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Find video protocols related to scientific articles indexed in Pubmed.
Emotion circuits differentiate symptoms of psychosis versus mania in adolescents.
Neurocase
PUBLISHED: 09-30-2014
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The diagnostic boundary between schizophrenia and bipolar disorder can be unclear, particularly with early onset. We assessed if emotion brain circuits differentiate psychosis versus mania symptoms in a series of six early onset patients. Symptoms were dissociated by direction, awareness condition, and brain regions. Greater psychosis symptoms were correlated with greater prefrontal, anterior cingulate, amygdala, and fusiform face area activation during masked fear processing. By contrast, greater mania symptoms were correlated with less amygdala activation during unmasked fear and happy processing. This suggests emotion dysfunction in schizophrenia versus bipolar disorder may arise from partially distinct neural mechanisms of susceptibility.
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Specific and common genes implicated across major mental disorders: A review of meta-analysis studies.
J Psychiatr Res
PUBLISHED: 09-15-2014
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Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
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Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing.
PLoS ONE
PUBLISHED: 09-03-2014
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There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1) individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2) that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral) faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing.
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Facial emotion identification in early-onset and first-episode psychosis: a systematic review with meta-analysis.
Schizophr. Res.
PUBLISHED: 08-30-2014
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Patients with chronic schizophrenia are characterized by deficits in identifying facial expressions of emotion, and these deficits relate to impaired social and occupational function. It is not yet known if these deficits are trait-like and present at the onset of psychosis, preceding a subsequent diagnosis of schizophrenia. Our objective was to systematically review and analyze the extant literature to assess if there is a consistent profile of emotion identification problems in early-onset and first-episode psychosis.
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Diffusion tensor imaging predictors of treatment outcomes in major depressive disorder.
Br J Psychiatry
PUBLISHED: 06-26-2014
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Functional neuroimaging studies implicate anterior cingulate and limbic dysfunction in major depressive disorder (MDD) and responsiveness to antidepressants. Diffusion tensor imaging (DTI) enables characterisation of white matter tracts that relate to these regions.
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Neural processing of facial expressions of emotion in first onset psychosis.
Psychiatry Res
PUBLISHED: 03-26-2014
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Schizophrenia is characterized by deficits in face and facial emotion processing. This is the first study using event-related potentials (ERPs) to investigate the corresponding neural activation in first onset psychosis. ERPs for 108 first onset psychosis participants and 108 matched healthy controls were recorded while they viewed facial expressions. Group differences on general (neutral) face processing and emotional valence were examined under both unmasked (conscious) and backward-masked (nonconscious implicit) conditions over frontal and temporo-occipital regions. Clinical significance was assessed by comparing diagnoses and correlating ERPs with symptoms. During general face processing, patients showed reduced activation within 70 ms and exaggerated later processing from 160 ms over the frontal region, with a negative shift in voltage over left temporal and occipital regions across the time course. In addition, from 70 ms onwards, patients showed a positive shift in voltage for disgust whereas controls showed a negative shift in voltage for fear and anger (both compared to happy) over temporo-occipital regions. Effects were related to disorganization and depression symptoms and (preliminarily) were apparent across psychotic diagnoses. These results suggest that first onset psychosis is characterized by general as well as emotion-specific face processing impairments from the earliest, automatic processing period.
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The heritability of mental health and wellbeing defined using COMPAS-W, a new composite measure of wellbeing.
Psychiatry Res
PUBLISHED: 03-20-2014
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Mental health is not simply the absence of mental illness; rather it is a distinct entity representing wellness. Models of wellbeing have been proposed that emphasize components of subjective wellbeing, psychological wellbeing, or a combination of both. A new 26-item scale of wellbeing (COMPAS-W) was developed in a cohort of 1669 healthy adult twins (18-61 years). The scale was derived using factor analysis of multiple scales of complementary constructs and confirmed using tests of reliability and convergent validity. Bivariate genetic modeling confirmed its heritability. From an original 89 items we identified six independent subcomponents that contributed to wellbeing. The COMPAS-W scale and its subcomponents showed construct validity against psychological and physical health behaviors, high internal consistency (average r=0.71, Wellbeing r=0.84), and 12-month test-retest reliability (average r=0.62, Wellbeing r=0.82). There was a moderate contribution of genetics to total Wellbeing (heritability h(2)=48%) and its subcomponents: Composure (h(2)=24%), Own-worth (h(2)=42%), Mastery (h(2)=40%), Positivity (h(2)=42%), Achievement (h(2)=32%) and Satisfaction (h(2)=43%). Multivariate genetic modeling indicated genetic variance was correlated across the scales, suggesting common genetic factors contributed to Wellbeing and its subcomponents. The COMPAS-W scale provides a validated indicator of wellbeing and offers a new tool to quantify mental health.
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Abnormal structural networks characterize major depressive disorder: a connectome analysis.
Biol. Psychiatry
PUBLISHED: 02-12-2014
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Major depressive disorder (MDD) has been shown to be associated with a disrupted topological organization of functional brain networks. However, little is known regarding whether these changes have a structural basis. Diffusion tensor imaging (DTI) enables comprehensive whole-brain mapping of the white matter tracts that link regions distributed throughout the entire brain, the so-called human connectome.
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Establishing the resting state default mode network derived from functional magnetic resonance imaging tasks as an endophenotype: A twins study.
Hum Brain Mapp
PUBLISHED: 01-22-2014
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The resting state default mode network (DMN) has been shown to characterize a number of neurological and psychiatric disorders. Evidence suggests an underlying genetic basis for this network and hence could serve as potential endophenotype for these disorders. Heritability is a defining criterion for endophenotypes. The DMN is measured either using a resting-state functional magnetic resonance imaging (fMRI) scan or by extracting resting state activity from task-based fMRI. The current study is the first to evaluate heritability of this task-derived resting activity. 250 healthy adult twins (79 monozygotic and 46 dizygotic same sex twin pairs) completed five cognitive and emotion processing fMRI tasks. Resting state DMN functional connectivity was derived from these five fMRI tasks. We validated this approach by comparing connectivity estimates from task-derived resting activity for all five fMRI tasks, with those obtained using a dedicated task-free resting state scan in an independent cohort of 27 healthy individuals. Structural equation modeling using the classic twin design was used to estimate the genetic and environmental contributions to variance for the resting-state DMN functional connectivity. About 9-41% of the variance in functional connectivity between the DMN nodes was attributed to genetic contribution with the greatest heritability found for functional connectivity between the posterior cingulate and right inferior parietal nodes (P<0.001). Our data provide new evidence that functional connectivity measures from the intrinsic DMN derived from task-based fMRI datasets are under genetic control and have the potential to serve as endophenotypes for genetically predisposed psychiatric and neurological disorders.
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Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress.
J Psychiatr Res
PUBLISHED: 01-21-2014
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Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression.
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Conversion disorder in children and adolescents: A disorder of cognitive control.
J Neuropsychol
PUBLISHED: 01-11-2014
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To assess cognitive function in children and adolescents presenting with acute conversion symptoms.
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Effects of antidepressant medication on emotion regulation in depressed patients: an iSPOT-D report.
J Affect Disord
PUBLISHED: 01-05-2014
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Antidepressant medication (ADM) is thought to reduce depressive symptoms by altering emotion-generative brain systems. However, it is unknown whether successful ADM treatment is associated with changes in psychobehavioral strategies used to regulate emotions. We examined depressive symptoms and emotion regulation strategies before and after ADM in the international Study to Predict Optimized Treatment in Depression (iSPOT-D).
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Tractography of the brainstem in major depressive disorder using diffusion tensor imaging.
PLoS ONE
PUBLISHED: 01-01-2014
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The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the brainstem's role in MDD has only been evaluated in limited reports. Using Diffusion Tensor Imaging (DTI), we investigated whether major brainstem white matter tracts that relate to these two circuits differ in MDD patients compared to healthy controls.
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Impact of early vs. late childhood early life stress on brain morphometrics.
Brain Imaging Behav
PUBLISHED: 12-18-2013
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Previous studies of early life trauma suggest that in addition to its emotional impact, exposure to early life stress (ELS) is associated with alterations in brain structure. However, little attention has been devoted to the relationship between emotional processing and brain integrity as a function of age of ELS onset. In the present study we examined whether ELS onset in older ages of youth rather than younger ages is associated with smaller limbic and basal ganglia volumes as measured by magnetic resonance imaging (MRI). We hypothesized that later age of manifestation during youth is associated with smaller volumetric morphology in limbic and basal ganglia volumes in adulthood. A total of 173 individuals were divided into three groups based on the age of self-reported ELS. The three groups included individuals only experiencing early childhood ELS (1 month-7 years, n = 38), those only experiencing later childhood ELS (8 years -17 years, n = 59), and those who have not experienced ELS (n = 76). Anterior cingulate cortex (ACC), hippocampus, amygdala, insula and caudate volumes were measured using a T1-weighted MRI. Analyses confirmed that later childhood ELS was associated with volumetric reductions in the ACC and insula volumes, while ELS experienced between the ages of 1 month and 7 years was not associated with lower brain volumes in these regions. The results may reflect the influence of more fully developed emotional processing of ELS on the developing brain and reinforce a body of research implicating both the ACC and insula in neuropsychiatric disorders and emotional regulation.
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Causal interactions between fronto-parietal central executive and default-mode networks in humans.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-18-2013
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Information processing during human cognitive and emotional operations is thought to involve the dynamic interplay of several large-scale neural networks, including the fronto-parietal central executive network (CEN), cingulo-opercular salience network (SN), and the medial prefrontal-medial parietal default mode networks (DMN). It has been theorized that there is a causal neural mechanism by which the CEN/SN negatively regulate the DMN. Support for this idea has come from correlational neuroimaging studies; however, direct evidence for this neural mechanism is lacking. Here we undertook a direct test of this mechanism by combining transcranial magnetic stimulation (TMS) with functional MRI to causally excite or inhibit TMS-accessible prefrontal nodes within the CEN or SN and determine consequent effects on the DMN. Single-pulse excitatory stimulations delivered to only the CEN node induced negative DMN connectivity with the CEN and SN, consistent with the CEN/SNs hypothesized negative regulation of the DMN. Conversely, low-frequency inhibitory repetitive TMS to the CEN node resulted in a shift of DMN signal from its normally low-frequency range to a higher frequency, suggesting disinhibition of DMN activity. Moreover, the CEN node exhibited this causal regulatory relationship primarily with the medial prefrontal portion of the DMN. These findings significantly advance our understanding of the causal mechanisms by which major brain networks normally coordinate information processing. Given that poorly regulated information processing is a hallmark of most neuropsychiatric disorders, these findings provide a foundation for ways to study network dysregulation and develop brain stimulation treatments for these disorders.
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Functional dysconnectivity in schizophrenia and its relationship to neural synchrony.
Expert Rev Neurother
PUBLISHED: 08-01-2013
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Schizophrenia is a debilitating disorder of unknown cause. There is increasing momentum to consider functional dysconnectivity as an endophenotype of schizophrenia, and in particular, how it relates to cognition as a core feature of the disorder. Here, the authors review the conceptual models of functional dysconnectivity in schizophrenia to date, the evidence they are based on and some of the limitations of these models. The authors then propose neural synchrony as a potential mechanism for functional dysconnectivity and review the current state of evidence for a link between neural synchrony and cognition in schizophrenia across behavioral, physiological, brain imaging, neurochemical and neurogenetic units of enquiry. The authors conclude by outlining the unmet needs in this field and give an outlook on how to fill these gaps.
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The long-term impact of early adversity on late-life psychiatric disorders.
Curr Psychiatry Rep
PUBLISHED: 02-28-2013
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Early adversity is a strong and enduring predictor of psychiatric disorders including mood disorders, anxiety disorders, substance abuse or dependence, and posttraumatic stress disorder. However, the mechanisms of this effect are not well understood. The purpose of this review is to summarize and integrate the current research knowledge pertaining to the long-term effects of early adversity on psychiatric disorders, particularly in late life. We explore definitional considerations including key dimensions of the experience such as type, severity, and timing of adversity relative to development. We then review the potential biological and environmental mediators and moderators of the relationships between early adversity and psychiatric disorders. We conclude with clinical implications, methodological challenges and suggestions for future research.
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Using multiple methods to characterize the phenotype of individuals with a family history of major depressive disorder.
J Affect Disord
PUBLISHED: 02-21-2013
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Unaffected relatives (URs) of individuals with major depressive disorder (MDD) are biologically more vulnerable to depression. We compare healthy URs and controls at the level of phenotype (symptoms and functioning) and endophenotype (negative emotion bias), and further investigate the interrelation between these and the contribution of environmental early life stress.
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Inhibitory neural activity predicts response to cognitive-behavioral therapy for posttraumatic stress disorder.
J Clin Psychiatry
PUBLISHED: 02-08-2013
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Despite cognitive-behavioral therapy (CBT) being an effective treatment for posttraumatic stress disorder (PTSD), many patients do not respond to CBT. Understanding the neural bases of treatment response may inform treatment refinement, thereby improving treatment response rates. Adequate working memory function is proposed to enable engagement in CBT.
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Brain imaging predictors and the international study to predict optimized treatment for depression: study protocol for a randomized controlled trial.
Trials
PUBLISHED: 02-04-2013
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Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD.
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Widespread reductions in gray matter volume in depression.
Neuroimage Clin
PUBLISHED: 01-01-2013
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Abnormalities in functional limbic-anterior cingulate-prefrontal circuits associated with emotional reactivity, evaluation and regulation have been implicated in the pathophysiology of major depressive disorder (MDD). However, existing knowledge about structural alterations in depression is equivocal and based on cohorts of limited sample size. This study used voxel-based morphometry (VBM) and surface-based cortical thickness to investigate the structure of these circuits in a large and well-characterized patient cohort with MDD. Non-geriatric MDD outpatients (n = 102) and age- and gender-matched healthy control participants (n = 34) provided T1-weighted magnetic resonance imaging data during their baseline visit as part of the International Study to Predict Optimized Treatment for Depression. Whole-brain VBM volumetric and surface-based cortical thickness assessments were performed voxel-wise and compared (at p < 0.05 corrected for multiple comparisons) between the MDD and control groups. MDD participants had reduced gray matter volume in the anterior cingulate cortex, regions of the prefrontal circuits, including dorsolateral and dorsomedial prefrontal cortices, and lateral and medial orbitofrontal cortices, but not in limbic regions. Additional reductions were observed cortically in the posterior temporal and parieto-occipital cortices and, subcortically in the basal ganglia and cerebellum. Focal cortical thinning in the medial orbitofrontal cortex was also observed for the MDD group. These alterations in volume and cortical thickness were not associated with severity of depressive symptoms. The findings demonstrate that widespread gray matter structural abnormalities are present in a well-powered study of patients with depression. The patterns of gray matter loss correspond to the same brain functional network regions that were previously established to be abnormal in MDD, which may support an underlying structural abnormality for these circuits.
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Early exposure to traumatic stressors impairs emotional brain circuitry.
PLoS ONE
PUBLISHED: 01-01-2013
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Exposure to early life trauma (ELT) is known to have a profound impact on mental development, leading to a higher risk for depression and anxiety. Our aim was to use multiple structural imaging methods to systematically investigate how traumatic stressors early in life impact the emotional brain circuits, typically found impaired with clinical diagnosis of depression and anxiety, across the lifespan in an otherwise healthy cohort. MRI data and self-reported histories of ELT from 352 healthy individuals screened for no psychiatric disorders were analyzed in this study. The volume and cortical thickness of the limbic and cingulate regions were assessed for all participants. A large subset of the cohort also had diffusion tensor imaging data, which was used to quantify white matter structural integrity of these regions. We found a significantly smaller amygdala volume and cortical thickness in the rostral anterior cingulate cortex associated with higher ELT exposure only for the adolescence group. White matter integrity of these regions was not affected. These findings demonstrate that exposure to early life trauma is associated with alterations in the gray matter of cingulate-limbic regions during adolescence in an otherwise healthy sample. These findings are interesting in the context that the affected regions are central neuroanatomical components in the psychopathology of depression, and adolescence is a peak period for risk and onset of the disorder.
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Dysregulation in cortical reactivity to emotional faces in PTSD patients with high dissociation symptoms.
Eur J Psychotraumatol
PUBLISHED: 01-01-2013
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Predominant dissociation in posttraumatic stress disorder (PTSD) is characterized by restricted affective responses to positive stimuli. To date, no studies have examined neural responses to a range of emotional expressions in PTSD with high dissociative symptoms.
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GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals.
PLoS ONE
PUBLISHED: 01-01-2013
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The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3? gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B?=?0.082, 95% confidence interval?=?0.037-0.128) and intracranial volume (summary B?=?0.113, 95% confidence interval?=?0.082-0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders.
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Patterns of emotional-cognitive functioning in pediatric conversion patients: implications for the conceptualization of conversion disorders.
Psychosom Med
PUBLISHED: 11-02-2011
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To examine patterns of emotion processing in children and adolescents with conversion disorders and to determine whether those patterns are associated with particular clusters of conversion symptoms. Autobiographical narratives were used to investigate the organization of information about distressing feelings and memories.
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Negative biases and risk for depression; integrating self-report and emotion task markers.
Depress Anxiety
PUBLISHED: 07-29-2011
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Negativity biases and their impact on reactivity to negative emotion are implicated in the mechanisms of risk for depression. The aim of this study was to determine whether self-reported negativity bias is related to objective cognitive measures of emotional reactivity.
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Testing the white matter retrogenesis hypothesis of cognitive aging.
Neurobiol. Aging
PUBLISHED: 05-16-2011
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The retrogenesis hypothesis postulates that late-myelinated white matter fibers are most vulnerable to age- and disease-related degeneration, which in turn mediate cognitive decline. While recent evidence supports this hypothesis in the context of Alzheimers disease, it has not been tested systematically in normal cognitive aging. In the current study, we examined the retrogenesis hypothesis in a group (n = 282) of cognitively normal individuals, ranging in age from 7 to 87 years, from the Brain Resource International Database. Participants were evaluated with a comprehensive neuropsychological battery and were imaged with diffusion tensor imaging. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (DA), measures of white matter coherence, were computed in 2 prototypical early-myelinated fiber tracts (posterior limb of the internal capsule, cerebral peduncles) and 2 prototypical late-myelinated fiber tracts (superior longitudinal fasciculus, inferior longitudinal fasciculus) chosen to parallel previous studies; mean summary values were also computed for other early- and late-myelinated fiber tracts. We examined age-associated differences in FA, RD, and DA in the developmental trajectory (ages 7-30 years) and degenerative trajectory (ages 31-87 years), and tested whether the measures of white matter coherence mediated age-related cognitive decline in the older group. FA and DA values were greater for early-myelinated fibers than for late-myelinated fibers, and RD values were lower for early-myelinated than late-myelinated fibers. There were age-associated differences in FA, RD, and DA across early- and late-myelinated fiber tracts in the younger group, but the magnitude of differences did not vary as a function of early or late myelinating status. FA and RD in most fiber tracts showed reliable age-associated differences in the older age group, but the magnitudes were greatest for the late-myelinated tract summary measure, inferior longitudinal fasciculus (late fiber tract), and cerebral peduncles (early fiber tract). Finally, FA in the inferior longitudinal fasciculus and cerebral peduncles and RD in the cerebral peduncles mediated age-associated differences in an executive functioning factor. Taken together, the findings highlight the importance of white matter coherence in cognitive aging and provide some, but not complete, support for the white matter retrogenesis hypothesis in normal cognitive aging.
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A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): rationale and design.
Trials
PUBLISHED: 03-13-2011
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The ACTION study (Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study.
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Regional heterogeneity in limbic maturational changes: evidence from integrating cortical thickness, volumetric and diffusion tensor imaging measures.
Neuroimage
PUBLISHED: 01-09-2011
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Magnetic resonance imaging (MRI) studies of structural brain development have suggested that the limbic system is relatively preserved in comparison to other brain regions with healthy aging. The goal of this study was to systematically investigate age-related changes of the limbic system using measures of cortical thickness, volumetric and diffusion characteristics. We also investigated if the "relative preservation" concept is consistent across the individual sub-regions of the limbic system. T1 weighted structural MRI and Diffusion Tensor Imaging data from 476 healthy participants from the Brain Resource International Database was used for this study. Age-related changes in grey matter (GM)/white matter (WM) volume, cortical thickness, diffusional characteristics for the pericortical WM and for the fiber tracts associated with the limbic regions were quantified. A regional variability in the aging patterns across the limbic system was present. Four important patterns of age-related changes were highlighted for the limbic sub-regions: 1. early maturation of GM with late loss in the hippocampus and amygdala; 2. an extreme pattern of GM preservation in the entorhinal cortex; 3. a flat pattern of reduced GM loss in the anterior cingulate and the parahippocampus and; 4. accelerated GM loss in the isthmus and posterior cingulate. The GM volumetric data and cortical thickness measures proved to be internally consistent, while the diffusional measures provided complementary data that seem consistent with the GM trends identified. This heterogeneity can be hypothesized to be associated with age-related changes of cognitive function specialized for that region and direct connections to the other brain regions sub-serving these functions.
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International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol.
Trials
PUBLISHED: 01-05-2011
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Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.
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An integrative neuroscience perspective on ADHD: linking cognition, emotion, brain and genetic measures with implications for clinical support.
Expert Rev Neurother
PUBLISHED: 10-08-2010
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There remains a translational gap between research findings and their implementation in clinical practice that applies to attention-deficit/hyperactivity disorder (ADHD), as well as to other major disorders of brain health in childhood, adolescence and adulthood. Research studies have identified potential markers to support diagnostic, functional assessment and treatment decisions, but there is little consensus about these markers. Of these potential markers, cognitive measures of thinking functions, such as sustaining attention and associated electrical brain activity, show promise in complementing the clinical management process. Emerging evidence highlights the relevance of emotional, as well as thinking, functions to ADHD. Here, we outline an integrative neuroscience framework for ADHD that offers one means to bring together cognitive measures of thinking functions with measures of emotion, and their brain and genetic correlates. Understanding these measures and the relationships between them is a first step towards the development of tools that will help to assess the heterogeneity of ADHD, and aid in tailoring treatment choices.
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Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood.
Depress Anxiety
PUBLISHED: 08-10-2010
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The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptors localization to brain regions central to emotion processing.
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Emotion brain alterations in anorexia nervosa: a candidate biological marker and implications for treatment.
J Psychiatry Neurosci
PUBLISHED: 07-06-2010
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Identification of the biological markers of anorexia nervosa (AN) is crucial for the development of new treatments. We aimed to determine whether AN is associated with disturbances in the nonconscious neural processing of innate signals of emotion and whether these disturbances persist after weight gain.
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Loss of white matter integrity in major depressive disorder: evidence using tract-based spatial statistical analysis of diffusion tensor imaging.
Hum Brain Mapp
PUBLISHED: 07-05-2010
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White matter (WM) has been shown to be affected in elderly patients with major depressive disorders (MDD). There is only limited evidence of WM structural abnormalities in nongeriatric MDD patients. This study investigates WM microstructural integrity in nongeriatric MDD patients recruited as part of the International Study to Predict Optimized Treatment in Depression clinical trial and establishes the validity of diffusion tensor imaging measures for the investigation of depression. Baseline diffusion tensor imaging data from 29 nongeriatric MDD participants (11 with melancholia) and 39 healthy control participants were used in this analysis. We performed tract-based spatial statistics analyses to evaluate WM microstructural integrity (1) between all healthy controls and all MDD participants, (2) between melancholic and nonmelancholic MDD participants, and (3) between each subgroup (melancholic and nonmelancholic) and controls. Significant WM integrity deficits were seen only for the melancholic MDD participants compared with controls. Compared with controls, melancholic participants showed an average reduction of 7.8% in fractional anisotropy over WM regions associated with the limbic system, dorsolateral prefrontal cortex, thalamic projection fibers, corpus callosum, and other association fibers. These fractional anisotropy deficits were also associated with decreased axial and increased radial diffusivity in these WM regions, suggesting a pattern of decreased myelination or other degeneration change. Our findings of WM structural abnormalities associated with the limbic system, the frontal cortex, and the thalamus support the prevailing theory of limbic-dorsolateral prefrontal cortex-thalamic dysfunction in depression. Our results also suggest that these deficits are most prominent in the melancholic subtype of MDD.
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Early life stress combined with serotonin 3A receptor and brain-derived neurotrophic factor valine 66 to methionine genotypes impacts emotional brain and arousal correlates of risk for depression.
Biol. Psychiatry
PUBLISHED: 02-17-2010
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Depression will be the second largest burden of disease by 2020. Developing new tools for identifying risk and ultimately prevention of depression relies on elucidating the integrative relationships between susceptibility markers from gene-stress interactions and how they impact emotional brain and arousal systems. They have largely been studied in isolation.
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Neural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorder.
J Abnorm Psychol
PUBLISHED: 02-10-2010
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Although women have a greater propensity than men to develop posttraumatic stress disorder (PTSD) following trauma, sex differences in neural activations to threat have received little investigation. This study tested the prediction that trauma would heighten activity in automatic fear-processing networks to a greater extent in women than in men. Functional magnetic resonance imaging (fMRI) data were recorded in 23 participants with PTSD (13 women, 10 men), 21 trauma-exposed controls (9 women, 12 men), and 42 non-trauma-exposed controls (22 women, 20 men) while they viewed masked facial expressions of fear. Exposure to trauma was associated with enhanced brainstem activity to fear in women, regardless of the presence of PTSD, but in men, it was associated only with the development of PTSD. Men with PTSD displayed greater hippocampal activity to fear than did women. Both men and women with PTSD showed enhanced amygdala activity to fear relative to controls. The authors conclude that greater brainstem activation to threat stimuli may contribute to the greater prevalence of PTSD in women, and greater hippocampal activation in men may subserve an enhanced capacity for contextualizing fear-related stimuli.
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Using brain-based cognitive measures to support clinical decisions in ADHD.
Pediatr. Neurol.
PUBLISHED: 02-02-2010
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Measures of cognition support diagnostic and treatment decisions in attention deficit hyperactivity disorder. We used an integrative neuroscience framework to assess cognition and associated brain-function correlates in large attention deficit hyperactivity disorder and healthy groups. Matched groups of 175 attention deficit hyperactivity disorder children/adolescents and 175 healthy control subjects were assessed clinically, with the touch screen-based cognitive assessment battery "IntegNeuro" (Brain Resource Ltd., Sydney, Australia) and the "LabNeuro" (Brain Resource Ltd., Sydney, Australia) platform for psychophysiologic recordings of brain function and body arousal. IntegNeuro continuous performance task measures of sustained attention classified 68% of attention deficit hyperactivity disorder patients with 76% specificity, consistent with previous reports. Our additional cognitive measures of impulsivity, intrusive errors, inhibition, and response variability improved sensitivity to 88%, and specificity to 91%. Positive predictive power was 96%, and negative predictive power, 88%. These metrics were stable across attention deficit hyperactivity disorder subtypes and age. Consistent with their brain-based validity, cognitive measures were correlated with corresponding brain-function and body-arousal measures. We propose a combination of candidate cognitive "markers" that define a signature for attention deficit hyperactivity disorder: "sustained attention," "impulsivity," "inhibition," "intrusions," and "response variability." These markers offer a frame of reference to support diagnostic and treatment decisions, and an objective benchmark for monitoring outcomes of interventions.
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COMT Val(108/158)Met polymorphism effects on emotional brain function and negativity bias.
Neuroimage
PUBLISHED: 01-22-2010
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Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with individual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders.
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Duration of posttraumatic stress disorder predicts hippocampal grey matter loss.
Neuroreport
PUBLISHED: 10-02-2009
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To examine the impact of environmental stress on grey matter volume in posttraumatic stress disorder (PTSD), we investigated the relationship between duration of PTSD and grey matter volume of hippocampus and anterior cingulate cortex. Twenty-one participants with PTSD and 17 trauma-exposed controls, matched for age and sex and with no history of substance dependence, underwent a T1-weighted structural MRI scan and voxel-based morphometry was employed. After controlling for age, depression and whole-brain volume, analysis of covariance revealed significant reductions in hippocampus and rostral anterior cingulate cortex in PTSD, and there was a significant negative correlation between right hippocampal volume and PTSD duration. This pattern suggests that prolonged PTSD may have cumulative adverse effects on hippocampal volume, highlighting the potential role of genetic-environmental interactions.
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Explicit identification and implicit recognition of facial emotions: II. Core domains and relationships with general cognition.
J Clin Exp Neuropsychol
PUBLISHED: 07-11-2009
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Both general and social cognition are important in providing endophenotypic markers and predicting real-world functional outcomes of clinical psychiatric disorders. However, to date, focus has been on general cognition, rather than on core domains of social/emotional cognition. This study sought to determine core domains of emotion processing for both explicit identification and implicit recognition and their relationships with core domains of general cognition. Age effects and sex differences were also investigated. A sample of 1,000 healthy individuals (6 to 91 years, 53.5% female) undertook the WebNeuro tests of emotion identification and recognition and tests of general cognitive function. Factor analysis revealed seven core domains of emotion processing: speed of explicit emotion identification, speed of implicit emotion recognition, implicit emotion recognition accuracy, "threat" processing, sadness-disgust identification, "positive emotion" processing, and general "face perception." Seven corresponding core domains of general cognition were identified: information-processing speed, executive function, sustained attention/vigilance, verbal memory, working-memory capacity, inhibition/impulsivity, and sensorimotor function. Factors of emotion processing generally showed positive associations with those of general cognitive function, suggesting commonality in processing speed in particular. Moreover, age had a consistent nonlinear impact on both emotion processing and general cognitive factors, while sex differences were more specific. These findings contribute to a normative and standardized structure for assessment of emotional and general cognition in clinical groups.
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Explicit identification and implicit recognition of facial emotions: I. Age effects in males and females across 10 decades.
J Clin Exp Neuropsychol
PUBLISHED: 07-11-2009
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A number of psychiatric and neurological disorders are characterized by impairments in facial emotion recognition. Recognition of individual emotions has implicated limbic, basal ganglionic, and frontal brain regions. Since these regions are also implicated in age-related decline and sex differences in emotion processing, an understanding of normative variation is important for assessing deficits in clinical groups. An internet-based test ("WebNeuro") was administered to 1,000 healthy participants (6 to 91 years, 53% female) to assess explicit identification of basic expressions of emotion (happiness, sadness, fear, anger, disgust, neutral). A subsequent implicit recognition condition was based on a priming protocol, in which explicit identification provided the "study" phase. Responses were most accurate for happiness and slowest for fear in the explicit condition, but least accurate for happiness and fastest for fear in the implicit condition. The effects of age, by contrast, showed a similar pattern for both explicit and implicit conditions, following a nonlinear distribution in which performance improved from childhood through adolescence and early adulthood and declined in later adulthood. Females were better than males at explicit identification of fear in particular. These findings are consistent with the priority of threat-related signals, but indicate opposing biases depending on whether emotion processing is conscious or nonconscious. The lifespan trends in emotion processing over 10 decades point to an interaction of brain-based (maturation, stability, and then atrophy of cortical and subcortical systems) and experiential contributing factors. These findings provide a robust normative platform for assessing clinical groups.
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Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness.
Hum Brain Mapp
PUBLISHED: 06-11-2009
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Altered hippocampal volume, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, and neuroticism have each been implicated in the etiology of psychiatric disorders, especially depression. However, the relationship between these variables is not well understood. Here, we determined the effects of the BDNF Val66met polymorphism on the five-factor personality dimensions (assessed using the NEO-FFI), trait depression (assessed with the DASS-21) in a cross-sectional cohort of 467 healthy volunteers. A large matched subset of this cohort was also assessed for grey matter volume of the hippocampus and contiguous temporal cortical regions using magnetic resonance imaging. In Met carriers, elevations in neuroticism and trait depression and stress were associated with lower mean hippocampal volume, but there were no such associations in Val homozygotes. Trait depression, in particular, was found to moderate the effects of BDNF genotypes on hippocampal volume. Met carriers with high trait depression showed a reduction in grey matter volume of the mean hippocampus compared with Val homozygotes. These findings suggest that even in otherwise healthy subjects, trait depression may contribute to the susceptibility of Met carriers to hippocampal grey matter loss.
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Impact of depression heterogeneity on attention: an auditory oddball event related potential study.
J Affect Disord
PUBLISHED: 05-18-2009
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Major depressive disorder is associated with a reduced ability to attend and concentrate, however, the extent to which attentional impairment is dependent on subtype remains to be clarified.
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Anterior cingulate activity to salient stimuli is modulated by autonomic arousal in posttraumatic stress disorder.
Psychiatry Res
PUBLISHED: 05-14-2009
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Reduced ventral anterior cingulate (vACC) activity to threat is thought to reflect an impairment in regulating arousal networks in posttraumatic stress disorder (PTSD). Concurrent functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) recording were used to examine neural functioning when arousal networks are engaged. Eleven participants with PTSD and 11 age- and sex-matched non-traumatized controls performed an oddball task that required responding to salient, non-trauma-related auditory target tones embedded in lower frequency background tones. Averaged target-background analyses revealed significantly greater dorsal ACC, supramarginal gyrus, and hippocampal activity in PTSD relative to control participants.With-SCR target responses resulted in increased vACC activity in controls, and dorsal ACC activity in PTSD. PTSD participants had reduced vACC activity relative to controls to target tones when SCR responses were present. This reduction in vACC in PTSD relative to controls was not apparent in without-SCR responses. These findings suggest that a reduction in vACC in PTSD occurs specifically when arousal networks are engaged.
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Disturbances in selective information processing associated with the BDNF Val66Met polymorphism: evidence from cognition, the P300 and fronto-hippocampal systems.
Biol Psychol
PUBLISHED: 05-09-2009
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In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the IntegNeuro computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.
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Delusions and dorso-medial frontal cortex volume in first-episode schizophrenia: a voxel-based morphometry study.
Psychiatry Res
PUBLISHED: 04-22-2009
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Of the few studies that have directly investigated the neuroanatomical correlates of delusions in patients with recent-onset schizophrenia, a number have paradoxically reported a positive correlation between delusion severity and regional grey matter volume. In order to explore this relationship, 31 patients with first-episode schizophrenia (FES) underwent a clinical interview and a T1-weighted structural MRI scan. Patients scores on the Delusions subscale of the Positive and Negative Syndrome Scale were correlated with the volume of every voxel in their grey matter images in SPM99. Patients delusion scores were found to correlate with the volume of a cluster of voxels located in the dorso-medial frontal cortex, centred on the medial frontal gyrus. Post-hoc analysis revealed that this region-of-correlation was volumetrically reduced in the FES patients relative to a group of 21 matched healthy controls. The results of this study support the hypothesis that while a certain level of structural brain atrophy is necessary for delusion formation in patients with FES, excessive structural atrophy may in fact preclude the formation of highly systematized delusions.
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Fronto-temporal alterations within the first 200 ms during an attentional task distinguish major depression, non-clinical participants with depressed mood and healthy controls: a potential biomarker?
Hum Brain Mapp
PUBLISHED: 04-10-2009
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Attentional impairment in depression is a cardinal feature of depression and has been proposed as a candidate endophenotype for major depressive disorder. Event-related potentials (ERPs) elicited by oddball signal detection tasks provide objective markers of selective stimulus processing, and are pertinent endophenotypic markers for depression. While previous studies have sought to determine objective markers for attentional impairment in depression, evidence is inconsistent and may involve heterogeneity in relatively small samples. Here, we brought together oddball ERP recording with source localization of neural correlates of selective attention in outpatients with major depressive disorder (MDD; n = 78) and participants with depressed mood (PDM; n = 127) relative to healthy controls (CTL; n = 116). The key finding was a dimensional exaggeration of the P200 (140-270 ms) to both target (signal) and non-target (noise) stimuli, most pronounced in MDD, followed by PDM, relative to CTL. This exaggeration was coupled with slower and more variable response times, suggesting that neural systems are attempting to compensate for a difficulty in discriminating signal from noise. P200 alterations were localised to limbic (hippocampal), temporal and ventral prefrontal regions, key components of the signal detection network. A subsequent reduction and delay in the P300 was also revealed for MDD indicating that the pronounced lack of discrimination in clinical depression may also lead to impaired stimulus evaluation. This P200 increase in depression could provide a potential mechanism for the attentional impairment frequently observed in depression and consequent alterations in the P300 may differentiate clinically significant depression.
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Small-world properties of nonlinear brain activity in schizophrenia.
Hum Brain Mapp
PUBLISHED: 04-10-2009
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A disturbance in the interactions between distributed cortical regions may underlie the cognitive and perceptual dysfunction associated with schizophrenia. In this article, nonlinear measures of cortical interactions and graph-theoretical metrics of network topography are combined to investigate this schizophrenia "disconnection hypothesis." This is achieved by analyzing the spatiotemporal structure of resting state scalp EEG data previously acquired from 40 young subjects with a recent first episode of schizophrenia and 40 healthy matched controls. In each subject, a method of mapping the topography of nonlinear interactions between cortical regions was applied to a widely distributed array of these data. The resulting nonlinear correlation matrices were converted to weighted graphs. The path length (a measure of large-scale network integration), clustering coefficient (a measure of "cliquishness"), and hub structure of these graphs were used as metrics of the underlying brain network activity. The graphs of both groups exhibited high levels of local clustering combined with comparatively short path lengths--features consistent with a "small-world" topology--as well as the presence of strong, central hubs. The graphs in the schizophrenia group displayed lower clustering and shorter path lengths in comparison to the healthy group. Whilst still "small-world," these effects are consistent with a subtle randomization in the underlying network architecture--likely associated with a greater number of links connecting disparate clusters. This randomization may underlie the cognitive disturbances characteristic of schizophrenia.
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Heterogeneity of non-conscious fear perception in posttraumatic stress disorder as a function of physiological arousal: an fMRI study.
Psychiatry Res
PUBLISHED: 03-24-2009
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While posttraumatic stress disorder (PTSD) is often characterised by an excessive fear response and hyperarousal, research has generally neglected other clinical characteristics including hypoarousal. Findings indicate that concurrent autonomic activity is associated with increased non-conscious processing of fear, highlighting that autonomic responsivity may be an important determinant in the degree of activation within the brainstem-amygdala-MPFC (medial prefrontal cortex) network.
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Total red blood cell concentrations of omega-3 fatty acids are associated with emotion-elicited neural activity in adolescent boys with attention-deficit hyperactivity disorder.
Prostaglandins Leukot. Essent. Fatty Acids
PUBLISHED: 02-20-2009
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Affective impairment is observed in children and adolescents with attention-deficit hyperactivity disorder (ADHD). Low levels of long-chain polyunsaturated fatty acids (LC-PUFA), specifically omega-3 (omega-3) fatty acids in blood measures have been linked to a range of behavioural and mood disorders including ADHD. However, nothing is known about the relationship between omega-3 and brain function in children with ADHD. In the current study, 20 adolescent boys with ADHD were assessed for total lipid fractions in red blood cells and their event-related potential (ERP) response to the presentation of facial expressions of happiness, sadness and fearfulness. The results supported the hypothesis of a positive association between eicosapentaenoic acid (EPA) and a cognitive bias in orientation to overt expressions of happiness over both sad and fearful faces as indexed by midline frontal P300 amplitude. Additional exploratory analyses revealed a positive association between levels of docosahexaenoic acid (DHA) and the right temporal N170 amplitude in response to covert expressions of fear. The arachidonic (AA)/DHA ratio was negatively associated with the right temporal N170 amplitude also to covert expressions of fear. These findings indicate that EPA and DHA may be involved in distinct aspects of affect processing in ADHD and have implications for understanding currently inconsistent findings in the literature on EFA supplementation in ADHD and depression.
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Self-protective organization in children with conversion and somatoform disorders.
J Psychosom Res
PUBLISHED: 02-05-2009
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Two centuries of clinical observations have suggested that conversion symptoms are associated with strong emotions or situations that threaten the individuals physical or psychological integrity. This study tested the hypothesis that childhood conversion reactions reflect the motor-sensory components of two distinct emotional responses (one inhibitory, one excitatory) that develop as adaptations to recurring threats within intimate relationships.
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Negativity bias in risk for depression and anxiety: brain-body fear circuitry correlates, 5-HTT-LPR and early life stress.
Neuroimage
PUBLISHED: 02-05-2009
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The INTEGRATE Model draws on the framework of integrative neuroscience to bring together brain-body and behavioral concepts of emotion, thinking and feeling and their regulation. The key organizing principle is the drive to minimize danger and maximize reward that determines what is significant to us at each point in time. Traits of negativity bias reflect the tendency to perceive danger rather than reward related information, and this bias influences emotion, thinking and feeling processes. Here, we examined a self-report measure of Negativity Bias in relation to its impact on brain and body correlates of emotion processing. The contributions of the serotonin transporter (5-HTT-LPR) allelic variants and early life stress to both negativity bias and these correlates were also examined. Data were accessed in collaboration with the Brain Resource International Database (BRID) which provides standardized data across these domains of measurement. From an initial sample of 303 nonclinical subjects from the BRID, subjects scoring one standard deviation below (n=55) and above (n=47) the mean on the measure of negativity bias were identified as Negativity Bias and Positivity Bias groups for analysis, respectively. These subjects had been genotyped for 5-HTT-LPR Short allele versus LL homozygote status, and completed the early life stress scale, and recording of startle responses and heart rate for conscious and nonconscious fear conditions. A matched subset (n=39) of BRID subjects completed functional MRI with the same facial emotion tasks. The Negativity Bias (compared to Positivity Bias) group was distinguished by both arousal and brain function correlates: higher startle amplitude, higher heart rate for conscious and nonconscious fear conditions, and heightened activation in neural circuitry for both fear conditions. Regions of heightened activation included brainstem and bilateral amygdala, anterior cingulate and ventral and dorsal medial prefrontal cortex (mPFC) for conscious fear, and brainstem and right-sided amygdala, anterior cingulate and ventral, mPFC for nonconscious fear. The 5-HTT-LPR Short allele (versus LL) conferred a similar pattern of arousal and neural activation. For those with the 5-HTT-LPR Short allele, the addition of early life stress contributed to enhanced negativity bias, and to further effects on heart rate and neural activation for nonconscious fear in particular. These findings suggest that traits of negativity bias impact brain-body arousal correlates of fear circuitry. Both genetic variation and life stressors contribute to the impact of negativity bias. Given that negativity bias is a feature of conditions such as depression and associated biological alterations, the findings have implications for translation into clinical decision support.
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A polymorphism of the MAOA gene is associated with emotional brain markers and personality traits on an antisocial index.
Neuropsychopharmacology
PUBLISHED: 02-04-2009
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Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial sample of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120-280ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression.
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Neural synchrony in patients with a first episode of schizophrenia: tracking relations with grey matter and symptom profile.
J Psychiatry Neurosci
PUBLISHED: 01-07-2009
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Although schizophrenia has been characterized by disruptions to neural synchrony, it remains unknown whether these disturbances are related to symptoms and loss of grey matter. We examined relations between 40 Hz Gamma band synchrony and grey matter in patients with schizophrenia at first episode and after 2.5 years.
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Emotion-elicited gamma synchrony in patients with first-episode schizophrenia: a neural correlate of social cognition outcomes.
J Psychiatry Neurosci
PUBLISHED: 01-04-2009
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Schizophrenia may be understood as a disorder of neural synchrony. There is also increasing evidence that emotional and social cognitive impairments are central to this disorder. In patients with first-episode schizophrenia, we examined whether emotion perception is associated with disruptions to high-frequency (40 Hz) gamma synchrony and whether these disruptions predict self-regulatory adaptive compensations reflected in social cognitive behaviours.
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Using standardized fMRI protocols to identify patterns of prefrontal circuit dysregulation that are common and specific to cognitive and emotional tasks in major depressive disorder: first wave results from the iSPOT-D study.
Neuropsychopharmacology
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Functional neuroimaging studies have implicated dysregulation of prefrontal circuits in major depressive disorder (MDD), and these circuits are a viable target for predicting treatment outcomes. However, because of the heterogeneity of tasks and samples used in studies to date, it is unclear whether the central dysfunction is one of prefrontal hyperreactivity or hyporeactivity. We used a standardized battery of tasks and protocols for functional magnetic resonance imaging, to identify the common vs the specific prefrontal circuits engaged by these tasks in the same 30 outpatients with MDD compared with 30 matched, healthy control participants, recruited as part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Reflecting cognitive neuroscience theory and established evidence, the battery included cognitive tasks designed to assess functions of selective attention, sustained attention-working memory and response inhibition, and emotion tasks to assess explicit conscious and implicit nonconscious viewing of facial emotion. MDD participants were distinguished by a distinctive biosignature of: hypoactivation of the dorsolateral prefrontal cortex during working memory updating and during conscious negative emotion processing; hyperactivation of the dorsomedial prefrontal cortex during working memory and response inhibition cognitive tasks and hypoactivation of the dorsomedial prefrontal during conscious processing of positive emotion. These results show that the use of standardized tasks in the same participants provides a way to tease out prefrontal circuitry dysfunction related to cognitive and emotional functions, and not to methodological or sample variations. These findings provide the frame of reference for identifying prefrontal biomarker predictors of treatment outcomes in MDD.
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Hippocampal volume varies with educational attainment across the life-span.
Front Hum Neurosci
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Socioeconomic disparities-and particularly differences in educational attainment-are associated with remarkable differences in cognition and behavior across the life-span. Decreased educational attainment has been linked to increased exposure to life stressors, which in turn have been associated with structural differences in the hippocampus and the amygdala. However, the degree to which educational attainment is directly associated with anatomical differences in these structures remains unclear. Recent studies in children have found socioeconomic differences in regional brain volume in the hippocampus and amygdala across childhood and adolescence. Here we expand on this work, by investigating whether disparities in hippocampal and amygdala volume persist across the life-span. In a sample of 275 individuals from the BRAINnet Foundation database ranging in age from 17 to 87, we found that socioeconomic status (SES), as operationalized by years of educational attainment, moderates the effect of age on hippocampal volume. Specifically, hippocampal volume tended to markedly decrease with age among less educated individuals, whereas age-related reductions in hippocampal volume were less pronounced among more highly educated individuals. No such effects were found for amygdala volume. Possible mechanisms by which education may buffer age-related effects on hippocampal volume are discussed.
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Sensitivity, specificity, and predictive power of the "Brief Risk-resilience Index for SCreening," a brief pan-diagnostic web screen for emotional health.
Brain Behav
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Few standardized tools are available for time-efficient screening of emotional health status across diagnostic categories, especially in primary care. We evaluated the 45-question Brief Risk-resilience Index for SCreening (BRISC) and the 15-question mini-BRISC in identifying poor emotional health and coping capacity across a range of diagnostic groups - compared with a detailed clinical assessment - in a large sample of adult outpatients. Participants 18-60 years of age (n = 1079) recruited from 12 medical research and clinical sites completed the computerized assessments. Three index scores were derived from the full BRISC and the mini-BRISC: one for risk (negativity-positivity bias) and two for coping (resilience and social capacity). Summed answers were converted to standardized z-scores. BRISC scores were compared with detailed health assessment and diagnostic interview (for current psychiatric, psychological, and neurological conditions) by clinicians at each site according to diagnostic criteria. Clinicians were blinded to BRISC scores. Clinical assessment stratified participants as having "clinical" (n = 435) or "healthy" (n = 644) diagnostic status. Receiver operating characteristic analyses showed that a z-score threshold of -1.57 on the full BRISC index of emotional health provided an optimal classification of "clinical" versus "healthy" status (sensitivity: 81.2%, specificity: 92.7%, positive predictive power: 80.2%, and negative predictive power: 93.1%). Comparable findings were revealed for the mini-BRISC. Negativity-positivity bias index scores contributed the most to prediction. The negativity-positivity index of emotional health was most sensitive to classifying major depressive disorder (100%), posttraumatic stress disorder (95.8%), and panic disorder (88.7%). The BRISC and mini-BRISC both offer a brief, clinically useful screen to identify individuals at risk of disorders characterized by poor emotion regulation, from those with good emotional health and coping.
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The presentation of early-onset psychotic disorders.
Aust N Z J Psychiatry
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This study aims to describe the clinical course of psychotic disorders, including the premorbid history, symptoms and level of functioning in a group of children and adolescents treated by paediatric mental health services, mainly as inpatients.
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Early life trauma predicts self-reported levels of depressive and anxiety symptoms in nonclinical community adults: relative contributions of early life stressor types and adult trauma exposure.
J Psychiatr Res
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Exposure to early life trauma is a known risk factor for depression and anxiety disorders in adulthood. This study aimed to evaluate the relative contributions of early life versus adult trauma in predicting levels of depressive and anxiety symptoms in nonclinical community adults. 1209 nonclinical community adults (18-70 years; 45% male) were assessed for mental health status, early life stressors, lifetime trauma exposure, and self-reported levels of depressive and anxiety symptoms. A subset of the full sample subjected to group comparisons (n = 1088) indicated that early life stressor exposure primarily accounted for significantly higher depressive and anxiety symptom scores when compared against adults reporting to be free of childhood stressor or adult trauma exposure. Subsequent hierarchical multiple regression analyses of this subset using five distinct early life stressor types, namely Interpersonal violation, Family breakup, Disasters/war, Familial health trauma/death and Personal health trauma derived from principal component analysis of a wide range of self-reported early stressor events in the full sample, showed childhood Interpersonal violation differentially predicted higher self-reported depressive and anxiety symptom scores in both males and females. Adult trauma exposure did not significantly predict these symptom scores. These findings underline the relative importance of exposure to interpersonal violation relative to other types of early life stressors and adult trauma in the risk of depressive and anxiety symptoms in nonclinical community adults.
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The TWIN-E project in emotional wellbeing: study protocol and preliminary heritability results across four MRI and DTI measures.
Twin Res Hum Genet
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Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18-65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene-environment and endophenotype contributions to treatment response. Preliminary heritability results are provided for the first 50% of the MRI subgroup (n = 142) for the grey matter volume, thickness, and surface area measures, and white matter diffuse tensor imaging fractional anisotropy.
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Finding a biosignature for melancholic depression.
Expert Rev Neurother
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Melancholia is typified by features of psychomotor slowing, anxiety, appetite loss and sleep changes. It is usually observed in 20-30% of individuals meeting diagnostic criteria for major depressive disorder (MDD). There is currently no agreement on whether melancholic MDD represents a distinct entity defined by neurobiological as well as clinical features or, rather, a specifier for MDD. This situation is reflected in the revisions to DSM, including in the DSM-5 due for release in 2013. With this context in mind, the authors review the origins of the construct of melancholia in MDD, its theoretical grounding and the defining characteristics that arose from this research. The authors then outline the state of knowledge on the neurobiology of melancholia. This second aspect is illustrative of the National Institutes of Mental Healths research domain criteria initiative, which offers a framework for redefining constructs along neurobiological dimensions. The authors also consider the outlook for identifying a useful biosignature of melancholia.
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Anxiety in Young People With ADHD: Clinical and Self-Report Outcomes.
J Atten Disord
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Objective: (a) To determine the prevalence of comorbid anxiety disorder in ADHD, defined by diagnostic criteria and (b) to compare anxiety as reported by parents and participants with clinician assessment. Method: Children with ADHD were assessed for comorbid anxiety disorder using the Anxiety Disorder Interview Schedule for Children. Parent report (Conners Parent Rating Scale-Revised: Long version) and self-report (State-Trait Anxiety Inventory and Brain Resource Inventory for Screening Cases-Child version) scales were used to assess anxiety. The ADHD-Rating Scale IV was used to measure ADHD symptoms. Results: Of 134 participants (11.0 ± 2.6 years), 31.3% had comorbid anxiety disorder. Comorbid anxiety disorder was associated with greater severity of ADHD. Anxiety symptoms from parent reports (p < .05) but not from child/self-report (p > .05) correlated with clinician assessment. Conclusion: Assessment for comorbid anxiety disorder and inclusion of parent rating in this assessment are important components of ADHD treatment in children and adolescents. (J. of Att. Dis. 2012; XX(X) 1-XX).
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Mapping inter-regional connectivity of the entire cortex to characterize major depressive disorder: a whole-brain diffusion tensor imaging tractography study.
Neuroreport
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Diffusion tensor imaging (DTI) can be used to study the organization of brain white matter noninvasively. The aim of this study was to present a proof of concept for integrating DTI with high-resolution anatomical (T1) images to map and assess inter-regional connectivity across the entire cortex in a cohort of healthy participants and compared with patients with major depressive disorder. We used MRI data of 23 patients and 23 matched controls, assessed as part of baseline testing in the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Freesurfer was used to analyze the T1 images to automatically label 35 gyral-based areas for each hemisphere. DTI tractography was performed to parcellate intercortical tracts using each of these areas in seed-target combinations. We quantified fractional anisotropy, number-of-fiber connections, and fiber path length for each DTI connection, with the goal of identifying the best measure or combination of measures to characterize major depression. The best classification accuracy for the individual measures was achieved using the number-of-fibers data, whereas the combination model provided a slight improvement. The most discriminant features between the two groups were for white matter associated with the limbic, frontal, and thalamic projection fibers and as part of cortical connections between the left inferior temporal and the postcentral cortex; the left parstriangularis and the left superior frontal; the left cuneus and the corpus callosum; the left lingual and the right lateral occipital, the right superior parietal and the right superior temporal cortices; and the right inferior parietal and the right insula and postcentral cortices.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.