuchi, Yuko; Shirayama, Yukihiko; Iyo, Masaomi; Hashimoto, Kenji
This study was undertaken to examine the effects of two acetylcholinesterase inhibitors (donepezil and physostigmine) on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (14 days) administration of donepezil (1.0 mg/kg/day), but not donepezil (0.1 mg/kg/day). Furthermore, the effect of donepezil (1.0 mg/kg/day) on PCP-induced cognitive deficits was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1.0 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of donepezil. In contrast, PCP-induced cognitive deficits were not improved by subsequent subchronic (14 days) administration of physostigmine (0.25 mg/kg/day). Moreover, repeated administration of PCP significantly caused the reduction of sigma-1 receptors in the hippocampus. The present study suggests that agonistic activity of donepezil at sigma-1 receptors plays a role in the active mechanisms of donepezil on PCP-induced cognitive deficits in mice. Therefore, it is likely that donepezil would be potential therapeutic drugs for the treatment of the cognitive deficits in schizophrenia.
Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Ontiveros, Esperanza; Gómez-Garza, Gilberto; Barragán-Mejía, Gerardo; Broadway, James; Chapman, Susan; Valencia-Salazar, Gildardo; Jewells, Valerie; Maronpot, Robert R; Henríquez-Roldán, Carlos; Pérez-Guillé, Beatriz; Torres-Jardón, Ricardo; Herrit, Lou; Brooks, Diane; Osnaya-Brizuela, Norma; Monroy, Maria E; González-Maciel, Angelica; Reynoso-Robles, Rafael; Villarreal-Calderon, Rafael; Solt, Anna C; Engle, Randall W
Exposure to air pollution is associated with neuroinflammation in healthy children and dogs in Mexico City. Comparative studies were carried out in healthy children and young dogs similarly exposed to ambient pollution in Mexico City. Children from Mexico City (n: 55) and a low polluted city (n:18) underwent psychometric testing and brain magnetic resonance imaging MRI. Seven healthy young dogs with similar exposure to Mexico City air pollution had brain MRI, measurement of mRNA abundance of two inflammatory genes cyclooxygenase-2, and interleukin 1 beta in target brain areas, and histopathological evaluation of brain tissue. Children with no known risk factors for neurological or cognitive disorders residing in a polluted urban environment exhibited significant deficits in a combination of fluid and crystallized cognition tasks. Fifty-six percent of Mexico City children tested showed prefrontal white matter hyperintense lesions and similar lesions were observed in dogs (57%). Exposed dogs had frontal lesions with vascular subcortical pathology associated with neuroinflammation, enlarged Virchow-Robin spaces, gliosis, and ultrafine particulate matter deposition. Based on the MRI findings, the prefrontal cortex was a target anatomical region in Mexico City children and its damage could have contributed to their cognitive dysfunction. The present work presents a groundbreaking, interdisciplinary methodology for addressing relationships between environmental pollution, structural brain alterations by MRI, and cognitive deficits/delays in healthy children.
Christakis, D. A.; Ramirez, J. S. B.; Ramirez, J. M.
Observational studies in humans have found associations between overstimulation in infancy via excessive television viewing and subsequent deficits in cognition and attention. We developed and tested a mouse model of overstimulation whereby p10 mice were subjected to audio (70 db) and visual stimulation (flashing lights) for six hours per day for a total of 42 days. 10 days later cognition and behavior were tested using the following tests: Light Dark Latency, Elevated Plus Maze, Novel Object Recognition, and Barnes Maze. In all tests, overstimulated mice performed significantly worse compared to controls suggesting increased activity and risk taking, diminished short term memory, and decreased cognitive function. These findings suggest that excessive non-normative stimulation during critical periods of brain development can have demonstrable untoward effects on subsequent neurocognitive function. PMID:22855702
Dockstader, Colleen; Wang, Frank; Bouffet, Eric; Mabbott, Donald J
Cognitive impairment is consistently reported in children treated for brain tumors, particularly in the categories of processing speed, memory, and attention. Although tumor site, hydrocephalus, chemotherapy, and cranial radiation therapy (CRT) are all associated with poorer function, CRT predicts the greatest deficits. There is a particularly high correlation between CRT and slowed information-processing speed. Cortical gamma-band oscillations have been associated with processing behaviorally relevant information; however, their role in the maintenance of cognition in individuals with processing deficits is unclear. We examined gamma oscillations using magnetoencephalography (MEG) in children undergoing CRT to test whether gamma characteristics can be a signature of cognitive impairment in this population. We collected resting-state data as well as data from baseline and active periods during two visual-motor reaction time tasks of varying cognitive loads from 18 healthy children and 20 patients. We found that only high-gamma oscillations (60-100 Hz), and not low-gamma oscillations (30-59 Hz), showed significant group differences in absolute power levels. Overall, compared with healthy children, patients showed the following: (1) lower total high-gamma (60-100 Hz) power during the resting state, as well as during task-related baseline and performance measures; (2) no change in gamma reactivity to increases in cognitive load; and (3) slower processing speeds both inside and outside MEG. Our findings show that high-gamma oscillations are disrupted in children after treatment for a brain tumor. The temporal dynamic of the high-gamma response during information processing may index cognitive impairment in humans with neurological injury.
Lieberman, Philip; Morey, Angie; Hochstadt, Jesse; Larson, Mara; Mather, Sandra
In deep-space missions, the basal ganglia and hippocampus, subcortical structures of the brain that play critical roles in motor activity, cognition, and memory, will be vulnerable to damage from cosmic rays. These metabolically active structures are also sensitive to damage arising from the low oxygen content of air at extreme altitudes. We have, therefore, used Mount Everest as an analogue for deep space, where astronauts will be subject to danger and stress as well as neural damage. We can ethically obtain data because our climber-subjects already intend to climb Mt. Everest. We record speech and test cognitive and linguistic performance before, during, and after exposure to hypoxic conditions. From these data we have derived and validated computer-implemented acoustic voice measures that track slight as well as profound cognitive impairment. Vowel duration and speech motor sequencing errors increase as climbers ascend, reflecting degraded basal ganglia activity. These metrics detect deficits in language comprehension and the ability to change plans in changing circumstances. Preliminary analyses also reveal memory deficits reflecting hippocampal damage. Our speech metrics are unobtrusive and do not reveal the content of a verbal message; they could be derived automatically, allowing space crews to detect subtle motor and cognitive deficits and invoke countermeasures before performance is profoundly impaired. In future work we will be validating the voice metrics of stress in collaboration with the Dinges NSBRI laboratory study of task-induced stress. Our procedures can also be applied in general aviation and in the treatment of Parkinson's disease, Alzheimer's dementia, and other neurological disorders.
Ganai, Ajaz Ahmad; Husain, Mohammad
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from acute liver failure. Previously, we demonstrated hepatoprotective effects of genistein in D-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF). In this study, we evaluated behavioural and neuroprotective effects of genistein in rat model of HE. HE was induced by intraperitonial administration of D-GalN (250 mg/kg BW) twice a week for 30 days Genistein was given as co-treatment through oral gavage daily at dose of 5 mg/kg BW. D-GalN administration significantly resulted in acute liver failure which was further associated with hyperammonemia, neurological dysfunction, as evident from behavioural and functional impairment and reduced learning ability in Morris water maze. Genistein significantly alleviated behavioural and functional impairment and restored learning ability in Morris water maze. Considerable histopathological changes, including portal inflammation, sinusoidal dilation, necrotic lesions and swelled astrocytes with pale nuclei, were seen in the liver and brain sections of D-GalN-challenged rats while genistein co-treated rats revealed normal cellular and morphological architecture as no pathological features were seen. Furthermore, pro-inflammatory markers (interleukin (IL)-10, IL-4, IL-1β and TNF-α) and membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA marked significant increase, while subunits GluR1 of AMPA receptors showed reduced expression in D-GalN-challenged rats leading to neuroinflammation and dysregulated neurotransmission. Genistein significantly normalized altered expression of pro-inflammatory cytokines and membrane receptor of GABA and GluR. Our study suggests strong therapeutic potential of genistein in animal model of HE. Genistein can be used a strong anti-oxidant to attenuate neurotoxic effects of xenobiotics.
Tajima, Miyuki; Kimura, Risa; Sasaki, Norio; Somemura, Hironori; Ito, Yukio; Okanoya, June; Yamamoto, Megumi; Nakamura, Saki; Tanaka, Katsutoshi
Background A number of psychoeducational programs based on cognitive behavioral therapy (CBT) to alleviate psychological distress have been developed for implementation in clinical settings. However, while these programs are considered critical components of stress management education in a workplace setting, they are required to be brief and simple to implement, which can hinder development. Objective The intent of the study was to examine the effects of a brief training program based on CBT in alleviating psychological distress among employees and facilitating self-evaluation of stress management skills, including improving the ability to recognize dysfunctional thinking patterns, transform dysfunctional thoughts to functional ones, cope with stress, and solve problems. Methods Of the 187 employees at an information technology company in Tokyo, Japan, 168 consented to participate in our non-blinded randomized controlled study. The training group received CBT group education by a qualified CBT expert and 1 month of follow-up Web-based CBT homework. The effects of this educational program on the psychological distress and stress management skills of employees were examined immediately after completion of training and then again after 6 months. Results Although the training group did exhibit lower mean scores on the Kessler-6 (K6) scale for psychological distress after 6 months, the difference from the control group was not significant. However, the ability of training group participants to recognize dysfunctional thinking was significantly improved both immediately after training completion and after 6 months. While the ability of participants to cope with stress was not significantly improved immediately after training, improvement was noted after 6 months in the training group. No notable improvements were observed in the ability of participants to transform thoughts from dysfunctional to functional or in problem-solving skills. A sub-analysis of participants who
Avtzon, Sarah Abitbol
Working memory, executive functions, and cognitive processes associated with specific academic areas, are empirically identified as being the core underlying cognitive deficits in students with specific learning disabilities. Using Hebb's theory of neuroplasticity and the principle of automaticity as theoretical bases, this experimental study…
Mohammed, Ali Mohammed Haidar
The present study aims to identify the level of cognitive skills and abilities of children who suffer from the Attention Deficit and Hyperactivity Disorder (ADHD) and the differences in the level of cognitive skills and abilities according to the age group and the level of academic achievement. To achieve the objective of the study, a…
Matzke, Dora; Hughes, Matthew; Badcock, Johanna C; Michie, Patricia; Heathcote, Andrew
We used Bayesian cognitive modelling to identify the underlying causes of apparent inhibitory deficits in the stop-signal paradigm. The analysis was applied to stop-signal data reported by Badcock et al. (Psychological Medicine 32: 87-297, 2002) and Hughes et al. (Biological Psychology 89: 220-231, 2012), where schizophrenia patients and control participants made rapid choice responses, but on some trials were signalled to stop their ongoing response. Previous research has assumed an inhibitory deficit in schizophrenia, because estimates of the mean time taken to react to the stop signal are longer in patients than controls. We showed that these longer estimates are partly due to failing to react to the stop signal ("trigger failures") and partly due to a slower initiation of inhibition, implicating a failure of attention rather than a deficit in the inhibitory process itself. Correlations between the probability of trigger failures and event-related potentials reported by Hughes et al. are interpreted as supporting the attentional account of inhibitory deficits. Our results, and those of Matzke et al. (2016), who report that controls also display a substantial although lower trigger-failure rate, indicate that attentional factors need to be taken into account when interpreting results from the stop-signal paradigm.
Jusyte, Aiste; Schönenberg, Michael
Aggressive behavior is assumed to be associated with certain patterns of social information processing. While some theories link aggression to a tendency to interpret ambiguous stimuli as hostile (i.e., enhanced sensitivity to anger), others assume an insufficient ability to perceive emotional expressions, particularly fear. Despite compelling evidence to support both theories, no previous study has directly investigated the predictions made by these two accounts in aggressive populations. The aim of the current study was to test processing patterns for angry and fearful facial expressions in violent offenders (VOs) and healthy controls (CTLs) and their association with self-reported aggression and psychopathy scores. In Experiment 1, we assessed perceptual sensitivity to neutral-emotional (angry, fearful, happy) blends in a task which did not require categorization, but an indication whether the stimulus is neutral or emotional. In Experiment 2, we assessed categorization performance for ambiguous fearful-happy and angry-happy blends. No group differences were revealed in Experiment 1, while Experiment 2 indicated a deficit in the categorization of ambiguous fearful blends in the VO group. Importantly, this deficit was associated with both self-reported psychopathy and aggression in the VO, but not the CTL group. The current study provides evidence for a deficient categorization of fearful expressions and its association with self-reported aggression and psychopathy in VOs, but no support for heightened sensitivity to anger. Furthermore, the current findings indicate that the deficit is tied to categorization but not detection stages of social information processing.
Gonzalez-Gadea, Maria Luz; Herrera, Eduar; Parra, Mario; Gomez Mendez, Pedro; Baez, Sandra; Manes, Facundo; Ibanez, Agustin
Emotion recognition and empathy abilities require the integration of contextual information in real-life scenarios. Previous reports have explored these domains in adolescent offenders (AOs) but have not used tasks that replicate everyday situations. In this study we included ecological measures with different levels of contextual dependence to evaluate emotion recognition and empathy in AOs relative to non-offenders, controlling for the effect of demographic variables. We also explored the influence of fluid intelligence (FI) and executive functions (EFs) in the prediction of relevant deficits in these domains. Our results showed that AOs exhibit deficits in context-sensitive measures of emotion recognition and cognitive empathy. Difficulties in these tasks were neither explained by demographic variables nor predicted by FI or EFs. However, performance on measures that included simpler stimuli or could be solved by explicit knowledge was either only partially affected by demographic variables or preserved in AOs. These findings indicate that AOs show contextual social-cognition impairments which are relatively independent of basic cognitive functioning and demographic variables. PMID:25374529
Lim, Tae Sung; Lee, Hyun Young; Barton, Jason J S; Moon, So Young
The fusiform gyrus is involved pathologically at an early stage of the amnestic form of mild cognitive impairment (aMCI), and is also known to be involved in the perceptual stage of face processing. We assessed face perception in patients with aMCI to determine if this cognitive skill was impaired. We compared 12 individuals (4 men) with aMCI and 12 age- and education-matched healthy controls on the ability to discriminate changes in the spatial configuration or color of the eyes or the mouth in faces. Patients with aMCI performed less quickly and accurately for all changes on trials with limited viewing duration. With unlimited duration, they could achieve normal perceptual accuracy for configural changes to the mouth, but remained impaired for changes to eye color or configuration. Patients with aMCI show deficits in face perception that are more pronounced for the highly salient ocular region, a pattern similar to that seen in acquired prosopagnosia. This form of perceptual impairment may be an early marker of additional cognitive deficits beyond memory in aMCI.
Hendry, Kathryn; Ownsworth, Tamara; Beadle, Elizabeth; Chevignard, Mathilde P.; Fleming, Jennifer; Griffin, Janelle; Shum, David H. K.
People with severe traumatic brain injury (TBI) often make errors on everyday tasks that compromise their safety and independence. Such errors potentially arise from the breakdown or failure of multiple cognitive processes. This study aimed to investigate cognitive deficits underlying error behavior on a home-based version of the Cooking Task (HBCT) following TBI. Participants included 45 adults (9 females, 36 males) with severe TBI aged 18–64 years (M = 37.91, SD = 13.43). Participants were administered the HBCT in their home kitchens, with audiovisual recordings taken to enable scoring of total errors and error subtypes (Omissions, Additions, Estimations, Substitutions, Commentary/Questions, Dangerous Behavior, Goal Achievement). Participants also completed a battery of neuropsychological tests, including the Trail Making Test, Hopkins Verbal Learning Test-Revised, Digit Span, Zoo Map test, Modified Stroop Test, and Hayling Sentence Completion Test. After controlling for cooking experience, greater Omissions and Estimation errors, lack of goal achievement, and longer completion time were significantly associated with poorer attention, memory, and executive functioning. These findings indicate that errors on naturalistic tasks arise from deficits in multiple cognitive domains. Assessment of error behavior in a real life setting provides insight into individuals' functional abilities which can guide rehabilitation planning and lifestyle support. PMID:27790099
Bender, Alex C.; Luikart, Bryan W.; Lenck-Santini, Pierre-Pascal
Brain oscillations play a critical role in information processing and may, therefore, be essential to uncovering the mechanisms of cognitive impairment in neurological disease. In Dravet syndrome (DS), a mutation in SCN1A, coding for the voltage-gated sodium channel Nav1.1, is associated with severe cognitive impairment and seizures. While seizure frequency and severity do not correlate with the extent of impairment, the slowing of brain rhythms may be involved. Here we investigate the role of Nav1.1 on brain rhythms and cognition using RNA interference. We demonstrate that knockdown of Nav1.1 impairs fast- and burst-firing properties of neurons in the medial septum in vivo. The proportion of neurons that fired phase-locked to hippocampal theta oscillations was reduced, and medial septal regulation of theta rhythm was disrupted. During a working memory task, this deficit was characterized by a decrease in theta frequency and was negatively correlated with performance. These findings suggest a fundamental role for Nav1.1 in facilitating fast-firing properties in neurons, highlight the importance of precise temporal control of theta frequency for working memory, and imply that Nav1.1 deficits may disrupt information processing in DS via a dysregulation of brain rhythms. PMID:26978272
Mokhtari-Zaer, Amin; Ghodrati-Jaldbakhan, Shahrbanoo; Vafaei, Abbas Ali; Miladi-Gorji, Hossein; Akhavan, Maziar M; Bandegi, Ahmad Reza; Rashidy-Pour, Ali
Chronic exposure to morphine results in cognitive deficits and alterations of apoptotic proteins in favor of cell death in the hippocampus, a brain region critically involved in learning and memory. Physical activity has been shown to have beneficial effects on brain health. In the current work, we examined the effects of voluntary and treadmill exercise on spontaneous withdrawal signs, the associated cognitive defects, and changes of apoptotic proteins in morphine-dependent rats. Morphine dependence was induced through bi-daily administrations of morphine (10mg/kg) for 10 days. Then, the rats were trained under two different exercise protocols: mild treadmill exercise or voluntary wheel exercise for 10 days. After exercise training, their spatial learning and memory and aversive memory were examined by a water maze and by an inhibitory avoidance task, respectively. The expression of the pro-apoptotic protein Bax and the anti-apoptotic protein Bcl-2 in the hippocampus were determined by immunoblotting. We found that chronic exposure to morphine impaired spatial and aversive memory and remarkably suppressed the expression of Bcl-2, but Bax expression remained constant. Both voluntary and treadmill exercise alleviated memory impairment, increased the expression of Bcl-2 protein, and only the later suppressed the expression of Bax protein in morphine-dependent animals. Moreover, both exercise protocols diminished the occurrence of spontaneous morphine withdrawal signs. Our findings showed that exercise reduces the spontaneous morphine-withdrawal signs, blocks the associated impairment of cognitive performance, and overcomes morphine-induced alterations in apoptotic proteins in favor of cell death. Thus, exercise may be a useful therapeutic strategy for cognitive and behavioral deficits in addict individuals.
Cai, Chenxi; Yuan, Kai; Yin, Junsen; Feng, Dan; Bi, Yanzhi; Li, Yangding; Yu, Dahua; Jin, Chenwang; Qin, Wei; Tian, Jie
Internet gaming disorder (IGD), identified in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) Section III as a condition warranting more clinical research, may be associated with impaired cognitive control. Previous IGD-related studies had revealed structural abnormalities in the prefrontal cortex, an important part of prefrontal-striatal circuits, which play critical roles in cognitive control. However, little is known about the relationship between the striatal nuclei (caudate, putamen, and nucleus accumbens) volumes and cognitive control deficit in individuals with IGD. Twenty-seven adolescents with IGD and 30 age-, gender- and education-matched healthy controls participated in this study. The volume differences of the striatum were assessed by measuring subcortical volume in FreeSurfer. Meanwhile, the Stroop task was used to detect cognitive control deficits. Correlation analysis was used to investigate the relationship between striatal volumes and performance in the Stroop task as well as severity in IGD. Relative to controls, the IGD committed more incongruent condition response errors during the Stroop task and showed increased volumes of dorsal striatum (caudate) and ventral striatum (nucleus accumbens). In addition, caudate volume was correlated with Stroop task performance and nucleus accumbens (NAc) volume was associated with the internet addiction test (IAT) score in the IGD group. The increased volumes of the right caudate and NAc and their association with behavioral characteristics (i.e., cognitive control and severity) in IGD were detected in the present study. Our findings suggest that the striatum may be implicated in the underlying pathophysiology of IGD.
Bogdanowicz, Katarzyna Maria; Łockiewicz, Marta; Bogdanowicz, Marta; Pąchalska, Maria
The present study was aimed at analysing cognitive deficits of dyslexic adults, and examining their written language skills in comparison with their peers. Our results confirm the presence of a certain profile of symptoms in adult dyslexics. We noticed deficits in: phonological (verbal) short-term memory, phonological awareness, rapid automatised naming (speed, self-corrections), visual perception and control, and visual-motor coordination. Moreover, the dyslexic participants, as compared with their nondyslexic peers, produced more word structure errors whilst writing an essay. However, there were no significant differences between the two groups in the length of the essay, the number of linguistic and punctuation errors, the number of adjectives, and stylistic devices.
Berridge, Craig W.; Devilbiss, David M.
Psychostimulants exert behavioral-calming and cognition-enhancing actions in the treatment of attention deficit hyperactivity disorder (ADHD). Contrary to early views, extensive research demonstrates that these actions are not unique to ADHD. Specifically, when administered at low and clinically-relevant doses, psychostimulants improve a variety of behavioral and cognitive processes dependent on the prefrontal cortex (PFC) in subjects with and without ADHD. Despite the longstanding clinical use of these drugs, the neural mechanisms underlying their cognition-enhancing/therapeutic actions have only recently begun to be examined. At behaviorally-activating doses, psychostimulants produce large and widespread increases in extracellular levels of brain catecholamines. In contrast, cognition-enhancing doses of psychostimulants exert regionally-restricted actions, elevating extracellular catecholamine levels and enhancing neuronal signal processing preferentially within the PFC. Additional evidence suggests a prominent role of PFC α2- and D1 receptors in the behavioral and electrophysiological actions of low-dose psychostimulants. These and other observations indicate a pivotal role of PFC catecholamines in the cognition-enhancing and therapeutic actions of psychostimulants as well as other drugs used in the treatment of ADHD. This information may be particularly relevant for the development of novel pharmacological treatments for ADHD and other conditions associated with PFC dysregulation. PMID:20875636
Wang, Zhen-Zhen; Zhang, Yi; Zhang, Han-Ting; Li, Yun-Feng
Phosphodiesterases (PDEs) are the only known enzymes to degrade intracellular cyclic AMP and/or cyclic GMP. The PDE superfamily consists of 11 families (PDE1- PDE11), each of which has 1 to 4 subtypes. Some of the subtypes may have multiple splice variants (e.g. PDE4D1-PDE4D11), leading to a total of more than 100 known proteins to date. Growing attention has been paid to the potential of PDEs as therapeutic targets for mood disorders and/or diseases affecting cognitive activity by controlling the rate of hydrolysis of the two aforementioned second messengers in recent years. The loss of cognitive functions is one of the major complaints most patients with CNS diseases face; it has an even more prominent negative impact on the quality of daily life. Cognitive dysfunction is usually a prognosis in patients suffering from neuropsychiatric and neurodegenerative diseases, including depression, schizophrenia, and Alzheimer's disease. This review will focus on the contributions of PDEs to the interface between cognitive deficits and neuropsychiatric and neurodegenerative disorders. It is expected to make for the understanding and discovery that selective PDE inhibitors have the therapeutic potential for cognitive dysfunctions associated with neuropsychiatric and neurodegenerative disorders.
Lennertz, Leonhard; An der Heiden, Wolfram; Kronacher, Regina; Schulze-Rauschenbach, Svenja; Maier, Wolfgang; Häfner, Heinz; Wagner, Michael
Most neuropsychological studies on schizophrenia suffer from sample selection bias, with male and chronic patients being overrepresented. This probably leads to an overestimation of cognitive impairments. The present study aimed to provide a less biased estimate of cognitive functions in schizophrenia using a population-representative catchment area sample. Schizophrenia patients (N = 89) from the prospective Mannheim ABC cohort were assessed 14 years after disease onset and first diagnosis, using a comprehensive neuropsychological test battery. A healthy control group (N = 90) was carefully matched according to age, gender, and geographic region (city, rural surrounds). The present sample was representative for the initial ABC cohort. In the comprehensive neuropsychological assessment, the schizophrenia patients were only moderately impaired as compared to the healthy control group (d = 0.56 for a general cognitive index, d = 0.42 for verbal memory, d = 0.61 for executive functions, d = 0.69 for attention). Only 33 % of the schizophrenia patients scored one standard deviation unit below the healthy control group in the general cognitive index. Neuropsychological performance did not correlate with measures of the clinical course including age at onset, number of hospital admissions, and time in paid work. Thus, in this population-representative sample of schizophrenia patients, neuropsychological deficits were less pronounced than expected from meta-analyses. In agreement with other epidemiological studies, this suggests a less devastating picture of cognition in schizophrenia.
Noreen, Husain; Yabuki, Yasushi; Fukunaga, Kohji
Methimazole (MMI) is a first-line therapy used to manage hyperthyroidism and Graves' disease. Despite its therapeutic benefit, chronic MMI administration can lead to hypothyroidism and perturb brain homeostasis in patients, resulting in neuropsychiatric disorders such as depression and cognitive dysfunction. We recently developed the spiroimidazopyridine derivative SAK3 as cognitive enhancer; however, mechanisms underlying its activity remained unclear. Here, we show that SAK3 potentially improves cognitive impairment seen following MMI-induced hypothyroidism. Twenty-four hours after MMI (75 mg/kg, i.p.) treatment, we administered SAK3 (0.1, 0.5 and 1 mg/kg, p.o.) to mice daily for 7 days. MMI treatment alone disrupted olfactory bulb (OB) glomerular structure, as assessed by staining with the olfactory marker protein (OMP), reduced the number of choline acetyl transferase (ChAT)-immunoreactive neurons in medial septum (MS), and significantly impaired cognition. SAK3 (0.5 and 1 mg/kg, p.o.) administration significantly restored the number of cholinergic MS neurons in MMI-treated mice, and SAK3 treatment at a higher dose significantly improved cognitive deficits seen in MMI-treated control mice. Overall, our study suggests that SAK3 treatment could antagonize such impairment in patients with hypothyroidism.
Houvenaghel, Jean-François; Le Jeune, Florence; Dondaine, Thibaut; Esquevin, Aurore; Robert, Gabriel Hadrien; Péron, Julie; Haegelen, Claire; Drapier, Sophie; Jannin, Pierre; Lozachmeur, Clément; Argaud, Soizic; Duprez, Joan; Drapier, Dominique; Vérin, Marc; Sauleau, Paul
Objective The decrease in verbal fluency in patients with Parkinson’s disease (PD) undergoing subthalamic nucleus deep brain stimulation (STN-DBS) is usually assumed to reflect a frontal lobe-related cognitive dysfunction, although evidence for this is lacking. Methods To explore its underlying mechanisms, we combined neuropsychological, psychiatric and motor assessments with an examination of brain metabolism using F-18 fluorodeoxyglucose positron emission tomography, in 26 patients with PD, 3 months before and after surgery. We divided these patients into two groups, depending on whether or not they exhibited a postoperative deterioration in either phonemic (10 patients) or semantic (8 patients) fluency. We then compared the STN-DBS groups with and without verbal deterioration on changes in clinical measures and brain metabolism. Results We did not find any neuropsychological change supporting the presence of an executive dysfunction in patients with a deficit in either phonemic or semantic fluency. Similarly, a comparison of patients with or without impaired fluency on brain metabolism failed to highlight any frontal areas involved in cognitive functions. However, greater changes in cognitive slowdown and apathy were observed in patients with a postoperative decrease in verbal fluency. Conclusions These results suggest that frontal lobe-related cognitive dysfunction could play only a minor role in the postoperative impairment of phonemic or semantic fluency, and that cognitive slowdown and apathy could have a more decisive influence. Furthermore, the phonemic and semantic impairments appeared to result from the disturbance of distinct mechanisms. PMID:26448131
Hashimoto, Kenji; Fujita, Yuko; Iyo, Masaomi
This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice. Therefore, sigma-1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.
Fitz, Nicholas F.; Carter, Alexis Y.; Tapias, Victor; Castranio, Emilie L.; Kodali, Ravindra; Lefterov, Iliya; Koldamova, Radosveta
ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoproteins and regulates the generation of high density lipoproteins. Previously, we have shown that lack of Abca1 significantly increases amyloid deposition and cognitive deficits in Alzheimer’s disease model mice expressing human amyloid-β protein precursor (APP). The goal of this study was to determine if ABCA1 plays a role in memory deficits caused by amyloid-β (Aβ) oligomers and examine neurite architecture of pyramidal hippocampal neurons. Our results confirm previous findings that Abca1 deficiency significantly impairs spatial memory acquisition and retention in the Morris water maze and long-term memory in novel object recognition of APP transgenic mice at a stage of early amyloid pathology. Neither test demonstrated a significant difference between Abca1ko and wild-type (WT) mice. We also examined the effect of intra-hippocampal infused Aβ oligomers on cognitive performance of Abca1ko mice, compared to control infusion of scrambled Aβ peptide. Age-matched WT mice undergoing the same infusions were also used as controls. In this model system, we found a statistically significant difference between WT and Abca1ko mice infused with scrambled Aβ, suggesting that Abca1ko mice are vulnerable to the effect of mild stresses. Moreover, examination of neurite architecture in the hippocampi revealed a significant decrease in neurite length, number of neurite segments, and branches in Abca1ko mice when compared to WT mice. We conclude that mice lacking ABCA1 have basal cognitive deficits that prevent them from coping with additional stressors, which is in part due to impairment of neurite morphology in the hippocampus. PMID:28106559
Ivanchak, Nikki; Fletcher, Kristen
Attentional deficits are frequently seen in isolation as the presenting sign and symptom of neurodegenerative disease, manifest as mild cognitive impairment (MCI). Persistent ADHD in the geriatric population could well be misconstrued as MCI, leading to the incorrect assumption that such persons are succumbing to a neurodegenerative disease process. Alternatively, the molecular, neuroanatomic, or neurochemical abnormalities seen in ADHD may contribute to the development of de novo late life neurodegenerative disease. The present review examines the issue of causality vs confound regarding the association of ADHD with MCI, suggesting that both are tenable hypotheses. PMID:22886581
Celsis, P; Agniel, A; Puel, M; Rascol, A; Marc-Vergnes, J P
Regional cerebral blood flow was investigated using single photon emission computed tomography and xenon-133 intravenous injection in six patients with dementia of the Alzheimer type (DAT) with atypical focal clinical presentation, and in 20 age-matched healthy volunteers. The patients had a progressive and preponderant cognitive deficit and a focal hypoperfusion that correlated with the neuropsychological findings, whereas the average flow did not significantly differ from that of controls. The assessment of concordant haemodynamic and neuropsychological focal abnormalities could be useful in the diagnosis of atypical cases of DAT. Images PMID:3501801
Tan, Lei; Chen, Xin; Wang, Wei; Zhang, Jianfang; Li, Shiyong; Zhao, Yilin; Wang, Jintao; Luo, Ailin
Evidence has shown that children exposed to repeated anesthesia in early childhood display long-term cognitive disabilities. However, the underlying mechanisms remain largely unclear. Our previous study has indicated the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in isoflurane-induced decrease of self-renewal capacity in hippocampal neural precursor cells. Additionally, it is demonstrated by others that PTEN inhibition could protect against cognitive impairment via reduction of tau phosphorylation in the alzheimer's disease model. Therefore, in the present in vivo study, we aimed to examine the effects of PTEN inhibition on the cognitive dysfunction and tau hyperphosphorylation caused by neonatal repeated exposures to isoflurane. Our results showed that the neonatal repeated exposures to isoflurane resulted in the activation of PTEN in the hippocampus. The treatment of PTEN inhibitor BPV (pic) restored PSD-95 synthesis, and attenuated tau phosphorylation as well as the cognitive dysfunction caused by the repeated isoflurane exposures. In addition, BPV (pic) treatment reversed the activation of NR2B-containing NMDARs induced by repeated isoflurane exposures, while in turn, the antagonism of NR2B subunit with ifenprodil alleviated tau phosphorylation, indicating a possible role of NR2B as the downstream of PTEN in mediating tau phosphorylation in the neonatal rats repeatedly exposed to isoflurane. In conclusion, our results reveal a novel role of PTEN in mediating tau phosphorylation and cognitive deficits caused by neonatal repeated exposures to isoflurane, implying that targeting on PTEN may be a potential therapeutic approach for the anesthetic-related cognitive decline in the developing brain.
Bissonette, Gregory B.; Bae, Mihyun H.; Suresh, Tejas; Jaffe, David E.; Powell, Elizabeth M.
Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition. PMID:24211452
Wang, Li; Almeida, Luis E F; de Souza Batista, Celia M; Khaibullina, Alfia; Xu, Nuo; Albani, Sarah; Guth, Kira A; Seo, Ji Sung; Quezado, Martha; Quezado, Zenaide M N
Strokes are perhaps the most serious complications of sickle cell disease (SCD) and by the fifth decade occur in approximately 25% of patients. While most patients do not develop strokes, mounting evidence indicates that even without brain abnormalities on imaging studies, SCD patients can present profound neurocognitive dysfunction. We sought to evaluate the neurocognitive behavior profile of humanized SCD mice (Townes, BERK) and to identify hematologic and neuropathologic abnormalities associated with the behavioral alterations observed in these mice. Heterozygous and homozygous Townes mice displayed severe cognitive deficits shown by significant delays in spatial learning compared to controls. Homozygous Townes also had increased depression- and anxiety-like behaviors as well as reduced performance on voluntary wheel running compared to controls. Behavior deficits observed in Townes were also seen in BERKs. Interestingly, most deficits in homozygotes were observed in older mice and were associated with worsening anemia. Further, neuropathologic abnormalities including the presence of large bands of dark/pyknotic (shrunken) neurons in CA1 and CA3 fields of hippocampus and evidence of neuronal dropout in cerebellum were present in homozygotes but not control Townes. These observations suggest that cognitive and behavioral deficits in SCD mice mirror those described in SCD patients and that aging, anemia, and profound neuropathologic changes in hippocampus and cerebellum are possible biologic correlates of those deficits. These findings support using SCD mice for studies of cognitive deficits in SCD and point to vulnerable brain areas with susceptibility to neuronal injury in SCD and to mechanisms that potentially underlie those deficits.
Pu, Shenghong; Nakagome, Kazuyuki; Itakura, Masashi; Iwata, Masaaki; Nagata, Izumi; Kaneko, Koichi
Schizophrenia-associated cognitive deficits are resistant to treatment and thus pose a lifelong burden. The Brief Assessment of Cognition in Schizophrenia (BACS) provides reliable and valid assessments across cognitive domains. However, because the prefrontal functional abnormalities specifically associated with the level of cognitive deficits in schizophrenia have not been examined, we explored this relationship. Patients with schizophrenia (N=87) and matched healthy controls (N=50) participated in the study. Using near-infrared spectroscopy (NIRS), we measured the hemodynamic responses in the prefrontal and superior temporal cortical surface areas during a working memory task. Correlation analyses revealed a relationship between the hemodynamics and the BACS composite and domain scores. Hemodynamic responses of the left dorsolateral prefrontal cortex (DLPFC) and left frontopolar cortex (FPC) in the higher-level-of-cognitive-function schizophrenia group were weaker than the responses of the controls but similar to those of the lower-level-of-cognitive-function schizophrenia group. However, hemodynamic responses in the right DLPFC, bilateral ventrolateral PFC (VLPFC), and right temporal regions decreased with increasing cognitive deficits. In addition, the hemodynamic response correlated positively with the level of cognitive function (BACS composite scores) in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions in schizophrenia. The correlation was driven by all BACS domains. Our results suggest that the linked functional deficits in the right DLPFC, bilateral VLPFC, right FPC, and bilateral temporal regions may be related to BACS-measured cognitive impairments in schizophrenia and show that linking the neurocognitive deficits and brain abnormalities can increase our understanding of schizophrenia pathophysiology.
Hulka, Lea M; Wagner, Michael; Preller, Katrin H; Jenni, Daniela; Quednow, Boris B
Specific blue-yellow colour vision impairment has been reported in dependent cocaine users and it was postulated that drug-induced changes in retinal dopamine neurotransmission are responsible. However, it is unclear whether these changes are confined to chronic cocaine users, whether they are specific for dopaminergic stimulants such as cocaine and amphetamine and whether they are related to cognitive functions such as working memory, encoding and consolidation. In 47 occasional and 29 dependent cocaine users, 23 MDMA (commonly known as 'ecstasy') users and 47 stimulant-naive controls, colour vision discrimination was measured with the Lanthony Desaturated Panel D-15 Test and memory performance with the Auditory Verbal Learning Test. Both occasional and dependent cocaine users showed higher colour confusion indices than controls. Users of the serotonergic stimulant MDMA (26%), occasional (30%) and dependent cocaine users (34%) exhibited more frequent blue-yellow colour vision disorders compared to controls (9%). Inferior performance of MDMA users was caused by a subgroup with high amphetamine co-use (55%), while MDMA use alone was not associated with decreased blue-yellow discrimination (0%). Cognitive performance was worse in cocaine users with colour vision disorder compared to users and controls with intact colour vision and both colour vision impairment and cognitive deficits were related to cocaine use. Occasional cocaine and amphetamine use might induce blue-yellow colour vision impairment, whereas the serotonergic stimulant MDMA does not impair colour vision. The association between colour vision impairment and cognitive deficits in cocaine users may reflect that retinal and cerebral dopamine alterations are linked to a certain degree.
do Nascimento, Sabrina N; Barth, Anelise; Göethel, Gabriela; Baierle, Marília; Charão, Mariele F; Brucker, Natália; Moro, Angela M; Bubols, Guilherme B; Sobreira, Johanna S; Sauer, Elisa; Rocha, Rafael; Gioda, Adriana; Dias, Ana Cristina; Salles, Jerusa F; Garcia, Solange C
Children are especially vulnerable to adverse effects of multiple metals exposure. The aim of this study was to assess some metals concentrations such as lead (Pb), arsenic (As), chromium (Cr), manganese (Mn) and iron (Fe) in whole blood, serum, hair and drinking water samples using inductively coupled plasma-mass spectrometry (ICP-MS) in rural and urban children. In addition, evaluate the adverse effects of multiple metals exposure on cognitive function and δ-aminolevulinate dehydratase (ALA-D) activity. The cognitive ability assessment was performed by the Raven's Colored Progressive Matrices (RCPM) test. The ALA-D activity and ALA-D reactivation index (ALA-RE) activity with DTT and ZnCl2 also were determined. Forty-six rural children and 23 urban children were enrolled in this study. Rural children showed percentile IQ scores in the RCPM test significantly decreased in relation to urban children. According to multiple linear regression analysis, the Mn and Fe in hair may account for the cognitive deficits of children. Manganese and Fe in hair also were positively correlated with Mn and Fe in drinking water, respectively. These results suggest that drinking water is possibly a source of metals exposure in children. ALA-D activity was decreased and ALA-RE with DTT and ZnCl2 was increased in rural children in comparison to urban children. Moreover, ALA-D inhibition was correlated with Cr blood levels and ALA-RE/DDT and ALA-RE/ZnCl2 were correlated with levels of Cr and Hg in blood. Thus, our results indicated some adverse effects of children's exposure to multiple metals, such as cognitive deficits and ALA-D inhibition, mainly associated to Mn, Fe, Cr and Hg.
Mostert, Jeanette C; Onnink, A Marten H; Klein, Marieke; Dammers, Janneke; Harneit, Anais; Schulten, Theresa; van Hulzen, Kimm J E; Kan, Cornelis C; Slaats-Willemse, Dorine; Buitelaar, Jan K; Franke, Barbara; Hoogman, Martine
Attention Deficit/Hyperactivity Disorder (ADHD) in childhood is associated with impaired functioning in multiple cognitive domains: executive functioning (EF), reward and timing. Similar impairments have been described for adults with persistent ADHD, but an extensive investigation of neuropsychological functioning in a large sample of adult patients is currently lacking. We systematically examined neuropsychological performance on tasks measuring EF, delay discounting, time estimation and response variability using univariate ANCOVA's comparing patients with persistent ADHD (N=133, 42% male, mean age 36) and healthy adults (N=132, 40% male, mean age 36). In addition, we tested which combination of variables provided the highest accuracy in predicting ADHD diagnosis. We also estimated for each individual the severity of neuropsychological dysfunctioning. Lastly, we investigated potential effects of stimulant medication and a history of comorbid major depressive disorder (MDD) on performance. Compared to healthy adults, patients with ADHD showed impaired EF, were more impulsive, and more variable in responding. However, effect sizes were small to moderate (range: 0.05-0.70) and 11% of patients did not show neuropsychological dysfunctioning. The best fitting model predicting ADHD included measures from distinct cognitive domains (82.1% specificity, 64.9% sensitivity). Furthermore, patients receiving stimulant medication or with a history of MDD were not distinctively impaired. To conclude, while adults with ADHD as a group are impaired on several cognitive domains, the results confirm that adult ADHD is neuropsychologically heterogeneous. This provides a starting point to investigate individual differences in terms of impaired cognitive pathways.
Klein, Marieke; Dammers, Janneke; Harneit, Anais; Schulten, Theresa; van Hulzen, Kimm J.E.; Kan, Cornelis C.; Slaats-Willemse, Dorine; Buitelaar, Jan K.
Attention Deficit / Hyperactivity Disorder (ADHD) in childhood is associated with impaired functioning in multiple cognitive domains: executive functioning (EF), reward and timing. Similar impairments have been described for adults with persistent ADHD, but an extensive investigation of neuropsychological functioning in a large sample of adult patients is currently lacking. We systematically examined neuropsychological performance on tasks measuring EF, delay discounting, time estimation and response variability using univariate ANCOVA's comparing patients with persistent ADHD (N = 133, 42% male, mean age 36) and healthy adults (N = 132, 40% male, mean age 36). In addition, we tested which combination of variables provided the highest accuracy in predicting ADHD diagnosis. We also estimated for each individual the severity of neuropsychological dysfunctioning. Lastly, we investigated potential effects of stimulant medication and a history of comorbid major depressive disorder (MDD) on performance. Compared to healthy adults, patients with ADHD showed impaired EF, were more impulsive, and more variable in responding. However, effect sizes were small to moderate (range: 0.05 – 0.70) and 11% of patients did not show neuropsychological dysfunctioning. The best fitting model predicting ADHD included measures from distinct cognitive domains (82.1% specificity, 64.9% sensitivity). Furthermore, patients receiving stimulant medication or with a history of MDD were not distinctively impaired. To conclude, while adults with ADHD as a group are impaired on several cognitive domains, the results confirm that adult ADHD is neuropsychologically heterogeneous. This provides a starting point to investigate individual differences in terms of impaired cognitive pathways. PMID:26336867
Pintana, Hiranya; Sripetchwandee, Jirapas; Supakul, Luerat; Apaijai, Nattayaporn; Chattipakorn, Nipon; Chattipakorn, Siriporn
Oxidative stress in the obese-insulin resistant condition has been shown to affect cognitive as well as brain mitochondrial functions. Garlic extract has exerted a potent antioxidant effect. However, the effects of garlic extract on the brain of obese-insulin resistant rats have never been investigated. We hypothesized that garlic extract improves cognitive function and brain mitochondrial function in obese-insulin resistant rats induced by long-term high-fat diet (HFD) consumption. Male Wistar rats were fed either normal diet or HFD for 16 weeks (n = 24/group). At week 12, rats in each dietary group received either vehicle or garlic extract (250 and 500 mg·kg(-1)·day(-1)) for 28 days. Learning and memory behaviors, metabolic parameters, and brain mitochondrial function were determined at the end of treatment. HFD led to increased body weight, visceral fat, plasma insulin, cholesterol, and malondialdehyde (MDA) levels, indicating the development of insulin resistance. Furthermore, HFD rats had cognitive deficit and brain mitochondrial dysfunction. HFD rats treated with both doses of garlic extract had decreased body weight, visceral fat, plasma cholesterol, and MDA levels. Garlic extract also improved cognitive function and brain mitochondrial function, which were impaired in obese-insulin resistant rats caused by HFD consumption.
Parikh, Vinay; Cole, Robert D.; Patel, Purav J.; Poole, Rachel L.; Gould, Thomas J.
Nicotine is a major psychoactive and addictive component of tobacco. Although cessation of tobacco use produces various somatic and affective symptoms, withdrawal-related cognitive deficits are considered to be a critical symptom that predict relapse. Therefore, delineating the cognitive mechanisms of nicotine withdrawal may likely provide gainful insights into the neurobiology of nicotine addiction. The present study was designed to examine the effects of nicotine withdrawal induced by mecamylamine, a non-specific nicotinic receptor (nAChR) antagonist, on cognitive control processes in mice using an operant strategy switching task. Brain-derived neurotrophic factor (BDNF) modulates synaptic transmission in frontostriatal circuits, and these circuits are critical for executive functions. Thus, we examined the effects of mecamylamine-precipitated nicotine withdrawal on prefrontal and striatal BDNF protein expression. Mice undergoing precipitated nicotine withdrawal required more trials to attain strategy switching criterion as compared to the controls. Error analysis indicated that impaired performance in these animals was mostly related to their inability to execute the new strategy. The striatal/prefrontal BDNF ratios robustly increased following precipitated nicotine withdrawal. Moreover, higher BDNF ratios were associated with longer task acquisition. Collectively, our findings illustrate that mecamylamine-induced nicotine withdrawal disrupts cognitive control processes and that these changes are possibly linked to perturbations in frontostriatal BDNF signaling. PMID:26775017
Hohsfield, Lindsay A; Ehrlich, Daniela; Humpel, Christian
A variety of cardiovascular and cerebrovascular diseases are associated with alterations in cholesterol levels and metabolism. Moreover, convincing evidence shows that high cholesterol diet can lead to learning and memory impairments. On the other hand, a significant body of research has also demonstrated that learning is improved by elevated dietary cholesterol. Despite these conflicting findings, it is clear that cholesterol plays an important role in these cognitive properties. However, it remains unclear how this blood-brain barrier (BBB)-impenetrable molecule affects the brain and under what circumstances it provides either detrimental or beneficial effects to learning and memory. The aim of this study was to characterize the effects of 5% cholesterol diet on six-month-old inbred Brown Norway rats. More important, we sought to examine the role that cholesterol can play when repeated anesthesia and intravenous infusion disrupts cognitive function. This present study supports previous work showing that enriched cholesterol diet leads to significant alterations in neuroinflammation and BBB disruption. Following repeated anesthesia and intravenous infusion of saline we observe that animals under normal diet conditions exhibit significant deficiencies in spatial learning and cholinergic neuron populations compared to animals under enriched cholesterol diet, which do not show such deficiencies. These findings indicate that cholesterol diet can protect against or counteract anesthesia/infusion-induced cognitive deficits. Ultimately, these results suggest that cholesterol homeostasis serves an important functional role in the brain and that altering this homeostasis can either exert positive or negative effects on cognitive properties.
Karageorgiou, Elissaios; Lewis, Scott M.; Riley McCarten, J.; Leuthold, Arthur C.; Hemmy, Laura S.; McPherson, Susan E.; Rottunda, Susan J.; Rubins, David M.; Georgopoulos, Apostolos P.
In previous work (Georgopoulos et al 2007 J. Neural Eng. 4 349-55) we reported on the use of magnetoencephalographic (MEG) synchronous neural interactions (SNI) as a functional biomarker in Alzheimer's dementia (AD) diagnosis. Here we report on the application of canonical correlation analysis to investigate the relations between SNI and cognitive neuropsychological (NP) domains in AD patients. First, we performed individual correlations between each SNI and each NP, which provided an initial link between SNI and specific cognitive tests. Next, we performed factor analysis on each set, followed by a canonical correlation analysis between the derived SNI and NP factors. This last analysis optimally associated the entire MEG signal with cognitive function. The results revealed that SNI as a whole were mostly associated with memory and language, and, slightly less, executive function, processing speed and visuospatial abilities, thus differentiating functions subserved by the frontoparietal and the temporal cortices. These findings provide a direct interpretation of the information carried by the SNI and set the basis for identifying specific neural disease phenotypes according to cognitive deficits.
Gill, Kathryn M.; Grace, Anthony A.
Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABAA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity. PMID:24345268
Background: Amongst schizophrenia patients, a large subgroup of up to 25% also suffers from comorbid obsessive-compulsive symptoms (OCSs). The association between comorbid OCSs in these patients and neuropsychological impairment remains unclear and somewhat contradictory. Longitudinal approaches investigating the stability of OCS-associated cognitive deficits are missing. Methods: Thirty-seven patients with schizophrenia and comorbid OCSs and 43 schizophrenia patients without OCS were assessed with a comprehensive cognitive test battery and compared at baseline and, again, 12 months later. Results: Schizophrenia patients with comorbid OCSs showed significant pronounced deficits, with increasing effect sizes over the 12-month assessment period in specific cognitive areas such as visuospatial perception and visual memory (WAIS-R block design, Rey–Osterrieth Complex Figure Test), executive functioning (perseveration in the Wisconsin Card Sorting test), and cognitive flexibility (Trail Making test B). These cognitive domains are correlated with OCS severity and are known to be candidate cognitive domains in obsessive-compulsive disorder (OCD). Conclusions: OCSs in schizophrenia is associated with specific and longitudinally stable cognitive deficits, strongly arguing for at least partially overlapping neurobiological mechanisms with OCD. Prospective studies involving patients with at-risk mental states for psychosis are necessary to decipher the interaction of cognitive impairment and the clinical manifestations of schizophrenia and OCSs. This might facilitate the definition of patients at high risk for OCSs, an early detection of subclinical levels, therapeutic interventions, and clinical monitoring. PMID:23104864
Skagerlund, Kenny; Träff, Ulf
This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with arithmetic fact dyscalculia (AFD) and a group with general dyscalculia (GD). Several different aspects of number magnitude processing were assessed in these two groups and compared with age-matched typically achieving children. The GD group displayed weaknesses with both symbolic and nonsymbolic number processing, whereas the AFD group displayed problems only with symbolic number processing. These findings provide evidence that the origins of DD in children with different profiles of mathematical problems diverge. Children with GD have impairment in the innate approximate number system, whereas children with AFD suffer from an access deficit. These findings have implications for researchers' selection procedures when studying dyscalculia, and also for practitioners in the educational setting.
Richter, Nils; Michel, Anne; Onur, Oezguer A; Kracht, Lutz; Dietlein, Markus; Tittgemeyer, Marc; Neumaier, Bernd; Fink, Gereon R; Kukolja, Juraj
In Alzheimer's disease (AD), white matter lesions (WMLs) are associated with an increased risk of progression from mild cognitive impairment (MCI) to dementia, while memory deficits have, at least in part, been linked to a cholinergic deficit. We investigated the relationship between WML load assessed with the Scheltens scale, cerebral acetylcholinesterase (AChE) activity measured with [(11)C]N-methyl-4-piperidyl acetate PET, and neuropsychological performance in 17 patients with MCI due to AD and 18 cognitively normal older participants. Only periventricular, not nonperiventricular, WML load negatively correlated with AChE activity in both groups. Memory performance depended on periventricular and total WML load across groups. Crucially, AChE activity predicted memory function better than WML load, gray matter atrophy, or age. The effects of WML load on memory were fully mediated by AChE activity. Data suggest that the contribution of WML to the dysfunction of the cholinergic system in MCI due to AD depends on WML distribution. Pharmacologic studies are warranted to explore whether this influences the response to cholinergic treatment.
Ma, Ping; Liu, Xudong; Wu, Jiliang; Yan, Biao; Zhang, Yuchao; Lu, Yu; Wu, Yang; Liu, Chao; Guo, Junhui; Nanberg, Eewa; Bornehag, Carl-Gustaf; Yang, Xu
Diisononyl phthalate (DINP) is a plasticizer that is frequently used as a substitute for other plasticizers whose use is prohibited in certain products. In vivo studies on the neurotoxicity of DINP are however, limited. This work aims to investigate whether DINP causes neurobehavioral changes in mice and to provide useful advice on preventing the occurrence of these adverse effects. Behavioral analysis showed that oral administration of 20 or 200 mg/kg/day DINP led to mouse cognitive deficits and anxiety. Brain histopathological observations, immunohistochemistry assays (cysteine-aspartic acid protease 3 [caspase-3], glial fibrillary acidic protein [GFAP]), oxidative stress assessments (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD] activities, 8-hydroxy-2-deoxyguanosine [8-OH-dG] and DNA-protein crosslinks [DPC]), and assessment of inflammation (tumor necrosis factor alpha [TNF-а] and interleukin-1 beta [IL-1β]) of mouse brains showed that there were histopathological alterations in the brain and increased levels of oxidative stress, and inflammation for these same groups. However, some of these effects were blocked by administration of melatonin (50 mg/kg/day). Down-regulation of oxidative stress was proposed to explain the neuroprotective effects of melatonin. The data suggests that DINP could cause cognitive deficits and anxiety in mice, and that melatonin could be used to avoid these adverse effects. PMID:26424168
Hunsberger, Holly C.; Weitzner, Daniel S; Rudy, Carolyn C.; Hickman, James E.; Libell, Eric M.; Speer, Rebecca R.; Gerhardt, Greg A.; Reed, Miranda N.
In the years preceding a diagnosis of Alzheimer’s disease (AD), hyperexcitability of the hippocampus is a commonly observed phenomenon in those at risk for AD. Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for ALS that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved memory performance that was associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole treatment also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1) and PSD-95 expression. Riluzole treatment also reduced tau pathology. These findings further elucidate the changes in glutamate regulation associated with tau pathology and open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD. PMID:26146790
Holland, Philip R; Searcy, James L; Salvadores, Natalia; Scullion, Gillian; Chen, Guiquan; Lawson, Greig; Scott, Fiona; Bastin, Mark E; Ihara, Masafumi; Kalaria, Rajesh; Wood, Emma R; Smith, Colin; Wardlaw, Joanna M; Horsburgh, Karen
Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood–brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies. PMID:25669904
Tarbali, Sepideh; Khezri, Shiva
Objective(s): Multiple sclerosis (MS) is a demyelinating disease. The prevalence of MS is highest where environmental supplies of vitamin D are low. Cognitive deficits have been observed in patients with MS. Oxidative damage may contribute to the formation of MS lesions. Considering the involvement of hippocampus in MS, an attempt is made in this study to investigate the effects of vitamin D3 on behavioral process and the oxidative status in the dorsal hippocampus (CA1 area) following the induction of experimental demyelination in rats. Materials and Methods: Animals were divided into six groups. Control group: animals received no surgery and treatment; saline group: animals received normal saline; sham group: animals received 150 μl sesame oil IP; vitamin D3 group: animals received 5 μg/kg vitamin D3 IP; lysophosphatidyl choline (LPC) group (toxic demyelination’s model): animals received LPC by stereotaxic intra-hippocampal injection of 2 μl LPC in CA1 area; Vitamin D3- treated group: animals were treated with vitamin D3 at doses of 5 μg/kg IP for 7 and 21 days post lesion. The spatial memory, biochemical parameters including catalase (CAT) activities and lipid peroxidation levels were investigated. Results: Animals in LPC group had more deficits in spatial memory than the control group in radial arm maze. Vitamin D3 significantly improved spatial memory compared to LPC group. Also, results indicated that vitamin D3 caused a decrease in lipid peroxidation levels and an increase in CAT activities. Conclusion: Current findings suggest that vitamin D3 may have a protective effect on cognitive deficits and oxidative stress in toxic demyelination’s model. PMID:27096068
Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane
Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268
Marseglia, Anna; Fratiglioni, Laura; Laukka, Erika J.; Santoni, Giola; Pedersen, Nancy L.; Bäckman, Lars; Xu, Weili
Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care–Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β – 1.10 [95% CI – 1.98, – 0.23]), category fluency (β – 1.27 [95% CI – 2.52, – 0.03]), and digit span forward (β – 0.35 [95% CI – 0.54, – 0.17]). Critically, these associations were present only among APOE ɛ4 non–carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations. PMID:27314527
Kanayama, Gen; Kean, Joseph; Hudson, James I.; Pope, Harrison G.
Background Millions of individuals worldwide have used anabolic-androgenic steroids (AAS) to gain muscle or improve athletic performance. Recently, in vitro investigations have suggested that supraphysiologic AAS doses cause apoptosis of neuronal cells. These findings raise the possibility, apparently still untested, that humans using high-dose AAS might eventually develop cognitive deficits. Methods We administered five cognitive tests from the computerized CANTAB battery (Pattern Recognition Memory, Verbal Recognition Memory, Paired Associates Learning, Choice Reaction Time, and Rapid Visual Information Processing) to 31 male AAS users and 13 non-AAS-using weightlifters age 29-55, recruited and studied in May 2012 in Middlesbrough, UK. Testers were blinded to participants’ AAS status and other historical data. Results Long-term AAS users showed no significant differences from nonusers on measures of response speed, sustained attention, and verbal memory. On visuospatial memory, however, AAS users performed significantly more poorly than nonusers, and within the user group, visuospatial performance showed a significant negative correlation with total lifetime AAS dose. These were large effects: on Pattern Recognition Memory, long-term AAS users underperformed nonusers by almost one standard deviation, based on normative population scores (adjusted mean difference in z-scores = 0.89; p = 0.036), and performance on this test declined markedly with increasing lifetime AAS dose (adjusted change in z-score = −0.13 per 100g of lifetime AAS dose; p = 0.002). These results remained stable in sensitivity analyses addressing potential confounding factors. Conclusions These preliminary findings raise the ominous possibility that long-term high-dose AAS exposure may cause cognitive deficits, notably in visuospatial memory. PMID:23253252
Feng, Dan; Yuan, Kai; Li, Yangding; Cai, Chenxi; Yin, Junsen; Bi, Yanzhi; Cheng, Jiadong; Guan, Yanyan; Shi, Sha; Yu, Dahua; Jin, Chenwang; Lu, Xiaoqi; Qin, Wei; Tian, Jie
Tobacco use during later adolescence and young adulthood may cause serious neurophysiological changes; rationally, it is extremely important to study the relationship between brain dysfunction and behavioral performances in young adult smokers. Previous resting state studies investigated the neural mechanisms in smokers. Unfortunately, few studies focused on spontaneous activity differences between young adult smokers and nonsmokers from both intra-regional and inter-regional levels, less is known about the association between resting state abnormalities and behavioral deficits. Therefore, we used fractional amplitude of low frequency fluctuation (fALFF) and resting state functional connectivity (RSFC) to investigate the resting state spontaneous activity differences between young adult smokers and nonsmokers. A correlation analysis was carried out to assess the relationship between neuroimaging findings and clinical information (pack-years, cigarette dependence, age of onset and craving score) as well as cognitive control deficits measured by the Stroop task. Consistent with previous addiction findings, our results revealed the resting state abnormalities within frontostriatal circuits, i.e., enhanced spontaneous activity of the caudate and reduced functional strength between the caudate and anterior cingulate cortex (ACC) in young adult smokers. Moreover, the fALFF values of the caudate were correlated with craving and RSFC strength between the caudate and ACC was associated with the cognitive control impairments in young adult smokers. Our findings could lead to a better understanding of intrinsic functional architecture of baseline brain activity in young smokers by providing regional and brain circuit spontaneous neuronal activity properties as well as their association with cognitive control impairments.
Braga-Neto, Pedro; Dutra, Lívia Almeida; Pedroso, José Luiz; Felício, André C; Alessi, Helena; Santos-Galduroz, Ruth F; Bertolucci, Paulo Henrique F; Castiglioni, Mário Luiz V; Bressan, Rodrigo Affonseca; de Garrido, Griselda Esther Jara; Barsottini, Orlando Graziani Povoas; Jackowski, Andrea
Cognitive and olfactory impairments have previously been demonstrated in patients with spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD)-SCA3/MJD. We investigated changes in regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) imaging in a cohort of Brazilian patients with SCA3/MJD. The aim of the present study was to evaluate the correlation among rCBF, cognitive deficits, and olfactory dysfunction in SCA3/MJD. Twenty-nine genetically confirmed SCA3/MJD patients and 25 control subjects were enrolled in the study. The severity of cerebellar symptoms was measured using the International Cooperative Ataxia Rating Scale and the Scale for the Assessment and Rating of Ataxia. Psychiatric symptoms were evaluated by the Hamilton Anxiety Scale and Beck Depression Inventory. The neuropsychological assessment consisted of Spatial Span, Symbol Search, Picture Completion, the Stroop Color Word Test, Trail Making Test (TMT), and Phonemic Verbal Fluency. Subjects were also submitted to odor identification evaluation using the 16-item Sniffin' Sticks. SPECT was performed using ethyl cysteine dimer labeled with technetium-99m. SCA3/MJD patients showed reduced brain perfusion in the cerebellum, temporal, limbic, and occipital lobes compared to control subjects (pFDR <0.001). A significant positive correlation was found between the Picture Completion test and perfusion of the left parahippocampal gyrus and basal ganglia in the patient group as well as a negative correlation between the TMT part A and bilateral thalamus perfusion. The visuospatial system is affected in patients with SCA3/MJD and may be responsible for the cognitive deficits seen in this disease.
Chang, Linda; Lim, Ahnate; Lau, Eric; Alicata, Daniel
HIV-infected individuals (HIV+) has 2-3 times the rate of tobacco smoking than the general population, and whether smoking may lead to greater psychiatric symptoms or cognitive deficits remains unclear. We evaluated the independent and combined effects of being HIV+ and chronic tobacco-smoking on impulsivity, psychopathological symptoms and cognition. 104 participants [27 seronegative (SN)-non-Smokers, 26 SN-Smokers, 29 HIV+ non-Smokers, 22 HIV+ Smokers] were assessed for psychopathology symptoms (Symptom Checklist-90, SCL-90), depressive symptoms (Center for Epidemiologic Studies-Depression Scale, CES-D), impulsivity (Barratt Impulsiveness Scale, BIS), decision-making (The Iowa Gambling Task, IGT, and Wisconsin Card Sorting Test, WCST), and cognition (seven neurocognitive domains). Both HIV+ and Smoker groups had higher SCL-90 and CES-D scores, with highest scores in HIV+ Smokers. On BIS, both HIV+ and Smokers had higher Total Impulsiveness scores, with higher behavioral impulsivity in Smokers, highest in HIV+ Smokers. Furthermore, across the four groups, HIV+ Smokers lost most money and made fewest advantageous choices on the IGT, and had highest percent errors on WCST. Lastly, HIV+ had lower z-scores on all cognitive domains, with the lowest scores in HIV+ Smokers. These findings suggest that HIV-infection and chronic tobacco smoking may lead to additive deleterious effects on impulsivity, psychopathological (especially depressive) symptoms and cognitive dysfunction. Although greater impulsivity may be premorbid in HIV+ and Smokers, the lack of benefits of nicotine in chronic Smokers on attention and psychopathology, especially those with HIV-infection, may be due to the negative effects of chronic smoking on dopaminergic and cardio-neurovascular systems. Tobacco smoking may contribute to psychopathology and neurocognitive disorders in HIV+ individuals.
Mori, Francesco; Rossi, Silvia; Sancesario, Giulia; Codecà, Claudia; Mataluni, Giorgia; Monteleone, Fabrizia; Buttari, Fabio; Kusayanagi, Hajime; Castelli, Maura; Motta, Caterina; Studer, Valeria; Bernardi, Giorgio; Koch, Giacomo; Bernardini, Sergio; Centonze, Diego
Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β(1-42) and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-β(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-β(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-β(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-β(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with θ burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-β(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between τ protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-β metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.
Wang, Zhen-Zhen; Yang, Wei-Xing; Zhang, Yi; Zhao, Nan; Zhang, You-Zhi; Liu, Yan-Qin; Xu, Ying; Wilson, Steven P.; O'Donnell, James M.; Zhang, Han-Ting; Li, Yun-Feng
Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices. PMID:26161529
Lewis, Freeman C.; Sarvi, Michael S.; Foley, Gillian M.; Crawley, Jacqueline N.
Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/−) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2+/− mice, confirming previous findings. A similarly robust deficit in object location memory was discovered in +/−, indicating impaired spatial novelty recognition. Generalizability of novelty recognition deficits in +/− mice extended to preference for social novelty. Robust learning deficits and cognitive inflexibility were detected using Bussey–Saksida touchscreen operant chambers. During acquisition of pairwise visual discrimination, +/− mice required significantly more training trials to reach criterion than wild-type littermates (+/+), and made more errors and correction errors than +/+. In the reversal phase, all +/+ reached criterion, whereas most +/− failed to reach criterion by the 30-d cutoff. Contextual and cued fear conditioning were normal in +/−. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/− mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome. PMID:26572653
Malik, Maninder; Rangel-Barajas, Claudia; Sumien, Nathalie; Su, Chang; Singh, Meharvan; Chen, Zhenglan; Huang, Ren-Qi; Meunier, Johann; Maurice, Tangui; Mach, Robert H; Luedtke, Robert R
Background and Purpose Cognitive deficits in patients with Alzheimer's disease, Parkinson's disease, traumatic brain injury and stroke often involve alterations in cholinergic signalling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory. Experimental Approach Scopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice given scopolamine (1 mg·kg−1) were used to evaluate the ability of LS-1–137, a novel sigma (σ1) receptor-selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration. Key Results LS-1–137 is a high-affinity (Ki = 3.2 nM) σ1 receptor agonist that is 80-fold selective for σ1, compared with σ2 receptors. LS-1–137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1–137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1–137 treatment was also found to trigger the release of brain-derived neurotrophic factor from rat astrocytes. Conclusions and Implications The σ1 receptor-selective compound LS-1–137 may represent a novel candidate cognitive enhancer for the treatment of muscarinic receptor-dependent cognitive deficits. PMID:25573298
Background Patients with carbon monoxide (CO) intoxication may develop ongoing neurological and psychiatric symptoms that ebb and flow, a condition often called delayed encephalopathy (DE). The association between morphologic changes in the brain and neuropsychological deficits in DE is poorly understood. Methods Magnetic resonance imaging and neuropsychological tests were conducted on 11 CO patients with DE, 11 patients without DE, and 15 age-, sex-, and education-matched healthy subjects. Differences in gray matter volume (GMV) between the subgroups were assessed and further correlated with diminished cognitive functioning. Results As a group, the patients had lower regional GMV compared to controls in the following regions: basal ganglia, left claustrum, right amygdala, left hippocampus, parietal lobes, and left frontal lobe. The reduced GMV in the bilateral basal ganglia, left post-central gyrus, and left hippocampus correlated with decreased perceptual organization and processing speed function. Those CO patients characterized by DE patients had a lower GMV in the left anterior cingulate and right amygdala, as well as lower levels of cognitive function, than the non-DE patients. Conclusions Patients with CO intoxication in the chronic stage showed a worse cognitive and morphologic outcome, especially those with DE. This study provides additional evidence of gray matter structural abnormalities in the pathophysiology of DE in chronic CO intoxicated patients. PMID:24083408
Mallucci, Giovanna R; White, Melanie D; Farmer, Michael; Dickinson, Andrew; Khatun, Husna; Powell, Andrew D; Brandner, Sebastian; Jefferys, John G R; Collinge, John
Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrP(C)) (the precursor of its disease-associated isoform, PrP(Sc)) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrP(C) is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.
Sanger, Maureen; Jordan, Lori; Pruthi, Sumit; Day, Matthew; Covert, Brittany; Merriweather, Brenda; Rodeghier, Mark; DeBaun, Michael; Kassim, Adetola
An estimated 25-60% of adults with sickle cell disease (SCD) are unemployed. Factors contributing to the high unemployment rate in this population are not well studied. With the known risk of cognitive deficits associated with SCD, we tested the hypothesis that unemployment is related to decrements in intellectual functioning. We conducted a retrospective chart review of 50 adults with sickle cell anemia who completed cognitive testing, including the Wechsler Adult Intelligence Scale-IV, as part of standard care. Employment status was recorded at the time of testing. Medical variables examined as possible risk factors for unemployment included disease phenotype, cerebral infarction, and pain frequency. The mean age of the sample was 30.7 years (range = 19-59); 56% were women. Almost half of the cohort (44%) were unemployed. In a multivariate logistic regression model, lower IQ scores (odds ratio = 0.88; p = .002, 95% confidence interval, CI [0.82, 0.96]) and lower educational attainment (odds ratio = 0.13; p = .012, 95% CI [0.03, 0.65]) were associated with increasing odds of unemployment. The results suggest that cognitive impairment in adults with sickle cell anemia may contribute to the risk of unemployment. Helping these individuals access vocational rehabilitation services may be an important component of multidisciplinary care.
Manassis, Katharina; Tannock, Rosemary; Young, Arlene; Francis-John, Shonna
Background Cognition in children with anxiety disorders (ANX) and comorbid Attention Deficit Disorder (ADHD) has received little attention, potentially impacting clinical and academic interventions in this highly disabled group. This study examined several cognitive features relative to children with either pure condition and to normal controls. Methods One hundred and eight children ages 8–12 and parents were diagnosed by semi-structured parent interview and teacher report as having: ANX (any anxiety disorder except OCD or PTSD; n = 52), ADHD (n = 21), or ANX + ADHD (n = 35). All completed measures of academic ability, emotional perception, and working memory. Clinical subjects were compared to 35 normal controls from local schools. Results Groups did not differ significantly on age, gender, or estimated IQ. On analyses of variance, groups differed on academic functioning (Wide Range Achievement Test, p < .001), perception of emotion (auditory perception of anger, p < .05), and working memory (backwards digits, p < .01; backwards finger windows, p < .05; Chipasat task, p < .001). ANX + ADHD and children with ADHD did poorly relative to controls on all differentiating measures except auditory perception of anger, where ANX + ADHD showed less sensitivity than children with ANX or with ADHD. Conclusion Though requiring replication, findings suggest that ANX + ADHD relates to greater cognitive and academic vulnerability than ANX, but may relate to reduced perception of anger. PMID:17224054
Hamilton, Joanne M; Salmon, David P; Galasko, Douglas; Raman, Rema; Emond, Jenn; Hansen, Lawrence A; Masliah, Eliezer; Thal, Leon J
Dementia with Lewy bodies (DLB) is often characterized by pronounced impairment in visuospatial skills, attention, and executive functions. However, the strength of the phenotypic expression of DLB varies and may be weaker in patients with extensive concomitant Alzheimer's disease (AD). To determine whether strength of the DLB clinical phenotype impacts cognitive decline, visuospatial and language tests were retrospectively used to predict 2-year rate of global cognitive decline in 22 autopsy-confirmed DLB patients (21 with concomitant AD) and 44 autopsy-confirmed "pure" AD patients. Generalized estimating equations (GEE) revealed a significant interaction such that poor baseline performances on tests of visuospatial skills were strongly associated with a rapid rate of cognitive decline in DLB but not AD (p < .001). No effect of confrontation naming was found. DLB patients with poor visuospatial skills had fewer neurofibrillary tangles and were more likely to experience visual hallucinations than those with better visuospatial skills. These results suggest that the severity of visuospatial deficits in DLB may identify those facing a particularly malignant disease course and may designate individuals whose clinical syndrome is impacted more by Lewy body formation than AD pathology.
Del'Guidice, Thomas; Lemay, Francis; Lemasson, Morgane; Levasseur-Moreau, Jean; Manta, Stella; Etievant, Adeline; Escoffier, Guy; Doré, François Y; Roman, François S; Beaulieu, Jean-Martin
Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT2C receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT2 receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms. PMID:24196946
Price, Catherine C.; Tanner, Jared; Nguyen, Peter T.; Schwab, Nadine A.; Mitchell, Sandra; Slonena, Elizabeth; Brumback, Babette; Okun, Michael S.; Mareci, Thomas H.; Bowers, Dawn
Objective This prospective investigation examined: 1) processing speed and working memory relative to other cognitive domains in non-demented medically managed idiopathic Parkinson’s disease, and 2) the predictive role of cortical/subcortical gray thickness/volume and white matter fractional anisotropy on processing speed and working memory. Methods Participants completed a neuropsychological protocol, Unified Parkinson’s Disease Rating Scale, brain MRI, and fasting blood draw to rule out vascular contributors. Within group a priori anatomical contributors included bilateral frontal thickness, caudate nuclei volume, and prefrontal white matter fractional anisotropy. Results Idiopathic Parkinson’s disease (n = 40; Hoehn & Yahr stages 1–3) and non-Parkinson’s disease ‘control’ peers (n = 40) matched on demographics, general cognition, comorbidity, and imaging/blood vascular metrics. Cognitively, individuals with Parkinson’s disease were significantly more impaired than controls on tests of processing speed, secondary deficits on working memory, with subtle impairments in memory, abstract reasoning, and visuoperceptual/spatial abilities. Anatomically, Parkinson’s disease individuals were not statistically different in cortical gray thickness or subcortical gray volumes with the exception of the putamen. Tract Based Spatial Statistics showed reduced prefrontal fractional anisotropy for Parkinson’s disease relative to controls. Within Parkinson’s disease, prefrontal fractional anisotropy and caudate nucleus volume partially explained processing speed. For controls, only prefrontal white matter was a significant contributor to processing speed. There were no significant anatomical predictors of working memory for either group. Conclusions Caudate nuclei volume and prefrontal fractional anisotropy, not frontal gray matter thickness, showed unique and combined significance for processing speed in Parkinson’s disease. Findings underscore the
Background Vitamin B12 deficiency is common in older people, and may be responsible for reversible dementia. Low serum vitamin B12 levels were also observed in patients with Mild Cognitive Impairment (MCI). It is not known whether patients with vitamin B12 deficiency have a distinctive profile of cognitive impairment different from the episodic memory deficit usually observed in MCI. Results From a cohort of 310 patients with MCI followed in a memory clinic in Lisbon, only 10 cases with vitamin B12 deficiency were found. From collaboration with other neurologists, 5 further patients with vitamin B12 deficiency were added. These cases were compared to MCI patients with normal vitamin B12 levels in a ratio 1:3. The duration of subjective cognitive symptoms was significantly shorter in MCI patients with B12 deficiency (1.2±1.0 years) as compared to MCI patients with normal vitamin B12 levels (3.4±3.0 years, p<0.001, Student’ t test). There were no statistically significant differences in the neuropsychological tests between MCI patients with and without vitamin B12 deficiency. Vitamin B12 was started in MCI patients with vitamin B12 deficiency, with no noticeable clinical improvement. Conclusion MCI patients with low levels of vitamin B12 had no particular profile of cognitive impairment, however vitamin B12 deficiency might have precipitated the onset of symptoms. The effect of vitamin B12 supplementation in patients with MCI and low vitamin B12 levels should be clarified by future prospective studies. PMID:24010640
Jankowsky, Joanna L; Melnikova, Tatiana; Fadale, Daniel J; Xu, Guilian M; Slunt, Hilda H; Gonzales, Victoria; Younkin, Linda H; Younkin, Steven G; Borchelt, David R; Savonenko, Alena V
Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid-beta (Abeta), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of Abeta-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state Abeta levels, because both endogenous and transgene-derived Abeta are increased in enriched animals. These results demonstrate that the generation of Abeta in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors.
Burkhardt, Luise; Lobitz, Stephan; Koustenis, Elisabeth; Rueckriegel, Stefan Mark; Hernáiz Driever, Pablo
Cerebrovascular disease is an important feature of pediatric sickle cell disease (SCD) and may lead to cognitive and motor impairment. Our cross-sectional study examined the incidence and severity of these impairments in a pediatric cohort without clinical cerebrovascular events from Berlin of mixed ethnic origin. Thirty-two SCD patients (mean age 11.14 years, range 7.0-17.25 years; males 14) were evaluated for full-scale intelligence (IQ) (German version WISC-III), fine motor function (digital writing tablet), and executive function (planning, attention, working memory, and visual-spatial abilities) with the Amsterdam Neuropsychological Tasks (ANT) program and the Tower of London (ToL). Data on clinical risk factors were retrieved from medical records. Full-scale IQ of patients was preserved, whereas performance IQ was significantly reduced (91.19 (SD 12.17) d = 0.7, p = 0.007). SCD patients scored significantly lower than healthy peers when tested for executive and fine motor functions, e.g., planning time in the ToL (6.73 s (SD 3.21) vs. 5.9 s in healthy peers (SD 2.33), d = 0.5, p = <0.001) and frequency on the writing tablet (mean z score -0.79, d = 0.7, p < 0.001). No clinical risk factors were significantly associated with incidence and severity of cognitive and motor deficits. Despite the preservation of full-scale IQ, our SCD cohort of mixed origin exhibited inferior executive abilities and reduced fine motor skills. Our study is limited by the small size of our cohort as well as the lack for control of sociodemographic and socioeconomic factors modulating higher functions but highlights the need for early screening, prevention, and specific interventions for these deficits.
He, Zhi; Liao, Yun; Zheng, Min; Zeng, Fan-Dian; Guo, Lian-Jun
Piracetam is the derivate of gamma-aminobutyric acid, which improves the cognition,memory,consciousness, and is widely applied in the clinical treatment of brain dysfunction. In the present experiments, we study the effects of piracetam on chronic cerebral hypoperfused rats and observe its influence on amino acids, synaptic plasticity in the Perforant path-CA3 pathway and apoptosis in vivo. Cerebral hypoperfusion for 30 days by occlusion of bilateral common carotid arteries induced marked amnesic effects along with neuron damage, including: (1) spatial learning and memory deficits shown by longer escape latency and shorter time spent in the target quadrant; (2) significant neuronal loss and nuclei condensation in the cortex and hippocampus especially in CA1 region; (3) lower induction rate of long term potentiation, overexpression of BAX and P53 protein, and lower content of excitatory and inhibitory amino acids in hippocampus. Oral administration of piracetam (600 mg/kg, once per day for 30 days) markedly improved the memory impairment, increased the amino acid content in hippocampus, and attenuated neuronal damage. The ability of piracetam to attenuate memory deficits and neuronal damage after hypoperfusion may be beneficial in cerebrovascular type dementia.
This paper discusses compassion failure and compassion deficits in health care, using two major reports by Robert Francis in the UK as a point of reference. Francis enquired into events at the Mid Staffordshire Hospital between 2005 and 2009, events that unequivocally warrant the description 'appalling care'. These events prompted an intense national debate, along with proposals for significant changes in the regulation of nursing and nurse education. The circumstances are specific to the UK, but the issues are international. I suggest that social psychology provides numerous hints about the mechanisms that might have been involved at Mid Staffs and about the reasons why outsiders are blind to these mechanisms. However, there have been few references to social psychology in the post-Francis debate (the Francis Report itself makes no reference to it at all). It is an enormously valuable resource, and it has been overlooked. Drawing on the social psychology literature, I express scepticism about the idea that there was a compassion deficit among the Mid Staff nurses - the assumption that the appalling care had something to do with the character, attitudes, and values of nurses - and argue that the Francis Report's emphasis on a 'culture of compassion and caring in nurse recruitment, training and education' is misconceived. It was not a 'failure of compassion' that led to the events in Mid Staffs but an interlocking set of contextual factors that are known to affect social cognition. These factors cannot be corrected or compensated for by teaching ethics, empathy, and compassion to student nurses.
Puccioni, Olga; Vallesi, Antonino
Several studies support the existence of a specific age-related difficulty in suppressing potentially distracting information. The aim of the present study is to investigate whether spatial conflict resolution is selectively affected by aging. The way aging affects individuals could be modulated by many factors determined by the socieconomic status: we investigated whether factors such as cognitive reserve (CR) and years of education may play a compensatory role against age-related deficits in the spatial domain. A spatial Stroop task with no feature repetitions was administered to a sample of 17 non-demented older adults (69–79 years-old) and 18 younger controls (18–34 years-old) matched for gender and years of education. The two age groups were also administered with measures of intelligence and CR. The overall spatial Stroop effect did not differ according to age, neither for speed nor for accuracy. The two age groups equally showed sequential effects for congruent trials: reduced response times (RTs) if another congruent trial preceded them, and accuracy at ceiling. For incongruent trials, older adults, but not younger controls, were influenced by congruency of trialn−1, since RTs increased with preceding congruent trials. Interestingly, such an age-related modulation negatively correlated with CR. These findings suggest that spatial conflict resolution in aging is predominantly affected by general slowing, rather than by a more specific deficit. However, a high level of CR seems to play a compensatory role for both factors. PMID:23248595
Yang, Mu; Lewis, Freeman C.; Sarvi, Michael S.; Foley, Gillian M.; Crawley, Jacqueline N.
Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/-) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2…
Research has demonstrated, in both human and animals, that cognitive functioning decreases with age, to include deficits in processing speed, executive function, memory, and spatial learning. The cause of these functional declines is not entirely understood; however, neuronal losses and the associat...
Leopold, Daniel R.; Christopher, Micaela E.; Burns, G. Leonard; Becker, Stephen P.; Olson, Richard K.; Willcutt, Erik G.
Background: Although multiple cross-sectional studies have shown symptoms of sluggish cognitive tempo (SCT) and attention-deficit/hyperactivity disorder (ADHD) to be statistically distinct, studies have yet to examine the temporal stability and measurement invariance of SCT in a longitudinal sample. To date, only six studies have assessed SCT…
Shillingford, Margaret Ann; Lambie, Glenn W.; Walter, Sara Meghan
Attention deficit hyperactive disorder (ADHD) is a prevalent diagnostic disorder for many students, which correlates with negative academic, social, and personal consequences. This article presents an integrative, cognitive-behavioral, systemic approach that offers behaviorally based interventions for professional school counselors to support…
Åsberg Johnels, Jakob; Kopp, Svenny; Gillberg, Christopher
Writing difficulties are common among children with attention-deficit/hyperactivity disorder (ADHD), but the nature of these difficulties has not been well studied. Here we relate behavioral, psycholinguistic, cognitive (memory/executive), and graphomotor measures to spelling skills in school-age girls with ADHD (n = 30) and an age-matched group…
Rubin, Eli Z.; And Others
To assess the effects of specialized retraining of cognitive, perceptual, and motor (CPM) deficits, a battery of tests was prepared and used with 200 behaviorally maladjusted and 200 problem-free children. The composite score indicated that 40% of the maladjusted group manifested major dysfunction whereas none of the problem-free group…
Cicchetti, Domenic V.; Kaufman, Alan S.; Sparrow, Sara S.
Our purpose in this report is to evaluate scientifically that body of literature relating the effects of prenatal and postnatal exposure to polychlorinated biphenyls (PCBs) upon neurobehavioral, health-related, and cognitive deficits in neonates, developing infants, children, and adults. The data derive from seven cohorts: six cohorts of mothers…
Crawford, Helen J.; Barabasz, Marianne
Quantitative EEG magnitude data were obtained from children with and without attention deficit disorder (ADD). The data suggest that the right fronto-centro-temporal region is not as "cognitively activated" relative to the left hemisphere in those children with ADD. Neurotherapy training of the right frontal and central regions in ADD…
Pompili, Maurizio; Lester, David; Girardi, Paolo; Tatarelli, Roberto
We report the case of attempted suicide by a 30-year-old man who had significant cognitive deficits that developed after at least three years of polysubstance use with cannabis, methylenedioxymethamphetamine (MDMA, "ecstasy") and cocaine. The patient reported increasing difficulties in his professional and interpersonal life which may have been…
MacKay, Donald G; James, Lori E
Two experiments compared the visual cognition performance of amnesic H.M. and memory-normal controls matched for age, background, intelligence, and education. In Experiment 1 H.M. exhibited deficits relative to the controls in detecting "erroneous objects" in complex visual scenes--for example, a bird flying inside a fishbowl. In Experiment 2 H.M. exhibited deficits relative to the controls in standard Hidden-Figure tasks when detecting unfamiliar targets but not when detecting familiar targets--for example, circles, squares, and right-angle triangles. H.M.'s visual cognition deficits were not due to his well-known problems in explicit learning and recall, inability to comprehend or remember the instructions, general slowness, motoric difficulties, low motivation, low IQ relative to the controls, or working-memory limitations. Parallels between H.M.'s selective deficits in visual cognition, language, and memory are discussed. These parallels contradict the standard "systems theory" account of H.M.'s condition but comport with the hypothesis that H.M. has difficulty representing unfamiliar but not familiar information in visual cognition, language, and memory. Implications of our results are discussed for binding theory and the ongoing debate over what counts as "memory" versus "not-memory."
Greer, Margaret K.; And Others
This case study illustrates the highly significant language difficulties, marked memory deficits, and propensity for physical aggression following temporal lobe damage brought about by herpes encephalitis, and presents the usefulness of a new diagnostic measure in delineating such a variable cognitive pattern. (Author)
Wang, Li; Almeida, Luis E.F.; de Souza Batista, Celia M.; Khaibullina, Alfia; Xu, Nuo; Albani, Sarah; Guth, Kira A.; Seo, Ji Sung; Quezado, Martha; Quezado, Zenaide M.N.
Strokes are perhaps the most serious complications of sickle cell disease (SCD) and by the fifth decade occur in approximately 25% of patients. While most patients do not develop strokes, mounting evidence indicates that even without brain abnormalities on imaging studies, SCD patients can present profound neurocognitive dysfunction. We sought to evaluate the neurocognitive behavior profile of humanized SCD mice (Townes, BERK) and to identify hematologic and neuropathologic abnormalities associated with the behavioral alterations observed in these mice. Heterozygous and homozygous Townes mice displayed severe cognitive deficits shown by significant delays in spatial learning compared to controls. Homozygous Townes also had increased depression- and anxiety-like behaviors as well as reduced performance on voluntary wheel running compared to controls. Behavior deficits observed in Townes were also seen in BERKs. Interestingly, most deficits in homozygotes were observed in older mice and were associated with worsening anemia. Further, neuropathologic abnormalities including the presence of large bands of dark/pyknotic (shrunken) neurons in CA1 and CA3 fields of hippocampus and evidence of neuronal dropout in cerebellum were present in homozygotes but not control Townes. These observations suggest that cognitive and behavioral deficits in SCD mice mirror those described in SCD patients and that aging, anemia, and profound neuropathologic changes in hippocampus and cerebellum are possible biologic correlates of those deficits. These findings support using SCD mice for studies of cognitive deficits in SCD and point to vulnerable brain areas with susceptibility to neuronal injury in SCD and to mechanisms that potentially underlie those deficits. PMID:26462816
Milman, A; Zohar, O; Maayan, R; Weizman, R; Pick, C G
Mild traumatic brain injury (mTBI) is characterized by diffused symptoms, which when combined are called "post-concussion syndrome". Dehydroepiandrosterone sulfate (DHEAS) is a neuroactive neurosteroid. Previously, we have reported that closed head mTBI causes long lasting cognitive deficits and depressive-like behavior. In the present study we describe the effects of DHEAS on the behavior of mice that suffered closed head mTBI. Following the induction of mTBI, mice were treated once a week with DHEAS (s.c. 20 mg/kg) and their performance in the passive avoidance test and the forced swimming test (FST) were evaluated 7, 30, 60 and 90 days post-injury. The most important interactions were between injury and injection (passive avoidance; p<0.001 and FST; p=0.001), meaning that DHEAS has beneficial effects only when given to injured animals. Our results demonstrate that the long-term cognitive and behavioral effects induced by mTBI may be improved by a repeated weekly treatment with DHEAS.
Corradini, Irene; Donzelli, Andrea; Antonucci, Flavia; Welzl, Hans; Loos, Maarten; Martucci, Roberta; De Astis, Silvia; Pattini, Linda; Inverardi, Francesca; Wolfer, David; Caleo, Matteo; Bozzi, Yuri; Verderio, Claudia; Frassoni, Carolina; Braida, Daniela; Clerici, Mario; Lipp, Hans-Peter; Sala, Mariaelvina; Matteoli, Michela
Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.
Colucci, Luisa; Bosco, Massimiliano; Ziello, Antonio Rosario; Rea, Raffaele; Amenta, Francesco; Fasanaro, Angiola Maria
Nootropics represent probably the first “smart drugs” used for the treatment of cognitive deficits. The aim of this paper is to verify, by a systematic analysis of the literature, the effectiveness of nootropics in this indication. The analysis was limited to nootropics with cholinergic activity, in view of the role played by acetylcholine in learning and memory. Acetylcholine was the first neurotransmitter identified in the history of neuroscience and is the main neurotransmitter of the peripheral, autonomic, and enteric nervous systems. We conducted a systematic review of the literature for the 5-year period 2006–2011. From the data reported in the literature, it emerges that nootropics may be an effective alternative for strengthening and enhancing cognitive performance in patients with a range of pathologies. Although nootropics, and specifically the cholinergic precursors, already have a long history behind them, according to recent renewal of interest, they still seem to have a significant therapeutic role. Drugs with regulatory indications for symptomatic treatment of Alzheimer’s disease, such as cholinesterase inhibitors and memantine, often have transient effects in dementia disorders. Nootropics with a cholinergic profile and documented clinical effectiveness in combination with cognate drugs such as cholinesterase inhibitors or alone in patients who are not suitable for these inhibitors should be taken into account and evaluated further. PMID:27186129
Titus, David J.; Sakurai, Atsushi; Kang, Yuan; Furones, Concepcion; Jergova, Stanislava; Santos, Rosmery; Sick, Thomas J.; Atkins, Coleen M.
Traumatic brain injury (TBI) modulates several cell signaling pathways in the hippocampus critical for memory formation. Previous studies have found that the cAMP-protein kinase A signaling pathway is downregulated after TBI and that treatment with a phosphodiesterase (PDE) 4 inhibitor rolipram rescues the decrease in cAMP. In the present study, we examined the effect of rolipram on TBI-induced cognitive impairments. At 2 weeks after moderate fluid-percussion brain injury or sham surgery, adult male Sprague Dawley rats received vehicle or rolipram (0.03 mg/kg) 30 min before water maze acquisition or cue and contextual fear conditioning. TBI animals treated with rolipram showed a significant improvement in water maze acquisition and retention of both cue and contextual fear conditioning compared with vehicle-treated TBI animals. Cue and contextual fear conditioning significantly increased phosphorylated CREB levels in the hippocampus of sham animals, but not in TBI animals. This deficit in CREB activation during learning was rescued in TBI animals treated with rolipram. Hippocampal long-term potentiation was reduced in TBI animals, and this was also rescued with rolipram treatment. These results indicate that the PDE4 inhibitor rolipram rescues cognitive impairments after TBI, and this may be mediated through increased CREB activation during learning. PMID:23516287
Korsch, Franziska; Petermann, Ulrike; Schmidt, Sören; Petermann, Franz
Studies show that ADHD, conduct disorders, and anxiety disorders are clinical disorders mostly diagnosed in schoolstarters. The preschool medical examination in Bremen was therefore extended by behavioral screenings. Based on their screening results from the SEU (health examination for school entry) 2011 in Bremen, 67 preschoolers were tested for behavioral disorders. Subsequently, children with behavioral or emotional symptoms (N = 56) were compared to symptomfree controls (N = 52) for their cognitive, motoric, linguistic, and social-emotional development. Psychosocial health was obtained through external assessment by the parents and kindergarten teachers. Results of the WPPSI-III, M-ABC-2, and ET 6-6 were included in the analysis. 32 children met the criteria for behavioral disorders. Children with behavioral or emotional symptoms showed significant lower scores on tests measuring cognitive, motoric, linguistic and emotional development compared to controls. Results suggest that there is necessity to screen all preschoolers for behavioral disorders before entering school. Because children with clinical or subclinical behavioral disorders showed major developmental deficits compared to children without behavioral symptoms, it is essential to conduct a multiple assessment on children with suspected behavioral disorders to ensure early developmental support and adequate interventional programs.
Leite, Jorge; Gonçalves, Oscar F; Carvalho, Sandra
Parkinson's disease (PD) is a progressive neurodegenerative disorder, primarily characterized by motor symptoms such as tremor, rigidity, bradykinesia, stiffness, slowness and impaired equilibrium. Although the motor symptoms have been the focus in PD, slight cognitive deficits are commonly found in non-demented and non-depressed PD patients, even in early stages of the disease, which have been linked to the subsequent development of pathological dementia. Thus, strongly reducing the quality of life (QoL). Both levodopa therapy and deep brain stimulation (DBS) have yield controversial results concerning the cognitive symptoms amelioration in PD patients. That does not seems to be the case with transcranial direct current stimulation (tDCS), although better stimulation parameters are needed. Therefore we hypothesize that simultaneously delivering cathodal tDCS (or ctDCS), over the right prefrontal cortex delivered with anodal tDCS (or atDCS) to left prefrontal cortex could be potentially beneficial for PD patients, either by mechanisms of homeostatic plasticity and by increases in the extracellular dopamine levels over the striatum.
Stine-Morrow, Elizabeth A. L.
Objectives. We examined the degree to which online sentence processing and offline sentence memory differed among older adults who showed risk for amnestic and nonamnestic varieties of mild cognitive impairment (MCI), based on psychometric classification. Method. Participants (N = 439) read a series of sentences in a self-paced word-by-word reading paradigm for subsequent recall and completed a standardized cognitive test battery. Participants were classified into 3 groups: unimpaired controls (N = 281), amnestic MCI (N = 94), or nonamnestic MCI (N = 64). Results. Relative to controls, both MCI groups had poorer sentence memory and showed reduced sentence wrap-up effects, indicating reduced allocation to semantic integration processes. Wrap-up effects predicted subsequent recall in the control and nonamnestic groups. The amnestic MCI group showed poorer recall than the nonamnestic MCI group, and only the amnestic MCI group showed no relationship between sentence wrap-up and recall. Discussion. Our findings suggest that psychometrically defined sub-types of MCI are associated with unique deficits in sentence processing and can differentiate between the engagement of attentional resources during reading and the effectiveness of engaging attentional resources in producing improved memory. PMID:25190209
Titus, David J; Sakurai, Atsushi; Kang, Yuan; Furones, Concepcion; Jergova, Stanislava; Santos, Rosmery; Sick, Thomas J; Atkins, Coleen M
Traumatic brain injury (TBI) modulates several cell signaling pathways in the hippocampus critical for memory formation. Previous studies have found that the cAMP-protein kinase A signaling pathway is downregulated after TBI and that treatment with a phosphodiesterase (PDE) 4 inhibitor rolipram rescues the decrease in cAMP. In the present study, we examined the effect of rolipram on TBI-induced cognitive impairments. At 2 weeks after moderate fluid-percussion brain injury or sham surgery, adult male Sprague Dawley rats received vehicle or rolipram (0.03 mg/kg) 30 min before water maze acquisition or cue and contextual fear conditioning. TBI animals treated with rolipram showed a significant improvement in water maze acquisition and retention of both cue and contextual fear conditioning compared with vehicle-treated TBI animals. Cue and contextual fear conditioning significantly increased phosphorylated CREB levels in the hippocampus of sham animals, but not in TBI animals. This deficit in CREB activation during learning was rescued in TBI animals treated with rolipram. Hippocampal long-term potentiation was reduced in TBI animals, and this was also rescued with rolipram treatment. These results indicate that the PDE4 inhibitor rolipram rescues cognitive impairments after TBI, and this may be mediated through increased CREB activation during learning.
Falkai, Peter; Steiner, Johann; Malchow, Berend; Shariati, Jawid; Knaus, Andreas; Bernstein, Hans-Gert; Schneider-Axmann, Thomas; Kraus, Theo; Hasan, Alkomiet; Bogerts, Bernhard; Schmitt, Andrea
In schizophrenia, previous stereological post-mortem investigations of anterior, posterior, and total hippocampal subfields showed no alterations in total neuron number but did show decreased oligodendrocyte numbers in CA4, an area that corresponds to the polymorph layer of the dentate gyrus (DG). However, these investigations identified oligodendrocytes only on the basis of morphological criteria in Nissl staining and did not assess alterations of interneurons with immunohistochemical markers. Moreover, the association of findings in the posterior hippocampus with cognitive deficits remains unknown. On the basis of the available clinical records, we compared patients with definite and possible cognitive dysfunction; nine patients had evidence in their records of either definite (n = 4) or possible (n = 5) cognitive dysfunction. Additionally, we assessed the density of two oligodendrocyte subpopulations immunostained by the oligodendrocyte transcription factors Olig1 and Olig2 and of interneurons immunolabeled by parvalbumin. We investigated posterior hippocampal subregions in the post-mortem brains of the same schizophrenia patients (SZ; n = 10) and healthy controls (n = 10) we examined in our previously published stereological studies. Our stereological studies found that patients with definite cognitive deficits had decreased total/Nissl-stained oligodendrocyte numbers in the left (p = 0.014) and right (p = 0.050) CA4, left CA2/3 (p = 0.050), left CA1 (p = 0.027), and left (p = 0.050) and right (p = 0.014) subiculum of the anterior part of the hippocampus compared to patients with possible cognitive deficits. In the present study, we found no significant influence of definite cognitive deficits in the posterior part of the hippocampus, whereas in the entire hippocampus SZ with definite cognitive deficits showed decreased oligodendrocyte numbers in the left (p = 0.050) and right (p = 0.050) DG and left CA2/3 (p = 0.050). We did not find significant differences in
Wilkos, Ewelina; Brown, Timothy JB; Slawinska, Ksenia; Kucharska, Katarzyna A
worse performance on Reading the Mind in the Eyes Test, revised version II. Neuropsychological assessment demonstrated some statistically significant deficits in learning and remembering both verbal and visual material, long-term information storing, problem solving, and executive functions such as verbal fluency. Conclusion Patients at early stage of unilateral thalamic stroke showed both neurocognitive and social cognitive deficits. Further research is needed to increase understanding about diagnosis, early treatment, and prognosis of patients with thalamic lesions. PMID:25914535
Walsh, Jennifer A.; Creighton, Sarah E.; Rutherford, M. D.
Some, but not all, relevant studies have revealed face processing deficits among those with autism spectrum disorder (ASD). In particular, deficits are revealed in face processing tasks that involve emotion perception. The current study examined whether either deficits in processing emotional expression or deficits in processing social cognitive…
Lithfous, Ségolène; Tromp, Delphine; Dufour, André; Pebayle, Thierry; Goutagny, Romain; Després, Olivier
The purpose of this study was to investigate the role of theta activity in cognitive mapping, and to determine whether age-associated decreased theta power may account for navigational difficulties in elderly individuals. Cerebral activity was recorded using electroencephalograph in young and older individuals performing a spatial memory task that required the creation of cognitive maps. Power spectra were computed in the frontal and parietal regions and correlated with recognition performance. We found that accuracy of cognitive mapping was positively correlated with left frontal theta activity during encoding in young adults but not in older individuals. Compared with young adults, older participants were impaired in the creation of cognitive maps and showed reduced theta and alpha activity at encoding. These results suggest that encoding processes are impaired in older individual, which may explain age-related cognitive mapping deficits.
Farhat, Syeda Mehpara; Mahboob, Aamra; Iqbal, Ghazala; Ahmed, Touqeer
Aluminum is associated with etiology of many neurodegenerative diseases specially Alzheimer's disease. Chronic exposure to aluminum via drinking water results in aluminum deposition in the brain that leads to cognitive deficits. The study aimed to determine the effects of aluminum on cholinergic biomarkers, i.e., acetylcholine level, free choline level, and choline acetyltransferase gene expression, and how cholinergic deficit affects novel object recognition and sociability in mice. Mice were treated with AlCl3 (250 mg/kg). Acetylcholine level, free choline level, and choline acetyltransferase gene expression were determined in cortex, hippocampus, and amygdala. The mice were subjected to behavior tests (novel object recognition and social novelty preference) to assess memory deficits. The acetylcholine level in cortex and hippocampus was significantly reduced in aluminum-treated animals, as compared to cortex and hippocampus of control animals. Acetylcholine level in amygdala of aluminum-treated animals remained unchanged. Free choline level in all the three brain parts was found unaltered in aluminum-treated mice. The novel object recognition memory was severely impaired in aluminum-treated mice, as compared to the control group. Similarly, animals treated with aluminum showed reduced sociability compared to the control mice group. Our study demonstrates that aluminum exposure via drinking water causes reduced acetylcholine synthesis in spite of normal free choline availability. This deficit is caused by reduced recycling of acetylcholine due to lower choline acetyltransferase level. This cholinergic hypofunction leads to cognitive and memory deficits. Moreover, hippocampus is the most affected brain part after aluminum intoxication.
Fisch, G.S.; Simensen, R.
Previously, researchers reported molecular-neurobehavioral or molecular-cognitive associations in individuals with fra(X) (fragile X) mutation. However, not all investigators have noted molecular-behavioral relationships. Consequently, we examined prospectively 30 fra(X) males age 3-15 years from four testing sites to determine whether there was a relationship between mutation size and degree of either cognitive or adaptive behavior deficit. To measure cognitive abilities, all individuals were administered the Stanford-Binet (4th edition) IQ test. To evaluate adaptive behavior (DQ) skills, all individuals were assessed using the Vineland Adaptive Behavior Scale. To determine fra(X) status, genomic DNA from all individuals was extracted and digested with EcoRI and EagI restriction enzymes. Southern blots were prepared and hybridized with the pE5.1 probe. The Pearson correlation coefficient between full mutation size and composite IQ score revealed a non-significant, near-zero association (r = 0.06; P > .76). The Pearson coefficient between mutation size and DQ also showed a non-significant, near-zero association (r = 0.06; P >.73). We conclude that while fra(X) mutation produces cognitive and behavior deficits in males who inherit the defective gene, there is no relationship between mutation size and degree of deficit. 14 refs., 2 figs.
Ishrat, Tauheed; Hoda, Md Nasrul; Khan, M Badruzzaman; Yousuf, Seema; Ahmad, Muzamil; Khan, Mohd Moshahid; Ahmad, Ajmal; Islam, Fakhrul
Recent evidence indicates that curcumin (CUR), the principal curcuminoid of turmeric, exhibits antioxidant potential and protects the brain against various oxidative stressors. The aim of the present study was to examine the modulating impacts of CUR against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ) infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with CUR (80 mg/kg) for three weeks. After two weeks of ICV-STZ infusion, rats were tested for cognitive performance using passive avoidance and water maze tasks and then sacrificed for biochemical and histopathological assays. ICV-STZ rats showed significant cognitive deficits, which were significantly improved by CUR supplementation. CUR supplementation significantly augmented increased 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA), thiobarbituric reactive substances (TBARS), hydrogen peroxide (H2O2), protein carbonyl (PC) and oxidized glutathione (GSSG); decreased levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) in the hippocampus and cerebral cortex; and increased choline acetyltransferase (ChAT) activity in the hippocampus of ICV-STZ rats. The study suggests that CUR is effective in preventing cognitive deficits, and might be beneficial for the treatment of sporadic dementia of Alzheimer's type (SDAT).
Bertoux, Maxime; de Souza, Leonardo Cruz; O'Callaghan, Claire; Greve, Andrea; Sarazin, Marie; Dubois, Bruno; Hornberger, Michael
Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.
Lebedev, Alexander V.; Westman, Eric; Simmons, Andrew; Lebedeva, Aleksandra; Siepel, Françoise J.; Pereira, Joana B.; Aarsland, Dag
Cognitive impairment is a common non-motor feature of Parkinson's disease (PD). Understanding the neural mechanisms of this deficit is crucial for the development of efficient methods for treatment monitoring and augmentation of cognitive functions in PD patients. The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson's Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with 123I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox (BCT) was used to extract nodal strength from all ROIs, and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain-behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable (LV) scores were matched with the performances in the three cognitive domains (memory, visuospatial, and executive) and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on the modularity of the “cognitive network” was analyzed. For the range of deficits studied, better executive performance was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This profile was also characterized by a relative preservation of nigrostriatal dopaminergic function. The profile associated with better memory performance correlated with increased
Carmona, Susana; Hoekzema, Elseline; Castellanos, Francisco X; García-García, David; Lage-Castellanos, Agustín; Van Dijk, Koene R A; Navas-Sánchez, Francisco J; Martínez, Kenia; Desco, Manuel; Sepulcre, Jorge
We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD.
Yerys, Benjamin E; Wallace, Gregory L; Sokoloff, Jennifer L; Shook, Devon A; James, Joette D; Kenworthy, Lauren
Recent estimates suggest that 31% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 24% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new problems unreported in ASD or ADHD; having no clear impact; or producing some combination of these scenarios. Children with ASD and co-morbid ADHD symptoms (ASD+ADHD; n = 21), children with ASD without ADHD (ASD; n = 28), and a typically developing control group (n = 21) were included in the study; all groups were matched on age, gender-ratio, IQ, and socioeconomic status. Data were collected on verbal and spatial working memory, response inhibition, global executive control (EC), autistic traits, adaptive functioning, and maladaptive behavior problems. In this sample, the presence of ADHD symptoms in ASD exacerbated impairments in EC and adaptive behavior and resulted in higher autistic trait, and externalizing behavior ratings. ADHD symptoms were also associated with greater impairments on a lab measure of verbal working memory. These findings suggest that children with ASD+ADHD symptoms present with exacerbated impairments in some but not all domains of functioning relative to children with ASD, most notably in adaptive behavior and working memory. Therefore, ADHD may moderate the expression of components of the ASD cognitive and behavioral phenotype, but ASD+ADHD may not represent an etiologically distinct phenotype from ASD alone.
Carmona, Susana; Hoekzema, Elseline; Castellanos, Francisco X.; García-García, David; Lage-Castellanos, Agustín; Dijk, Koene R.A.Van; Navas-Sánchez, Francisco J.; Martínez, Kenia; Desco, Manuel; Sepulcre, Jorge
We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex—visual, auditory, and somatosensory—we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. PMID:25821110
Yerys, Benjamin E.; Wallace, Gregory L.; Sokoloff, Jennifer L.; Shook, Devon A.; James, Joette D.; Kenworthy, Lauren
Recent estimates suggest that over 30% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 20% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new problems unreported in ASD or ADHD; having no clear impact; or producing some combination of these scenarios. Children with ASD and co-morbid ADHD symptoms (ASD+ADHD; n=21), children with ASD without ADHD (ASD; n=28), and a typically developing control group (n=21) were included in the study; all groups were matched on age, gender-ratio, IQ, and socioeconomic status. Data were collected on verbal and spatial working memory, response inhibition, global executive control, autistic traits, adaptive functioning, and maladaptive behavior problems. In this sample, the presence of ADHD symptoms in ASD exacerbated impairments in executive control and adaptive behavior and resulted in higher autistic trait, and externalizing behavior ratings. ADHD symptoms were also associated with greater impairments on a lab measure of verbal working memory. These findings suggest that children with ASD+ADHD symptoms present with exacerbated impairments in some but not all domains of functioning relative to children with ASD, most notably in adaptive behavior and working memory. Therefore, ADHD may moderate the expression of components of the ASD cognitive and behavioral phenotype, but ASD+ADHD may not represent an etiologically distinct phenotype from ASD alone. PMID:19998356
Brega, Angela G; Goodrich, Glenn; Bennett, Rachael E; Hessl, David; Engle, Karen; Leehey, Maureen A; Bounds, Lanee S; Paulich, Marsha J; Hagerman, Randi J; Hagerman, Paul J; Cogswell, Jennifer B; Tassone, Flora; Reynolds, Ann; Kooken, Robert; Kenny, Michael; Grigsby, Jim
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation trinucleotide repeat expansion in the fragile X mental retardation 1 gene. Symptoms include gait ataxia, action tremor, and cognitive impairment. The objectives of the study were to clarify the nature of the dysexecutive syndrome observed in FXTAS and to assess the contribution of executive impairment to deficits in nonexecutive cognitive functions. Compared to controls, men with FXTAS demonstrated significant executive impairment, which was found to mediate group differences in most other cognitive abilities. Asymptomatic premutation carriers performed similarly to controls on all but two measures of executive functioning. These findings suggest that the impairment of nonexecutive cognitive skills in FXTAS is in large part secondary to executive dysfunction.
Mullick, Aditi A.; Subramanian, Sandeep K.; Levin, Mindy F.
Abstract Purpose: Motor and cognitive impairments are common and often coexist in patients with stroke. Although evidence is emerging about specific relationships between cognitive deficits and upper-limb motor recovery, the practical implication of these relationships for rehabilitation is unclear. Using a structured review and meta-analyses, we examined the nature and strength of the associations between cognitive deficits and upper-limb motor recovery in studies of patients with stroke. Methods: Motor recovery was defined using measures of upper limb motor impairment and/or activity limitations. Studies were included if they reported on at least one measure of cognitive function and one measure of upper limb motor impairment or function. Results: Six studies met the selection criteria. There was a moderate association (r = 0.43; confidence interval; CI:0.09– 0.68, p = 0.014) between cognition and overall arm motor recovery. Separate meta-analyses showed a moderately strong association between executive function and motor recovery (r = 0.48; CI:0.26– 0.65; p < 0.001), a weak positive correlation between attention and motor recovery (r = 0.25; CI:0.04– 0.45; p = 0.023), and no correlation between memory and motor recovery (r = 0.42; CI:0.16– 0.79; p = 0.14). Conclusion: These results imply that information on the presence of cognitive deficits should be considered while planning interventions for clients in order to design more personalized interventions tailored to the individual for maximizing upper-limb recovery. PMID:26410581
Deshpande, Laxmikant S; Phillips, Kristin; Huang, Beverly; DeLorenzo, Robert J
Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment.
Li, Xiaohang; Cui, Jin; Ding, Jianqing; Wang, Ying; Zeng, Xianglu; Ling, Yun; Shen, Xiaoheng; Chen, Shengdi; Huang, Chenggang; Pei, Gang
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aβ generation, whereas AT and PRP exerted neuroprotective effects against Aβ. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease. PMID:25386946
Saxbe, Catherine; Barkley, Russell A
Sluggish cognitive tempo (SCT) refers to an impairment of attention in hypoactive-appearing individuals that first presents in childhood. At this time, it exists only as a research entity that has yet to debut in official diagnostic taxonomies. However, it seems likely that a constellation of characteristic features of SCT may form the criteria for a newly defined childhood disorder in the foreseeable future, provided limitations in the extant findings can be addressed by future research. Most clinicians who assess and treat cases of attention- deficit/hyperactivity disorder (ADHD) have likely seen and treated someone who falls within the parameters for SCT. This article outlines the history of SCT and reviews the current understanding of the disorder, how it is distinguishable from and similar to other attention disorders, and what future directions research and treatment may take. Based on this review and their clinical experience, the authors conjecture that SCT is probably distinct from ADHD rather than being an ADHD subtype, although there is notable overlap with the ADHD predominantly inattentive and combined presentations.
Monyak, Rachel E.; Emerson, Danielle; Schoenfeld, Brian P.; Zheng, Xiangzhong; Chambers, Daniel B.; Rosenfelt, Cory; Langer, Steven; Hinchey, Paul; Choi, Catherine H.; McDonald, Thomas V.; Bolduc, Francois V.; Sehgal, Amita; McBride, Sean M.J.; Jongens, Thomas A.
Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low IQ and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin-signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore we showed that treatment with the FDA approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients. PMID:27090306
Mehrotra, Arpit; Kanwal, Abhinav; Banerjee, Sanjay Kumar; Sandhir, Rajat
Huntington's disease (HD) is a chronic neurodegenerative condition involving impaired mitochondrial functions. The present study evaluates the therapeutic potential of combined administration of mitochondrial modulators: alpha-lipoic acid and acetyl-l-carnitine on mitochondrial dysfunctions in 3-NP-induced HD. Our results reveal 3-NP administration resulted in compromise of mitochondrial functions in terms of: (1) impaired activity of mitochondrial respiratory chain enzymes, altered cytochrome levels, reduced histochemical staining of complex-II and IV, reduced in-gel activity of complex-I to V, and reduced mRNA expression of respiratory chain complexes; (2) enhanced mitochondrial oxidative stress indicated by increased malondialdehyde, protein carbonyls, reactive oxygen species and nitrite levels, along with decreased Mn-superoxide dismutase and catalase activity; (3) mitochondrial structural changes measured by mitochondrial swelling, reduced mitochondrial membrane potential and ultra-structure changes; (4) increased cytosolic cytochrome c levels, caspase-3 and -9 activity along with altered expression of apoptotic proteins (AIF, Bim, Bad, and Bax); and (5) impaired cognitive functions assessed using Morris water maze and Y-maze. Combination of mitochondrial modulators (alpha-lipoic acid + acetyl-l-carnitine) on the other hand ameliorated 3-NP-induced mitochondrial dysfunctions, oxidative stress, histologic alterations, and behavioral deficits, suggesting their therapeutic efficacy in the management of HD.
Li, Yue; Stockton, Michael E.; Bhuiyan, Ismat; Eisinger, Brian E.; Gao, Yu; Miller, Jessica L.; Bhattacharyya, Anita; Zhao, Xinyu
Fragile X syndrome, the most common form of inherited intellectual disability, is caused most often by a lack of fragile X mental retardation protein (FMRP). However, the mechanism remains unclear and effective treatment is lacking. Here we show that a loss of FMRP leads to activation of adult neural stem cells (NSCs) and a subsequent reduction in neuronal production. We identified ubiquitin ligase MDM2 as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP results in elevated mRNA and MDM2 protein levels. We further found that increased MDM2 levels lead to reduced P53 in NSCs, which alters NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for cancer, specifically inhibits MDM2 and P53 interaction, and rescues the neurogenic and cognitive deficits in FMRP-deficient mice. Our data unveil a regulatory role for FMRP and a potential new treatment for fragile X syndrome. PMID:27122614
Pandolfo, Pablo; Machado, Nuno J; Köfalvi, Attila; Takahashi, Reinaldo N; Cunha, Rodrigo A
Attention deficit hyperactivity disorder (ADHD) likely involves dopaminergic dysfunction in the frontal cortex and striatum, resulting in cognitive and motor abnormalities. Since both adenosine and dopamine modulation systems are tightly intertwined, we tested if caffeine (a non-selective adenosine receptor antagonist) attenuated the behavioral and neurochemical changes in adolescent spontaneously hypertensive rats (SHR, a validated ADHD animal model) compared to their control strain (Wistar Kyoto rats, WKY). SHR were hyperactive and had poorer performance in the attentional set-shifting and Y-maze paradigms and also displayed increased dopamine transporter (DAT) density and increased dopamine uptake in frontocortical and striatal terminals compared with WKY rats. Chronic caffeine treatment was devoid of effects in WKY rats while it improved memory and attention deficits and also normalized dopaminergic function in SHR. Additionally, we provide the first direct demonstration for the presence of adenosine A2A receptors (A2AR) in frontocortical nerve terminals, whose density was increased in SHR. These findings underscore the potential for caffeine treatment to normalize frontocortical dopaminergic function and to abrogate attention and cognitive changes characteristic of ADHD.
Background Neuroinflammation is associated with many conditions that lead to dementia, such as cerebrovascular disorders or Alzheimer’s disease. However, the specific role of neuroinflammation in the progression of cognitive deficits remains unclear. To understand the molecular mechanisms underlying these events we used a rodent model of focal cerebral stroke, which causes deficits in hippocampus-dependent cognitive function. Methods Cerebral stroke was induced by middle cerebral artery occlusion (MCAO). Hippocampus-dependent cognitive function was evaluated by a contextual fear conditioning test. The glial neuroinflammatory responses were investigated by immunohistochemical evaluation and diffusion tensor MRI (DTI). We used knockout mice for P2Y1 (P2Y1KO), a glial ADP/ATP receptor that induces the release of proinflammatory cytokines, to examine the links among P2Y1-mediated signaling, the neuroinflammatory response, and cognitive function. Results Declines in cognitive function and glial neuroinflammatory response were observed after MCAO in both rats and mice. Changes in the hippocampal tissue were detected by DTI as the mean diffusivity (MD) value, which corresponded with the cognitive decline at 4 days, 1 week, 3 weeks, and 2 months after MCAO. Interestingly, the P2Y1KO mice with MCAO showed a decline in sensory-motor function, but not in cognition. Furthermore, the P2Y1KO mice showed neither a hippocampal glial neuroinflammatory response (as assessed by immunohistochemistry) nor a change in hippocampal MD value after MCAO. In addition, wild-type mice treated with a P2Y1-specific antagonist immediately after reperfusion did not show cognitive decline. Conclusion Our findings indicate that glial P2Y1 receptors are involved in the hippocampal inflammatory response. The findings from this study may contribute to the development of a therapeutic strategy for brain infarction, targeting the P2Y1 receptor. PMID:23890321
Ford, Andrew H; Almeida, Osvaldo P; Flicker, Leon; Garrido, Griselda J; Greenop, Kathryn R; Foster, Jonathan K; Etherton-Beer, Christopher; van Bockxmeer, Frank M; Lautenschlager, Nicola T
Reduced awareness of cognitive deficits in mild cognitive impairment (MCI) is associated with poorer outcomes although little is known about the anatomical correlates of this. We examined the association of insight and grey matter volume using a voxel-based morphometry approach in 65 volunteers with MCI and 55 healthy age-matched controls. Participants with MCI had multiple areas of subtle grey matter volume loss compared with controls, although these did not survive correction for multiple comparisons. These were predominantly in the temporal and anterior portions of the brain. Individuals with MCI did not differ from each other on a number of demographic and cognitive variables according to level of insight. Reduced awareness of cognitive deficits was associated with few differences in grey matter volume apart from a subtle loss of grey matter in the medial frontal gyri. Given the modest nature of these findings, the routine assessment of insight in non-clinical populations of individuals with MCI is therefore not supported. Prospective data in larger samples, however, would be helpful to clarify this further and determine if impaired insight predicts brain atrophy and cognitive decline.
Esposito, Giuseppe; Sarnelli, Giovanni; Capoccia, Elena; Cirillo, Carla; Pesce, Marcella; Lu, Jie; Calì, Gaetano; Cuomo, Rosario; Steardo, Luca
Alzheimer's disease (AD) is characterized by chronic deposition of β-amyloid (Aβ) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deficits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Aβ which starts a neuroinflammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (EGCs). Here we show that the autologous transplantation of EGCs into the brain of Aβ-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Aβ-induced neuroinflammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deficits typical of Aβ-associated disease. Our data indicate that autologous EGCs transplantation may provide an efficient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD.
Creed, Jennifer A.; DiLeonardi, Ann Mae; Fox, Douglas P.; Tessler, Alan R.
Abstract Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function. PMID:21299360
Hwang-Gu, Shoou-Lian; Gau, Susan Shur-Fen
The literature has suggested timing processing as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD); however, whether the subjective internal clock speed presented by verbal estimation and limited attention capacity presented by time reproduction could be endophenotypes for ADHD is still unknown. We assessed 223 youths with DSM-IV ADHD (age range: 10-17 years), 105 unaffected siblings, and 84 typically developing (TD) youths using psychiatric interviews, intelligence tests, verbal estimation and time reproduction tasks (single task and simple and difficult dual tasks) at 5-second, 12-second, and 17-second intervals. We found that youths with ADHD tended to overestimate time in verbal estimation more than their unaffected siblings and TD youths, implying that fast subjective internal clock speed might be a characteristic of ADHD, rather than an endophenotype for ADHD. Youths with ADHD and their unaffected siblings were less precise in time reproduction dual tasks than TD youths. The magnitude of estimated errors in time reproduction was greater in youths with ADHD and their unaffected siblings than in TD youths, with an increased time interval at the 17-second interval and with increased task demands on both simple and difficult dual tasks versus the single task. Increased impaired time reproduction in dual tasks with increased intervals and task demands were shown in youths with ADHD and their unaffected siblings, suggesting that time reproduction deficits explained by limited attention capacity might be a useful endophenotype of ADHD. PMID:25992899
Holm, Thomas Hellesøe; Isaksen, Toke Jost; Glerup, Simon; Heuck, Anders; Bøttger, Pernille; Füchtbauer, Ernst-Martin; Nedergaard, Steen; Nyengaard, Jens Randel; Andreasen, Mogens; Nissen, Poul; Lykke-Hartmann, Karin
The Na+/K+-ATPases maintain Na+ and K+ electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na+/K+-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α3+/D801Y) was generated. The α3+/D801Y mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α3+/D801Y mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na+/K+-ATPase α3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission. PMID:27549929
Zhu, Yao-Feng; Li, Xian-Hui; Yuan, Zhi-Peng; Li, Chun-Yan; Tian, Rong-Bo; Jia, Wei; Xiao, Zhu-Ping
Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases including Alzheimer's disease (AD), in which dysregulation of double-stranded RNA-dependent protein kinase (PKR)-like ER-resident kinase (PERK) is considered to play a critical role. Allicin, a garlic extract, has been demonstrated a protective role in AD model. The present study was designed to investigate the possible protective effect of allicin on ER stress-induced cognitive deficits and underlying mechanisms in rats. In this study, 72h of lateral ventricular infusion of tunicamycin (TM), an ER stress stimulator, induced significant cognitive deficits. TM increased tau phosphorylation, Aβ42 deposit, and oxidative stress, and reduced antioxidative enzymes activity in the hippocampus. TM moderately elevated the expression of PERK and its downstream substrate nuclear factor erythroid-derived 2-like 2 (Nrf2) in the hippocampus. All these impaired changes by TM were significantly improved by allicin pretreatment. Allicin markedly increased PERK and Nrf2 expression in the hippocampus. Thus, our data demonstrate the protective role of allicin in ER stress-related cognitive deficits, and suggest that PERK/Nrf2 antioxidative signaling pathway underlies the action mechanism.
Song, Hai; Xu, Lincheng; Zhang, Rongping; Cao, Zhenzhen; Zhang, Huan; Yang, Li; Guo, Zeyun; Qu, Yongqiang; Yu, Jianyun
In this study, we investigated whether Rosemary extract (RE) improved cognitive deficits in repetitive mild Traumatic brain injury (rmTBI) rats and its potential mechanisms. The present results showed that rmTBI caused cognitive deficits, such as increased latency to find platform and decreased time spent in target quadrant in Morris water maze (MWM). These behavioral alterations were accompanying with the increased neuronal degeneration and glial fibrillary acidic protein (GFAP)-positive cells, increased Reactive oxygen species (ROS) generation, decreased activity of Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx) and Catalase (CAT), elevated protein level of IL-1β, IL-6 and TNF-α in hippocampus. Treatment with RE prevented these changes above. Our findings confirmed the effect of rosemary extract on improvement of cognitive deficits and suggested its mechanisms might be mediated by anti-oxidative and anti-inflammatory. Therefore, rosemary extract may be a potential treatment to improve cognitive deficits in rmTBI patients.
Park, Heeyoung; Lombardino, Linda J
Processing speed deficits along with phonological awareness deficits have been identified as risk factors for dyslexia. This study was designed to examine the behavioral profiles of two groups, a younger (6-8 years) and an older (10-15 years) group of dyslexic children for the purposes of (1) evaluating the degree to which phonological awareness and processing speed deficits occur in the two developmental cohorts; (2) determining the strength of relationships between the groups' respective mean scores on cognitive tasks of phonological awareness and processing speed and their scores on component skills of reading; and (3) evaluating the degree to which phonological awareness and processing speed serve as concurrent predictors of component reading skills for each group. The mean scaled scores for both groups were similar on all but one processing speed task. The older group was significantly more depressed on a visual matching test of attention, scanning, and speed. Correlations between reading skills and the cognitive constructs were very similar for both age-groups. Neither of the two phonological awareness tasks correlated with either of the two processing speed tasks or with any of the three measures of reading. One of the two processing speed measures served as a concurrent predictor of word- and text-level reading in the younger, however, only the rapid naming measure functioned as a concurrent predictor of word reading in the older group. Conversely, phonological processing measures did not serve as concurrent predictors for word-level or text-level reading in either of the groups. Descriptive analyses of individual subjects' deficits in the domains of phonological awareness and processing speed revealed that (1) both linguistic and nonlinguistic processing speed deficits in the younger dyslexic children occurred at higher rates than deficits in phonological awareness and (2) cognitive deficits within and across these two domains were greater in the older
Oshiro, W M; Beasley, T E; McDaniel, K L; Evansky, P A; Martin, S A; Moser, V C; Gilbert, M E; Bushnell, P J
any choice reaction time measure. Finally, no response inhibition deficit was observed in a differential reinforcement of low rate (DRL) response schedule in males or females in the E15 or E85 experiments. In summary, prenatal exposure to these fuel blends produced few deficits in adult offspring on these cognitive tests. Significant effects found during a water maze probe trial and choice reaction time tests were observed at vapor concentrations of 6000 ppm or higher, a concentration that is 4-6 orders of magnitude higher than those associated with normal automotive fueling operations and garages. Similar effects were not consistently observed in a previous study of inhaled ethanol, and thus these effects cannot be attributed to the concentration of ethanol in the mixture.
Pieruccini-Faria, F; Jones, J A; Almeida, Q J
Cognitive and sensorimotor processes are both needed for successful planning of footsteps during complex gait situations, but the interaction between these factors during motor planning, as well as their response to dopaminergic treatment is poorly understood in Parkinson's disease (PD). In the current study, we evaluated walking and gaze behaviors of individuals with PD while planning an approach toward an obstacle to be stepped over. The obstacle clearance task was completed both ON and OFF dopaminergic medication by individuals with Parkinson's disease (n=20) and compared to healthy age-matched control participants (n=19), as well as with and without an auditory digit monitoring dual task. In this novel protocol of synchronized gaze and gait data collection, each trial was split into an early and late phase prior to the obstacle, providing a unique opportunity to examine dopamine-dependent planning deficits in PD. Interestingly, only patients in the OFF medication state showed greater deceleration in the late phase (i.e., just before the obstacle) (F(1,37)=45.42, p<0.001), as well as an increase in step time variability (also in this late phase) with the additional demands of a dual task (F(2,74)=3.49, p=0.035). Only gait deceleration between approaching phases improved with dopaminergic treatment (F(1,18)=59.20; p<0.001). Although groups showed different walking behaviors, gaze behaviors were the same for all participants, in that they planned for the obstacle more so in the early phase (p<0.05), and fixations were reduced across participants with the presence of the dual task (p<0.001). Surprisingly, the gaze behavior of the PD OFF group showed no interactions with phase or condition suggesting that the deceleration and increased variability when approaching an obstacle is the result of a greater demand for online sensory feedback that cannot be compensated for with visual strategies. We conclude that dopamine influences planning by limiting sensorimotor
Jeong, Hyun Uk; Park, Gunhyuk; Kim, Hocheol; Lim, Yunsook; Oh, Myung Sook
Obesity has become a global health problem, contributing to various diseases including diabetes, hypertension, cancer, and dementia. Increasing evidence suggests that obesity can also cause neuronal damage, long-term memory loss, and cognitive impairment. The leaves and the fruits of Morus alba L., containing active phytochemicals, have been shown to possess antiobesity and hypolipidemic properties. Thus, in the present study, we assessed their effects on cognitive functioning in mice fed a high-fat diet by performing immunohistochemistry, using antibodies against c-Fos, synaptophysin, and postsynaptic density protein 95 and a behavioral test. C57BL/6 mice fed a high-fat diet for 21 weeks exhibited increased body weight, but mice coadministered an optimized Mori Folium and Mori Fructus extract mixture (2 : 1; MFE) for the final 12 weeks exhibited significant body weight loss. Additionally, obese mice exhibited not only reduced neural activity, but also decreased presynaptic and postsynaptic activities, while MFE-treated mice exhibited recovery of these activities. Finally, cognitive deficits induced by the high-fat diet were recovered by cotreatment with MFE in the novel object recognition test. Our findings suggest that the antiobesity effects of MFE resulted in recovery of the cognitive deficits induced by the high-fat diet by regulation of neural and synaptic activities. PMID:25945108
Alegret, Montserrat; Vinyes-Junqué, Georgina; Boada, Mercè; Martínez-Lage, Pablo; Cuberas, Gemma; Espinosa, Ana; Roca, Isabel; Hernández, Isabel; Valero, Sergi; Rosende-Roca, Maitée; Mauleón, Ana; Becker, James T.; Tárraga, Lluís
Background Visuoperceptual processing is impaired early in the clinical course of Alzheimer’s disease (AD). The 15-Objects Test (15-OT) detects such subtle performance deficits in Mild Cognitive Impairment (MCI) and mild AD. Reduced brain perfusion in the temporal, parietal and prefrontal regions have been found in early AD and MCI patients. Objectives To confirm the role of the 15-OT in the diagnosis of MCI and AD, and to investigate the brain perfusion correlates of visuoperceptual dysfunction (15-OT) in subjects with MCI, AD and normal aging. Methods Forty-two AD, 42 MCI and 42 healthy elderly control (EC) subjects underwent a brain Single Photon Emission Tomography (SPECT) and separately completed the 15-OT. An analysis of variance compared 15-OT scores between groups. SPM5 was used to analyse the SPECT data. Results 15-OT performace was impaired in the MCI and AD patients. In terms of the SPECT scans, AD patients showed reduced perfusion in temporal-parietal regions, while the MCI subjects had decreased perfusion in the middle and posterior cingulate. When MCI and AD groups were compared, a significant brain perfusion reduction was found in temporo-parietal regions. In the whole sample, 15-OT performance was significantly correlated with the clinical dementia rating scores, and with the perfusion in the bilateral posterior cingulate and the right temporal pole, with no significant correlation in each separate group. Conclusion Our findings suggest that the 15-OT performance provides a useful gradation of impairment from normal aging to AD, and it seems to be related to perfusion in the bilateral posterior cingulate and the right temporal pole. PMID:20555146
Busciglio, J; Capone, G; O'Bryan, J; O'Byran, J P; Gardiner, K J
Down syndrome (DS) is caused by an extra copy of all or part of the long arm of human chromosome 21 (HSA21). While the complete phenotype is both complex, involving most organs and organ systems, and variable in severity among individuals, intellectual disability (ID) is seen in all people with DS and may have the most significant impact on quality of life. Because the worldwide incidence of DS remains at approximately 1 in 1,000 live births, DS is the most common genetic cause of ID. In recent years, there have been important advances in our understanding of the functions of genes encoded by HSA21 and in the number and utility of in vitro and in vivo systems for modeling DS. Of particular importance, several pharmacological treatments have been shown to rescue learning and memory deficits in one mouse model of DS, the Ts65Dn. Because adult mice were used in the majority of these experiments, there is considerable interest in extending the studies to human clinical trials, and a number of trials have been completed, are in progress or are being planned. A recent conference brought together researchers with a diverse array of expertise and interests to discuss (1) the functions of HSA21 genes with relevance to ID in DS, (2) the utility of model systems including Caenorhabditis elegans, zebrafish and mouse, as well as human neural stem cells and induced pluripotent stems cells, for studies relevant to ID in DS, (3) outcome measures used in pharmacological treatment of mouse models of DS and (4) outcome measures suitable for clinical trials for cognition in adults and children with DS.
Richwine, Amy F.; Sparkman, Nathan L.; Dilger, Ryan N.; Buchanan, Jessica B.; Johnson, Rodney W.
Interleukin (IL)-10 is important for regulating inflammation but whether it protects against infection-related deficits in cognitive function is unknown. Therefore, the current study evaluated sickness behavior, hippocampal-dependent matching-to-place performance and several inflammatory cytokines and neurotrophins in wild type (IL-10+/+) and IL-10-deficient (IL-10−/−) mice after i.p. injection of lipopolysaccharide (LPS). Additionally, morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus was assessed. Treatment with LPS increased IL-1β, IL-6, and tumor necrosis factor alpha (TNFα) mRNA in all brain areas examined including the hippocampus, in both IL-10+/+ and IL-10−/− mice but the increase was largest in IL-10−/− mice. Plasma IL-1β, IL-6 and TNFα were also higher in IL-10−/− mice compared to IL-10+/+ mice after LPS. Consistent with increased inflammatory cytokines in IL-10−/− mice after LPS treatment, were a more lengthy sickness behavior syndrome and a more prominent reduction in hippocampal levels of nerve growth factor mRNA; brain-derived neurotrophic factor mRNA was reduced similarly in both genotypes after LPS. In a test of hippocampal-dependent learning and memory that required mice to integrate new information with previously learned information and switch strategies to master a task, IL-10−/− mice were found to be less efficient after LPS than were similarly treated wild type mice. LPS did not affect morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus in either genotype. Taken together the results are interpreted to suggest that during peripheral infection IL-10 inhibits sickness behavior and tribulations in hippocampal-dependent working memory via its propensity to mitigate inflammation. We conclude that IL-10 is critical for maintaining normal neuro-immune communication during infection. PMID:19272439
Wang, Xiao-Dong; Chen, Yuncai; Wolf, Miriam; Wagner, Klaus V.; Liebl, Claudia; Scharf, Sebastian H.; Harbich, Daniela; Mayer, Bianca; Wurst, Wolfgang; Holsboer, Florian; Deussing, Jan M.; Baram, Tallie Z.; Müller, Marianne B.; Schmidt, Mathias V.
Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders. PMID:21296667
Neill, Jo C; Grayson, Ben; Kiss, Béla; Gyertyán, István; Ferguson, Paul; Adham, Nika
Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.
Barkley, Russell A
Symptoms of sluggish cognitive tempo (SCT) have been recognized for nearly 30 years as comprising a semi-independent set(s) of symptoms from the inattentive (IN) and hyperactive-impulsive (HI) symptoms involved in attention-deficit/hyperactivity disorder (ADHD). It has only been within the past decade that research focusing specifically on SCT symptoms and on samples of SCT cases chosen independently from ADHD samples has increased so as to address the question of whether SCT is a distinct condition from ADHD or other disorders. All but two of these studies have focused on children but the two extant large scale studies on adults have replicated those findings. This Commentary highlights not only those findings concerning SCT that appear to be relatively robust, but also those patterns that appear to be emerging yet in need of further research to corroborate their association with SCT, as well as those barely or unexplored areas that may deserve more research. Evidence to date, including the many findings in this special issue, is nearing a critical mass that likely supports the conclusion that SCT is a distinct disorder of attention from ADHD, yet one that may overlap with it in about half of all cases. SCT has unique symptom dimensions and comorbidities from ADHD, probably distinct though lesser domains of impairment and demographic correlates, and perhaps unique cognitive deficits, causes and life course risks. These latter areas, however, are in need of substantially more research as is SCT in adults and treatments specifically designed for cases of SCT. Meanwhile, the name of the condition is premature, implying a known cognitive deficit that is as yet unknown, and is proving derogatory and offensive to patients, leading this author to recommend a change to Concentration Deficit Disorder.
Wang, Zhiqiang; Fan, Jin; Wang, Jian; Li, Yuxia; Duan, Dan; Du, Guo; Wang, Qingsong
Synaptic dysfunction underlies cognitive deficits induced by chronic cerebral hypoperfusion (CCH). There are silent synapses in neural circuits, but the effect of CCH on silent synapses is unknown. The present study was designed to explore learning and memory deficits and dynamic changes in silent synapses by direct visualization in a rat model of CCH. Adult male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) to reproduce CCH. Learning and memory effects were examined at 1, 4, 12, and 24 weeks after BCCAO. In addition, immunofluorescent confocal microscopy was used to detect AMPA and N-methyl-d-aspartate receptors colocalized with synaptophysin, and Golgi-Cox staining was used to observe dendritic spine density. We found that BCCAO rats exhibited recognition memory deficits from 4 weeks; spatial learning and memory, as well as working memory impairment began at 1 week and persistent to 24 weeks after surgery. Following BCCAO, the percentage of silent synapses increased by 29.81-55.08% compared with the controls at different time points (P<0.001). Compared with control groups, dendritic spine density in the CA1 region of BCCAO groups significantly decreased (P<0.001). Thus, the present study suggests that CCH can induce long-lasting cognitive deficits and long-term increase in the number of silent synapses. Furthermore, the decrease in dendritic spine density was correlated with the decrease in the number of functional synapses. The results suggest a potential mechanism by which CCH can induce learning and memory deficits.
Fan, Guangqin; Feng, Chang; Wu, Fengyun; Ye, Weiwei; Lin, Fen; Wang, Chunhong; Yan, Ji; Zhu, Gaochun; Xiao, Yuanmei; Bi, Yongyi
The principal effects of Pb(2+) exposure in children are attention, memory and learning deficits that persist into adulthood. The application of the conventional chelators in children is somewhat prohibited by adverse health effects and is not effective in reversing learning deficits once they have occurred. In this study, we applied the nutrients, methionine and choline, to prevent Pb(2+)-induced cognitive impairment. Male weanling Sprague-Dawley rats were divided into five groups. Three groups of rats were exposed to Pb(2+) in drinking water containing 400mg/L Pb(2+) acetate, of which two groups were concurrently administered by oral gavage once a day, 6 days per week, with low or high doses of methionine and choline for 60 days. The normal control group received distilled water alone, and the reagent control received methionine choline chloride alone. Methionine choline treatment reversed long-term deficits in spatial learning and memory caused by Pb(2+) exposure in rats. Enhanced learning performance of Pb(2+)-exposed rats was associated with recovery of deficits in N-methyl-d-aspartate receptor (NMDAR) subunit 1 (NR1) mRNA and protein expression in the hippocampus. The effect of methionine choline on NR1 gene and protein expression was somewhat specific to Pb(2+)-exposed rats and did not affect the NR2A and NR2B subunits of the NMDAR measured in the same animals. Moreover, methionine choline treatment did not lower brain Pb(2+) content in Pb(2+)-exposed rats, although it reduced blood and bone Pb(2+) content. Methionine and choline reversed cognitive and NR1 deficits induced by Pb(2+) exposure, a beneficial effect that has significant clinical implications for the treatment of childhood Pb(2+) intoxication.
Salkovic-Petrisic, Melita; Osmanovic-Barilar, Jelena; Knezovic, Ana; Hoyer, Siegfried; Mosetter, Kurt; Reutter, Werner
Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD.
Moraes, Carolina A; Santos, Gabriel; de Sampaio e Spohr, Tania Cristina Leite; D'Avila, Joana C; Lima, Flávia Regina Souza; Benjamim, Claudia Farias; Bozza, Fernando A; Gomes, Flávia Carvalho Alcantara
Recent clinical studies have shown that sepsis survivors may develop long-term cognitive impairments. The cellular and molecular mechanisms involved in these events are not well understood. This study investigated synaptic deficits in sepsis and the involvement of glial cells in this process. Septic animals showed memory impairment and reduced numbers of hippocampal and cortical excitatory synapses, identified by synaptophysin/PSD-95 co-localization, 9 days after disease onset. The behavioral deficits and synaptophysin/PSD-95 co-localization were rescued to normal levels within 30 days post-sepsis. Septic mice presented activation of microglia and reactive astrogliosis, which are hallmarks of brain injury and could be involved in the associated synaptic deficits. We treated neuronal cultures with conditioned medium derived from cultured astrocytes (ACM) and microglia (MCM) that were either non-stimulated or stimulated with lipopolysaccharide (LPS) to investigate the molecular mechanisms underlying synaptic deficits in sepsis. ACM and MCM increased the number of synapses between cortical neurons in vitro, and these effects were antagonized by LPS stimulation. LPS-MCM reduced the number of synapses by 50%, but LPS-ACM increased the number of synapses by 500%. Analysis of the composition of these conditioned media revealed increased levels of IL-1β in LPS-MCM. Furthermore, inhibition of IL-1β signaling through the addition of a soluble IL-1β receptor antagonist (IL-1 Ra) fully prevented the synaptic deficit induced by LPS-MCM. These results suggest that sepsis induces a transient synaptic deficit associated with memory impairments mediated by IL-1β secreted by activated microglia.
Boland, Elaine M.; Alloy, Lauren B.
Bipolar disorder is frequently associated with a number of poor outcomes including, but not limited to, a significant impairment in the ability to return to premorbid levels of occupational and psychosocial functioning, often despite the remission of mood symptoms. Sleep disturbance is an oft-reported residual symptom of manic and depressive episodes that has likewise been associated with the onset of manic episodes. Also present during affective episodes as well as the inter-episode periods are reports of deficits in cognitive functioning, which many reports have shown to play an important role in this persistent disability. Despite the presence of deficits in these two domains of functioning during affective episodes as well as the inter-episode phase, there has been no evaluation of the degree to which these systems may interact to maintain such high rates of functional disability. The aim of this review is to examine evidence for the study of the relationship between sleep disturbance and cognitive impairments in bipolar disorder as well as the ways in which deficits in these domains may work together to maintain functional impairment. PMID:23123569
Robbins, T W; James, M; Owen, A M; Lange, K W; Lees, A J; Leigh, P N; Marsden, C D; Quinn, N P; Summers, B A
Groups of patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy or Steele-Richardson-Olszewski syndrome, matched for overall clinical disability, were compared using three computerised cognitive tests previously shown to be sensitive to frontal lobe dysfunction. On a test of planning based on the Tower of London task, all three groups were impaired, but in different ways. The groups with palsy and Parkinson's disease were slower in the measure of initial thinking time, whereas the group with multiple system atrophy was only slower in a measure of thinking time subsequent to the first move, resembling patients with frontal lobe damage. On a test of spatial working memory, each group showed deficits relative to their matched control groups, but the three groups differed in their strategy for dealing with this task. On a test of attentional set shifting, each group was again impaired, mainly at the extradimensional shifting stage, but the group with Steele-Richardson-Olszewski syndrome exhibited the greatest deficit. The results are compared with previous findings in patients with Alzheimer's disease or frontal lobe damage. It is concluded that these basal ganglia disorders share a distinctive pattern of cognitive deficits on tests of frontal lobe dysfunction, but there are differences in the exact nature of the impairments, in comparison not only with frontal lobe damage but also with one another. PMID:8301310
Hamm, Valentine; Héraud, Céline; Bott, Jean-Bastien; Herbeaux, Karine; Strittmatter, Carole; Mathis, Chantal; Goutagny, Romain
Alzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Aβ levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and γ oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Aβ-independent. Our results could partly explain the limited efficacy of Aβ-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD.
Bagot, Kara Simone; Kaminer, Yifrah
Background and Aims Increasing prescription stimulant abuse among youth without diagnoses of attention deficit hyperactivity disorder (ADHD) is of concern. The most frequently cited motive for abuse is improved academic achievement via neurocognitive enhancement. Our aim in reviewing the literature was to identify neurocognitive effects of prescription stimulants in non-ADHD youth. Methods A systematic review was conducted for youth aged 12–25 years using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Fourteen papers were included. Results Modafinil appears to improve reaction time (P ≤ 0.04), logical reasoning (P ≤ 0.05) and problem-solving. Methylphenidate appears to improve performance in novel tasks and attention-based tasks (P ≤ 0.05), and reduces planning latency in more complex tasks (P ≤ 0.05). Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall. Across all three types of prescription stimulants, research shows improved attention with lack of consensus on whether these improvements are limited to simple versus complex tasks in varying youth populations. Conclusions The heterogeneity of the non-attention deficit hyperactivity disorder youth population, the variation in cognitive task characteristics and lack of replication of studies makes assessing the potential global neurocognitive benefits of stimulants among non-attention deficit hyper-activity disorder youth difficult; however, some youth may derive benefit in specific cognitive domains. PMID:24749160
Reiner, Anton; Heldt, Scott A; Presley, Chaela S; Guley, Natalie H; Elberger, Andrea J; Deng, Yunping; D'Surney, Lauren; Rogers, Joshua T; Ferrell, Jessica; Bu, Wei; Del Mar, Nobel; Honig, Marcia G; Gurley, Steven N; Moore, Bob M
We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50-60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50-60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.
Solomon, Marjorie; Ozonoff, Sally J.; Ursu, Stefan; Ravizza, Susan; Cummings, Neil; Ly, Stanford; Carter, Cameron S.
Executive function deficits are among the most frequently reported symptoms of autism spectrum disorders (ASDs), however, there have been few functional magnetic resonance imaging (fMRI) studies that investigate the neural substrates of executive function deficits in ASDs, and only one in adolescents. The current study examined cognitive…
Valdois, Sylviane; Bosse, Marie-Line; Tainturier, Marie-Josephe
There is strong converging evidence suggesting that developmental dyslexia stems from a phonological processing deficit. However, this hypothesis has been challenged by the widely admitted heterogeneity of the dyslexic population, and by several reports of dyslexic individuals with no apparent phonological deficit. In this paper, we discuss the…
Schulz, Daniela; Henn, Fritz A; Petri, David; Huston, Joseph P
Principles of negative reinforcement learning may play a critical role in the etiology and treatment of depression. We examined the integrity of positive reinforcement learning in congenitally helpless (cH) rats, an animal model of depression, using a random ratio schedule and a devaluation-extinction procedure. Furthermore, we tested whether an antidepressant dose of the monoamine oxidase (MAO)-B inhibitor deprenyl would reverse any deficits in positive reinforcement learning. We found that cH rats (n=9) were impaired in the acquisition of even simple operant contingencies, such as a fixed interval (FI) 20 schedule. cH rats exhibited no apparent deficits in appetite or reward sensitivity. They reacted to the devaluation of food in a manner consistent with a dose-response relationship. Reinforcer motivation as assessed by lever pressing across sessions with progressively decreasing reward probabilities was highest in congenitally non-helpless (cNH, n=10) rats as long as the reward probabilities remained relatively high. cNH compared to wild-type (n=10) rats were also more resistant to extinction across sessions. Compared to saline (n=5), deprenyl (n=5) reduced the duration of immobility of cH rats in the forced swimming test, indicative of antidepressant effects, but did not restore any deficits in the acquisition of a FI 20 schedule. We conclude that positive reinforcement learning was impaired in rats bred for helplessness, possibly due to motivational impairments but not deficits in reward sensitivity, and that deprenyl exerted antidepressant effects but did not reverse the deficits in positive reinforcement learning.
Washington, Patricia M.; Forcelli, Patrick A.; Wilkins, Tiffany; Zapple, David N.; Parsadanian, Maia
Abstract Traumatic brain injury (TBI) can cause a broad array of behavioral problems including cognitive and emotional deficits. Human studies comparing neurobehavioral outcomes after TBI suggest that cognitive impairments increase with injury severity, but emotional problems such as anxiety and depression do not. To determine whether cognitive and emotional impairments increase as a function of injury severity we exposed mice to sham, mild, moderate, or severe controlled cortical impact (CCI) and evaluated performance on a variety of neurobehavioral tests in the same animals before assessing lesion volume as a histological measure of injury severity. Increasing cortical impact depth successfully produced lesions of increasing severity in our model. We found that cognitive impairments in the Morris water maze increased with injury severity, as did the degree of contralateral torso flexion, a measure of unilateral striatal damage. TBI also caused deficits in emotional behavior as quantified in the forced swim test, elevated-plus maze, and prepulse inhibition of acoustic startle, but these deficits were not dependent on injury severity. Stepwise regression analyses revealed that Morris water maze performance and torso flexion predicted the majority of the variability in lesion volume. In summary, we find that cognitive deficits increase in relation to injury severity, but emotional deficits do not. Our data suggest that the threshold for emotional changes after experimental TBI is low, with no variation in behavioral deficits seen between mild and severe brain injury. PMID:22642287
Ross, Kimberley A.; Dorris, Liam; McMillan, Tom
Aim: It is now generally accepted that paediatric acquired brain injury (ABI) can have an impact on a child's cognitive, social, and behavioural functioning. However, the lack of guidelines on effective interventions for the affected children and their families, particularly beyond the acute recovery phase, can limit access to effective support.…
Qvist, Per; Rajkumar, Anto P; Redrobe, John P; Nyegaard, Mette; Christensen, Jane H; Mors, Ole; Wegener, Gregers; Didriksen, Michael; Børglum, Anders D
Schizophrenia is a debilitating brain disorder characterized by disturbances of emotion, perception and cognition. Cognitive impairments predict functional outcome in schizophrenia and are detectable even in the prodromal stage of the disorder. However, our understanding of the underlying neurobiology is limited and procognitive treatments remain elusive. We recently demonstrated that mice heterozygous for an inactivated allele of the schizophrenia-associated Brd1 gene (Brd1(+/)(-) mice) display behaviors reminiscent of schizophrenia, including impaired social cognition and long-term memory. Here, we further characterize performance of these mice by following the preclinical guidelines recommended by the 'Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)' and 'Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS)' initiatives to maximize translational value. Brd1(+/-) mice exhibit relational encoding deficits, compromised working and long term memory, as well as impaired executive cognitive functioning with cognitive behaviors relying on medial prefrontal cortex being particularly affected. Akin to patients with schizophrenia, the cognitive deficits displayed by Brd1(+/)(-) mice are not global, but selective. Our results underline the value of Brd1(+/)(-) mice as a promising tool for studying the neurobiology of cognitive deficits in schizophrenia.
Raveendran, Anju Thoppil; Skaria, Paulose Cheramadatikudiyil
Hypoxic brain injury during neonatal development can lead to neuronal damage and produce learning and cognitive impairments. TOPRO-3 staining was used to visualize cell loss and real-time polymerase chain reaction (PCR) analysis of BAX mRNA was used to evaluate the level of apoptosis in the cerebral cortex, cerebellum, brain stem, and striatum of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen, and epinephrine. The long-term effects of neonatal hypoxic insult on cognition and behavior were studied using Morris water maze experiment on 1-month-old rats exposed to neonatal hypoxia. In hypoxic neonatal rats, a significant cell loss (p < .001) within the brain regions was observed in TOPRO-3 staining and BAX mRNA expression was significantly upregulated (p < .001). Immediate resuscitation of hypoxic neonates with glucose, alone and along with oxygen, significantly downregulated (p < .001) BAX mRNA expression. The BAX expression in epinephrine resuscitated and 100% oxygen resuscitated groups were found to be upregulated in the brain regions. In water maze experiment, 1-month-old rats exposed to neonatal hypoxia spent lesser time in the platform quadrant (p < .001) and showed longer escape latency (p < .001) highlighting the learning and cognitive deficits. Our study revealed the effect of glucose resuscitation alone and along with oxygenation in ameliorating the spatial memory and learning deficits induced by neonatal hypoxic insult mediated brain cell loss.
Translational Aspects of the Novel Object Recognition Task in Rats Abstinent Following Sub-Chronic Treatment with Phencyclidine (PCP): Effects of Modafinil and Relevance to Cognitive Deficits in Schizophrenia
Redrobe, John P.; Bull, Sascha; Plath, Niels
Phencyclidine (PCP) induces a behavioral syndrome in rodents that bears remarkable similarities to some of the core symptoms observed in schizophrenic patients, among those cognitive deficits. The successful alleviation of cognitive impairments associated with schizophrenia (CIAS) has become a major focus of research efforts as they remain largely untreated. The aim of the present study was to investigate the effects of selected antipsychotic and cognition enhancing drugs, namely haloperidol, risperidone, donepezil, and modafinil in an animal model widely used in preclinical schizophrenia research. To this end, the novel object recognition (NOR) task was applied to rats abstinent following sub-chronic treatment with PCP. Rats were administered either PCP (5 mg/kg, i.p.) or vehicle twice a day for 7 days, followed by a 7-day washout period, before testing in NOR. Upon testing, vehicle-treated rats successfully discriminated between novel and familiar objects, an effect abolished in rats that had previously been exposed to PCP treatment. Acute treatment with modafinil (64 mg/kg, p.o.) ameliorated the PCP-induced deficit in novel object exploration, whereas haloperidol (0.1 mg/kg, s.c.), risperidone (0.2 mg/kg, i.p.), and donepezil (3 mg/kg, p.o.) were without significant effect. Given the negligible efficacy of haloperidol and risperidone, and the contradictory data with donepezil to treat CIAS in the clinic, together with the promising preliminary pro-cognitive effects of modafinil in certain subsets of schizophrenic patients, the sub-chronic PCP–NOR abstinence paradigm may represent an attractive option for the identification of potential novel treatments for CIAS. PMID:21423454
de Paula, Jonas Jardim; Cintra, Marco Túlio Gualberto; Miranda, Débora Marques; Bicalho, Maria Aparecida Camargos; Moares, Edgar Nunes; Malloy-Diniz, Leandro Fernandes
Mild cognitive impairment is a clinical condition more frequent in patients with Parkinson's disease than in general population. The nonamnestic presentations, usually characterized by executive dysfunction, are most prevalent. We present a case report of a Parkinson's disease patient diagnosed with nonamnestic mild cognitive impairment that showed complete remission of cognitive symptoms after one year. We discuss the possible causes for the remission, focusing on the treatment of medical conditions such as a major depressive episode and vitamin B12 deficiency, in addition to the change of pharmacological treatment. In a third assessment, cognitive performance remained normal. The case report highlights the importance of controlling clinical comorbidities on the assessment and followup of mild cognitive impairment, especially on Parkinson's disease. PMID:23193494
de Paula, Jonas Jardim; Cintra, Marco Túlio Gualberto; Miranda, Débora Marques; Bicalho, Maria Aparecida Camargos; Moares, Edgar Nunes; Malloy-Diniz, Leandro Fernandes
Mild cognitive impairment is a clinical condition more frequent in patients with Parkinson's disease than in general population. The nonamnestic presentations, usually characterized by executive dysfunction, are most prevalent. We present a case report of a Parkinson's disease patient diagnosed with nonamnestic mild cognitive impairment that showed complete remission of cognitive symptoms after one year. We discuss the possible causes for the remission, focusing on the treatment of medical conditions such as a major depressive episode and vitamin B12 deficiency, in addition to the change of pharmacological treatment. In a third assessment, cognitive performance remained normal. The case report highlights the importance of controlling clinical comorbidities on the assessment and followup of mild cognitive impairment, especially on Parkinson's disease.
Choi, Dong-Hee; Lee, Kyoung-Hee; Lee, Jongmin
Chronic cerebral hypoperfusion (CCH) is strongly correlated with progressive cognitive decline in neurological diseases, such as vascular dementia (VaD) and Alzheimer's disease. Exercise can enhance learning and memory, and delay age-related cognitive decline. However, exercise-induced hippocampal neurogenesis in experimental animals submitted to CCH has not been investigated. The present study aimed to investigate whether hippocampal neurogenesis induced by exercise can improve cognitive deficit in a rat model of VaD. Male Wistar rats (age, 8 weeks; weight, 292±3.05 g; n=12-13/group) were subjected to bilateral common carotid artery occlusion (2VO) or sham‑surgery and each group was then subdivided randomly into no exercise and treadmill exercise groups. Exercise groups performed treadmill exercise daily at 15 m/min for 30 min for 4 weeks from the third to the seventh week after 2VO. It was demonstrated that the number of neural progenitor cells and mature neurons in the subgranular zone of 2VO rats was increased by exercise, and cognitive impairment in 2VO rats was attenuated by treadmill exercise. In addition, mature brain‑derived neurotrophic factor (BDNF) levels in the hippocampus were increased in the exercise groups. Thus the present study suggests that exercise delays cognitive decline by the enhancing neurogenesis and increasing BDNF expression in the context of VaD.
Goetz, Michal; Schwabova, Jaroslava Paulasova; Hlavka, Zdenek; Ptacek, Radek; Surman, Craig BH
Background Attention-deficit hyperactivity disorder (ADHD) is linked to the presence of motor deficiencies, including balance deficits. The cerebellum serves as an integrative structure for balance control and is also involved in cognition, including timing and anticipatory regulation. Cerebellar development may be delayed in children and adolescents with ADHD, and inconsistent reaction time is commonly seen in ADHD. We hypothesized that dynamic balance deficits would be present in children with ADHD and they would correlate with attention and cerebellar functions. Methods Sixty-two children with ADHD and no other neurological conditions and 62 typically developing (TD) children were examined with five trials of the Phyaction Balance Board, an electronic balancing platform. Cerebellar clinical symptoms were evaluated using an international ataxia rating scale. Conners’ Continuous Performance Test was used to evaluate patterns of reaction. Results Children with ADHD had poorer performance on balancing tasks, compared to TD children (P<0.001). They exhibited significantly greater sway amplitudes than TD children (P<0.001) in all of the five balancing trials. The effect size of the difference between the groups increased continuously from the first to the last trial. Balance score in both groups was related to the variation in the reaction time, including reaction time standard error (r =0.25; P=0.0409, respectively, r =0.31; P=0.0131) and Variability of Standard Error (r =0.28; P=0.0252, respectively, r =0.41; P<0.001). The burden of cerebellar symptoms was strongly related to balance performance in both groups (r =0.50, P<0.001; r =0.49, P=0.001). Conclusion This study showed that ADHD may be associated with poor dynamic balance control. Furthermore, we showed that maintaining balance correlates with neuropsychological measures of consistency of reaction time. Balance deficits and impaired cognitive functioning could reflect a common cerebellar dysfunction in ADHD
Dagan, Yaron; Doljansky, Julia T
Cognitive performance at night exhibits a substantial drop, typically before dawn. One of the means of dealing with this phenomenon, as well as with the accompanying sleepiness during sustained wakefulness, is the administration of stimulants. The most widely used and well-documented stimulants are caffeine, amphetamines, and modafinil. Of these, amphetamines are the least recommended, as they may severely affect behavior. Caffeine and modafinil seem to produce relatively milder side effects and usually only at high doses. Previous comparison studies have revealed equal efficacy of both the stimulants in maintaining alertness and performance during sustained wakefulness. However, these studies used relatively high, and thus not completely safe, doses of these drugs (600 mg caffeine and 400 mg modafinil). Therefore, the aim of the present study was to assess the efficacy of a low and medically safe dose of caffeine (200 mg) and modafinil (200 mg) in maintaining cognitive performance during sustained wakefulness. A flight simulation task was chosen for the assessment of the stimulants in a counter-balanced, within-subject design under four different conditions: baseline (no drugs), placebo, caffeine (200 mg), and modafinil (200 mg). The equal effectiveness of both drugs in abolishing the nocturnal drop in cognitive performance, as well as of oral temperature and blood pressure, supported the use of low doses of caffeine and modafinil for the maintenance of alertness in healthy subjects during sustained wakefulness.
Kasbe, Prajapati; Jangra, Ashok; Lahkar, Mangala
Mangiferin is a phytochemical primarily present in the stem, leaves and bark of Mangifera indica. It offers neuroprotection mainly through inhibition of oxidative stress, and decreasing proinflammatory cytokines level in the brain. Aluminium has been reported to cause oxidative stress-associated damage in the brain. In the present investigation, protective effect of mangiferin against aluminium chloride (AlCl3)-induced neurotoxicity and cognitive impairment was studied in male Swiss albino mice. AlCl3 (100 mg/kg) was administered once daily through oral gavage for 42 days. Mangiferin (20 and 40 mg/kg, p.o.) was given to mice for last 21 days of the study. We found cognitive dysfunction in AlCl3-treated group, which was assessed by Morris water maze test, and novel object recognition test. AlCl3-treated group showed elevated level of oxidative stress markers, proinflammatory cytokines level and lowered hippocampal brain-derived neurotrophic factor (BDNF) content. Mangiferin (40 mg/kg) prevented the cognitive deficits, hippocampal BDNF depletion, and biochemical anomalies induced by AlCl3-treatment. In conclusion, our data demonstrated that mangiferin offers neuroprotection in AlCl3-induced neurotoxicity and it may be a potential therapeutic approach in the treatment of oxido-nitrosative stress and inflammation-associated neurotoxicity.
Nair, Deepti; Ramesh, Vijay; Li, Richard C; Schally, Andrew V; Gozal, David
Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep.
Guo, Xiao-dan; Sun, Guang-long; Zhou, Ting-ting; Xu, Xin; Zhu, Zhi-yuan; Rukachaisirikul, Vatcharin; Hu, Li-hong; Shen, Xu
Aim: Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice. Methods: Cell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg−1·d−1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains. Results: LX2343 (5–20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP
Zhang, Songyun; Li, Hongyan; Zhang, Lihui; Li, Jie; Wang, Ruiying; Wang, Mian
Increasing evidence demonstrates an association between diabetes and hippocampal neuron damage. This study aimed to determine the effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits (GCLM and GCLC) in the hippocampus of streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. At 12weeks after streptozotocin injection, T1DM rats were randomly divided into 4 groups (n=15 each group) to receive no treatment (T1DM), saline (T1DM+saline), alpha-lipoic acid (T1DM+alpha-lipoic acid), and troxerutin (T1DM+troxerutin), respectively, for 6weeks. Meanwhile, 10 control animals (NC group) were assessed in parallel. Learning performance was evaluated by the Morris water maze. After treatment, hippocampi were collected for pathological examination by hematoxylin and eosin (H&E) staining. Next, hippocampal superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were assessed. Finally, glutamate cysteine ligase catalytic (GCLC) and glutamate cysteine ligase modifier (GCLM) subunit mRNA and protein levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Compared with T1DM and T1DM+saline groups, escape latency was overtly reduced in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Significantly increased GCLM and GCLC mRNA levels, GCLC protein amounts, SOD activity, and GSH levels, and reduced MDA amounts were observed in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. In T1DM and T1DM+saline groups, H&E staining showed less pyramidal cells in the hippocampus, with disorganized layers, karyopyknosis, decreased endochylema, and cavitation, effects relieved in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Troxerutin alleviates oxidative stress and promotes learning in streptozotocin-induced T1DM rats, a process involving GCLC expression.
Hashimoto, Kenji; Fujita, Yuko; Ishima, Tamaki; Chaki, Shigeyuki; Iyo, Masaomi
Accumulating evidence suggests that the glycine modulatory site on the NMDA receptor could be potential therapeutic target for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the glycine transporter-1 (GlyT-1) inhibitor, (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS), on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of NFPS (1.0 and 3.0 mg/kg/day) or D-serine (600 mg/kg/day). However, PCP-induced cognitive deficits were not improved by a single administration of NFPS (3.0 mg/kg). Furthermore, Western blot analysis revealed that levels of GlyT-1 in the hippocampus, but not frontal cortex, of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly higher than those of saline-treated mice. An in vivo microdialysis study revealed that repeated PCP administration significantly decreased the extracellular levels of glycine in the hippocampus, but not frontal cortex, of mice. These findings suggest that repeated PCP administration increased the density of GlyT-1 in the hippocampus of mouse brain, and that the GlyT-1 inhibitor NFPS could ameliorate cognitive deficits in mice after repeated administration of PCP.
Kurtz, Matthew M; Gagen, Emily; Rocha, Nuno B F; Machado, Sergio; Penn, David L
Recent advances in psychosocial treatments for schizophrenia have targeted social cognitive deficits. A critical literature review and effect-size (ES) analysis was conducted to investigate the efficacy of comprehensive programs of social cognitive training in schizophrenia. Results revealed 16 controlled studies consisting of seven models of comprehensive treatment with only three of these treatment models investigated in more than one study. The effects of social cognitive training were reported in 11/15 studies that included facial affect recognition skills (ES=.84) and 10/13 studies that included theory-of-mind (ES=.70) as outcomes. Less than half (4/9) of studies that measured attributional style as an outcome reported effects of treatment, but effect sizes across studies were significant (ESs=.30-.52). The effect sizes for symptoms were modest, but, with the exception of positive symptoms, significant (ESs=.32-.40). The majority of trials were randomized (13/16), selected active control conditions (11/16) and included at least 30 participants (12/16). Concerns for this area of research include the absence of blinded outcome raters in more than 50% of trials and low rates of utilization of procedures for maintaining treatment fidelity. These findings provide preliminary support for the broader use of comprehensive social cognitive training procedures as a psychosocial intervention for schizophrenia.
Jichao, Sun; Xianguo, Ren; Dongqi, Yin; Rongyi, Zhou; Shuang, Lei; Yue, You; Yuchen, Song; Jingnan, Ying
The disturbed dopamine availability and brain-derived neurotrophic factor (BDNF) expression are due in part to be associated with attention deficit hyperactivity disorder (ADHD). In this study, we investigated the therapeutical effect of saikosaponin a (SSa) isolated from Bupleurum Chinese DC, against spontaneously hypertensive rat (SHR) model of ADHD. Methylphenidate and SSa were orally administered for 3 weeks. Activity was assessed by open-field test and Morris water maze test. Dopamine (DA) and BDNF were determined in specific brain regions. The mRNA or protein expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicles monoamine transporter (VMAT) was also studied. Both MPH and SSa reduced hyperactivity and improved the spatial learning memory deficit in SHRs. An increased DA concentration in the prefrontal cortex (PFC) and striatum was also observed after treating with the SSa. The increased DA concentration may partially be attributed to the decreased mRNA and protein expression of DAT in PFC while SSa exhibited no significant effects on the mRNA expression of TH and VMAT in PFC of SHRs. In addition, BDNF expression in SHRs was also increased after treating with SSa or MPH. The obtained result suggested that SSa may be a potential drug for treating ADHD. PMID:28293263
Moritz, Steffen; Thoering, Teresa; Kühn, Simone; Willenborg, Bastian; Westermann, Stefan; Nagel, Matthias
The majority of patients with schizophrenia display neurocognitive deficits (e.g., memory impairment) as well as inflated cognitive biases (e.g., jumping to conclusions). Both cognitive domains are implicated in the pathogenesis of the disorder and are known to compromise functional outcome. At present, there is a dearth of effective treatment options. A total of 90 patients with schizophrenia were recruited online (a diagnosis of schizophrenia had been confirmed in a large subgroup during a previous hospital admission). Subsequent to a baseline assessment encompassing psychopathology, self-reported cognition as well as objective memory and reasoning tests, patients were randomized to one of three conditions: standard cognitive remediation (mybraintraining), metacognition-augmented cognition remediation (CR) condition (variant of mybraintraining which encouraged patients to reduce speed of decision-making and attenuate response confidence when participants made high-confidence judgements and hasty incorrect decisions) and a waitlist control group. Patients were retested after 6 weeks and again 3 months after the second assessment. Groups did not differ on psychopathology and neurocognitive parameters at any timepoint. However, at follow-up the metacognitive-augmented CR group displayed a significant reduction on jumping to conclusions and overconfidence. Treatment adherence correlated with a reduction of depression; gains in the training exercises from the standard mybraintraining condition were correlated with improved objective memory performance. The study suggests that metacognition-augmented CR may ameliorate cognitive biases but not neurocognition. The study ties in well with prior research showing that neurocognitive dysfunctions are rather resistant to change; the failure to detect significant improvement of CR or metacognition-augmented CR on psychopathology and neurocognition over time may partly be attributed to a number of methodological limitations of
Fujita, Yuko; Ishima, Tamaki; Hashimoto, Kenji
Prenatal maternal infection contributes to the etiology of schizophrenia, with D-serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, playing a role in the pathophysiology of this disease. We examined whether supplementation with D-serine during juvenile and adolescent stages could prevent the onset of cognitive deficits, prodromal and the core symptoms of schizophrenia in adult offspring after maternal immune activation (MIA). Juvenile offspring exposed prenatally to poly(I:C) showed reduced expression of NMDA receptor subunits in the hippocampus. Supplementing drinking water with D-serine (600 mg/L from P28 to P56) prevented the onset of cognitive deficits in adult offspring after MIA, in a significant manner. This study shows that supplementing offspring with D-serine during juvenile and adolescent stages could prevent the onset of psychosis in adulthood, after MIA. Therefore, early intervention with D-serine may prevent the occurrence of psychosis in high-risk subjects. PMID:27853241
Liu, Xudong; Zhang, Yuchao; Li, Jinquan; Wang, Dong; Wu, Yang; Li, Yan; Lu, Zhisong; Yu, Samuel C T; Li, Rui; Yang, Xu
Single-walled carbon nanotubes (SWCNTs) have shown increasing promise in the field of biomedicine, especially in applications related to the nervous system. However, there are limited studies available on the neurotoxicity of SWCNTs used in vivo. In this study, neurobehavioral changes caused by SWCNTs in mice and oxidative stress were investigated. The results of ethological analysis (Morris water maze and open-field test), brain histopathological examination, and assessments of oxidative stress (reactive oxygen species [ROS], malondialdehyde [MDA], and glutathione [GSH]), inflammation (nuclear factor κB, tumor necrosis factor α, interleukin-1β), and apoptosis (cysteine-aspartic acid protease 3) in brains showed that 6.25 and 12.50 mg/kg/day SWCNTs in mice could induce cognitive deficits and decreased locomotor activity, brain histopathological alterations, and increased levels of oxidative stress, inflammation, and apoptosis in mouse brains; however, 3.125 mg/kg/day SWCNTs had zero or minor adverse effects in mice, and these effects were blocked by concurrent administration of ascorbic acid. Down-regulation of oxidative stress, inflammation, and apoptosis were proposed to explain the neuroprotective effects of ascorbic acid. This work suggests SWCNTs could induce cognitive deficits and decreased locomotor activity, and provides a strategy to avoid the adverse effects.
Esposito, Giuseppe; Sarnelli, Giovanni; Capoccia, Elena; Cirillo, Carla; Pesce, Marcella; Lu, Jie; Calì, Gaetano; Cuomo, Rosario; Steardo, Luca
Alzheimer’s disease (AD) is characterized by chronic deposition of β-amyloid (Aβ) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deficits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Aβ which starts a neuroinflammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (EGCs). Here we show that the autologous transplantation of EGCs into the brain of Aβ-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Aβ-induced neuroinflammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deficits typical of Aβ-associated disease. Our data indicate that autologous EGCs transplantation may provide an efficient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD. PMID:26940982
Rotondi, Armando J; Sinkule, Jennifer; Haas, Gretchen L; Spring, Michael B; Litschge, Christine M; Newhill, Christina E; Ganguli, Rohan; Anderson, Carol M
The purpose of this study was to develop an understanding of the design elements that influence the ability of persons with severe mental illness (SMI) and cognitive deficits to use a website, and to use this knowledge to design a web-based telehealth application to deliver a psychoeducation program to persons with schizophrenia and their families. Usability testing was conducted with 98 persons with SMI. First, individual website design elements were tested. Based on these results, theoretical website design models were used to create several alternative websites. These designs were tested for their ability to facilitate use by persons with SMI. The final website design is presented. The results indicate that commonly prescribed design models and guidelines produce websites that are poorly suited and confusing to persons with SMI. Our findings suggest an alternative model that should be considered when designing websites and other telehealth interventions for this population. Implications for future studies addressing the characteristics of accessible designs for persons with SMI and cognitive deficits are discussed.
Sokal, Michael M
Despite widespread interest in individual life histories, few biographies of scientists make use of insights derived from psychology, another discipline that studies people, their thoughts, and their actions. This essay argues that recent theoretical work in psychology and tools developed for clinical psychological practice can help biographical historians of science create and present fuller portraits of their subjects' characters and temperaments and more nuanced analyses of how these traits helped shape their subjects' scientific work. To illustrate this thesis, the essay examines the early career of James McKeen Cattell--an influential late nineteenth- and early twentieth-century experimental psychologist--through a lens offered by psychology and argues that Cattell's actual laboratory practices derived from an "accommodation" to a long-standing "cognitive deficit." These practices in turn enabled Cattell to achieve more precise experimental results than could any of his contemporaries; and their students readily adopted them, along with their behavioral implications. The essay concludes that, in some ways, American psychology's early twentieth-century move toward a behavioral understanding of psychological phenomena can be traced to Cattell's personal cognitive deficit. It closes by reviewing several "remaining general questions" that this thesis suggests.
Saha, Manas Ranjan; Dey, Priyankar; Begum, Sainiara; De, Bratati; Chaudhuri, Tapas Kr.; Sarker, Dilip De; Das, Abhaya Prasad; Sen, Arnab
In human body, several categories of degenerative processes are largely determined by free radicals originating in cell. Free radicals are also known to have correlated with a variety of cognitive disorders (CDs) resulting in neuronal injury and eventually to death. Alzheimer’s disease (AD) and Parkinson's disease (PD) are such kind of killer CDs that occur due to dysfunction of cholinergic and dopaminergic neurons. Plant parts of Ginkgo biloba, Bacopa monnieri etc. are being used for the treatment of cognitive disorders in several countries. The present study was aimed to explore the detailed antioxidant and anti-cholinesterase activity of Acaciacatechu leaf (ACL) over CDs. Gas chromatography-Mass spectroscopy (GC-MS) analysis and Nuclear Magnetic Resonance (NMR) were employed to identify the bioactive components present in ACL. Furthermore, the extract was evaluated to check the cytotoxic effects of ACL on normal cells. Amongst several antioxidant assays, DPPH assay, hydroxyl radical, nitric oxide radical and hypochlorous acid inhibitory activities were found to be greater in ACL than that of the respective standards while other assays exhibited a moderate or at per inhibitory activity with standards. Total phenolic and flavonoid content were also found to be present in decent amount. In addition, we found, a greater acetylcholinesterase (AChE) inhibitory activity of ACL when compared to other medicinally important plants, indicating its positive effect over CDs. Forty one bioactive components were explored through GC-MS. Of these, gallic acid, epicatechin, catechin, isoquercitrin etc. were found, which are potent antioxidant and a few of them have anti-neurodegenerative properties. Eventually, ACL was found to be nontoxic and safer to consume. Further studies with animal or human model however, would determine its efficacy as a potential anti-schizophrenic drug. PMID:26949964
Saha, Manas Ranjan; Dey, Priyankar; Begum, Sainiara; De, Bratati; Chaudhuri, Tapas Kr; Sarker, Dilip De; Das, Abhaya Prasad; Sen, Arnab
In human body, several categories of degenerative processes are largely determined by free radicals originating in cell. Free radicals are also known to have correlated with a variety of cognitive disorders (CDs) resulting in neuronal injury and eventually to death. Alzheimer's disease (AD) and Parkinson's disease (PD) are such kind of killer CDs that occur due to dysfunction of cholinergic and dopaminergic neurons. Plant parts of Ginkgo biloba, Bacopa monnieri etc. are being used for the treatment of cognitive disorders in several countries. The present study was aimed to explore the detailed antioxidant and anti-cholinesterase activity of Acaciacatechu leaf (ACL) over CDs. Gas chromatography-Mass spectroscopy (GC-MS) analysis and Nuclear Magnetic Resonance (NMR) were employed to identify the bioactive components present in ACL. Furthermore, the extract was evaluated to check the cytotoxic effects of ACL on normal cells. Amongst several antioxidant assays, DPPH assay, hydroxyl radical, nitric oxide radical and hypochlorous acid inhibitory activities were found to be greater in ACL than that of the respective standards while other assays exhibited a moderate or at per inhibitory activity with standards. Total phenolic and flavonoid content were also found to be present in decent amount. In addition, we found, a greater acetylcholinesterase (AChE) inhibitory activity of ACL when compared to other medicinally important plants, indicating its positive effect over CDs. Forty one bioactive components were explored through GC-MS. Of these, gallic acid, epicatechin, catechin, isoquercitrin etc. were found, which are potent antioxidant and a few of them have anti-neurodegenerative properties. Eventually, ACL was found to be nontoxic and safer to consume. Further studies with animal or human model however, would determine its efficacy as a potential anti-schizophrenic drug.
Ibáñez, Agustin; Petroni, Agustin; Urquina, Hugo; Torrente, Fernando; Torralva, Teresa; Hurtado, Esteban; Guex, Raphael; Blenkmann, Alejandro; Beltrachini, Leandro; Muravchik, Carlos; Baez, Sandra; Cetkovich, Marcelo; Sigman, Mariano; Lischinsky, Alicia; Manes, Facundo
Although it has been shown that adults with attention-deficit hyperactivity disorder (ADHD) have impaired social cognition, no previous study has reported the brain correlates of face valence processing. This study looked for behavioral, neuropsychological, and electrophysiological markers of emotion processing for faces (N170) in adult ADHD compared to controls matched by age, gender, educational level, and handedness. We designed an event-related potential (ERP) study based on a dual valence task (DVT), in which faces and words were presented to test the effects of stimulus type (faces, words, or face-word stimuli) and valence (positive versus negative). Individual signatures of cognitive functioning in participants with ADHD and controls were assessed with a comprehensive neuropsychological evaluation, including executive functioning (EF) and theory of mind (ToM). Compared to controls, the adult ADHD group showed deficits in N170 emotion modulation for facial stimuli. These N170 impairments were observed in the absence of any deficit in facial structural processing, suggesting a specific ADHD impairment in early facial emotion modulation. The cortical current density mapping of N170 yielded a main neural source of N170 at posterior section of fusiform gyrus (maximum at left hemisphere for words and right hemisphere for faces and simultaneous stimuli). Neural generators of N170 (fusiform gyrus) were reduced in ADHD. In those patients, N170 emotion processing was associated with performance on an emotional inference ToM task, and N170 from simultaneous stimuli was associated with EF, especially working memory. This is the first report to reveal an adult ADHD-specific impairment in the cortical modulation of emotion for faces and an association between N170 cortical measures and ToM and EF.
Objective: Normal aging in animals and humans is accompanied by a decline in cognitive performance which is thought to be due to the long-term effects of oxidative stress and inflammation on neurological processes. Previous findings have suggested that protection against age-related cognitive declin...
Davenport, Richard K.; And Others
According to transfer index testing, chimpanzees who had been reared in restricted laboratory environments for the first two years of life were inferior in cognitive skills to wild born control subjects. Findings are discussed in terms of the role of early experience in cognitive development. (DP)
Zheng, Hai-zhen; Jiang, Wei; Zhao, Xiao-feng; Du, Jing; Liu, Pan-gong; Chang, Li-dan; Li, Wen-bo; Hu, Han-tong; Shi, Xue-min
Electroacupuncture has been shown to improve cerebral blood flow in animal models of stroke. However, it is unclear whether electroacupuncture alters miRNA expression in the cortex. In this study, we examined changes in the cerebral cortical miRNA profile, cerebral blood flow and neurological function induced by electroacupuncture in a rat model of stroke. Electroacupuncture was performed at Renzhong (GV26) and Neiguan (PC6), with a frequency of 2 Hz, continuous wave, current intensity of 3.0 mA, and stimulation time of 1 minute. Electroacupuncture increased cerebral blood flow and alleviated neurological impairment in the rats. miRNA microarray profiling revealed that the vascular endothelial growth factor signaling pathway, which links cell proliferation with stroke, was most significantly affected by electroacupuncture. Electroacupuncture induced changes in expression of rno-miR-206-3p, rno-miR-3473, rno-miR-6216 and rno-miR-494-3p, and these changes were confirmed by quantitative real-time polymerase chain reaction. Our findings suggest that changes in cell proliferation-associated miRNA expression induced by electroacupuncture might be associated with the improved cerebral blood supply and functional recovery following stroke. PMID:28197190
Wang, Tao; Kong, Xiang-Chen; Tai, Wen-Jiao; Sun, Hua; Zhang, Dan
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ’s neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ’s inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β. PMID:24223757
Saavedra, Ana; Giralt, Albert; Arumí, Helena; Alberch, Jordi; Pérez-Navarro, Esther
Huntington’s disease (HD) patients and mouse models show learning and memory impairment associated with hippocampal dysfunction. The neuronal nitric oxide synthase/3',5'-cyclic guanosine monophosphate (nNOS/cGMP) pathway is implicated in synaptic plasticity, and in learning and memory processes. Here, we examined the nNOS/cGMP pathway in the hippocampus of HD mice to determine whether it can be a good therapeutic target for cognitive improvement in HD. We analyzed hippocampal nNOS and phosphodiesterase (PDE) 5 and 9 levels in R6/1 mice, and cGMP levels in the hippocampus of R6/1, R6/2 and HdhQ7/Q111 mice, and of HD patients. We also investigated whether sildenafil, a PDE5 inhibitor, could improve cognitive deficits in R6/1 mice. We found that hippocampal cGMP levels were 3-fold lower in 12-week-old R6/1 mice, when they show deficits in object recognition memory and in passive avoidance learning. Consistent with hippocampal cGMP levels, nNOS levels were down-regulated, while there were no changes in the levels of PDE5 and PDE9 in R6/1 mice. A single intraperitoneal injection of sildenafil (3 mg/Kg) immediately after training increased cGMP levels, and improved memory in R6/1 mice, as assessed by using the novel object recognition and the passive avoidance test. Importantly, cGMP levels were also reduced in R6/2 mouse and human HD hippocampus. Therefore, the regulation of hippocampal cGMP levels can be a suitable treatment for cognitive impairment in HD. PMID:24040016
Sokhadze, Estate M.; Tasman, Allan; Sokhadze, Guela E.; El-Baz, Ayman S.; Casanova, Manuel F.
Abnormalities in motor skills have been regarded as part of the symptomatology characterizing autism spectrum disorder (ASD). It has been estimated that 80% of subjects with autism display “motor dyspraxia” or clumsiness that are not readily identified in a routine neurological examination. In this study we used behavioral measures, event-related potentials (ERP), and lateralized readiness potential (LRP) to study cognitive and motor preparation deficits contributing to the dyspraxia of autism. A modified Posner cueing task was used to analyze motor preparation abnormalities in children with autism and in typically developing children (N=30/per group). In this task, subjects engage in preparing motor response based on a visual cue, and then execute a motor movement based on the subsequent imperative stimulus. The experimental conditions, such as the validity of the cue and the spatial location of the target stimuli were manipulated to influence motor response selection, preparation, and execution. Reaction time and accuracy benefited from validly cued targets in both groups, while main effects of target spatial position were more obvious in the autism group. The main ERP findings were prolonged and more negative early frontal potentials in the ASD in incongruent trials in both types of spatial location. The LRP amplitude was larger in incongruent trials and had stronger effect in the children with ASD. These effects were better expressed at the earlier stages of LRP, specifically those related to response selection, and showed difficulties at the cognitive phase of stimulus processing rather that at the motor execution stage. The LRP measures at different stages reflect the chronology of cognitive aspects of movement preparation and are sensitive to manipulations of cue correctness, thus representing very useful biomarker in autism dyspraxia research. Future studies may use more advance and diverse manipulations of movement preparation demands in testing more
Sokhadze, Estate M; Tasman, Allan; Sokhadze, Guela E; El-Baz, Ayman S; Casanova, Manuel F
Abnormalities in motor skills have been regarded as part of the symptomatology characterizing autism spectrum disorder (ASD). It has been estimated that 80 % of subjects with autism display "motor dyspraxia" or clumsiness that are not readily identified in a routine neurological examination. In this study we used behavioral measures, event-related potentials (ERP), and lateralized readiness potential (LRP) to study cognitive and motor preparation deficits contributing to the dyspraxia of autism. A modified Posner cueing task was used to analyze motor preparation abnormalities in children with autism and in typically developing children (N = 30/per group). In this task, subjects engage in preparing motor response based on a visual cue, and then execute a motor movement based on the subsequent imperative stimulus. The experimental conditions, such as the validity of the cue and the spatial location of the target stimuli were manipulated to influence motor response selection, preparation, and execution. Reaction time and accuracy benefited from validly cued targets in both groups, while main effects of target spatial position were more obvious in the autism group. The main ERP findings were prolonged and more negative early frontal potentials in the ASD in incongruent trials in both types of spatial location. The LRP amplitude was larger in incongruent trials and had stronger effect in the children with ASD. These effects were better expressed at the earlier stages of LRP, specifically those related to response selection, and showed difficulties at the cognitive phase of stimulus processing rather that at the motor execution stage. The LRP measures at different stages reflect the chronology of cognitive aspects of movement preparation and are sensitive to manipulations of cue correctness, thus representing very useful biomarker in autism dyspraxia research. Future studies may use more advance and diverse manipulations of movement preparation demands in testing more
Young, J W; Geyer, M A
Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. While antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult, however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition.
Chronis, Andrea M.; Gamble, Stephanie A.; Roberts, John E.; Pelham, William E., Jr.
An adaptation of the Coping With Depression Course (CWDC) was evaluated in mothers of children with attention-deficit/hyperactivity disorder (ADHD), a population at risk for depression. Mothers were randomly assigned to receive the CWDC either immediately following an intensive summer treatment program targeting their child's behavior or after a…
Heaton, Pamela; Allen, Rory; Williams, Kerry; Cummins, Omar; Happe, Francesca
Children with autism experience difficulties in understanding social affective cues, and it has been suggested that such deficits will generalize to music. In order to investigate this proposal, typically developing individuals and children with autism and Down syndrome were compared on tasks measuring perception of affective and movement states…
Foley, Avery M; Ammar, Zeena M; Lee, Robert H; Mitchell, Cassie S
Amyloid-β (Aβ) is believed to directly affect memory and learning in Alzheimer's disease (AD). It is widely suggested that there is a relationship between Aβ40 and Aβ42 levels and cognitive performance. In order to explore the validity of this relationship, we performed a meta-analysis of 40 peer-reviewed, published AD transgenic mouse studies that quantitatively measured Aβ levels in brain tissue after assessing cognitive performance. We examined the relationship between Aβ levels (Aβ40, Aβ42, or the ratio of Aβ42 to Aβ40) and cognitive function as measured by escape latency times in the Morris water maze or exploratory preference percentage in the novel object recognition test. Our systematic review examined five mouse models (Tg2576, APP, PS1, 3xTg, APP(OSK)-Tg), gender, and age. The overall result revealed no statistically significant correlation between quantified Aβ levels and experimental measures of cognitive function. However, enough of the trends were of the same sign to suggest that there probably is a very weak qualitative trend visible only across many orders of magnitude. In summary, the results of the systematic review revealed that mice bred to show elevated levels of Aβ do not perform significantly worse in cognitive tests than mice that do not have elevated Aβ levels. Our results suggest two lines of inquiry: 1) Aβ is a biochemical "side effect" of the AD pathology; or 2) learning and memory deficits in AD are tied to the presence of qualitatively "high" levels of Aβ but are not quantitatively sensitive to the levels themselves.
Berthelot, Nicolas; Paccalet, Thomas; Gilbert, Elsa; Moreau, Isabel; Mérette, Chantal; Gingras, Nathalie; Rouleau, Nancie; Maziade, Michel
Background Millions of children are born to parents affected by major psychoses. Cognitive dysfunctions seen in patients are already detectable in these children. In parallel, childhood maltreatment increases the risk of adult psychoses through unknown mechanisms. We investigated whether high-risk offspring exposed to abuse/neglect displayed more cognitive precursors of adult psychoses in childhood and adolescence than nonexposed offspring. Methods We used a stepwise selection strategy from a 25-year follow-up of 48 densely affected kindreds including 1500 adults (405 patients with schizophrenia or bipolar disorder) to select high-risk offspring aged 6–22 years for inclusion in our study. All offspring were assessed for childhood trauma from direct interviews with the offspring, parents and relatives and from the review of lifetime medical records of parents and children and administered a neuropsychological battery including IQ and 4 of the most impaired neuropsychological domains in psychoses. Results Our study included 66 high-risk offspring. Those who were exposed to abuse/neglect had significantly lower IQ (effect size [ES] = 0.61) than nonexposed offspring and displayed poorer cognitive performance in visual episodic memory (ES = 0.67) and in executive functions of initiation (ES = 1.01). Moreover, exposed offspring presented more combinations of cognitive deficits that were associated with lower Global Assessment of Functioning scores. Limitations Exposure to abuse/neglect was not assessed in the control group, thus the study could not test whether the effect of childhood maltreatment occured only in a high-risk setting and not in the general population. Conclusion In high-risk youths, maltreatment in childhood/adolescence may negatively impact cognitive domains known to be impaired in adults with psychoses, suggesting an early mediating effect in the association between abuse/neglect and adult psychoses. This finding provides a target for future
0 weeks ) will be associated with cognitive improvement (SRT total recall and modified ADAS-cog) from baseline to 26 weeks and 52 weeks of donepezil...treatment. 2. Increase in UPSIT scores from baseline to 8 weeks of donepezil treatment will be associated with cognitive improvement from baseline to...26 and 52 weeks . Exploratory Hypothesis. The acute atropine-induced decrease in UPSIT scores, and increase in UPSIT scores from baseline to 8
Shi, Zhe; Sun, Xiuping; Liu, Xinmin; Chen, Shanguang; Chang, Qi; Chen, Lingling; Song, Guangqing; Li, Haiqing
Alzheimer's disease (AD) is the most common form of dementia. It is a progressive neurodegenerative disorder that leads to gradual loss of cognitive and functional abilities, and development of behavioral disturbances. Previous studies using Aβ(1-40) microinjection in animal models focused on cognitive deficits in spatial learning and avoidance conditioning. However, no attempt has been made to determine the sensitivity of an Aβ(1-40)-manipulated animal model in tasks involving reward-directed instrumental learning (RDIL). Thus, the present study was designed to investigate the effects of intra hippocampal microinjection of Aβ(1-40) on the acquisition and maintenance of a basic instrumental response (lever-pressing), then on the goal directed (higher response ratio) and habit (visual signal discrimination and extinction) learning, as well as on neurotransmitter changes which could potentially alter the regulatory processes involved in instrumental learning. Our present findings demonstrated that the focal hippocampal microinjection of Aβ(1-40) rendered rats unable to process new cue/contextual information in the formation of causal relation, rather than affecting the operant action itself. Although the injected Aβ(1-40) did not directly influence performance, it did prevent the information from being translated into action. Moreover, the neurotransmitter results indicated that multiple neural signaling might be involved in the regulation of RDIL in the Aβ(1-40) injection model. In conclusion, results suggested that our series of instrumental learning tasks may have potential in dementia research as a novel method for testing cognitive behavior.
Zetsche, Ulrike; Rief, Winfried; Westermann, Stefan; Exner, Cornelia
The present study examines the interplay between cognitive deficits and emotional context in obsessive-compulsive disorder (OCD) and social phobia (SP). Specifically, this study examines whether the inflexible use of efficient learning strategies in an emotional context underlies impairments in probabilistic classification learning (PCL) in OCD, and whether PCL impairments are specific to OCD. Twenty-three participants with OCD, 30 participants with SP and 30 healthy controls completed a neutral and an OCD-specific PCL task. OCD participants failed to adopt efficient learning strategies and showed fewer beneficial strategy switches than controls only in an OCD-specific context, but not in a neutral context. Additionally, OCD participants did not show any explicit memory impairments. Number of beneficial strategy switches in the OCD-specific task mediated the difference in PCL performance between OCD and control participants. Individuals with SP were impaired in both PCL tasks. In contrast to neuropsychological models postulating general cognitive impairments in OCD, the present findings suggest that it is the interaction between cognition and emotion that is impaired in OCD. Specifically, activated disorder-specific fears may impair the flexible adoption of efficient learning strategies and compromise otherwise unimpaired PCL. Impairments in PCL are not specific to OCD.
Forslund, Tommie; Brocki, Karin C; Bohlin, Gunilla; Granqvist, Pehr; Eninger, Lilianne
This study examined the contributions of several important domains of functioning to attention-deficit/hyperactivity disorder (ADHD) symptoms and conduct problems. Specifically, we investigated whether cognitive inhibition, emotion regulation, emotionality, and disorganized attachment made independent and specific contributions to these externalizing behaviour problems from a multiple pathways perspective. The study included laboratory measures of cognitive inhibition and disorganized attachment in 184 typically developing children (M age = 6 years, 10 months, SD = 1.7). Parental ratings provided measures of emotion regulation, emotionality, and externalizing behaviour problems. Results revealed that cognitive inhibition, regulation of positive emotion, and positive emotionality were independently and specifically related to ADHD symptoms. Disorganized attachment and negative emotionality formed independent and specific relations to conduct problems. Our findings support the multiple pathways perspective on ADHD, with poor regulation of positive emotion and high positive emotionality making distinct contributions to ADHD symptoms. More specifically, our results support the proposal of a temperamentally based pathway to ADHD symptoms. The findings also indicate that disorganized attachment and negative emotionality constitute pathways specific to conduct problems rather than to ADHD symptoms.
Iggena, Deetje; Winter, York; Steiner, Barbara
Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6 hours for 3 weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.
Kordas, Katarzyna; Canfield, Richard L; López, Patricia; Rosado, Jorge L; Vargas, Gonzalo García; Cebrián, Mariano E; Rico, Javier Alatorre; Ronquillo, Dolores; Stoltzfus, Rebecca J
Elevated blood lead levels in children are associated with lower scores on tests of cognitive functioning. Recent studies have reported inverse relations between lifetime exposure and intellectual functioning at blood lead concentrations below 10 microg/dL, the Centers for Disease Control and Prevention's (CDC) level of concern. We report associations between blood lead and cognitive performance for first-grade Mexican children living near a metal foundry. Using a cross-sectional design, we examined the relation between children's concurrent blood lead concentrations (mean (SD) 11.4 microg/dL (6.1)) and their performance on 14 tests of global or specific cognitive functions. The blood lead-cognition relations were modeled using both linear and nonlinear methods. After adjustment for covariates, a higher blood lead level was associated with poorer cognitive performance on several cognitive tests. Segmented linear regressions revealed significant effects of lead but only for the segments defined by a concurrent blood lead concentration below 10-14 microg/dL. One implication of these findings is that at the age of 7 years, even in the absence of information on lead exposure in infancy and early childhood, a test result with blood lead < 10 microg/dL should not be considered safe. Together with other recent findings, these results add to the empirical base of support available for evaluating the adequacy of current screening guidelines and for motivating efforts at primary prevention of childhood lead exposure.
Young, J.W.; Geyer, M.A.
Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. Whilst antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition. PMID:25516372
Eack, Shaun M; Greeno, Catherine G; Pogue-Geile, Michael F; Newhill, Christina E; Hogarty, Gerard E; Keshavan, Matcheri S
The emotion management subscale of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) has recently been recommended by the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia committee as the sole measure of social cognition for trials of cognitive enhancement in schizophrenia, yet the psychometric properties of this subscale and the larger instrument in schizophrenia patients have not been thoroughly examined. This research presents a psychometric investigation of the MSCEIT in a sample of 64 early course outpatients with schizophrenia, schizoaffective, or schizophreniform disorder. Results demonstrated that the MSCEIT possesses adequate internal consistency reliability among its branch and total scales and that patients' branch and overall test performance was significantly below normative levels. Estimates of discriminant and concurrent validity indicated that the MSCEIT diverged from measures of neurocognitive functioning and psychopathology, but was only modestly related with objective measures of functional outcome. Convergent validity estimates suggested that, contrary to expectations, the MSCEIT did not correlate with a behavioral measure of social cognition. Finally, exploratory factor analyses suggested the possibility of a shift in the latent structure of emotional intelligence in schizophrenia, compared with studies with healthy individuals. These findings support the use of the MSCEIT as a reliable and potentially valid method of assessing the emotional components of social cognition in schizophrenia, but also point to a need for additional measurement development efforts to assess broader social-cognitive domains that may exhibit stronger relations with functional outcome. Further investigation is warranted to examine the instrument's latent factor structure and convergence with other measures of social cognition.
Lai, Wen-Sung; Chang, Chia-Yuan; Wong, Wan-Rong; Pei, Ju-Chun; Chen, Ya-Shan; Hung, Wei-Li
Schizophrenia and other psychiatric disorders are generally diagnosed based on a collection of symptoms defined by a combination of an individual's feelings, perceptions, and behaviors. Many of these disorders are characterized by specific cognitive and social deficits. Although it is nearly impossible to recapitulate the full phenotypic spectrum of schizophrenia in mice, mouse models play an indispensable role in understanding the pathogenesis of this disorder and the development of new therapeutics. Genetic mouse models of schizophrenia and mouse behavioral tests provide a feasible approach for elucidating causal relationships between susceptibility gene(s) and schizophrenia-related symptoms. There has been a proliferation of studies characterizing basic behavioral phenotypes in mice. Since there is no way to completely model human psychiatric symptoms in mice, the major role of behavioral tests is to provide insights into underlying affected circuitry and pathophysiology. Given that the recovery of cognitive and social abilities significantly benefits functional outcomes, there has been an increasing interest in characterizing cognitive and social functions in mutant mice; however, these functions are not easy to measure. In this review, a selection of conventional behavioral tasks was briefly described and three specific behavioral tasks aimed at characterizing social communication, attentional function, and choice behavior in mice were highlighted. The choice of specific behavioral tasks during experimental planning should take into consideration a variety of factors, including their validity, reliability, sensitivity, utility, and specificity. Based upon the hypothetical hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated signaling pathways in the involvement of cognitive and social impairments in schizophrenia, three NMDAR-related compounds/drugs, D-serine, sarcosine, and D-cycloserine, are discussed as an example.
Umbricht, Daniel; Keefe, Richard S E; Murray, Stephen; Lowe, David A; Porter, Richard; Garibaldi, George; Santarelli, Luca
Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms.
Background Alzheimer's Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a β-sheet-rich pathological isoform. In AD the normal soluble Aβ (sAβ) forms oligomers and fibrils which assemble into neuritic plaques. The most toxic form of Aβ is thought to be oligomeric. A recent study reveals the cellular prion protein, PrPC, to be a receptor for Aβ oligomers. Aβ oligomers suppress LTP signal in murine hippocampal slices but activity remains when pretreated with the PrP monoclonal anti-PrP antibody, 6D11. We hypothesized that targeting of PrPC to prevent Aβ oligomer-related cognitive deficits is a potentially novel therapeutic approach. APP/PS1 transgenic mice aged 8 months were intraperitoneally (i.p.) injected with 1 mg 6D11 for 5 days/week for 2 weeks. Two wild-type control groups were given either the same 6D11 injections or vehicle solution. Additional groups of APP/PS1 transgenic mice were given either i.p. injections of vehicle solution or the same dose of mouse IgG over the same period. The mice were then subjected to cognitive behavioral testing using a radial arm maze, over a period of 10 days. At the conclusion of behavioral testing, animals were sacrificed and brain tissue was analyzed biochemically or immunohistochemically for the levels of amyloid plaques, PrPC, synaptophysin, Aβ40/42 and Aβ oligomers. Results Behavioral testing showed a marked decrease in errors in 6D11 treated APP/PS1 Tg mice compared with the non-6D11 treated Tg groups (p < 0.0001). 6D11 treated APP/PS1 Tg mice behaved the same as wild-type controls indicating a recovery in cognitive learning, even after this short term 6D11 treatment. Brain tissue analysis from both treated and vehicle treated APP/PS1 groups indicate no significant differences in amyloid plaque burden, Aβ40/42, PrPC or Aβ oligomer levels. 6D11 treated APP/PS1 Tg mice had significantly greater synaptophysin
Kennedy, R. S.; Dunlap, W. P.; Banderet, L. E.; Smith, M. G.; Houston, C. S.
Cognitive function at simulated altitude was investigated in a repeated-measures within-subject study of performance by seven volunteers in a hypobaric chamber, in which atmospheric pressure was systematically lowered over a period of 40 d to finally reach a pressure equivalent to 8845 m, the approximate height of Mount Everest. The automated performance test system employed compact computer design; automated test administrations, data storage, and retrieval; psychometric properties of stability and reliability; and factorial richness. Significant impairments of cognitive function were seen for three of the five tests in the battery; on two tests, grammatical reasoning and pattern comparison, every subject showed a substantial decrement.
Drummond, Cláudia; Coutinho, Gabriel; Fonseca, Rochele Paz; Assunção, Naima; Teldeschi, Alina; de Oliveira-Souza, Ricardo; Moll, Jorge; Tovar-Moll, Fernanda; Mattos, Paulo
Language batteries used to assess the skills of elderly individuals, such as naming and semantic verbal fluency, present some limitations in differentiating healthy controls from patients with amnestic mild cognitive impairment (a-MCI). Deficits in narrative discourse occur early in dementia caused by Alzheimer's disease (AD), and the narrative discourse abilities of a-MCI patients are poorly documented. The present study sought to propose and evaluate parameters for investigating narrative discourse in these populations. After a pilot study of 30 healthy subjects who served as a preliminary investigation of macro- and micro-linguistic aspects, 77 individuals (patients with AD and a-MCI and a control group) were evaluated. The experimental task required the participants to narrate a story based on a sequence of actions visually presented. The Control and AD groups differed in all parameters except narrative time and the total number of words recalled. The a-MCI group displayed mild discursive difficulties that were characterized as an intermediate stage between the Control and AD groups' performances. The a-MCI and Control groups differed from the AD group with respect to global coherence, discourse type and referential cohesion. The a-MCI and AD groups were similar to one another but differed from the Control group with respect to the type of words recalled, the repetition of words in the same sentence, the narrative structure and the inclusion of irrelevant propositions in the narrative. The narrative parameter that best distinguished the three groups was the speech effectiveness index. The proposed task was able to reveal differences between healthy controls and groups with cognitive decline. According to our findings, patients with a-MCI already present narrative deficits that are characterized by mild discursive difficulties that are less severe than those found in patients with AD.
Knapman, A; Heinzmann, J-M; Holsboer, F; Landgraf, R; Touma, C
Increased stress reactivity has repeatedly been reported in patients suffering from psychiatric diseases including schizophrenia and major depression. These disorders also have other symptoms in common, such as cognitive deficits and psychotic-like behavior. We have therefore investigated if increased stress reactivity is associated with these phenotypic endpoints in an animal model of affective disorders. The stress reactivity mouse model used in this study consists of three CD-1-derived mouse lines, that have been selectively bred for high (HR), intermediate (IR) or low (LR) stress reactivity. Male mice from these three breeding lines were subjected to a reversal learning task and latent inhibition (Li) was assessed using a conditioned taste aversion paradigm. Furthermore, as the dopaminergic system is involved in both Li and reversal learning, the dopamine 1 receptor (D1R), dopamine 2 receptor (D2R) and dopamine transporter (DAT) mRNA expression levels were assessed in relevant brain areas of these animals. The results demonstrate that HR mice show perseveration in the reversal learning task and have disrupted Li. Furthermore, compared to LR mice, HR mice have decreased D2R mRNA levels in the ventral tegmental area, as well as decreased D1R mRNA levels in the cingulate cortex, and an increased expression of D2R mRNA in the nucleus accumbens. Taken together, these results demonstrate that the HR mice display cognitive deficits associated with psychotic-like behavior, similar to those observed in patients suffering from schizophrenia and major depression and could be utilized in the search for better treatment strategies for these symptoms of psychiatric disorders.
Yu, Yu-Wen; Hsieh, Tsung-Hsun; Chen, Kai-Yun; Wu, John Chung-Che; Hoffer, Barry J.; Greig, Nigel H.; Li, Yazhou; Lai, Jing-Huei; Chang, Cheng-Fu; Lin, Jia-Wei; Chen, Yu-Hsin
Abstract Mild traumatic brain injury (mTBI) is a major public health issue, representing 75–90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13–15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-β precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment. PMID:26972789
Drummond, Cláudia; Coutinho, Gabriel; Fonseca, Rochele Paz; Assunção, Naima; Teldeschi, Alina; de Oliveira-Souza, Ricardo; Moll, Jorge; Tovar-Moll, Fernanda; Mattos, Paulo
Language batteries used to assess the skills of elderly individuals, such as naming and semantic verbal fluency, present some limitations in differentiating healthy controls from patients with amnestic mild cognitive impairment (a-MCI). Deficits in narrative discourse occur early in dementia caused by Alzheimer's disease (AD), and the narrative discourse abilities of a-MCI patients are poorly documented. The present study sought to propose and evaluate parameters for investigating narrative discourse in these populations. After a pilot study of 30 healthy subjects who served as a preliminary investigation of macro- and micro-linguistic aspects, 77 individuals (patients with AD and a-MCI and a control group) were evaluated. The experimental task required the participants to narrate a story based on a sequence of actions visually presented. The Control and AD groups differed in all parameters except narrative time and the total number of words recalled. The a-MCI group displayed mild discursive difficulties that were characterized as an intermediate stage between the Control and AD groups' performances. The a-MCI and Control groups differed from the AD group with respect to global coherence, discourse type and referential cohesion. The a-MCI and AD groups were similar to one another but differed from the Control group with respect to the type of words recalled, the repetition of words in the same sentence, the narrative structure and the inclusion of irrelevant propositions in the narrative. The narrative parameter that best distinguished the three groups was the speech effectiveness index. The proposed task was able to reveal differences between healthy controls and groups with cognitive decline. According to our findings, patients with a-MCI already present narrative deficits that are characterized by mild discursive difficulties that are less severe than those found in patients with AD. PMID:26074814
Becker, Stephen P; Ciesielski, Heather A; Rood, Jennifer E; Froehlich, Tanya E; Garner, Annie A; Tamm, Leanne; Epstein, Jeffery N
Despite the burgeoning scientific literature examining the sluggish cognitive tempo (SCT) construct, very little is known about the clinical presentation of SCT. In clinical cases where SCT is suspected, it is critical to carefully assess not only for attention-deficit/hyperactivity disorder (ADHD) but also for other comorbidities that may account for the SCT-related behaviors, especially internalizing symptoms and sleep problems. The current case study provides a clinical description of SCT in a 7-year-old girl, offering a real-life portrait of SCT while also providing an opportunity to qualitatively differentiate between SCT and ADHD, other psychopathologies (e.g. depression, anxiety), and potentially related domains of functioning (e.g. sleep, executive functioning [EF]). "Jessica" was described by herself, parents, and teacher as being much slower than her peers in completing schoolwork, despite standardized testing showing Jessica to have above average intelligence and academic achievement. Jessica's parents completed rating scales indicating high levels of SCT symptoms and daytime sleepiness, as well as mildly elevated EF deficits. More research is needed to determine how to best conceptualize, assess, and treat SCT, and Jessica's case underscores the importance of further work in this area.
Pelham, W E; Sturges, J; Hoza, J; Schmidt, C; Bijlsma, J J; Milich, R; Moorer, S
Two studies were conducted to investigate the relative effects of sustained release methylphenidate (Ritalin [SR-20]) and standard methylphenidate (Ritalin, 10 mg, administered twice daily). In the first study, 13 boys with attention deficit disorder participating in a summer treatment program went through a double-blind, within-subject trial of each form of methylphenidate and placebo. Measures of social and cognitive behavior were gathered in classroom and play settings. Although group analyses of the data showed that both drugs were effective and there were few differences between them, standard methylphenidate was superior to SR-20 on several important measures of disruptive behavior. Furthermore, analyses of individual responsivity showed clearly that most boys responded more positively to standard methylphenidate than to SR-20. The second study involved a partially overlapping group of nine boys with attention deficit disorder participating in the same summer treatment program. Also double-blind, within-subject, and placebo controlled, this study tracked the time courses of the two forms of methylphenidate. Both were shown to have similar time courses on the Abbreviated Conners Rating Scale and other measures, but SR-20 had a slower onset than did the standard drug form on a continuous performance task. Effects of SR-20 were still evident eight hours after ingestion.
Hu, Yu; Lai, Jinsheng; Wan, Baoquan; Liu, Xingfa; Zhang, Yemao; Zhang, Jiangong; Sun, Dongsheng; Ruan, Guoran; Liu, Enjie; Liu, Gong-Ping; Chen, Chen; Wang, Dao Wen
Although numerous studies have reported the influence of extremely low frequency magnetic field (ELF-MF) exposure on human health, its effects on cognitive deficits in Alzheimer's disease (AD) have remained under debate. Moreover, the influence of ELF-MF on hyperphosphorylated tau, which is one of the most common pathological hallmarks of AD, has not been reported to date. Therefore, transgenic mice (3xTg) were used in the present study. 3xTg mice, which express an APP/PS1 mutation combined with a tau (P301L) mutation and that develop cognitive deficits at 6 months of age, were subjected to ELF-MF (50Hz, 500μT) exposure or sham exposure daily for 3 months. We discovered that ELF-MF exposure ameliorated cognitive deficits and increased synaptic proteins in 3xTg mice. The protective effects of ELF-MF exposure may have also been caused by the inhibition of apoptosis and/or decreased oxidative stress levels that were observed in the hippocampus tissues of treated mice. Furthermore, tau hyperphosphorylation was decreased in vivo because of ELF-MF exposure, and this decrease was induced by the inhibition of GSK3β and CDK5 activities and activation of PP2Ac. We are the first to report that exposure to ELF-MF can attenuate tau phosphorylation. These findings suggest that ELF-MF exposure could act as a valid therapeutic strategy for ameliorating cognitive deficits and attenuating tau hyperphosphorylation in AD.
Riggs, Paula D.; Winhusen, Theresa; Davies, Robert D.; Leimberger, Jeffrey D.; Mikulich-Gilbertson, Susan; Klein, Constance; Macdonald, Marilyn; Lohman, Michelle; Bailey, Genie L.; Haynes, Louise; Jaffee, William B.; Haminton, Nancy; Hodgkins, Candace; Whitmore, Elizabeth; Trello-Rishel, Kathlene; Tamm, Leanne; Acosta, Michelle C.; Royer-Malvestuto, Charlotte; Subramaniam, Geetha; Fishman, Marc; Holmes, Beverly W.; Kaye, Mary Elyse; Vargo, Mark A.; Woody, George E.; Nunes, Edward V.; Liu, David
Objective: To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). Method: This was a…
Murray, Donna E; Durazzo, Timothy C; Schmidt, Thomas P; Abé, Christoph; Guydish, Joseph; Meyerhoff, Dieter J
Objective Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence. Methods Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiate-dependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions. Results Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits. Conclusion The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment. PMID:27695638
Martinez, Sarah; Davalos, Deana
Objective: Executive dysfunction in college students who have had an acute traumatic brain injury (TBI) was investigated. The cognitive, behavioral, and metacognitive effects on college students who endorsed experiencing a brain injury were specifically explored. Participants: Participants were 121 college students who endorsed a mild TBI, and 121…
Developmental exposure to inhaled ethanol-gasoline fuel blends is a potential public health concern. Here we assessed cognitive functions in adult offspring of pregnant rats that were exposed to vapors of gasoline blended with a range of ethanol concentrations, including gasoli...
Diamond, Adele; Prevor, Meredith B.; Druin, Donald P.; Callender, Glenda
Hypothesized that elevated ratio of phenylalanine to tyrosine in blood of children with phenylketonuria uniquely affects cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in tyrosine. Found that children whose phenylalanine levels were three to five…
Sarkamo, Teppo; Tervaniemi, Mari; Soinila, Seppo; Autti, Taina; Silvennoinen, Heli M.; Laine, Matti; Hietanen, Marja
Recent evidence on amusia suggests that our ability to perceive music might be based on the same neural resources that underlie other higher cognitive functions, such as speech perception and spatial processing. We studied the neural correlates of acquired amusia by performing extensive neuropsychological assessments on 53 stroke patients with a…
Miller, Haylie L.; Ragozzino, Michael E.; Cook, Edwin H.; Sweeney, John A.; Mosconi, Matthew W.
The neurocognitive impairments associated with restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD) are not yet clear. Prior studies indicate that individuals with ASD show reduced cognitive flexibility, which could reflect difficulty shifting from a previously learned response pattern or a failure to maintain a new…
neurotransmitter systems. KEY RESEARCH ACCOMPLISHMENTS 1. Homologous recombination in mouse embryonic stem cells to generate an inducible...focus on cognitive dysfunction associated with defective myelin. We have developed this model using homologous recombination in embryonic stem cells ...our progress toward completion of our goals. We have now repeated the homologous recombinant experiments and are screening for embryonic stem cell
Huh, Eugene; Kim, Hyo Geun; Park, Hanbyeol; Kang, Min Seo; Lee, Bongyong; Oh, Myung Sook
Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer’s disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD. PMID:25009697
Doom, Jenalee R.; Gunnar, Megan R.; Georgieff, Michael K.; Kroupina, Maria G.; Frenn, Kristin; Fuglestad, Anita J.; Carlson, Stephanie M.
Children adopted from institutions have been studied as models of the impact of stimulus deprivation on cognitive development (Nelson, Bos, Gunnar, & Sonuga-Barke, 2011), but these children may also suffer from micronutrient deficiencies (Fuglestad et al., 2008). The contributions of iron deficiency (ID) and duration of deprivation on…
Garner, Annie A.; Marceaux, Janice; Mrug, Sylvie; Patterson, Cryshelle; Hodgens, Bart
The present study examined Sluggish Cognitive Tempo (SCT) in relation to ADHD symptoms, clinical diagnosis, and multiple aspects of adjustment in a clinical sample. Parent and teacher reports were gathered for 322 children and adolescents evaluated for behavioral, emotional, and/or learning problems at a university clinic. Confirmatory factor…
Malarbi, Stephanie; Muscara, Frank; Stargatt, Robyn
Studies investigating the neuropsychological functioning of children who experience trauma have predominantly focused on maltreated populations. This article presents a case study that details the longitudinal outcome of a girl who experienced a motor vehicle accident at 5 years of age. It highlights the clinical relevance of research investigating the neuropsychological impact of single-incident trauma on children. It illustrates difficulties clinicians face in discriminating between the effects of developmental delay, traumatic brain injury, attention-deficit/hyperactivity disorder, trauma, and posttraumatic stress symptoms or posttraumatic stress disorder, especially in children with compensable injuries. The state of the current literature is discussed, and directions for future research are provided.
Munia, Tamanna T K; Gendreau, Jeffrey L; Verma, Ajay K; Johnson, Benjamin D; Romanick, Mark; Tavakolian, Kouhyar; Fazel-Rezai, Reza
Assessment, treatment, and management of sport-related concussions are a widely recognized public health issue. Although several neuropsychological and motor assessment tools have been developed and implemented for sports teams at various levels and ages, the sensitivity of these tests has yet to be validated with more objective measures to make return-to-play (RTP) decisions more confidently. The present study sought to analyze the residual effect of concussions on a sample of adolescent athletes who sustained one or more previous concussions compared to those who had no concussion history. For this purpose, a wide variety of assessment tools containing both neurocognitive and electroencephalogram (EEG) elements were used. All clinical testing and EEG were repeated at 8 months, 10 months, and 12 months post-injury for both healthy and concussed athletes. The concussed athletes performed poorer than healthy athletes on processing speed and impulse control subtest of neurocognitive test on month 8, but no alterations were marked in terms of visual and postural stability. EEG analysis revealed significant differences in brain activities of concussed athletes through all three intervals. These long-term neurocognitive and EEG deficits found from this ongoing sport-related concussion study suggest that the post-concussion physiological deficits may last longer than the observed clinical recovery.
Aron, Adam R; Poldrack, Russell A
Psychological functions that are behaviorally and neurally well specified may serve as endophenotypes for attention-deficit/hyperactivity disorder (ADHD) research. Such endophenotypes, which lie between genes and symptoms, may relate more directly to relevant genetic variability than does the clinical ADHD syndrome itself. Here we review evidence in favor of response inhibition as an endophenotype for ADHD research. We show that response inhibition--operationalized by Go/NoGo or Stop-signal tasks--requires the prefrontal cortex (PFC), in particular the right inferior frontal cortex (IFC); that patients with ADHD have significant response inhibition deficits and show altered functional activation and gray matter volumes in right IFC; and that a number of studies indicate that response inhibition performance is heritable. Additionally, we review evidence concerning the role of the basal ganglia in response inhibition, as well as the role of neuromodulatory systems. All things considered, a combined right IFC structure/function/response inhibition phenotype is a particularly good candidate for future heritability and association studies. Moreover, a dissection of response inhibition into more basic components such as rule maintenance, vigilance, and target detection may provide yet better targets for association with genes for neuromodulation and brain development.
Yan, Tingxu; Shang, Lei; Wang, Mengshi; Zhang, Chenning; Zhao, Xu; Bi, Kaishun; Jia, Ying
The aim of this study was to explore the neuroprotective effects of active compounds from Schisandra chinensis (Trucz.) Baill. (Magnoliaceae) against the D-galactose (D-gal)-induced neurotoxicity in rat. The Wistar rats were subcutaneously injected with D-gal (150 mg/(kg day)) for six weeks and orally administered with water extract or 95 % ethanol extract (partitioned with petroleum ether (PE), chloroform (CF), ethyl acetate (EA) and n-Butanol (NB), respectively) of the fruits of Schisandra chinensis simultaneously. The alteration of cognitive functions was assessed by using Morris water maze and Step-down type passive avoidance test. The results demonstrated that PE fraction was the most effective fraction to ameliorate cognitive deficits. Further biochemical examination indicated that PE could attenuate the activities decreasing of superoxide dismutase (SOD), catalase (CAT), the total antioxidant (T-AOC) induced by D-gal, and maintain the normal levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) in the serum, prefrontal cortex, striatum and hippocampus of the brain of related rat, selectively. Meanwhile, the compounds of PE fraction were also identified as mainly lignans, thus, these results suggest that lignans from the PE fraction of Schisandra chinensis represented a potential source of medicine for the treatment of the aging-associated neurodegenerative diseases.
Campagna, Roberta; Brunelli, Laura; Airoldi, Luisa; Fanelli, Roberto; Hakansson, Helen; Heimeier, Rachel A; De Boever, Patrick; Boix, Jordi; Llansola, Marta; Felipo, Vicente; Pastorelli, Roberta
Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals by mechanisms that remain unknown. Recently, it has been shown that developmental exposure to 2,2',3,4,4',5'-hexachlorobiphenyl (PCB138), a food-relevant PCB congener, decreases the learning ability of young rats. The aim of this study was to characterize the effect of perinatal exposure to PCB138 on the brain proteome profile in young rats in order to gain insight into the mechanisms underlying PCB138 neurotoxicity. Comparison of the cerebellum proteome from 3-month-old unexposed and PCB138-exposed male offspring was performed using state-of-the-art label-free semiquantitative mass spectrometry method. Biological pathways associated with Ca(2+) homeostasis and androgen receptor signaling pathways were primarily disrupted. These perturbations may contribute toward a premature ageing-like proteome profile of the cerebellum that is triggered by PCB138 exposure in males. Our proteomic data provide insights into the phenomena that may be contributing to the PCB138 neurotoxicity effects observed in laboratory rodents and correlate with PCB exposure and decreased cognitive functions in humans. As such, this study highlights the importance of PCB138 as a risk factor in developmental neurotoxicity in laboratory rodents and humans.
Arteaga, Olatz; Revuelta, Miren; Urigüen, Leyre; Álvarez, Antonia; Montalvo, Haizea; Hilario, Enrique
Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.
Arteaga, Olatz; Revuelta, Miren; Urigüen, Leyre; Álvarez, Antonia; Montalvo, Haizea; Hilario, Enrique
Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia. PMID:26544861
Kim, Hye Yun; Lee, Dongkeun K; Chung, Bo-Ryehn; Kim, Hyunjin V; Kim, YoungSoo
Amyloid-β (Aβ) is a major pathological mediator of both familial and sporadic Alzheimer's disease (AD). In the brains of AD patients, progressive accumulation of Aβ oligomers and plaques is observed. Such Aβ abnormalities are believed to block long-term potentiation, impair synaptic function, and induce cognitive deficits. Clinical and experimental evidences have revealed that the acute increase of Aβ levels in the brain allows development of Alzheimer-like phenotypes. Hence, a detailed protocol describing how to acutely generate an AD mouse model via the intracerebroventricular (ICV) injection of Aβ is necessary in many cases. In this protocol, the steps of the experiment with an Aβ-injected mouse are included, from the preparation of peptides to the testing of behavioral abnormalities. The process of preparing the tools and animal subjects before the injection, of injecting the Aβ into the mouse brain via ICV injection, and of assessing the degree of cognitive impairment are easily explained throughout the protocol, with an emphasis on tips for effective ICV injection of Aβ. By mimicking certain aspects of AD with a designated injection of Aβ, researchers can bypass the aging process and focus on the downstream pathology of Aβ abnormalities.
Ceaser, Alan E.; Barch, Deanna M.
A recent meta-analysis has shown that a large dopamine abnormality exists in the striatum when comparing patients with schizophrenia and controls, and this abnormality is thought to contribute to aberrant salience assignment (or a misattribution of relevance to irrelevant stimuli). This abnormality may also disrupt striatal contributions to cognitive control processing. We examined the relationship between striatal involvement in cognition and aberrant salience symptoms using a task of cognitive control that involves updating, interference control, and simple maintenance. The current study included a sample of 22 patients with schizophrenia and 20 healthy controls and used a slow event-related fMRI design. We predicted that (1) aberrant salience symptoms would be greater for patient's, (2) patients would demonstrate increased errors during interference control trials, given that patients may be inappropriately assigning salience to distracters, and (3) striatal activity during those errors would be correlated with aberrant salience symptoms. We found a trend toward a significant difference between patients and controls on aberrant salience symptoms, and a significant difference between groups on select task conditions. During interference control trials, patients were more likely to inappropriately encode distracters. For patients, both prefrontal and striatal activity was significantly greater when patients inappropriately identified the distracter as correct compared to activity during distracter rejection. During updating, patient prefrontal and striatal activity was significantly lower for incorrect than correct updating trials. Finally, as predicted, for patients the increase of activity during incorrect distracter trials was positively correlated with aberrant salience symptoms, but only for the striatal region. These relationships may have implications for treatments that improve cognitive function and reduce symptom expression. PMID:26869912
Yamada, Maki K
Whole brain radiation therapy for the treatment of tumors can sometimes cause cognitive impairment. Memory deficits were noted in up to 50% of treated patients over a short period of several months. In addition, an increased rate of dementia in young patients has been noted over the longer term, i.e. years. A deficit in neurogenesis after irradiation has been postulated to be the main cause of cognitive decline in patients, but recent data on irradiation therapy for limited parts of the brain appear to indicate other possibilities. Irradiation can directly damage various types of cells other than neuronal stem cells. However, this paper will focus on injury to brain vasculature leading to cognitive decline since vessels represent a better therapeutic target for drug development than other cells in the brain because of the blood-brain barrier.
Graybeal, Carolyn; Kiselycznyk, Carly
Stress is associated with a number of neuropsychiatric disorders, many of which are characterized by altered cognition and emotionality. Rodent models of stress have shown parallel behavioral changes such as impaired working memory, cognitive flexibility and fear extinction. This coincides with morphological changes to pyramidal neurons in the prefrontal cortex, hippocampus and amygdala, key cortical regions mediating these behaviors. Increasing evidence suggests that alteration in the function of the glutamatergic system may contribute to the pathology seen in neuropsychiatric disorders. Stress can alter glutamate transmission in the prefrontal cortex, hippocampus and amygdala and altered glutamate transmission has been linked to neuronal morphological changes. More recently, genetic manipulations in rodent models have allowed for subunit-specific analysis of the role of AMPA and NMDA receptors as well as glutamate transporters in behaviors shown to be altered by stress. Together these data point to a role for glutamate in mediating the cognitive and emotional changes observed in neuropsychiatric disorders. Furthering our understanding of how stress affects glutamate receptors and related signaling pathways will ultimately contribute to the development of improved therapeutics for individuals suffering from neuropsychiatric disorders. PMID:22261703
Maimaiti, Shaniya; Anderson, Katie L.; DeMoll, Chris; Brewer, Lawrence D.; Rauh, Benjamin A.; Gant, John C.; Blalock, Eric M.; Porter, Nada M.
Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer’s disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca2+-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP. PMID:25659889
Bioque, Miquel; Cabrera, Bibiana; García-Bueno, Borja; Mac-Dowell, Karina S; Torrent, Carla; Saiz, Pilar A; Parellada, Mara; González-Pinto, Ana; Lobo, Antonio; Leza, Juan C; Bernardo, Miguel
Among etiological explanations for psychosis, several hypotheses involving alterations on the immune/inflammatory system have been proposed. The endocannabinoid system (ECS) is an endogenous neuroprotective, anti-inflammatory system that modulates cognitive processes. Its altered expression has been associated with psychotic disorders. 73 patients with a first episode of psychoses (FEP) and 67 healthy controls were recruited in 5 university centers in Spain. The protein expression of the main peripheral ECS components was determined in peripheral blood mononuclear cells. The cognition function was assessed following the MATRICS consensus. After controlling for potential confounding factors, working memory statistically correlated to the peripheral N-acyl phosphatidylethanolamine phospholipase expression (p = 0.039). The short-term verbal memory correlated to the Diacylglycerol lipase (p = 0.043) and the fatty acid amide hydrolase (p = 0.026) expression. Finally, attention measures correlated to the Monoacylglycerol lipase expression, by means of the CPT-II commissions (p = 0.036) and detectability (p = 0.026) scores. The ECS may regulate the activation of key mediators in immune and inflammatory responses that may be involved in the primary neuronal stress phenomenon that occurs from the onset of psychotic illness. This study points a relationship between the ECS and the cognitive function in early psychosis and suggests the use of some of the ECS elements as biomarkers and/or pharmacological targets for FEP.
Kubas, Hanna A; Backenson, Erica M; Wilcox, Gabrielle; Piercy, Jamie C; Hale, James B
Focusing on behavioral criteria for attention-deficit/hyperactivity disorder (ADHD) diagnosis leads to considerable neuropsychological profile heterogeneity among diagnosed children, as well as variable response to methylphenidate (MPH) treatment. Documenting "cold" executive working memory (EWM) or "hot" self-regulation (SR) neuropsychological impairments could aid in the differential diagnosis of ADHD subtypes and may help to determine the optimal MPH treatment dose. In this study, children with ADHD inattentive type (n = 19), combined type (n = 33), and hyperactive-impulse type (n = 4) underwent randomized controlled MPH trials; neuropsychological, behavioral, and observational data were collected to evaluate the children's responses. Those with moderate or significant baseline EWM/SR impairment showed robust MPH response, whereas response for those with lower baseline impairment was equivocal. Implications for medication use and titration, academic achievement, and long-term treatment efficacy are examined.
Kim, Jieun E; Kim, Geon Ha; Hwang, Jaeuk; Kim, Jung Yoon; Renshaw, Perry F; Yurgelun-Todd, Deborah A; Kim, Binna; Kang, Ilhyang; Jeon, Saerom; Ma, Jiyoung; Lyoo, In Kyoon; Yoon, Sujung
The adolescent brain, with ongoing prefrontal maturation, may be more vulnerable to drug use-related neurotoxic changes as compared to the adult brain. We investigated whether the use of methamphetamine (MA), a highly addictive psychostimulant, during adolescence affect metabolic and cognitive functions of the anterior cingulate cortex (ACC). In adolescent MA users (n = 44) and healthy adolescents (n = 53), the levels of N-acetyl aspartate (NAA), a neuronal marker, were examined in the ACC using proton magnetic resonance spectroscopy. The Stroop color-word task was used to assess Stroop interference, which may reflect cognitive functions of behavior monitoring and response selection that are mediated by the ACC. Adolescent MA users had lower NAA levels in the ACC (t = -2.88, P = 0.005) and relatively higher interference scores (t = 2.03, P = 0.045) than healthy adolescents. Moreover, there were significant relationships between lower NAA levels in the ACC and worse interference scores in adolescent MA users (r = -0.61, P < 0.001). Interestingly, early onset of MA use, as compared to late onset, was related to both lower NAA levels in the ACC (t = -2.24, P = 0.03) as well as lower performance on interference measure of the Stroop color-word task (t = 2.25, P = 0.03). The current findings suggest that metabolic dysfunction in the ACC and its related cognitive impairment may play an important role in adolescent-onset addiction, particularly during early adolescence.
Oh, M. Matthew; Simkin, Dina; Disterhoft, John F.
Aging-related cognitive deficits have been attributed to dysfunction of neurons due to failures at synaptic or intrinsic loci, or both. Given the importance of the hippocampus for successful encoding of memory and that the main output of the hippocampus is via the CA1 pyramidal neurons, much of the research has been focused on identifying the aging-related changes of these CA1 pyramidal neurons. We and others have discovered that the postburst afterhyperpolarization (AHP) following a train of action potentials is greatly enlarged in CA1 pyramidal neurons of aged animals. This enlarged postburst AHP is a significant factor in reducing the intrinsic excitability of these neurons, and thus limiting their activity in the neural network during learning. Based on these data, it has largely been thought that aging-related cognitive deficits are attributable to reduced activity of pyramidal neurons. However, recent in vivo and ex vivo studies provide compelling evidence that aging-related deficits could also be due to a converse change in CA3 pyramidal neurons, which show increased activity with aging. In this review, we will incorporate these recent findings and posit that an interdependent dynamic dysfunctional change occurs within the hippocampal network, largely due to altered intrinsic excitability in CA1 and CA3 hippocampal pyramidal neurons, which ultimately leads to the aging-related cognitive deficits. PMID:27375440
Badre, David; Hoffman, Joshua; Cooney, Jeffrey W; D'Esposito, Mark
Cognitive control permits us to make decisions about abstract actions, such as whether to e-mail versus call a friend, and to select the concrete motor programs required to produce those actions, based on our goals and knowledge. The frontal lobes are necessary for cognitive control at all levels of abstraction. Recent neuroimaging data have motivated the hypothesis that the frontal lobes are organized hierarchically, such that control is supported in progressively caudal regions as decisions are made at more concrete levels of action. We found that frontal damage impaired action decisions at a level of abstraction that was dependent on lesion location (rostral lesions affected more abstract tasks, whereas caudal lesions affected more concrete tasks), in addition to impairing tasks requiring more, but not less, abstract action control. Moreover, two adjacent regions were distinguished on the basis of the level of control, consistent with previous functional magnetic resonance imaging results. These results provide direct evidence for a rostro-caudal hierarchical organization of the frontal lobes.
Alústiza, Irene; Radua, Joaquim; Pla, Marta; Martin, Raquel; Ortuño, Felipe
Schizophrenia (SZ) and Bipolar Disorder (BD) are associated with deficits in both timing and cognitive control functions. However, the underlying neurological dysfunctions remain poorly understood. The main goal of this study was to identify brain structures activated both by increases in cognitive activity and during timing tasks in patients with SZ and BD relative to controls. We conducted two signed differential mapping (SDM) meta-analyses of functional magnetic resonance imaging studies assessing the brain response to increasing levels of cognitive difficulty: one concerned SZ, and the other BD patients. We conducted a similar SDM meta-analysis on neuroimaging of timing in SZ (no studies in BD could be included). Finally, we carried out a multimodal meta-analysis to identify common brain regions in the findings of the two previous meta-analyses. We found that SZ patients showed hypoactivation in timing-related cortical-subcortical areas. The dysfunction observed during timing partially coincided with deficits for cognitive control functions. We hypothesize that a dysfunctional temporal/cognitive control network underlies the persistent cognitive impairment observed in SZ.
Shirai, Yumi; Fujita, Yuko; Hashimoto, Ryota; Ohi, Kazutaka; Yamamori, Hidenaga; Yasuda, Yuka; Ishima, Tamaki; Suganuma, Hiroyuki; Ushida, Yusuke; Takeda, Masatoshi; Hashimoto, Kenji
Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood. PMID:26107664
Umbricht, Daniel; Keefe, Richard SE; Murray, Stephen; Lowe, David A; Porter, Richard; Garibaldi, George; Santarelli, Luca
Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2–8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: −1.95 (1.39); 50 mg: −1.13 (1.37); p=0.2–0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (−4.45 (p=0.04) and −4.75 (p=0.02), respectively) and global (−0.39 (p=0.04) and −0.55 (p=0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms. PMID:24549101
Kertz, Sarah J; Belden, Andy C; Tillman, Rebecca; Luby, Joan
Although depression and anxiety are common in youth (Costello et al. 2003), factors that put children at risk for such symptoms are not well understood. The current study examined associations between early childhood cognitive control deficits and depression and anxiety over the course of development through school age. Participants were 188 children (at baseline M = 5.42 years, SD = 0.79 years) and their primary caregiver. Caregivers completed ratings of children's executive functioning at preschool age and measures of depression and anxiety severity over seven assessment waves (a period of approximately 7.5 years). Longitudinal multilevel linear models were used to examine the effect of attention shifting and inhibition deficits on depression and anxiety. Inhibition deficits at preschool were associated with significantly greater depression severity scores at each subsequent assessment wave (up until 7.5 years later). Inhibition deficits were associated with greater anxiety severity from 3.5 to 7.5 years later. Greater shifting deficits at preschool age were associated with greater depression severity up to 5.5 years later. Shifting deficits were also associated with significantly greater anxiety severity up to 3.5 years later. Importantly, these effects were significant even after accounting for the influence of other key predictors including assessment wave/time, gender, parental education, IQ, and symptom severity at preschool age, suggesting that effects are robust. Overall, findings indicate that cognitive control deficits are an early vulnerability factor for developing affective symptoms. Timely assessment and intervention may be beneficial as an early prevention strategy.
Valls-Llagostera, Cristina; Vidal, Raquel; Abad, Alfonso; Corrales, Montse; Richarte, Vanesa; Casas, Miguel; Ramos-Quiroga, Josep A
Introduccion. El trastorno por deficit de atencion/hiperactividad (TDAH) es un trastorno del neurodesarrollo que se puede manifestar a lo largo de la vida. Un 50-70% de los niños diagnosticados presenta el trastorno en la adolescencia. Los jovenes con TDAH tienen elevadas tasas de comorbilidad con otros trastornos psiquiatricos y una elevada afectacion funcional. Objetivo. Revisar la bibliografia de las intervenciones cognitivo-conductuales que se han aplicado al tratamiento del TDAH en la adolescencia. Desarrollo. Se revisan los estudios sobre tratamiento psicologico, clasificando las intervenciones en: tratamientos psicosociales, tratamiento en mindfulness y tratamiento cognitivo-conductual (individual y en formato de grupo). Se revisa el unico estudio publicado sobre terapia cognitivo-conductual para adolescentes con TDAH, asi como un nuevo protocolo de intervencion en formato de grupo diseñado en el Hospital Universitari Vall d'Hebron. Conclusiones. Aunque recientemente se ha incrementado el numero de publicaciones sobre el tratamiento psicologico del TDAH en el adolescente, se requiere un desarrollo mayor de protocolos de intervencion y estudios sobre la eficacia/efectividad de estos.
Ohwada, Kei; Takeda, Hironobu; Yamazaki, Makiko; Isogai, Hirosi; Nakano, Masahiko; Shimomura, Masao; Fukui, Koji; Urano, Shiro
The effects of pyrroloquinoline quinone (PQQ) and coenzyme Q10 (Co Q10), either alone or together, on the learning ability and memory function of rats were investigated. Rats fed a PQQ-supplemented diet showed better learning ability than rats fed a CoQ10-supplemented diet at the early stage of the Morris water maze test. The combination of both compounds resulted in no significant improvement in the learning ability compared with the supplementation of PQQ alone. At the late stage of the test, rats fed PQQ-, CoQ10- and PQQ + CoQ10-supplemented diets showed similar improved learning abilities. When all the groups were subjected to hyperoxia as oxidative stress for 48 h, rats fed the PQQ- and CoQ10 supplemented diets showed better memory function than the control rats. The concurrent diet markedly improved the memory deficit of the rats caused by oxidative stress. Although the vitamin E-deficient rats fed PQQ or CoQ10 improved their learning function even when subjected to hyperoxia, their memory function was maintained by PQQ rather than by CoQ10 after the stress. These results suggest that PQQ is potentially effective for preventing neurodegeneration caused by oxidative stress, and that its effect is independent of either antioxidant’s interaction with vitamin E. PMID:18231627
Miller, Haylie L; Ragozzino, Michael E; Cook, Edwin H; Sweeney, John A; Mosconi, Matthew W
The neurocognitive impairments associated with restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD) are not yet clear. Prior studies indicate that individuals with ASD show reduced cognitive flexibility, which could reflect difficulty shifting from a previously learned response pattern or a failure to maintain a new response set. We examined different error types on a test of set-shifting completed by 60 individuals with ASD and 55 age- and nonverbal IQ-matched controls. Individuals with ASD were able to initially shift sets, but they exhibited difficulty maintaining new response sets. Difficulty with set maintenance was related to increased severity of RRBs. General difficulty maintaining new response sets and a heightened tendency to revert to old preferences may contribute to RRBs.
Adeosun, Samuel O; Hou, Xu; Zheng, Baoying; Stockmeier, Craig; Ou, Xiaoming; Paul, Ian; Mosley, Thomas; Weisgraber, Karl; Wang, Jun Ming
Apolipoprotein E4 (apoE4) allele is the major genetic risk factor for sporadic Alzheimer disease (AD) due to the higher prevalence and earlier onset of AD in apoE4 carriers. Accumulating data suggest that the interaction between the N- and the C-terminal domains in the protein may be the main pathologic feature of apoE4. To test this hypothesis, we used Arg-61 mice, a model of apoE4 domain interaction, by introducing the domain interaction feature of human apoE4 into native mouse apoE. We carried out hippocampus-dependent learning and memory tests and related cellular and molecular assays on 12- and 3-month-old Arg-61 and age-matched background C57BL/6J mice. Learning and memory task performance were impaired in Arg-61 mice at both old and young ages compared with C57BL/6J mice. Surprisingly, young Arg-61 mice had more mitotic doublecortin-positive cells in the subgranular zone; mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB were also higher in 3-month-old Arg-61 hippocampus compared with C57BL/6J mice. These early-age neurotrophic and neurogenic (proliferative) effects in the Arg-61 mouse may be an inadequate compensatory but eventually detrimental attempt by the system to "repair" itself. This is supported by the higher cleaved caspase-3 levels in the young animals that not only persisted, but increased in old age, and the lower levels of doublecortin at old age in the hippocampus of Arg-61 mice. These results are consistent with human apoE4-dependent cognitive and neuro-pathologic changes, supporting the principal role of domain interaction in the pathologic effect of apoE4. Domain interaction is, therefore, a viable therapeutic/prophylactic target for cognitive impairment and AD in apoE4 subjects.
Goudarzvand, Mahdi; Choopani, Samira; Shams, Alireza; Javan, Mohammad; Khodaii, Zohreh; Ghamsari, Farhad; Naghdi, Naser; Piryaei, Abbas; Haghparast, Abbas
Introduction: Memory and cognitive impairments are some of devastating outcomes of Multiple Sclerosis (MS) plaques in hippocampus, the gray matter part of the brain. The present study aimed to evaluate the intrahippocampal injection of Ethidium Bromide (EB) as a simple and focal model to assess cognition and gray matter demyelination. Methods: Thirty Wistar rats were divided into three groups: control group, which received saline, as solvent of EB, into the hippocampus; and two experimental groups, which received 3 μL of EB into the hippocampus, and then, were evaluated 7 and 28 days after EB injection (n=10 in each group), using a 5-day protocol of Morris Water Maze (MWM) task as well as Transmission Electron Microscopy (TEM) assay. Results: Seven days after EB injection, the behavioral study revealed a significance increase in travelled distance for platform finding in the experimental group compared to the control group. In addition, the nucleus of oligodendrocyte showed the typical clumped chromatin, probably attributed to apoptosis, and the myelin sheaths of some axons were unwrapped and disintegrated. Twenty-eight days after EB injection, the traveled distance and the time spent in target quadrant significantly decreased and increased, respectively in experimental groups compared to the control group. Also, TEM micrographs revealed a thin layer of remyelination around the axons in 28 days lesion group. Discussion: While intracerebral or intraventricular injection of EB is disseminated in different parts of the brain and can affect the other motor and sensory systems, this model is confined locally and facilitates behavioral study. Also, this project could show improvement of memory function subsequent to the physiological repair of the gray matter of the hippocampus. PMID:27303601
Weisskopf, Marc G; Hu, Howard; Mulkern, Robert V; White, Roberta; Aro, Antonio; Oliveira, Steve; Wright, Robert O
Seventy-one-year-old identical twin brothers with chronic lead poisoning were identified from an occupational medicine clinic roster. Both were retired painters, but one brother (J.G.) primarily removed paint and had a history of higher chronic lead exposure. Patella and tibia bone lead concentrations measured by K-X-ray fluorescence in each brother were 5-10 times those of the general population and about 2.5 times higher in J.G. than in his brother (E.G.). Magnetic resonance spectroscopy (MRS) studies examined N-acetylaspartate:creatine ratios, a marker of neuronal density. Ratios were lower in J.G. than in his brother. Scores on neurocognitive tests that assess working memory/executive function were below expectation in both twins. Short-term memory function was dramatically worse in J.G. than in his brother. These results demonstrate some of the more subtle long-term neurologic effects of chronic lead poisoning in adults. In particular, they suggest the presence of frontal lobe dysfunction in both twins, but more dramatic hippocampal dysfunction in the brother with higher lead exposure. The MRS findings are consistent with the hypothesis that chronic lead exposure caused neuronal loss, which may contribute to the impairment in cognitive function. Although a causal relation cannot be inferred, the brothers were genetically identical, with similar life experiences. Although these results are promising, further study is necessary to determine whether MRS findings correlate both with markers of lead exposure and tests of cognitive function. Nevertheless, the results point to the potential utility of MRS in determining mechanisms of neurotoxicity not only for lead but also for other neurotoxicants as well. PMID:15064171
Turner, Lorinda; Mustafa, Syed; Hatton, Alex; Smith, Kenneth G. C.; Lyons, Paul A.; Bullmore, Edward T.
Background Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states. Methods We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls. Results Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage. Conclusions Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients. PMID:27244229
Chang, Hsiao-Fu; Su, Chun-Lin; Chang, Chih-Hua; Chen, Yu-Wen; Gean, Po-Wu
Leptin, a 167 amino acid peptide, is synthesized predominantly in the adipose tissues and plays a key role in the regulation of food intake and body weight. Recent studies indicate that leptin receptor is expressed with high levels in many brain regions that may regulate synaptic plasticity. Here we show that deprivation of rapid eye movement (REMD) sleep resulted in impairment of both cue and contextual fear memory. In parallel, surface expression of GluR1 was reduced in the amygdala. Intraperitoneal injection of leptin to the REMD mice rescued memory impairment and reversed surface GluR1 reduction. Using whole-cell recording to evaluate the synaptic function of the thalamus-lateral amygdala (LA) pathway, we found a decrease in frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) concomitant with reduced AMPA/NMDA ratios in the REMD mice. By contrast, paired-pulse facilitation (PPF) was increased. The effects of REMD on mEPSCs and AMPA/NMDA ratio could be reversed by leptin treatment, whereas on PPR it could not. Phosphatase and tensin homolog (PTEN), a dual protein/lipid phosphatase, down-regulates the effect of the PI-3 kinase pathway. Fear conditioning increased whereas REMD led to a decrease in the phosphorylated states of PTEN, Akt, and glycogen synthase kinase-3β (GSK3β), and the effects of REMD were reversed by leptin. These results suggest that both pre- and postsynaptic functions of the thalamus-LA pathway were altered by fear conditioning and REMD in opposite directions. Leptin treatment reversed REMD-induced memory deficits primarily by a postsynaptic action by restoring surface expression of GluR1 without affecting PPR.
Gay, Olivier; Plaze, Marion; Oppenheim, Catherine; Gaillard, Raphael; Olié, Jean-Pierre; Krebs, Marie-Odile; Cachia, Arnaud
Background Several clinical and radiological markers of early neurodevelopmental deviations have been independently associated with cognitive impairment in patients with schizophrenia. The aim of our study was to test the cumulative and/or interactive effects of these early neurodevelopmental factors on cognitive control (CC) deficit, a core feature of schizophrenia. Methods We recruited patients with first-episode schizophrenia-spectrum disorders, who underwent structural MRI. We evaluated CC efficiency using the Trail Making Test (TMT). Several markers of early brain development were measured: neurological soft signs (NSS), handedness, sulcal pattern of the anterior cingulate cortex (ACC) and ventricle enlargement. Results We included 41 patients with schizophrenia in our analysis, which revealed a main effect of ACC morphology (p = 0.041) as well as interactions between NSS and ACC morphology (p = 0.005), between NSS and handedness (p = 0.044) and between ACC morphology and cerebrospinal fluid (CSF) volume (p = 0.005) on CC measured using the TMT-B score – the TMT-A score. Limitations No 3- or 4-way interactions were detected between the 4 neurodevelopmental factors. The sample size was clearly adapted to detect main effects and 2-way interactions, but may have limited the statistical power to investigate higher-order interactions. The effects of treatment and illness duration were limited as the study design involved only patients with first-episode psychosis. Conclusion To our knowledge, our study provides the first evidence of cumulative and interactive effects of different neurodevelopmental markers on CC efficiency in patients with schizophrenia. Such findings, in line with the neurodevelopmental model of schizophrenia, support the notion that CC impairments in patients with schizophrenia may be the final common pathway of several early neurodevelopmental mechanisms. PMID:28245174
Alfieri, Julio A.; Silva, Pablo R.; Igaz, Lionel M.
Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases associated to mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). To investigate in depth the behavioral phenotype associated with this proteinopathy, we used as a model transgenic (Tg) mice conditionally overexpressing human wild-type TDP 43 protein (hTDP-43-WT) in forebrain neurons. We previously characterized these mice at the neuropathological level and found progressive neurodegeneration and other features that evoke human TDP-43 proteinopathies of the FTD/ALS spectrum. In the present study we analyzed the behavior of mice at multiple domains, including motor, social and cognitive performance. Our results indicate that young hTDP-43-WT Tg mice (1 month after post-weaning transgene induction) present a normal motor phenotype compared to control littermates, as assessed by accelerated rotarod performance, spontaneous locomotor activity in the open field test and a mild degree of spasticity shown by a clasping phenotype. Analysis of social and cognitive behavior showed a rapid installment of deficits in social interaction, working memory (Y-maze test) and recognition memory (novel object recognition test) in the absence of overt motor abnormalities. To investigate if the motor phenotype worsen with age, we analyzed the behavior of mice after long-term (up to 12 months) transgene induction. Our results reveal a decreased performance on the rotarod test and in the hanging wire test, indicating a motor phenotype that was absent in younger mice. In addition, long-term hTDP-43-WT expression led to hyperlocomotion in the open field test. In sum, these results demonstrate a time-dependent emergence of a motor phenotype in older hTDP-43-WT Tg mice, recapitulating aspects of clinical FTD presentations with motor involvement in human patients, and providing a complementary animal model for studying TDP-43 proteinopathies. PMID:28066234
Alfieri, Julio A; Silva, Pablo R; Igaz, Lionel M
Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases associated to mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). To investigate in depth the behavioral phenotype associated with this proteinopathy, we used as a model transgenic (Tg) mice conditionally overexpressing human wild-type TDP 43 protein (hTDP-43-WT) in forebrain neurons. We previously characterized these mice at the neuropathological level and found progressive neurodegeneration and other features that evoke human TDP-43 proteinopathies of the FTD/ALS spectrum. In the present study we analyzed the behavior of mice at multiple domains, including motor, social and cognitive performance. Our results indicate that young hTDP-43-WT Tg mice (1 month after post-weaning transgene induction) present a normal motor phenotype compared to control littermates, as assessed by accelerated rotarod performance, spontaneous locomotor activity in the open field test and a mild degree of spasticity shown by a clasping phenotype. Analysis of social and cognitive behavior showed a rapid installment of deficits in social interaction, working memory (Y-maze test) and recognition memory (novel object recognition test) in the absence of overt motor abnormalities. To investigate if the motor phenotype worsen with age, we analyzed the behavior of mice after long-term (up to 12 months) transgene induction. Our results reveal a decreased performance on the rotarod test and in the hanging wire test, indicating a motor phenotype that was absent in younger mice. In addition, long-term hTDP-43-WT expression led to hyperlocomotion in the open field test. In sum, these results demonstrate a time-dependent emergence of a motor phenotype in older hTDP-43-WT Tg mice, recapitulating aspects of clinical FTD presentations with motor involvement in human patients, and providing a complementary animal model for studying TDP-43 proteinopathies.
Belichenko, Pavel V; Madani, Rime; Rey-Bellet, Lorianne; Pihlgren, Maria; Becker, Ann; Plassard, Adeline; Vuillermot, Stephanie; Giriens, Valérie; Nosheny, Rachel L; Kleschevnikov, Alexander M; Valletta, Janice S; Bengtsson, Sara K S; Linke, Gordon R; Maloney, Michael T; Hickman, David T; Reis, Pedro; Granet, Anne; Mlaki, Dorin; Lopez-Deber, Maria Pilar; Do, Long; Singhal, Nishant; Masliah, Eliezer; Pearn, Matthew L; Pfeifer, Andrea; Muhs, Andreas; Mobley, William C
In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer's disease (AD). At present, no treatment targets Aβ-related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1-15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS.
Truong, Lisa; Mandrell, David; Mandrell, Rick; Simonich, Michael; Tanguay, Robert L
A substantial body of evidence has correlated the human body burdens of some polybrominated diphenyl ether (PBDE) flame retardants with cognitive and other behavioral deficits. Adult zebrafish exhibit testable learning and memory, making them an increasingly attractive model for neurotoxicology. Our goal was to develop a rapid throughput means of identifying the cognitive impact of developmental exposure to flame retardants in the zebrafish model. We exposed embryos from 6h post fertilization to 5 days post fertilization to either PBDE 47 (0.1μM), PBDE 99 (0.1μM) or PBDE 153 (0.1μM), vehicle (0.1% DMSO), or embryo medium (EM). The larvae were grown to adulthood and evaluated for the rate at which they learned an active-avoidance response in an automated shuttle box array. Zebrafish developmentally exposed to PBDE 47 learned the active avoidance paradigm significantly faster than the 0.1% DMSO control fish (P<0.0001), but exhibited significantly poorer performance when retested suggestive of impaired memory retention or altered neuromotor activity. Learning in the PBDE 153 group was not significantly different from the DMSO group. Developmental exposure to 0.1% DMSO impaired adult active avoidance learning relative to the sham group (n=39; P<0.0001). PBDE 99 prevented the DMSO effect, yielding a learning rate not significantly different from the sham group (n=36; P>0.9). Our results underscore the importance of vehicle choice in accurately assessing chemical effects on behavior. Active avoidance response in zebrafish is an effective model of learning that, combined with automated shuttle box testing, will provide a highly efficient platform for evaluating persistent neurotoxic hazard from many chemicals.
De Filippis, Bianca; Valenti, Daniela; Chiodi, Valentina; Ferrante, Antonella; de Bari, Lidia; Fiorentini, Carla; Domenici, Maria Rosaria; Ricceri, Laura; Vacca, Rosa Anna; Fabbri, Alessia; Laviola, Giovanni
Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondrial dysfunction has been proposed to be involved in the mechanism of the disease pathogenesis. Here we demonstrate that modulation of Rho GTPases by CNF1 rescues the reduced mitochondrial ATP production via oxidative phosphorylation in the brain of MeCP2-308 heterozygous female mice, the condition which more closely recapitulates that of RTT patients. In RTT mouse brain, CNF1 also restores the alterations in the activity of the mitochondrial respiratory chain (MRC) complexes and of ATP synthase, the molecular machinery responsible for the majority of cell energy production. Such effects were achieved through the upregulation of the protein content of those MRC complexes subunits, which were defective in RTT mouse brain. Restored mitochondrial functionality was accompanied by the rescue of deficits in cognitive function (spatial reference memory in the Barnes maze), synaptic plasticity (long-term potentiation) and Tyr1472 phosphorylation of GluN2B, which was abnormally enhanced in the hippocampus of RTT mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RTT and provide the first evidence that RTT brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases.
Rey-Bellet, Lorianne; Pihlgren, Maria; Becker, Ann; Plassard, Adeline; Vuillermot, Stephanie; Giriens, Valérie; Nosheny, Rachel L.; Kleschevnikov, Alexander M.; Valletta, Janice S.; Bengtsson, Sara K. S.; Linke, Gordon R.; Maloney, Michael T.; Hickman, David T.; Reis, Pedro; Granet, Anne; Mlaki, Dorin; Lopez-Deber, Maria Pilar; Do, Long; Singhal, Nishant; Masliah, Eliezer; Pearn, Matthew L.; Pfeifer, Andrea; Muhs, Andreas; Mobley, William C.
In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer’s disease (AD). At present, no treatment targets Aβ–related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1–15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS. PMID:27023444
Bakhtadze, Sophia; Beridze, Maia; Geladze, Nana; Khachapuridze, Nana; Bornstein, Natan
Attention deficit hyperactivity disorder (ADHD) is one of the most common developmental disorders in school-aged children. Symptoms consistent with ADHD have been observed in 8-77 % of children with epilepsy. Researchers have been motivated to search for alternative forms of treatment because 30 % of patients with ADHD cannot be treated by psychostimulants. Several studies support the use of a multimodal treatment approach that includes neurofeedback (NF) for the long-term management of ADHD. These studies have shown that NF provides a sustained effect, even without concurrent treatment with stimulants. We aimed to assess cognitive flexibility in ADHD children with and without temporal lobe epilepsy (TLE), and to evaluate the effects of NF on cognitive flexibility in these groups of children. We prospectively evaluated 69 patients with ADHD aged 9-12 years. The control group was 26 ADHD children without TLE who received no treatment. The first experimental group comprised 18 children with ADHD. The second experimental group comprised 25 age-matched ADHD children with TLE. This group was further divided in two subgroups. One subgroup comprised those with mesial temporal lobe epilepsy (16 patients, 9 with hippocampal sclerosis and 7 with hippocampal atrophy), and the other with lateral temporal lobe epilepsy (9 patients, 5 with temporal lobe dysplasia, 3 with temporal lobe cysts, and 1 with a temporal lobe cavernoma). We treated their ADHD by conducting 30 sessions of EEG NF. Reaction time and error rates on the Trail Making Test Part B were compared before and after treatment, and significant differences were found for all groups of patients except those who had mesial temporal lobe epilepsy with hippocampal atrophy. Our results demonstrate that in most cases, NF can be considered an alternative treatment option for ADHD children even if they have TLE. Additional studies are needed to confirm our results.
Scratch, Shannon E.; Doyle, Lex W.; Thompson, Deanne K.; Ahmadzai, Zohra M.; Greaves, Ronda F.; Inder, Terrie E.; Hunt, Rodney W.
Context and Objectives: Little is known regarding the influence of GH on brain development, especially in infants born very preterm (VP; <30 weeks' gestation). Preterm infants are thought to have higher levels of GH in the first days of life compared with full-term infants. VP infants experience cognitive difficulties in childhood and have a diffuse pattern of structural brain abnormalities. This study aimed to explore the relationship between postnatal GH concentrations following VP birth and its association with cognitive functioning and brain volumes at age 7 years. Methods: Eighty-three infants born VP had GH concentrations measured at eight time points postnatally, and 2- and 6-week area under the curve (AUC) summary measures were calculated. Followup at age 7 years included neuropsychological assessment and brain magnetic resonance imaging. Univariable and multivariable regression modeling were used where AUC for GH was the main predictor of neurodevelopmental outcome at age 7 years. Results: Univariable modeling revealed that higher GH levels (2-week AUC) were related to poorer performance on a verbal working memory (P = .04) and shifting attention task (P = .01). These relationships persisted on multivariable modeling and when the 6-week AUC was analyzed; working memory (P = .03), immediate spatial memory (P = .02), and delayed spatial memory (P = .03) deficits were found. Higher GH levels were also associated with larger amygdala volumes after adjustment for potential confounders (P = .002, 2-week AUC; P = .03, 6-week AUC). Conclusions: Higher postnatal GH levels may potentially contribute to the documented neurodevelopmental abnormalities seen in children born VP at school age. PMID:25974734
Ho, Beng-Choon; Wassink, Thomas H.; Ziebell, Steven; Andreasen, Nancy C.
Marijuana exposure during the critical period of adolescent brain maturation may disrupt neuro-modulatory influences of endocannabinoids and increase schizophrenia susceptibility. Cannabinoid receptor 1 (CB1/CNR1) is the principal brain receptor mediating marijuana effects. No study to-date has systematically investigated the impact of CNR1 on quantitative phenotypic features in schizophrenia and inter-relationships with marijuana misuse. We genotyped 235 schizophrenia patients using 12 tag single nucleotide polymorphisms (tSNPs) that account for most of CB1 coding region genetic variability. Patients underwent a high-resolution anatomic brain magnetic resonance scan and cognitive assessment. Almost a quarter of the sample met DSM marijuana abuse (14%) or dependence (8%) criteria. Effects of CNR1 tSNPs and marijuana abuse/dependence on brain volumes and neurocognition were assessed using ANCOVA, including co-morbid alcohol/non-marijuana illicit drug misuse as covariates. Significant main effects of CNR1 tSNPs (rs7766029, rs12720071, and rs9450898) were found in white matter (WM) volumes. Patients with marijuana abuse/dependence had smaller fronto-temporal WM volumes than patients without heavy marijuana use. More interestingly, there were significant rs12720071 genotype-by-marijuana use interaction effects on WM volumes and neurocognitive impairment; suggestive of gene-environment interactions for conferring phenotypic abnormalities in schizophrenia. In this comprehensive evaluation of genetic variants distributed across the CB1 locus, CNR1 genetic polymorphisms were associated with WM brain volume variation among schizophrenia patients. Our findings suggest that heavy cannabis use in the context of specific CNR1 genotypes may contribute to greater WM volume deficits and cognitive impairment, which could in turn increase schizophrenia risk. PMID:21420833
Marx, Ivo; Weirich, Steffen; Berger, Christoph; Herpertz, Sabine C.; Cohrs, Stefan; Wandschneider, Roland; Höppner, Jacqueline; Häßler, Frank
Dysfunctions in perceptual timing have been reported in children with ADHD, but so far only from studies that have not used the whole set of timing paradigms available from the literature, with the diversity of findings complicating the development of a unified model of timing dysfunctions and its determinants in ADHD. Therefore, we employed a comprehensive set of paradigms (time discrimination, time estimation, time production, and time reproduction) in order to explore the perceptual timing deficit profile in our ADHD sample. Moreover, we aimed to detect predictors responsible for timing task performance deficits in children with ADHD and how the timing deficits might be positively affected by methylphenidate. Male children with ADHD and healthy control children, all aged between 8 and 13 years, participated in this longitudinal study with three experimental sessions, where children with ADHD were medicated with methylphenidate at the second session but discontinued their medication at the remaining sessions. The results of our study reveal that children with ADHD were impaired in all timing tasks, arguing for a general perceptual timing deficit in ADHD. In doing so, our predictor analyses support the notion that distinct but partially overlapping cognitive mechanisms might exist for discriminating, estimating/producing, and reproducing time intervals. In this sense, working memory deficits in terms of an abnormally fast internal counting process might be common to dysfunctions in the time estimation/time production tasks and in the time reproduction task, with attention deficits (e.g., in terms of disruptions of the counting process) additionally contributing to time estimation/time production deficits and motivational alterations additionally contributing to time reproduction deficits. Methylphenidate did not significantly alter performance of the ADHD sample, presumably due to limited statistical power of our study. The findings of our study demonstrate a
Wang, Xiaoli; Cao, Qingjiu; Wang, Jinhui; Wu, Zhaomin; Wang, Peng; Sun, Li; Cai, Taisheng; Wang, Yufeng
Cognitive-behavioral therapy (CBT) is an efficacious psychological treatment for adults with attention-deficit/hyperactivity disorder (ADHD), but the neural processes underlying the benefits of CBT are not well understood. This study aims to unravel psychosocial mechanisms for treatment ADHD by exploring the effects of CBT on functional brain networks. Ten adults with ADHD were enrolled and resting-state functional magnetic resonance imaging scans were acquired before and after a 12-session CBT. Twelve age- and gender-matched healthy controls were also scanned. We constructed whole-brain functional connectivity networks using graph-theory approaches and further computed the changes of regional functional connectivity strength (rFCS) between pre- and post-CBT in ADHD for measuring the effects of CBT. The results showed that rFCS was increased in the fronto-parietal network and cerebellum, the brain regions that were most often affected by medication, in adults with ADHD following CBT. Furthermore, the enhanced functional coupling between bilateral superior parietal gyrus was positively correlated with the improvement of ADHD symptoms following CBT. Together, these findings provide evidence that CBT can selectively modulate the intrinsic network connectivity in the fronto-parietal network and cerebellum and suggest that the CBT may share common brain mechanism with the pharmacology in adults with ADHD.
Agay, Nirit; Yechiam, Eldad; Carmel, Ziv; Levkovitz, Yechiel
We compare the view that the effect of methylphenidate (MPH) is selective to individuals with attention-deficit/hyperactivity disorder (ADHD) with an alternative approach suggesting that its effect is more prominent for individuals with weak baseline capacities in relevant cognitive tasks. To evaluate theses 2 approaches, we administered sustained attention, working memory, and decision-making tasks to 20 ADHD adults and 19 control subjects, using a within-subject placebo-controlled design. The results demonstrated no main effects of MPH in the decision-making tasks. In the sustained attention and working-memory tasks, MPH enhanced performance of both ADHD and non-ADHD adults to a similar extent compared with placebo. Hence, the effect of MPH was not selective to ADHD adults. In addition, those benefitting most from MPH in all 3 task domains tended to be individuals with poor task performance. However, in most tasks, individuals whose performance was impaired by MPH were not necessarily better (or worse) performers. The findings suggest that the administration of MPH to adults with ADHD should consider not only clinical diagnosis but also their functional (performance-based) profile.
van Dijk, Fiona; Schellekens, Arnt; van den Broek, Pieter; Kan, Cornelis; Verkes, Robbert-Jan; Buitelaar, Jan
This study examined whether cognitive measures of response inhibition derived from the AX-CPT are able to differentiate between adult attention deficit/hyperactivity disorder (ADHD), borderline personality disorder (BPD), and healthy controls (HC). Current DSM-IV-TR symptoms of ADHD and BPD were assessed by structured diagnostic interviews, and parent developmental interviews were used to assess childhood ADHD symptoms. Patients (14 ADHD, 12 BPD, 7 ADHD and BPD, and 37 HC) performed the AX-CPT. Seventy percent of AX-CPT trials were target (AX) trials, creating a bias to respond with a target response to X probes in the nontarget (AY, BX, BY) trials. On BX trials, context, i.e. the non-'A' letter, must be used to inhibit this prepotent response tendency. On AY trials context actually causes individuals to false alarm. The effects of ADHD and BPD on AX-CPT outcome were tested using two-way ANOVA. BPD was associated with higher percentage of errors across the task and more errors and slower responses on BX trials, whereas ADHD was associated with slower responses on AY trials. The findings suggest response inhibition problems to be present in both ADHD and BPD, and patients with BPD to be particularly impaired due to poor context processing.
Diestel, Stefan; Schmidt, Klaus-Helmut
The present study examines whether cognitive control deficits (CCDs) as a personal vulnerability factor amplify the relationship between emotional dissonance (ED; perceived discrepancy between felt and expressed emotions) and burnout symptoms (emotional exhaustion and depersonalization) as well as absenteeism. CCDs refer to daily failures and impairments of attention regulation, impulse control, and memory. The prediction of the moderator effect of CCDs draws on the argument that portraying emotions which are not genuinely felt is a form of self-regulation taxing and depleting a limited resource capacity. Interindividual differences in the resource capacity are reflected by the measure of CCDs. Drawing on two German samples (one cross-sectional and one longitudinal sample; NTOTAL = 645) of service employees, the present study analyzed interactive effects of ED and CCDs on exhaustion, depersonalization, and two indicators of absenteeism. As was hypothesized, latent moderated structural equation modeling revealed that the adverse impacts of ED on both burnout symptoms and absence behavior were amplified as a function of CCDs. Theoretical and practical implications of the present results will be discussed.
Åsberg Johnels, Jakob; Kopp, Svenny; Gillberg, Christopher
Writing difficulties are common among children with attention-deficit/hyperactivity disorder (ADHD), but the nature of these difficulties has not been well studied. Here we relate behavioral, psycholinguistic, cognitive (memory/executive), and graphomotor measures to spelling skills in school-age girls with ADHD (n = 30) and an age-matched group of typically developed spellers (TYPSP, n = 35). When subdividing the ADHD group into those with poor (ADHDPSP, n = 19) and typical spelling (ADHDTYPSP, n = 11), the two subgroups did not differ with regard to inattentive or hyperactive-impulsive symptom severity according to parent or teacher ratings. Both ADHD subgroups also had equally severe difficulties in graphomotor control-handwriting and (parent ratings of) written expression as compared to the TYPSP group. In contrast, ADHDPSP had problems relative to ADHDTYPSP and TYPSP on phonological and orthographic recoding (choice tasks) and verbal memory (digit span) and were more likely to make commissions on a continuous performance task (CPT). Further analyses using the collapsed ADHD group showed that both digit span and the presence of CPT commissions predicted spelling performance independently of each other. Finally, results showed that phonological recoding skills mediated the association between digit span and spelling performance in ADHD. Theoretical and educational implications are discussed.
Lakhan, Shaheen E; Kirchgessner, Annette
Prescription stimulants are often used to treat attention deficit hyperactivity disorder (ADHD). Drugs like methylphenidate (Ritalin, Concerta), dextroamphetamine (Dexedrine), and dextroamphetamine-amphetamine (Adderall) help people with ADHD feel more focused. However, misuse of stimulants by ADHD and nonaffected individuals has dramatically increased over recent years based on students' misconceptions or simple lack of knowledge of associated risks. In this review, we discuss recent advances in the use and increasing misuse of prescription stimulants among high school and college students and athletes. Given the widespread belief that stimulants enhance performance, there are in fact only a few studies reporting the cognitive enhancing effects of stimulants in ADHD and nonaffected individuals. Student athletes should be apprised of the very serious consequences that can emerge when stimulants are used to improve sports performance. Moreover, misuse of stimulants is associated with dangers including psychosis, myocardial infarction, cardiomyopathy, and even sudden death. As ADHD medications are prescribed for long-term treatment, there is a need for long-term safety studies and education on the health risks associated with misuse is imperative. PMID:23139911
Langberg, Joshua M; Becker, Stephen P; Dvorsky, Melissa R
The purpose of the study was to evaluate the relation between Sluggish Cognitive Tempo (SCT) and academic functioning in a sample of 52 adolescents (40 males, 12 females) with Attention-Deficit/Hyperactivity Disorder (ADHD; M age = 13.75). This study builds on prior work by utilizing an empirically-based and psychometrically validated measure of SCT, collecting ratings of SCT from both parents and teachers, and examining associations with multiple domains of academic functioning from both the parent and teacher perspective as well as grade point average (GPA). Both SCT and DSM-IV symptoms of inattention were significantly correlated with domains of academic functioning. Multiple regression analyses demonstrated that the parent-rated SCT Slow subscale predicted overall academic functioning, organizational skills impairment, and homework problems above and beyond ADHD symptoms and child and demographic characteristics known to be associated with academics, including intelligence, academic achievement, and family income. The teacher-rated SCT Low Initiation/Persistence subscale also predicted homework problems and was the only SCT variable to predict school grades above and beyond ADHD symptoms and relevant covariates. Both the SCT Slow and Low Initiation/Persistence subscales include items related to youth seeming apathetic, unmotivated, and lacking initiative, behaviors that are strongly related to ADHD symptoms of inattention but not currently captured by the DSM-IV. Implications of these findings towards supporting the external validity of the SCT construct are discussed along with potential implications for intervention.
Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A
The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.
Fan, Jia; Jacobson, Sandra W.; Taylor, Paul A.; Molteno, Christopher D.; Dodge, Neil C.; Stanton, Mark E.; Jacobson, Joseph L.; Meintjes, Ernesta M.
Fetal alcohol spectrum disorders comprise the spectrum of cognitive, behavioral, and neurological impairments caused by prenatal alcohol exposure (PAE). Diffusion tensor imaging (DTI) was performed on 54 children (age 10.1 ±1.0 years) from the Cape Town Longitudinal Cohort, for whom detailed drinking histories obtained during pregnancy are available: 26 with full fetal alcohol syndrome (FAS) or partial FAS (PFAS), 15 nonsyndromal heavily exposed (HE), and 13 controls. Using voxelwise analyses, children with FAS/PFAS showed significantly lower fractional anisotropy (FA) in four white matter (WM) regions and higher mean diffusivity (MD) in seven; three regions of FA and MD differences (left inferior longitudinal fasciculus (ILF), splenium, and isthmus) overlapped, and the fourth FA cluster was located in the same WM bundle (right ILF) as an MD cluster. HE children showed lower FA and higher MD in a subset of these regions. Significant correlations were observed between three continuous alcohol measures and DTI values at cluster peaks, indicating that WM damage in several regions is dose dependent. Lower FA in the regions of interest was attributable primarily to increased radial diffusivity rather than decreased axonal diffusivity, suggesting poorer axon packing density and/or myelination. Multiple regression models indicated that this cortical WM impairment partially mediated adverse effects of PAE on information processing speed and eyeblink conditioning. PMID:27219850
Yang, Jie; Pan, Ying; Li, Xuejing; Wang, Xianying
Neuronal damage in the hippocampal formation is more sensitive to ischemic stimulation and easily injured, causing severe learning and memory impairment. Therefore, protection of hippocampal neuronal damage is the main contributor for learning and memory impairment during cerebral ischemia. Atorvastatin has been reported to ameliorate ischemic brain damage after ischemia reperfusion (I/R). However, its molecular mechanism has not been elucidated clearly. In this study, we established four-vessel occlusion model in rats with cerebral ischemia. Here, we demonstrated that atorvastatin significantly improves the behavior of I/R-rat in open field tasks. We also found that atorvastatin significantly shortens the distance and time of loading onto the hidden platform in the positioning navigation process, decreases the latency in the space exploration process when cognitive testing with Morris water maze was performed during ischemic stroke in rats. Furthermore, the survival rate of neurons in the CA1 area of the hippocampus and the phosphorylation of Akt (Ser473) in the neurons are increased, whereas the expression of caspase-3 are inhibited by atorvastatin. However, after an intracerebroventricular injection of LY294002 (an inhibitor of Akt1), the above neuroprotective effects of atorvastatin are attenuated. In summary, our results imply atorvastatin may improve the survival rate of hippocampal neurons and reduce the impairment of learning and memory by downregulating the activation of the caspase-3 via increasing the phosphorylation of Akt1 during ischemia/reperfusion.
Delgado-Alvarado, Manuel; de la Riva, Patricia; Jiménez-Urbieta, Haritz; Gago, Belén; Gabilondo, Alazne; Bornstein, Belén; Rodríguez-Oroz, María Cruz
Polymerase γ (POLG) is the enzyme responsible for the replication and maintenance of mitochondrial DNA (mtDNA). Mutations in the POLG1 gene can lead to mitochondrial dysfunction, producing a wide range of neurological and non-neurological phenotypes. Neurological manifestations include ataxia, muscular weakness, epilepsy, progressive external ophthalmoplegia (PEO), ptosis, neuropathy, psychiatric disorders and, more rarely, parkinsonism. We present the case of an 80-year old female patient with a history of PEO, ptosis, childish behaviour, obsessive disorder, cognitive decline, and parkinsonism. A comprehensive study showed striatal dopamine deficiency on DaT Scan and ragged red fibres as evidenced by Gomori staining in a biopsy of the biceps brachii. Multiple deletions of mtDNA were detected, and sequencing of the POLG1 gene identified a novel substitution, 2834A>T, in exon 18, changing the p.His945Leu amino acid. In silico analysis using PolyPhen-2 (http://genetics.bwh.hardvard.edu/pph2/) predicted that this change is probably damaging, with a score of 1.0 (0-1).
Boseck, Justin J; Davis, Andrew S; Cassady, Jerrell C; Finch, W Holmes; Gelder, Barbara C
Children with fetal alcohol spectrum disorder (FASD) often present with comorbid attention-deficit hyperactivity disorder (ADHD), which can complicate diagnosis and treatment planning. This study investigated the cognitive and adaptive profiles of 81 children with ADHD/FASD and 147 children with ADHD. Multivariate analysis of variance and follow-up discriminant analysis indicated that the two groups had similar profiles on the Wechsler Intelligence Scale for Children-Fourth Edition and Vineland Adaptive Behavior Scales, although the children with comorbid ADHD/FASD demonstrated significantly more impairment in verbal ability, perceptual reasoning, working memory, processing speed, and overall adaptive skills. The results suggested that when compared with children with ADHD alone, children with ADHD/FASD exhibit significantly more impaired cognitive processing and adaptive skill deficits that are essential for school success and healthy social, behavioral, and emotional functioning. Research evaluating the profiles of these groups is likely to facilitate earlier and more accurate diagnosis and intervention.
Levy-Gigi, Einat; Richter-Levin, Gal; Kéri, Szabolcs
Studies on first responders who are repeatedly exposed to traumatic events report low levels of PTSD symptoms and diagnosis. However, neuroimaging and behavioral studies show that traumatic exposure is associated with brain and cognitive dysfunctions. Taking together it may suggest that traumatic exposure have a price, which is not sufficiently defined by the standard PTSD measures. In a recent study we revealed that similar to individuals with PTSD, non-PTSD highly exposed firefighters display a selective impairment in hippocampal related functions. In the current study we aimed to test whether different first responders display a similar impairment. We concentrated on unique populations of active duty firefighters and criminal scene-investigators (CSI) police, who are frequently exposed to similar levels and types of traumatic events, and compared them to civilian matched-controls with no history of trauma-exposure. We used a hippocampal dependent cue-context reversal paradigm, which separately evaluates reversal of negative and positive outcomes of cue and context related information. We predicted and found that all participants were equally able to acquire and retain stimulus-outcome associations. However, there were significant differences in reversal learning between the groups. Performance among firefighters replicated our prior findings; they struggled to learn that a previously negative context is later associated with a positive outcome. CSI police on the other hand showed a selective impairment in reversing the outcome of a negative cue. Hence after learning that a specific cue is associated with a negative outcome, they could not learn that later it is associated with a positive outcome. Performance in both groups did not correlate with levels of PTSD, anxiety, depression or behavioral inhibition symptoms. The results provide further evidence of the hidden price of traumatic exposure, suggesting that this price may differ as a function of occupation
Gong, Wei-Gang; Wang, Yan-Juan; Zhou, Hong; Li, Xiao-Li; Bai, Feng; Ren, Qing-Guo; Zhang, Zhi-Jun
Our previous experiments demonstrated that social isolation (SI) caused AD-like tau hyperphosphorylation and spatial memory deficits in middle-aged rats. However, the underlying mechanisms of SI-induced spatial memory deficits remain elusive. Middle-aged rats (10 months) were group or isolation reared for 8 weeks. Following the initial 4-week period of rearing, citalopram (10 mg/kg i.p.) was administered for 28 days. Then, pathophysiological changes were assessed by performing behavioral, biochemical, and pathological analyses. We found that SI could cause cognitive dysfunction and decrease synaptic protein (synaptophysin or PSD93) expression in different brain regions associated with cognition, such as the prefrontal cortex, dorsal hippocampus, ventral hippocampus, amygdala, and caudal putamen, but not in the entorhinal cortex or posterior cingulate. Citalopram could significantly improve learning and memory and partially restore synaptophysin or PSD93 expression in the prefrontal cortex, hippocampus, and amygdala in SI rats. Moreover, SI decreased the number of dendritic spines in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus, which could be reversed by citalopram. Furthermore, SI reduced the levels of BDNF, serine-473-phosphorylated Akt (active form), and serine-9-phosphorylated GSK-3β (inactive form) with no significant changes in the levels of total GSK-3β and Akt in the dorsal hippocampus, but not in the posterior cingulate. Our results suggest that decreased synaptic plasticity in cognition-associated regions might contribute to SI-induced cognitive deficits, and citalopram could ameliorate these deficits by promoting synaptic plasticity mainly in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus. The BDNF/Akt/GSK-3β pathway plays an important role in regulating synaptic plasticity in SI rats.
Huang, Fang; Sun, Li; Qian, Ying; Liu, Lu; Ma, Quan-Gang; Yang, Li; Cheng, Jia; Cao, Qing-Jiu; Su, Yi; Gao, Qian; Wu, Zhao-Min; Li, Hai-Mei; Qian, Qiu-Jin; Wang, Yu-Feng
Background: The cognitive function of children with either attention deficit hyperactivity disorder (ADHD) or learning disabilities (LDs) is known to be impaired. However, little is known about the cognitive function of children with comorbid ADHD and LD. The present study aimed to explore the cognitive function of children and adolescents with ADHD and learning difficulties in comparison with children with ADHD and healthy controls in different age groups in a large Chinese sample. Methods: Totally, 1043 participants with ADHD and learning difficulties (the ADHD + learning difficulties group), 870 with pure ADHD (the pure ADHD group), and 496 healthy controls were recruited. To investigate the difference in cognitive impairment using a developmental approach, all participants were divided into three age groups (6–8, 9–11, and 12–14 years old). Measurements were the Chinese-Wechsler Intelligence Scale for Children, the Stroop Color-Word Test, the Trail-Making Test, and the Behavior Rating Inventory of Executive Function-Parents (BRIEF). Multivariate analysis of variance was used. Results: The results showed that after controlling for the effect of ADHD symptoms, the ADHD + learning difficulties group was still significantly worse than the pure ADHD group, which was, in turn, worse than the control group on full intelligence quotient (98.66 ± 13.87 vs. 105.17 ± 14.36 vs. 112.93 ± 13.87, P < 0.001). The same relationship was also evident for shift function (shifting time of the Trail-Making Test, 122.50 [62.00, 194.25] s vs. 122.00 [73.00, 201.50] s vs. 66.00 [45.00, 108.00] s, P < 0.001) and everyday life executive function (BRIEF total score, 145.71 ± 19.35 vs. 138.96 ± 18.00 vs. 122.71 ± 20.45, P < 0.001) after controlling for the effect of the severity of ADHD symptoms, intelligence quotient, age, and gender. As for the age groups, the differences among groups became nonsignificant in the 12–14 years old group for inhibition (meaning interference of
Elcioğlu, H Kübra; Aslan, Ersin; Ahmad, Sarfraz; Alan, Saadet; Salva, Emine; Elcioglu, Ö Haluk; Kabasakal, Levent
Neuroinflammation plays pivotal roles in the pathogenesis of Alzheimer's disease (AD). IL-6 is pleiotropic cytokine which plays significant pathological role in inflammatory diseases and causes prolonged inflammation. Additionally, IL-6 activates microglia cells and enhances the accumulation of amyloid-β peptides. Moreover, IL-6 signal transduction is mediated by membrane-bound and soluble IL-6 receptors. Tocilizumab which is a humanized anti-human IL-6 receptor (IL-6R) monoclonal antibody binds to both of these receptors and inhibits IL-6 signaling by this route. The objective was to investigate tocilizumab's potential effects in the treatment of AD. Male Sprague-Dawley rats were divided into three groups: sham (control), streptozotocin (STZ), and tocilizumab-STZ. We used a single dose of intracerebroventricular (ICV) tocilizumab, beginning 1 h prior to injection of STZ for 3 weeks. The rats in STZ and tocilizumab-STZ groups were given ICV-STZ (3 mg/kg). Behavioral parameters were evaluated on days 17-20 and the rats were sacrificed on day-21 to examine histopathological changes. STZ injection caused significant decrease in the mean escape latency in passive avoidance and also declined the performance improvement in Morris water maze tests. Tocilizumab-STZ group significantly improved learning and spatial memory functions by increasing RLT in the passive avoidance and by shortening escape latency in reaching the platform in the Morris water maze. Histopathological changes were examined using hematoxylin and eosin and immunohistochemical (IHC) stainings. IHC analysis revealed that while protein expressions of amyloid-ß (3.5 ± 0.2) and IL-6 (2.9 ± 0.4) showed intense immune-positivity in STZ group, amyloid-ß (1.3 ± 0.1) and IL-6 (1.5 ± 0.2) immunoreactivities were substantially decreased in tocilizumab treatment group. We conclude that tocilizumab treatment attenuated significantly STZ-induced cognitive impairment and histopathological changes
Li, Jie; Ooi, Evelyn; Bloom, Jonathan; Poon, Carrie; Lax, Daniel; Rosenbaum, Daniel M.; Barone, Frank C.
Persistent neurobehavioral deficits and brain changes need validation for brain restoration. Two hours middle cerebral artery occlusion (tMCAO) or sham surgery was performed in male Sprague-Dawley rats. Neurobehavioral and cognitive deficits were measured over 10 weeks included: (1) sensory, motor, beam balance, reflex/abnormal responses, hindlimb placement, forepaw foot fault and cylinder placement tests, and (2) complex active place avoidance learning (APA) and simple passive avoidance retention (PA). Electroretinogram (ERG), hemispheric loss (infarction), hippocampus CA1 neuronal loss and myelin (Luxol Fast Blue) staining in several fiber tracts were also measured. In comparison to Sham surgery, tMCAO surgery produced significant deficits in all behavioral tests except reflex/abnormal responses. Acute, short lived deficits following tMCAO were observed for forelimb foot fault and forelimb cylinder placement. Persistent, sustained deficits for the whole 10 weeks were exhibited for motor (p<0.001), sensory (p<0.001), beam balance performance (p<0.01) and hindlimb placement behavior (p<0.01). tMCAO produced much greater and prolonged cognitive deficits in APA learning (maximum on last trial of 604±83% change, p<0.05) but only a small, comparative effect on PA retention. Hemispheric loss/atrophy was measured 10 weeks after tMCAO and cross-validated by two methods (e.g., almost identical % ischemic hemispheric loss of 33.4±3.5% for H&E and of 34.2±3.5% for TTC staining). No visual dysfunction by ERG and no hippocampus neuronal loss were detected after tMCAO. Fiber tract damage measured by Luxol Fast Blue myelin staining intensity was significant (p<0.01) in the external capsule and striatum but not in corpus callosum and anterior commissure. In summary, persistent neurobehavioral deficits were validated as important endpoints for stroke restorative research in the future. Fiber myelin loss appears to contribute to these long term behavioral dysfunctions and can be
Zhou, Jin; Zhuang, Jian; Li, Jie; Ooi, Evelyn; Bloom, Jonathan; Poon, Carrie; Lax, Daniel; Rosenbaum, Daniel M; Barone, Frank C
Persistent neurobehavioral deficits and brain changes need validation for brain restoration. Two hours middle cerebral artery occlusion (tMCAO) or sham surgery was performed in male Sprague-Dawley rats. Neurobehavioral and cognitive deficits were measured over 10 weeks included: (1) sensory, motor, beam balance, reflex/abnormal responses, hindlimb placement, forepaw foot fault and cylinder placement tests, and (2) complex active place avoidance learning (APA) and simple passive avoidance retention (PA). Electroretinogram (ERG), hemispheric loss (infarction), hippocampus CA1 neuronal loss and myelin (Luxol Fast Blue) staining in several fiber tracts were also measured. In comparison to Sham surgery, tMCAO surgery produced significant deficits in all behavioral tests except reflex/abnormal responses. Acute, short lived deficits following tMCAO were observed for forelimb foot fault and forelimb cylinder placement. Persistent, sustained deficits for the whole 10 weeks were exhibited for motor (p<0.001), sensory (p<0.001), beam balance performance (p<0.01) and hindlimb placement behavior (p<0.01). tMCAO produced much greater and prolonged cognitive deficits in APA learning (maximum on last trial of 604±83% change, p<0.05) but only a small, comparative effect on PA retention. Hemispheric loss/atrophy was measured 10 weeks after tMCAO and cross-validated by two methods (e.g., almost identical % ischemic hemispheric loss of 33.4±3.5% for H&E and of 34.2±3.5% for TTC staining). No visual dysfunction by ERG and no hippocampus neuronal loss were detected after tMCAO. Fiber tract damage measured by Luxol Fast Blue myelin staining intensity was significant (p<0.01) in the external capsule and striatum but not in corpus callosum and anterior commissure. In summary, persistent neurobehavioral deficits were validated as important endpoints for stroke restorative research in the future. Fiber myelin loss appears to contribute to these long term behavioral dysfunctions and can be
Kay, Catherine L; Green, Jonathan M
Children entering out-of-home (OoH) care have often experienced multiple forms of maltreatment and are at risk of psychiatric disorder and poor long-term outcome. Recent evidence shows high rates of disinhibited attachment disorder (DAD) among maltreated adolescents in U.K. OoH care (Kay & Green, 2013). This study aimed to further understand the mechanisms of outcome in this group through investigation of social cognitive functioning. Patterns of theory of mind (ToM) and social information processing were assessed alongside DAD behavior and psychopathology in 63 adolescents in U.K. OoH care (mean age = 176 months, SD = 22; 48% male; 89% White British) and 69 low-risk comparison adolescents (mean age = 171 months, SD = 17; 46% male; 87% White British). Compared to low risk, OoH adolescents showed a hostile attribution bias and ToM deficit, but this was confounded by language ability. ToM was associated with reduced hostile attribution and responding biases and increased social competence, which was further associated with lower levels of externalizing psychopathology. There was no association between social cognition and core features of DAD. Social cognitive deficits and biases may play a role in the high rates of externalizing psychopathology and relationship functioning difficulties in maltreated samples. Future research should assess alternative cognitive mechanisms for DAD.
Becker, Stephen P; Luebbe, Aaron M; Langberg, Joshua M
This study examined separate inattentive, hyperactive, and impulsive dimensions of attention-deficit/hyperactivity disorder (ADHD), as well as sluggish cognitive tempo (SCT) symptoms, in relation to college students' sleep functioning. Participants were 288 college students (ages 17-24; 65 % female; 90 % non-Hispanic White; 12 % self-reported having an ADHD diagnoses) who completed measures of ADHD/SCT symptoms and sleep functioning. Participants reported obtaining an average of 6.8 h of sleep per night (only 26 % reported obtaining ≥8 h of sleep) and having a sleep onset latency of 25 min. 63 % were classified as "poor sleepers," and poor sleepers had higher rates of ADHD and SCT symptoms than "good sleepers". Path analysis controlling for ADHD status and psychiatric medication use was used to determine associations between psychopathology and sleep functioning domains. Above and beyond covariates and other psychopathologies, hyperactivity (but not impulsivity) was significantly associated with poorer sleep quality, longer sleep latency, shorter sleep duration, and more use of sleep medications. SCT symptoms (but not inattention) were significantly associated with poorer sleep quality and increased nighttime sleep disturbance (e.g., having bad dreams, waking up in the middle of the night, feeling too cold or too hot). Both inattention and SCT were associated with greater daytime dysfunction. Regression analyses demonstrated that hyperactivity predicted sleep quality above and beyond the influence of daytime dysfunction, and inattention and SCT predicted daytime dysfunction above and beyond sleep quality. Further studies are needed to examine the interrelations of nighttime sleep functioning, ADHD/SCT, and daytime dysfunction, as well to elucidate mechanisms contributing to related functional impairments.
Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. PMID:23659787
Zhu, Li; Zhong, Minghao; Elder, Gregory A.; Sano, Mary; Holtzman, David M.; Gandy, Sam; Cardozo, Christopher; Haroutunian, Vahram; Robakis, Nikolaos K.; Cai, Dongming
The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD. PMID:26372964
Davie, Briana J; Christopoulos, Arthur; Scammells, Peter J
Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues.
McBurnett, Keith; Villodas, Miguel; Burns, G Leonard; Hinshaw, Stephen P; Beaulieu, Allyson; Pfiffner, Linda J
We evaluated the latent structure and validity of an expanded pool of Sluggish Cognitive Tempo (SCT) items. An experimental rating scale with 44 candidate SCT items was administered to parents and teachers of 165 children in grades 2-5 (ages 7-11) recruited for a randomized clinical trial of a psychosocial intervention for Attention-Deficit/Hyperactivity Disorder, Predominantly Inattentive Type. Exploratory factor analyses (EFA) were used to extract items with high loadings (>0.59) on primary factors of SCT and low cross-loadings (0.30 or lower) on other SCT factors and on the Inattention factor of ADHD. Items were required to meet these criteria for both informants. This procedure reduced the pool to 15 items. Generally, items representing slowness and low initiative failed these criteria. SCT factors (termed Daydreaming, Working Memory Problems, and Sleepy/Tired) showed good convergent and discriminant validity in EFA and in a confirmatory model with ADHD factors. Simultaneous regressions of impairment and comorbidity on SCT and ADHD factors found that Daydreams was associated with global impairment, and Sleepy/Tired was associated with organizational problems and depression ratings, across both informants. For teachers, Daydreams also predicted ODD (inversely); Sleepy/Tired also predicted poor academic behavior, low social skills, and problem social behavior; and Working Memory Problems predicted organizational problems and anxiety. When depression, rather than ADHD, was included among the predictors, the only SCT-related associations rendered insignificant were the teacher-reported associations of Daydreams with ODD; Working Memory Problems with anxiety, and Sleepy/Tired with poor social skills. SCT appears to be meaningfully associated with impairment, even when controlling for depression. Common behaviors resembling Working Memory problems may represent a previously undescribed factor of SCT.
McClure, Margaret M; Harvey, Philip D; Goodman, Marianne; Triebwasser, Joseph; New, Antonia; Koenigsberg, Harold W; Sprung, Larry J; Flory, Janine D; Siever, Larry J
Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD). Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders. In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D(1) and D(2) receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance. We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory. These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.
Kanai, Chieko; Hashimoto, Ryuichiro; Itahashi, Takashi; Tani, Masayuki; Yamada, Takashi; Ota, Haruhisa; Iwanami, Akira; Kato, Nobumasa
The cognitive profile differences between adult patients with autism spectrum disorder (ASD) and those with attention-deficit/hyperactivity disorder (ADHD) are not well characterized. We examined the cognitive profiles of adults having either ASD (n=120) or ADHD (n=76) with no intellectual disabilities (IQ≥70) using the Wechsler Intelligence Scale III (WAIS-III). Verbal Intelligence (VIQ) - Performance Intelligence (PIQ) difference discrepancies were detected between the two groups. Information subtest scores of the Verbal Comprehension index and Arithmetic and Digit Span subtests of the Freedom from Distractibility index were significantly higher in ASD than in ADHD, while the Picture Completion subtest was significantly lower in ASD. To our knowledge, this is the first study to evaluate the difference in the cognitive profiles of adults with ASD and those with ADHD based on the WAIS III with a large number of participants.
Iwata, Y; Nakajima, S; Suzuki, T; Keefe, RSE; Plitman, E; Chung, JK; Caravaggio, F; Mimura, M; Graff-Guerrero, A; Uchida, H
Hypofunction of N-methyl-D-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N = 1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD = 0.08, 95% confidence interval = − 0.06 to 0.23) (11 studies, n = 858) nor each of eight cognitive domains (SMDs = − 0.03 to 0.11) (n = 367–940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies. PMID:26077694
Hamm, Valentine; Héraud, Céline; Bott, Jean-Bastien; Herbeaux, Karine; Strittmatter, Carole; Mathis, Chantal; Goutagny, Romain
Alzheimer’s disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Aβ levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and γ oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Aβ-independent. Our results could partly explain the limited efficacy of Aβ-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD. PMID:28275722
Lou, Jie; Teng, Zhipeng; Zhang, Liangke; Yang, Jiadan; Ma, Lianju; Wang, Fang; Tian, Xiaocui; An, Ruidi; Yang, Mei; Zhang, Qian; Xu, Lu; Dong, Zhi
This work was conducted to prepare β-caryophyllene-hydroxypropyl-β-cyclodextrin inclusion complex (HPβCD/BCP) and investigate its effects and mechanisms on cognitive deficits in vascular dementia (VD) rats. First, HPβCD/BCP was prepared, optimized, characterized, and evaluated. HPβCD/BCP and AM630 were then administered to VD rats to upregulate and downregulate the cannabinoid receptor type 2 (CB2). Results showed that HPβCD/BCP can significantly increase the bioavailability of BCP. Through the Morris water maze test, HPβCD/BCP can attenuate learning and memory deficits in rats. Cerebral blood flow (CBF) monitoring results indicated that HPβCD/BCP can promote the recovery of CBF. Moreover, molecular biology experiments showed that HPβCD/BCP can increase the expression levels of CB2 in brain tissues, particularly the hippocampus and white matter tissues, as well as the expression levels of PI3K and Akt. Overall, the findings demonstrated the protective effects of HPβCD/BCP against cognitive deficits induced by chronic cerebral ischemia and suggested the potential of HPβCD/BCP in the therapy of vascular dementia in the future. PMID:28154534
Laasonen, Marja; Leppamaki, Sami; Tani, Pekka; Hokkanen, Laura
The project Adult Dyslexia and Attention Deficit Disorder in Finland (Project DyAdd) compares adults (n = 119, 18-55 years) with dyslexia, attention-deficit/hyperactivity disorder (ADHD), dyslexia together with ADHD (comorbid), and healthy controls with neuropsychological, psychophysical, and biological methods. The focus of this article is on the…
Kofler, Michael J; Larsen, Ross; Sarver, Dustin E; Tolan, Patrick H
Middle school is a critical yet understudied period of social behavioral risks and opportunities that may be particularly difficult for emerging adolescents with attention-deficit/hyperactivity disorder (ADHD) given their childhood social difficulties. Relatively few ADHD studies have examined social behavior and social-cognitive problem solving beyond the elementary years, or examined aspects of positive (prosocial) behavior. The current study examined how middle school students with clinically elevated ADHD symptoms differ from their non-ADHD peers on baseline (6th grade) and age-related changes in prosocial and aggressive behavior, and the extent to which social-cognitive problem solving strategies mediate these relations. Emerging adolescents with (n = 178) and without (n = 3,806) clinically elevated, teacher-reported ADHD-combined symptoms were compared longitudinally across 6th through 8th grades using parallel process latent growth curve modeling, accounting for student demographic characteristics, oppositional-defiant disorder (ODD) symptoms, deviant peer association, school climate, and parental monitoring. Sixth graders with elevated ADHD symptoms engaged in somewhat fewer prosocial behaviors (d = -0.44) and more aggressive behavior (d = 0.20) relative to their peers. These small social behavioral deficits decreased but were not normalized across the middle school years. Contrary to hypotheses, social-cognitive problem solving was not impaired in the ADHD group after accounting for co-occurring ODD symptoms and did not mediate the association between ADHD and social behavior during the middle school years. ADHD and social-cognitive problem solving contributed independently to social behavior, both in 6th grade and across the middle school years; the influence of social-cognitive problem solving on social behavior was highly similar for the ADHD and non-ADHD groups.
Spurlock, Markus S; Ahmed, Aminul Islam; Rivera, Karla N; Yokobori, Shoji; Lee, Stephanie W; Sam, Pingdewinde N; Shear, Deborah A; Hefferan, Michael P; Hazel, Thomas G; Johe, Karl K; Gajavelli, Shyam; Tortella, Frank C; Bullock, Ross
Penetrating traumatic brain injury (PTBI) is one of the major cause of death and disability worldwide. Previous studies in penetrating ballistic-like brain injury (PBBI), a PTBI rat model revealed widespread peri-lesional neurodegeneration, similar to that seen in humans following gunshot wound to head, which is unmitigated by any available therapies to date. Therefore, we evaluated human neural stem cell (hNSC) engraftment to putatively exploit the potential of cell therapy that has been seen in other central nervous system injury models. Towards this, green fluorescent protein (GFP) labeled hNSCs (400,000 per animal) were transplanted in immunosuppressed Sprague Dawley (SD), Fisher, and athymic (ATN) PBBI rats one week after injury. Tacrolimus (3mg/kg two days prior to transplantation, then 1mg/kg/day), Methylprednisolone (10mg/kg on day of transplant, 1mg/kg/week thereafter), and Mycophenolate mofetil (30mg/kg/day) for seven days following transplantation were used to confer immunosuppression. Engraftment in SD and ATN was comparable at 8-weeks post transplantation. Evaluation of hNSC differentiation and distribution revealed increased neuronal differentiation of transplanted cells with time. At 16-weeks post-transplantation neither cell proliferation nor glial lineage markers expression was detected. Transplanted cell morphology was similar to neighboring host neurons and there was relatively little migration of cells from the peri-transplant site. By 16 weeks, GFP positive processes extended both rostro-caudally and bilaterally into parenchyma, spreading along host white matter tracts, traversing internal capsule, extending ~13 mm caudally from transplantation site reaching into the brain stem. In a Morris water maze test at 8-weeks post-transplantation, animals with transplants had shorter latency to platform compared to vehicle treated animals. However, weak injury-induced cognitive deficits in the control group at the delayed time point confounded benefits
Sharif, Farkhondeh; Zarei, Shekufe; Alavi Shooshtari, Ali; Vossoughi, Mehrdad
Background: Attention deficit hyperactivity disorder is one of the most common psychiatric disorders in children. Objectives: The study aimed to evaluate the effectiveness of stress management program using cognitive behavior approach on mental health of the mothers of the children with attention deficit hyperactivity disorder. Patients and Methods: In this interventional study, 90 mothers of the children with attention deficit hyperactivity disorder were randomly allocated into three intervention, placebo, and control groups. The general health questionnaire was used to measure mental health. Besides, stress was assessed through the depression-anxiety-stress scale. The two instruments were completed at baseline, immediately after, and one month after the intervention by the mothers. Afterwards, within group comparisons were made using one-sample repeated measurement ANOVA. One-way ANOVA was used for inter group comparisons. Mothers in the placebo group only participated in meetings to talk and express feelings without receiving any interventions. Results: At the baseline, no significant difference was found among the three groups regarding the means of stress, anxiety, depression, and mental health. However, a significant difference was observed in the mean score of stress immediately after the intervention (P = 0.033). The results also showed a significant difference among the three groups regarding the mean score of mental health (P < 0.001). One month after the intervention, the mean difference of mental health score remained significant only in the intervention group (P < 0.001). Conclusions: The study findings confirmed the effectiveness of stress management program utilizing cognitive behavior approach in mental health of the mothers of the children with attention deficit hyperactivity disorder. PMID:26199709
Torello, Michael W., Jr.; And Others
Until recently it has been possible only to measure the behavioral products of cognitive processing, e.g. reaction time. However, this is a rather indirect way of studying brain substrates of cognition. Psychophysiological techniques can be used to study the neural mechanisms of cognition. In this experiment brain electrical activity was measured…
Izzo, Nicholas J.; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F.; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M.
Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1–42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD
Izzo, Nicholas J; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M
Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta