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BackgroundInternet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom.MethodsWe did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683.FindingsWe identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD −1·83 [95% credible interval (CrI) −2·90 to −0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0·32 [95% CrI 0·13 to 0·93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components.InterpretationThe individual patient data cNMA revealed potentially helpful, less helpful, or harmful components and delivery formats for iCBT packages. iCBT packages aiming to be effective and efficient might choose to include beneficial components and exclude ones that are potentially detrimental. Our web app can facilitate shared decision making by therapist and patient in choosing their preferred iCBT package.FundingJapan Society for the Promotion of Science.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Gamma-aminobutyric acid (GABA) metabolism is implicated in posttraumatic stress disorder (PTSD) and may be altered in prefrontal-limbic brain regions involved in arousal regulation. This study used proton magnetic resonance spectroscopy (MRS) to test the hypothesis that PTSD and trauma-exposed non-PTSD comparison (TENC) adults have significantly different GABA than healthy comparison (HC) subjects in two brain areas implicated in arousal (medial prefrontal cortex, insula) but not in a control brain area (posterior temporal cortex). We also examined whether GABA alterations correlated with hyperarousal and dissociation symptoms. One hundred and fourteen participants (39 PTSD, 34 TENC, 41 HC) underwent 3T MRS of the medial prefrontal, right insular, and right posterior temporal cortices, and the GABA plus macromolecule signal (GABA+) was normalized to creatine (Cr). The Clinician Administered PTSD Scale measured hyperarousal symptoms, including sleep disruption. The Dissociative Experiences Scale assessed dissociation symptoms. PTSD and TENC participants had significantly lower mPFC GABA+/Cr than HC participants, and this deficit was significantly correlated with greater dissociation. Compared with HC, PTSD patients but not TENC had significantly lower insula GABA+/Cr. Total hyperarousal symptoms and sleep disruption were not significantly associated with GABA+/Cr alterations in either region. Our findings point to lower GABA in cortical areas implicated in arousal regulation in PTSD and suggest that GABA alterations are associated with symptoms of trauma-related psychopathology but not always a biomarker of diagnosis. These findings also add to evidence that dissociation has distinct neural correlates within PTSD, including high excitability of medial prefrontal cortex.

Background Prefrontal subregions, including the ventromedial prefrontal cortex (PFC), dorsomedial PFC, and dorsolateral PFC (DLPFC), are differentially implicated in the pathophysiology of posttraumatic stress disorder (PTSD), though few existing studies have examined subregional differences in resting-state functional connectivity (rsFC). We hypothesized that PTSD would involve weaker positive rsFC between ventromedial PFC, dorsomedial PFC, and other default mode network regions and increased negative rsFC between DLPFC and posterior default mode network regions. Additionally, we hypothesized that prefrontal regions exhibiting group differences in rsFC would be characterized by alterations in cortical thickness. Methods Participants included 36 healthy control subjects, 30 trauma-exposed control subjects, and 21 individuals with current DSM-IV PTSD resulting from community-acquired trauma. Participants completed the Clinician Administered PTSD Scale, questionnaires (Childhood Trauma Questionnaire, Adverse Childhood Events, Life Events Checklist, Beck Depression Inventory), structural neuroimaging, and resting-state functional magnetic resonance imaging. rsFC of DLPFC, ventromedial PFC, and dorsomedial PFC seeds was evaluated in SPM12 and CONN. Cortical thickness for regions with significant rsFC findings was assessed using FreeSurfer. Results Relative to both healthy control and trauma-exposed control subjects, individuals with PTSD showed increased negative rsFC between the DLPFC and a region of precuneus. This finding was associated with increased overall symptom severity but not with trauma load or childhood trauma exposure. Greater negative DLPFC-precuneus connectivity was associated with greater bilateral precuneus thickness. Conclusions Given participation of precuneus subregions in the central executive network, increased anticorrelation between right DLPFC and precuneus in this sample may reflect increased opposition between anterior and posterior central executive network hubs in PTSD.

IntroductionCortical thickness (CT) and surface area (SA) are established biomarkers of brain pathology in posttraumatic stress disorder (PTSD). Structural covariance networks (SCN) constructed from CT and SA may represent developmental associations, or unique interactions between brain regions, possibly influenced by a common causal antecedent. The ENIGMA-PGC PTSD Working Group aggregated PTSD and control subjects’ data from 29 cohorts in five countries (n=3439).MethodsUsing Destrieux Atlas, we built SCNs and compared centrality measures between PTSD subjects and controls. Centrality is a graph theory measure derived using SCN.ResultsNotable nodes with higher CT-based centrality in PTSD compared to controls were left fusiform gyrus, left superior temporal gyrus, and right inferior temporal gyrus. We found sex-based centrality differences in bilateral frontal lobe regions, left anterior cingulate, left superior occipital cortex and right ventromedial prefrontal cortex (vmPFC). Comorbid PTSD and MDD showed higher CT-based centrality in the right anterior cingulate gyrus, right parahippocampal gyrus and lower SA-based centrality in left insular gyrus.ConclusionUnlike previous studies with smaller sample sizes (≤318), our study found differences in centrality measures using a sample size of 3439 subjects. This is the first cross-sectional study to examine SCN interactions with age, sex, and comorbid MDD. Although limited to group level inferences, centrality measures offer insights into a node’s relationship to the entire functional connectome unlike approaches like seed-based connectivity or independent component analysis. Nodes having higher centrality have greater structural or functional connections, lending them invaluable for translational treatments like neuromodulation.

Importance: Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them.Objective: To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information.Data Sources: We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019.Study Selection: Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization.Data Extraction and Synthesis: We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression.Main Outcomes and Measures: Patient Health Questionnaire-9 (PHQ-9) scores.Results: Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-0 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, -0.8; 95% CI, -1.4 to -0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9.Conclusions and Relevance: In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.

Background Reward processing deficits have been increasingly associated with trauma exposure and are a core feature of posttraumatic stress disorder (PTSD). While altered resting-state functional connectivity (rsFC) of ventral striatal regions, including the nucleus accumbens (NAcc), has been associated with anhedonia in some stress-related disorders, relationships between NAcc rsFC and anhedonia have not previously been investigated in trauma-exposed individuals. Additionally, relationships between anhedonia and reward-related decision making remain unexplored in relation to trauma exposure. We hypothesized that elevated anhedonia would be associated with altered rsFC between NAcc and default mode network regions and with increased delay discounting. Methods The sample included 51 participants exposed to a DSM-IV PTSD Criterion A event related to community trauma. Participants completed the Clinician Administered PTSD Scale, the Snaith-Hamilton Pleasure Scale, the Beck Depression Inventory, a computerized delay discounting paradigm, and resting-state functional magnetic resonance imaging. rsFC data were analyzed in SPM12 and CONN. Results Higher levels of anhedonia were associated with increased rsFC between seed regions of bilateral NAcc and areas of right dorsomedial prefrontal cortex. This relationship remained significant after accounting for Clinician Administered PTSD Scale total scores, Beck Depression Inventory total scores, or diagnostic group in the regression. Additionally, anhedonia was associated with elevated (increased) delay discounting. Conclusions Greater anhedonia was related to higher positive connectivity between NAcc and right dorsomedial prefrontal cortex and to increased delay discounting, i.e., greater preference for smaller immediate versus larger delayed rewards. These findings contribute to a growing body of literature emphasizing the importance of anhedonia in trauma-exposed individuals.

Background Rostral and subgenual anterior cingulate cortex (rACC and sgACC) activity and, to a lesser extent, volume have been shown to predict depressive symptom improvement across different antidepressant treatments. This study extends prior work by examining whether rACC and/or sgACC morphology predicts treatment response to Internet-based cognitive behavioral therapy (iCBT) for major depressive disorder. This is the first study to examine neural predictors of response to iCBT. Methods Hierarchical linear modeling tested whether pretreatment rACC and sgACC volumes predicted depressive symptom improvement during a six-session (10-week) randomized clinical trial of iCBT ( n = 35) versus a monitored attention control condition ( n = 38). Analyses also tested whether pretreatment rACC and sgACC volumes differed between patients who achieved depression remission versus patients who did not remit. Results Larger pretreatment right rACC volume was a significant predictor of greater depressive symptom improvement in iCBT even when controlling for demographic (age, gender, race) and clinical (baseline depression, anhedonia, and anxiety) variables previously linked to treatment response. In addition, pretreatment right rACC volume was larger among patients receiving iCBT whose depression eventually remitted relative to patients who did not remit. Corresponding analyses in the monitored attention control group and for the sgACC were not significant. Conclusions rACC volume before iCBT demonstrated incremental predictive validity beyond clinical and demographic variables previously found to predict symptom improvement. Such findings may help inform our understanding of the mediating anatomy of iCBT and, if replicated, may suggest neural targets to augment treatment response (e.g., via modulation of rACC function).

The World Health Organization (WHO) estimates that during a given 12-month period approximately 34 million people suffering from major depressive disorder go untreated in Europe and the Americas alone.1 Barriers to treatment include geographic distance, lack of mental health insurance, prohibitive cost of treatment, long wait-lists, and perceived stigma. Over the past two decades internet-based cognitive behavioral therapy (iCBT) programs have proliferated. A growing body of research supports the efficacy of iCBT for depression and other psychiatric conditions, and these programs may help address barriers that hinder access to effective treatment. The present review describes common iCBT programs along with the evidence base supporting their efficacy in reducing symptoms of depression, reviews research on moderators of treatment response, and provides suggestions for future directions in research and care.

BACKGROUND Most studies of brain white matter (WM) in posttraumatic stress disorder (PTSD) have focused on combat trauma, and often were confounded by neurological and substance dependence comorbidity. This study used tract-based spatial statistics (TBSS) and probabilistic tractography to characterize WM microstructure in a mixed-sex community sample of PTSD patients exposed to diverse and multiple traumas, and in trauma-exposed normal comparison (TENC) subjects. METHODS TBSS compared diffusion measures between 20 adults with DSM-IV PTSD and 17 TENC, using a whole-brain voxel-wise approach. Probabilistic tractography using Freesurfer's TRACULA was employed to measure diffusion tensor imaging (DTI) metrics within anatomically defined pathways. DTI metrics were compared between groups and correlated with PTSD symptom severity and trauma load. RESULTS Controlling for age, sex, and motion, PTSD subjects had significantly reduced fractional anisotropy (FA) in a left frontal lobe cluster compared with TENC, at p < .05, family-wise error corrected. Tractography identified significant group differences in the inferior longitudinal fasciculus (ILF), including lower FA and higher radial diffusivity in PTSD compared with TENC. Within the PTSD group, FA values were not correlated with symptom severity or trauma load. Results remained significant after removing participants using psychotropic medication or those with comorbid major depression. CONCLUSIONS PTSD patients had reduced WM integrity in left hemisphere frontal WM and temporal-occipital WM tracts, compared to trauma-exposed controls. Reduced frontal FA is consistent with compromised top-down attentional control and emotion regulation in PTSD, while reduced ILF FA may be related to sensory processing and gating abnormalities in this disorder.

Hippocampus atrophy is implicated in posttraumatic stress disorder (PTSD), and may partly reflect stress-induced glutamate excitotoxicity that culminates in neuron injury and manifests as re-experiencing symptoms and other memory abnormalities. This study used high-field proton magnetic resonance spectroscopy (MRS) to determine whether PTSD is associated with lower hippocampus levels of the neuron marker N-acetyl aspartate (NAA), along with higher levels of glutamate (Glu) and Glu/NAA. We also predicted that metabolite levels would correlate with re-experiencing symptoms and lifetime trauma load. Twenty-four adult PTSD patients and 23 trauma-exposed normal controls (TENC) underwent 4T MRS of the left and right hippocampus. Participants received psychiatric interviews, and completed the Traumatic Life Events Questionnaire to define lifetime trauma load. Relative to TENC participants, PTSD patients exhibited significantly lower NAA in right and left hippocampi, and significantly higher Glu and Glu/NAA in the right hippocampus. Re-experiencing symptoms were negatively correlated with left and right NAA, and positively correlated with right Glu and right Glu/NAA. Trauma load was positively correlated with right Glu/NAA in PTSD patients. When re-experiencing symptoms and trauma load were examined together in relation to right Glu/NAA, only re-experiencing symptoms remained a significant correlate. This represents the first report that PTSD is associated with MRS markers of hippocampus Glu excess, together with indices of compromised neuron integrity. Their robust associations with re-experiencing symptoms affirm that MRS indices of hippocampus neuron integrity and glutamate metabolism may reflect biomarkers of clinically significant disease variation in PTSD.

Background Childhood maltreatment may contribute to brain alterations in posttraumatic stress disorder (PTSD). We previously found that PTSD was associated with white matter compromise, or lower fractional anisotropy (FA), in the left inferior longitudinal fasciculus (ILF). In this study, including non‐PTSD controls, we examined whether ILF FA was associated with maltreatment exposures, including those that meet DSM‐IV criterion A (physical abuse, sexual abuse) and those that typically do not (emotional abuse, emotional neglect, physical neglect). We hypothesized that lower FA would be associated with PTSD diagnosis and with both categories of maltreatment. Methods Ninety‐three participants (51 female), ages 20–50, were enrolled, including 32 with lifetime DSM‐IV PTSD, 27 trauma‐exposed non‐PTSD controls, and 34 healthy controls. Participants completed structured interviews, the Childhood Trauma Questionnaire (CTQ), and diffusion‐weighted imaging (36 directions). Probabilistic tractography (using FreeSurfer's TRACULA) was used to assess diffusion metrics in the ILF. Results Contrary to our hypothesis, there was no significant effect of diagnostic group on FA. In contrast, higher CTQ scores were significantly associated with lower FA in the ILF bilaterally. This association of maltreatment with lower FA remained statistically significant after controlling for diagnostic group, and it was significant for both criterion‐A‐type and noncriterion‐A‐type maltreatment categories. Conclusions This work contributes to a growing body of literature indicating that different forms of childhood maltreatment are associated with altered white matter microstructure in the ILF, an association pathway involved in integrating visual information from occipital regions with emotion processing functions of the anterior temporal lobe., Childhood maltreatment, but not posttraumatic stress disorder (PTSD) diagnostic status, is associated with altered diffusion in occipito‐temporal white matter pathways including lower fractional anisotropy in the inferior longitudinal fasciculus. This work contributes to a growing body of literature indicating that different forms of childhood maltreatment are associated with altered white matter microstructure in the ILF, an association pathway involved in integrating visual information from occipital regions with emotion processing functions of the anterior temporal lobe.

Social anhedonia has been proposed to contribute to social isolation in several psychiatric disorders, but it has not been examined in relation to deficits in social connection that also characterize posttraumatic stress disorder (PTSD). A growing body of evidence emphasizes the health importance of structural features of social networks, including their size and complexity. The current study examined the association between social anhedonia and social network features in a sample of trauma-exposed participants with and without PTSD as well as in non-trauma-exposed controls. Participants (N = 101; n = 37 healthy controls, n = 23 trauma-exposed without PTSD; n = 41 lifetime PTSD) completed self-report measures of social anhedonia (Revised Social Anhedonia Scale) and structural social network features, including social network size, diversity, and the number of embedded networks (Social Network Index). Relative to healthy controls, participants with PTSD reported significantly lower social network sizes and fewer embedded networks. In the combined trauma-exposed sample, higher ratings of social anhedonia were associated with lower social network diversity, r(62) = -.43, p < .001, an effect that remained statistically significant after controlling for PTSD and depression symptom severity. These results suggest that elevated social anhedonia in trauma-exposed individuals may contribute to disruptions in social network structure consistent with social isolation.

Background Prior research has shown that the Sadness Program, a technician-assisted Internet-based cognitive behavioral therapy (iCBT) intervention developed in Australia, is effective for treating major depressive disorder (MDD). The current study aimed to expand this work by adapting the protocol for an American population and testing the Sadness Program with an attention control group. Methods In this parallel-group, randomized controlled trial, adult MDD participants (18–45 years) were randomized to a 10-week period of iCBT (n = 37) or monitored attention control (MAC; n = 40). Participants in the iCBT group completed six online therapy lessons, which included access to content summaries and homework assignments. During the 10-week trial, iCBT and MAC participants logged into the web-based system six times to complete self-report symptom scales, and a nonclinician technician contacted participants weekly to provide encouragement and support. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), and the secondary outcomes were the Patient Health Questionnaire-9 and Kessler-10. Results Intent-to-treat analyses revealed significantly greater reductions in depressive symptoms in iCBT compared with MAC participants, using both the self-report measures and the clinician-rated HRSD (d = −0.80). Importantly, iCBT participants also showed significantly higher rates of clinical response and remission. Exploratory analyses did not support illness severity as a moderator of treatment outcome. Conclusions The Sadness Program led to significant reductions in depression and distress symptoms. With its potential to be delivered in a scalable, cost-efficient manner, iCBT is a promising strategy to enhance access to effective care.

article i nfo Background: Structural alterations of the lateral temporal cortex (LTC) in association with memory impairments have been reported in schizophrenia. This study investigated whether alterations of LTC structure were linked with impaired facial and/or verbal memory in young first-degree relatives of people with schizophrenia and, thus, may be indicators of vulnerability to the illness. Methods: Subjects included 27 non-psychotic, first-degree relatives of schizophrenia patients, and 48 healthy controls, between the ages of 13 and 28. Participants underwent high-resolution magnetic resonance imaging (MRI) at 1.5 Tesla. The LTC was parcellated into superior temporal gyrus, middle temporal gyrus, inferior tempo- ral gyrus, and temporal pole. Total cerebral and LTC volumes were measured using semi-automated morphom- etry. The Wechsler Memory Scale — Third Edition and the Children's Memory Scale — Third Edition assessed facial and verbal memory. General linear models tested for associations among LTC subregion volumes, familial risk and memory. Results: Compared with controls, relatives had significantly smaller bilateral middle temporal gyri. Moreover, right middle temporal gyral volume showed a significant positive association with delayed facial memory in rel- atives. Conclusion: These results support the hypothesis that smaller middle temporal gyri are related to the genetic li- ability to schizophrenia and may be linked with reduced facial memory in persons at genetic risk for the illness. The findings add to the growing evidence that children at risk for schizophrenia on the basis of positive family history have cortical and subcortical structural brain abnormalities well before psychotic illness occurs.

Neuroimaging studies of individuals with family histories of alcoholism provide evidence suggesting neurobiological risk factors for alcoholism. Youth family history positive (FH+) for alcoholism exhibit increased impulsivity compared to family history negative (FH−) peers in conjunction with altered functional activation in prefrontal cortex, including anterior cingulate cortex (ACC). This study examined glutamate (Glu) and glutamine (Gln), amino acids vital to protein synthesis, cellular metabolism and neurotransmission, acquired from ACC and parieto-occipital cortex (POC) using magnetic resonance spectroscopy (MRS) at 4T. Participants were 28 adolescents (13 male, 12–14 yrs) and 31 emerging adults (16 male, 18–25 yrs), stratified into FH− and FH+ groups. Significantly higher ACC Gln/Glu was observed in emerging adults versus adolescents in FH− but not FH+ groups. In FH− adolescents, higher impulsivity was significantly associated with higher ACC Gln/Glu. In FH+ emerging adults, higher impulsivity was negatively associated with ACC Gln/Glu. No differences or associations were observed for POC. These findings provide preliminary evidence that family history of alcoholism is associated with a neurochemical profile that may influence normative age differences in glutamatergic metabolites and their association with impulse control, which together could confer greater genetic risk of addiction later in life.

Human functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) studies, as well as animal studies, indicate that the amygdala and frontomedial brain regions are critically involved in conditioned fear and that frontomedial oscillations in the theta range (4–8 Hz) may support communication between these brain regions. However, few studies have used a multimodal approach to probe interactions among these key regions in humans. Here, our goal was to bridge the gap between prior human fMRI, EEG, and animal findings. Using simultaneous EEG–fMRI recordings 24 h after fear conditioning and extinction, conditioned stimuli presented (CS+E, CS−E) and not presented during extinction (CS+N, CS−N) were compared to identify effects specific to extinction versus fear recall. Differential (CS+ vs. CS−) electrodermal, frontomedial theta (EEG) and amygdala responses (fMRI) were reduced for extinguished versus nonextinguished stimuli. Importantly, effects on theta power covaried with effects on amygdala activation. Fear and extinction recall as indicated by theta explained 60% of the variance for the analogous effect in the right amygdala. Our findings show for the first time the interplay of amygdala and frontomedial theta activity during fear and extinction recall in humans and provide insight into neural circuits consistently linked with top-down amygdala modulation in rodents.

There is currently a critical need to establish an improved understanding of time-dependent differences in brain structure following mild traumatic brain injury (mTBI). We compared differences in brain structure, specifically cortical thickness (CT), cortical volume (CV), and cortical surface area (CSA) in 54 individuals who sustained a recent mTBI and 33 healthy controls (HCs). Individuals with mTBI were split into three groups, depending on their time since injury. By comparing structural measures between mTBI and HC groups, differences in CT reflected cortical thickening within several areas following 0-3 (time-point, TP1) and 3-6 months (TP2) post-mTBI. Compared with the HC group, the mTBI group at TP2 showed lower CSA within several areas. Compared with the mTBI group at TP2, the mTBI group during the most chronic stage (TP3: 6-18 months post-mTBI) showed significantly higher CSA in several areas. All the above reported differences in CT and CSA were significant at a cluster-forming p < .01 (corrected for multiple comparisons). We also found that in the mTBI group at TP2, CT within two clusters (i.e., the left rostral middle frontal gyrus (L. RMFG) and the right postcentral gyrus (R. PostCG)) was negatively correlated with basic attention abilities (L. RMFG: r = -.41, p = .05 and R. PostCG: r = -.44, p = .03). Our findings suggest that alterations in CT and associated neuropsychological assessments may be more prominent during the early stages of mTBI. However, alterations in CSA may reflect compensatory structural recovery during the chronic stages of mTBI.

Highlights • Human connectome project examining adolescent anxiety and depression. • N = 225 planned, clinical and control adolescents, ages 14–17. • Description of clinical and functional imaging measures from first 140 participants. • Data publicly available via national institute of health data archive., We present a Human Connectome Project study tailored toward adolescent anxiety and depression. This study is one of the first studies of the Connectomes Related to Human Diseases initiative and is collecting structural, functional, and diffusion-weighted brain imaging data from up to 225 adolescents (ages 14–17 years), 150 of whom are expected to have a current diagnosis of an anxiety and/or depressive disorder. Comprehensive clinical and neuropsychological evaluations and longitudinal clinical data are also being collected. This article provides an overview of task functional magnetic resonance imaging (fMRI) protocols and preliminary findings (N = 140), as well as clinical and neuropsychological characterization of adolescents. Data collection is ongoing for an additional 85 adolescents, most of whom are expected to have a diagnosis of an anxiety and/or depressive disorder. Data from the first 140 adolescents are projected for public release through the National Institutes of Health Data Archive (NDA) with the timing of this manuscript. All other data will be made publicly-available through the NDA at regularly scheduled intervals. This article is intended to serve as an introduction to this project as well as a reference for those seeking to clinical, neurocognitive, and task fMRI data from this public resource.

Highlights • Human Connectome Project examining adolescent anxiety and depression. • N = 225 planned, clinical and control adolescents, ages 14–17. • Description of acquisition protocols and quality assurance measurements. • Harmonized protocols with HCP projects related to anxiety and/or depression. • Data publicly available via National Institute of Mental Health Data Archive., The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14–17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and differences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA)., Graphical abstract Image, graphical abstract

Background Clues to the etiology and pathophysiology of schizophrenia can be examined in their first-degree relatives because they are genetically related to an ill family member, and have few confounds like medications. Brain abnormalities observed in young relatives are neurobiological indicators of vulnerability to illness. We examined the hypothesis that the hippocampus and parahippocampus are structurally abnormal and are related to default mode network (DMN) function and cognitive abnormalities in relatives of probands. Methods Subjects were 27 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 48 normal controls, ages 13 to 28, undergoing high-resolution magnetic resonance imaging (MRI) at 1.5 T. After structural scan acquisition a subset of subjects performed 2-back working memory (WM) and 0-back tasks during functional MRI (fMRI) alternating with rest. fMRI data were analyzed using SPM-8. Volumes of total cerebrum, hippocampus, and parahippocampal gyrus were measured using semi-automated morphometry. Results Compared to controls, relatives had significantly smaller left hippocampi, without volumetric reduction in the parahippocampus. Relatives showed significantly less suppression of DMN activity in the left parahippocampal gyrus. Left hippocampal and posterior parahippocampal volumes were inversely and significantly associated with DMN processing (smaller volumes, less suppression) in relatives. Task suppression in parahippocampal gyrus significantly correlated with WM performance within the relatives. Conclusion Results support the hypothesis that the vulnerability to schizophrenia includes smaller hippocampi and DMN suppression deficits, and these are associated with poorer WM. Findings suggest a primary structural, neurodevelopmental, medial temporal lobe abnormality associated with altered DMN function independent of psychosis.

Emotional suppression (ES) is a critical component of the ability to self-regulate emotion. However, people who chronically use ES as a primary strategy often experience heightened anxiety or depression. Although functional neuroimaging studies have extensively mapped the brain regions involving in emotional regulation, the neural substrates of ES as a trait construct remain relatively unexplored. Using a validated backward masked facial affect paradigm, we examined the association between ES and functional brain responses to masked angry, fearful, and happy faces. Healthy adults underwent functional MRI and completed the Courtauld Emotional Control Scale as a measure of ES. Correlations between self-reported ES and brain responses to the facial affect stimuli (affective>neutral) were evaluated within the brain regions involved in emotional processing, including the amygdala, insula, anterior cingulate cortex, medial prefrontal cortex, and orbitofrontal cortex. In response to angry faces, higher trait tendency to suppress anger and anxiety was significantly correlated with increased activation within the rostral anterior cingulate cortex, whereas no correlation was observed for masked happy or fearful faces. This finding suggests that the rostral anterior cingulate cortex contributes to the unconscious suppression of emotional responses to angry facial affect and may play a role in the mediating anatomy of trait ES.

As a step toward addressing limitations in the current psychiatric diagnostic system, the National Institute of Mental Health recently developed the Research Domain Criteria (RDoC) to stimulate integrative research—spanning self-report, behavior, neural circuitry, and molecular/genetic mechanisms—on core psychological processes implicated in mental illness. Here, we use the RDoC conceptualization to review research on threat responses, reward processing, and their interaction. The first section of the manuscript highlights the pivotal role of exaggerated threat responses—mediated by circuits connecting the frontal cortex, amygdala, and midbrain—in anxiety, and reviews data indicating that genotypic variation in the serotonin system is associated with hyperactivity in this circuitry, which elevates the risk for anxiety and mood disorders. In the second section, we describe mounting evidence linking anhedonic behavior to deficits in psychological functions that rely heavily on dopamine signaling, especially cost/benefit decision making and reward learning. The third section covers recent studies that document negative effects of acute threats and chronic stress on reward responses in humans. The mechanisms underlying such effects are unclear, but the fourth section reviews new optogenetic data in rodents indicating that GABAergic inhibition of midbrain dopamine neurons, driven by activation of the habenula, may play a fundamental role in stress-induced anhedonia. In addition to its basic scientific value, a better understanding of interactions between the neural systems that mediate threat and reward responses may offer relief from the burdensome condition of anxious depression. Depression and Anxiety 31:233– 249, 2014. C � 2013 Wiley Periodicals, Inc.

Background The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels. Methods Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents ( n =30) and emerging adults ( n = 20). Results ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males. Conclusions These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety.

Background: Exaggerated amygdala and reduced ventromedial prefrontal cortex (vmPFC) responsiveness during emotional processing have been reported in studies examining individual anxiety disorders. Studies are needed, however, which directly compare activation of amygdalo-cortical circuitry across multiple anxiety disorders within the same study. Here we compared cortico-limbic neurocircuitry across three different anxiety disorders using a well-validated emotional probe task. Methods: Sixty-five adult volunteers, including 22 healthy controls (HC) and participants meeting DSM-IV criteria for either posttraumatic stress disorder (14 PTSD), panic disorder (14 PD), or specific animal phobia (15 SP), underwent functional magnetic resonance imaging (fMRI) at 3 T while passively viewing backward-masked images of faces expressing fear, happy, and neutral emotions. Results: A group comprising all three anxiety disorders showed greater activation within the left amygdala and reduced activation within the vmPFC compared to the HC group during the masked fear versus neutral condition. Pairwise group comparisons showed that amygdala activation only reached significance for the PTSD versus HCs, whereas decreased vmPFC was only evident for SP and PD groups versus the HC group. Furthermore, activation did not differ among the anxiety groups when contrasted directly with one another. A similar pattern was observed for masked happy versus neutral faces. Conclusions: Exclusive of specific diagnostic category, anxiety disorders were generally associated with increased activation of the amygdala and reduced activation within vmPFC. Categorical distinctions were generally weak or not observed and suggest that functional differences may reflect the magnitude of responses within a

Background Increased reactivity of the insular cortex and decreased activity of the dorsal anterior cingulate (ACC) are seen in functional imaging studies of post-traumatic stress disorder (PTSD), and may partly explain the persistent fear- and anxiety-proneness that characterize the disorder. A possible neurochemical correlate is altered function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). We report results from what we believe is the first study applying proton magnetic resonance spectroscopy (1H-MRS) to measure brain GABA in PTSD.

Posttraumatic stress disorder (PTSD) is associated with functional abnormalities within a neurocircuitry that includes the hippocampus, amygdala, and medial prefrontal cortex. Evidence of structural abnormalities within these regions, and their association with PTSD severity and symptom burden is, however, sparse. The present study evaluated the relation between indices of gray matter volume and PTSD symptom severity using voxel-based morphometry. Fifteen individuals meeting DSM-IV criteria for PTSD completed the Clinician Administered PTSD Scale and underwent structural magnetic resonance imaging. Greater PTSD severity and avoidance/numbing were correlated with increased gray matter volume of the right amygdala-hippocampal complex. Greater hyper-arousal was associated with reduced gray matter volume in the left superior medial frontal gyrus. Findings are consistent with current neurocircuitry models of PTSD, which posit that the disorder is associated with structural and functional variance within this distributed network.

Chronic marijuana (MRJ) use is associated with altered cognition and mood state, altered brain metabolites, and functional and structural brain changes. The objective of this study was to apply proton magnetic resonance spectroscopic imaging (MRSI) to compare proton metabolite levels in 15 young men with MRJ dependence and 11 healthy non-using (NU) young men. Spectra were acquired at 4.0 Tesla using 2D J-resolved MRSI to resolve coupled resonances in J-space and to quantify the entire J-coupled spectral surface of metabolites from voxels containing basal ganglia and thalamus, temporal and parietal lobes, and occipital white and gray matter. This method permitted investigation of high-quality spectra for regression analyses to examine metabolites relative to tissue type. Distribution of myo-inositol (mI)/creatine (Cr) was altered in the MRJ group whereas the NU group exhibited higher mI/Cr in WM than GM, this pattern was not observed in MRJ subjects. Significant relationships observed between global mI/Cr and distribution in WM, and self-reported impulsivity and mood symptoms were also unique between MRJ and NU groups. These preliminary findings suggest that mI, and distribution of this glial metabolite in WM, is altered by MRJ use and is associated with behavioral and affective features reported by young MRJ-dependent men.

Background: Regional prefrontal cortex gray matter reductions have been identified in schizophrenia, likely reflecting a combination of genetic vulnerability and disease effects. Few morphometric studies to date have examined regional prefrontal abnormalities in non-psychotic biological relatives who have not passed through the age range of peak risk for onset of psychosis. We conducted a region-of-interest morphometric study of prefrontal subregions in adolescent and young adult relatives of schizophrenia patients. Methods: Twenty-seven familial high-risk (FHR) first-degree relatives of schizophrenia patients and forty-eight control subjects without a family history of psychosis (ages 13–28) underwent high-resolution magnetic resonance imaging at 1.5 Tesla. The prefrontal cortex was parcellated into polar, dorsolateral, ventrolateral, ventromedial and orbital subregions. The Chapman scales measured subpsychotic symptoms. General linear models examined associations of prefrontal subregion volumes with familial risk and subpsychotic symptoms. Results: FHR subjects had significantly reduced bilateral ventromedial prefrontal and frontal pole gray matter volumes compared with controls. Ventromedial volume was significantly negatively correlated with magical ideation and anhedonia scores in FHR subjects. Conclusions: Selective, regional prefrontal gray matter reductions may differentially mark genetic vulnerability and early symptom processes among non-psychotic young adults at familial risk for schizophrenia.

Objective Deficits in cognitive flexibility and response inhibition have been linked to perturbations in cortico-striatal-thalamic circuitry in adult obsessive-compulsive disorder (OCD). Although similar cognitive deficits have been identified in pediatric OCD, few neuroimaging studies have been conducted to examine its neural correlates in the developing brain. In this study, we tested hypotheses regarding group differences in the behavioral and neural correlates of cognitive flexibility in a pediatric OCD and a healthy comparison (HC) sample. Method In this functional magnetic resonance imaging (fMRI) study, a pediatric sample of 10- to 17-year-old subjects, 15 with OCD and 20 HC, completed a set-shifting task. The task, requiring an extradimensional shift to identify a target, examines cognitive flexibility. Within each block, the dimension (color or shape) that identified the target either alternated (i.e., mixed) or remained unchanged (i.e., repeated). Results Compared with the HC group, the OCD group tended to be slower to respond to trials within mixed blocks. Compared with the HC group, the OCD group exhibited less left inferior frontal gyrus/BA47 activation in the set-shifting contrast (i.e., HC > OCD, mixed versus repeated); only the HC group exhibited significant activation in this region. The correlation between set shifting-induced right caudate activation and shift cost (i.e., reaction time differential in response to mixed versus repeated trials) was significantly different between HC and OCD groups, in that we found a positive correlation in HC and a negative correlation in OCD. Conclusions In pediatric OCD, less fronto-striatal activation may explain previously identified deficits in shifting cognitive sets.

To clarify the relationship between amygdala-hippocampal volume and cognitive performance in schizophrenia and bipolar disorder.Abnormalities of the amygdala-hippocampal complex and memory deficits have been reported in both schizophrenia and bipolar illness.We examined memory performance and its relationship to the volumes of the whole brain, lateral ventricles, hippocampus, and amygdala using morphometric magnetic resonance imaging in 19 patients with schizophrenia, 11 bipolar patients, and 20 healthy controls.Schizophrenia patients performed more poorly than bipolar patients and controls on indices of memory functioning, whereas patients with bipolar disorder showed milder impairments relative to controls. The schizophrenia group showed reduced total cerebral volume and enlarged ventricles relative to controls, but no group differences were found for amygdala or hippocampal volume. Left amygdala volume was predictive of memory performance in both groups, correlating positively with better immediate and delayed verbal memory for bipolar patients and negatively with immediate and delayed verbal recall for schizophrenia patients. Amygdala volume was unrelated to memory performance in healthy subjects.Schizophrenia and bipolar disorder both seem to be associated with anomalous and differential limbic volume-function relationships, such that the amygdala may facilitate hippocampal-dependent memory processes in bipolar disorder but impair these same processes in schizophrenia.

Although a number of investigations have reported cognitive deficits in patients with bipolar disorder, relatively few have focused on the relationship between these impairments and clinical outcome.In order to help clarify the pattern of and extent to which cognitive deficits are present at the onset of illness and their relationship to outcome, we examined 26 bipolar patients during their first hospitalization and 20 psychiatrically healthy control subjects. All subjects completed tests of frontal/executive control, psychomotor speed and memory function at baseline and self-reports of clinical recovery (time to recover in days) at 12 months post study enrollment.At baseline, first episode bipolar patients demonstrated greater deficits relative to control subjects on neurocognitive measures, and a significant association was detected between time to recover and performance on a measure of frontal/executive function (interference condition of the Stroop; p=.05; derived interference: p=.04). A trend towards significance was also demonstrated between time to clinical recovery and verbal fluency (p=.06).These findings indicate that neuropsychological deficits are seen early in the course of bipolar disorder, prior to the effects of multiple or prolonged episodes, and may be associated with clinical outcome. Future studies are needed to determine whether changes in inhibitory processing or other cognitive function predict clinical outcome or are associated with treatment response.

Alexithymia, or "no words for feelings", is highly prevalent in samples with childhood maltreatment and posttraumatic stress disorder (PTSD). The dorsal anterior cingulate cortex (dACC) has been identified as a key region involved in alexithymia, early life trauma, and PTSD. Functional alterations in the dACC also have been associated with alexithymia in PTSD. This study examined whether dACC morphology is a neural correlate of alexithymia in child maltreatment-related PTSD. Sixteen adults with PTSD and a history of childhood sexual abuse, physical abuse, or exposure to domestic violence, and 24 healthy controls (HC) completed the Toronto Alexithymia Scale 20 (TAS-20) and underwent magnetic resonance imaging. Cortical thickness of the dACC was measured using FreeSurfer, and values were correlated with TAS-20 scores, controlling for sex and age, in both groups. Average TAS-20 score was significantly higher in the PTSD than the HC group. TAS-20 scores were significantly positively associated with dACC thickness only in the PTSD group. This association was strongest in the left hemisphere and for TAS-20 subscales that assess difficulty identifying and describing feelings. We found that increasing dACC gray matter thickness is a neural correlate of greater alexithymia in the context of PTSD with childhood maltreatment. While findings are correlational, they motivate further inquiry into the relationships between childhood adversity, emotional awareness and expression, and dACC morphologic development in trauma-related psychopathology.

It is well established that objective early life stressors increase risk for anxiety disorders and that environmental stressors interact with dispositional factors such as trait anxiety. There is less information on how subjective perception of stress during childhood relates to later clinical anxiety. This study tested whether childhood perceived stress and trait anxiety were independently and interactively associated with adult anxiety disorders. Forty-seven adults diagnosed with anxiety disorders ( M age = 34 yr., SD=11) and 29 healthy participants ( M = 33 yr., SD=13) completed the adult Perceived Stress Scale, the State-Trait Anxiety Inventory, and the Global Perceived Early Life Events Scale as a measure of perceived stress during childhood. In a logistic regression model, high childhood perceived stress (β = 0.64) and trait anxiety (β = 0.11) were associated with significantly greater odds of adult anxiety disorder. The association between childhood perceived stress and adult anxiety remained significant when controlling for adult perceived stress. These findings suggest that children's perception of stress in their daily lives may be an important target of intervention to prevent the progression of stress into clinically significant anxiety.

Background: The purpose of this study was to measure amygdala and hippocampus volumes in pediatric major depressive disorder (MDD) and to address the question of neuroanatomical continuity with adult-onset depression. Methods: We studied 20 children and adolescents with MDD (17 female subjects) and 24 healthy comparison subjects (16 female subjects) using 1.5 Tesla magnetic resonance imaging. Group differences in left and right amygdala and hippocampus volumes were examined using repeated measures analyses of covariance, adjusting for age, gender, and whole brain volume. Results: Depressed children had significant reductions of left and right amygdala volumes compared with healthy subjects. Hippocampus volumes did not differ between the groups. No significant correlations were found between amygdala volumes and depressive symptom severity, age at onset, or illness duration. Conclusions: Smaller amygdalas are present early in the course of pediatric depression and may predispose to the development of this disorder or perhaps more generally of childhood mood disorders. Future research should examine the longitudinal course and functional correlates of amygdala volume abnormalities in childhood-onset depression, including their possible moderation by gender.

Background Rostral and subgenual anterior cingulate cortex (rACC and sgACC) activity and, to a lesser extent, volume, have been shown to predict depressive symptom improvement across different antidepressant treatments. This study extends prior work by examining whether rACC and/or sgACC morphology predicts treatment response to internet-based cognitive behavioral therapy (iCBT) for major depressive disorder (MDD). This is the first study to examine neural predictors of response to iCBT.

Sleep deprivation (SD) can degrade cognitive functioning, but growing evidence suggests that there are large individual differences in the vulnerability to this effect. Some evidence suggests that baseline differences in the responsiveness of a fronto-parietal attention system that is activated during working memory (WM) tasks may be associated with the ability to sustain vigilance during sleep deprivation. However, the neurocircuitry underlying this network remains virtually unexplored. In this study, we employed diffusion tensor imaging (DTI) to investigate the association between the microstructure of the axonal pathway connecting the frontal and parietal regions--i.e., the superior longitudinal fasciculus (SLF)--and individual resistance to SD. Thirty healthy participants (15 males) aged 20-43 years underwent functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) at rested wakefulness prior to a 28-hour period of SD. Task-related fronto-parietal fMRI activation clusters during a Sternberg WM Task were localized and used as seed regions for probabilistic fiber tractography. DTI metrics, including fractional anisotropy, mean diffusivity, axial and radial diffusivity were measured in the SLF. The psychomotor vigilance test (PVT) was used to evaluate resistance to SD. We found that activation in the left inferior parietal lobule (IPL) and dorsolateral prefrontal cortex (DLPFC) positively correlated with resistance. Higher fractional anisotropy of the left SLF comprising the primary axons connecting IPL and DLPFC was also associated with better resistance. These findings suggest that individual differences in resistance to SD are associated with the functional responsiveness of a fronto-parietal attention system and the microstructural properties of the axonal interconnections.

Background: Obsessive-compulsive disorder (OCD) is a common and debilitating neuropsychiatric illness thought to involve abnormal connectivity of widespread brain networks, including frontal-striatal-thalamic circuits. At least half of OCD cases arise in childhood and their underlying neuropathology may differ at least in part from that of adult-onset OCD. Yet, only a few studies have examined brain white matter (WM) integrity in childhood-onset OCD using diffusion tensor imaging (DTI), and none have examined potential associations with age at onset. Results In this study, 17 youth with OCD and 19 healthy control subjects, ages 10 to 19 years, underwent DTI on a 3T Siemens scanner. DSM-IV diagnoses were established with standardized interviews, and OCD symptom severity was evaluated using the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Voxel-wise analyses were conducted on data processed with tract-based spatial statistics (TBSS) to derive measures of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). OCD patients had significantly lower FA in seven WM clusters, with over 80% of significant voxels in bilateral frontal cortex and corpus callosum (CC). There were no regions of significantly higher FA in patients compared with controls. Patients also had significantly higher RD in right frontal cortex and right body of the CC. Earlier age at onset of OCD correlated significantly with lower FA in the right thalamus and with higher RD in the right CC. FA and RD were not significantly associated with symptom severity. Conclusions These findings point to compromised WM integrity and reduced myelination in some brain regions of children with OCD, particularly the CC and fiber tracts that connect the frontal lobes to widespread cortical and subcortical targets. They also suggest that age at onset may be a moderator of some of the WM changes in pediatric OCD.

While schizophrenia is substantially heritable, the disorder's molecular genetic basis remains elusive. These efforts have been hindered by an inability to detect non-clinically-penetrant carriers of the predisposing genes and by uncertainties concerning the nature of the non-genetic influences and the extent of locus heterogeneity. The endophenotype approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly-inherited traits. Here we describe the application of this method to measures of brain structure and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). Our results suggest that there are likely to be multiple heritable dimensions of the central nervous system pathology in schizophrenia, each under the influence of a partially distinct set of genes, one of which involves disturbances in the structure and functioning of frontal lobe systems involved in working memory and another of which appears to render the brain more susceptible to damage to subcortical systems involved in long-term memory following oxygen deprivation in utero. Measures sensitive to quantitative variation in these dimensions of the central nervous system compromise should allow non-penetrant gene carriers to become informative for genetic linkage and facilitate detection of different genetic loci contributing to discrete aspects of disease liability.

Neuromotor dysfunction is a consistent finding in high-risk and archival studies of schizophrenia, but the sources of this dysfunction and its role in the developmental course of the disorder remain poorly understood. This study examined childhood motor predictors of adult psychiatric outcome in a birth cohort sample (72 patients with schizophrenia or schizoaffective disorder, 63 unaffected siblings, and 7,941 nonpsychiatric controls), evaluated prospectively with neurologic examinations at 8 months, 4 years, and 7 years of age. Deviance on motor coordination measures at 7 years was associated with both adult schizophrenia and unaffected sibling status, suggesting that a co-familial (and perhaps genetic) factor underlies motor coordination deficits in schizophrenia. Unusual movements at ages 4 and 7 predicted adult schizophrenia but not unaffected sibling status, indicating that these deficits may be specific to those who will develop the clinical phenotype. None of the motor precursors were confined to patients with an early age at first treatment contact. Fetal hypoxia predicted unusual movements at 4 but not 7 years among the preschizophrenia subjects, suggesting neurodevelopmental dependence of its functional effects. Neither prenatal complications nor birth weight were associated with motor dysfunction in preschizophrenia subjects or their unaffected siblings at any age. Finally, preschizophrenia children did not show the expected developmental decline in unusual movements, perhaps reflecting aberrant functional maturation of cortical-subcortical pathways.

BACKGROUND: Binge alcohol consumption is associated with multiple neurobiological consequences, including altered neurophysiology, brain structure, and functional activation. Magnetic resonance spectroscopy (MRS) studies have demonstrated neurochemical alterations in the frontal lobe of alcohol users, although most studies focused on older, alcohol-dependent subjects. METHODS: In this study, neurochemical data were acquired using MRS at 4.0 Tesla from emerging adults (18 to 24 years old) who were binge alcohol drinkers (BD, n = 23) or light drinkers (LD, n = 31). Since binge drinking is also associated with increased prevalence of experiencing an alcohol-induced blackout, BD were stratified into alcohol-induced blackout (BDBO) and non-blackout (BDN) groups. RESULTS: Overall, BD had significantly lower gamma amino-butyric acid (GABA) and N-acetyl-aspartate (NAA) in the anterior cingulate cortex (ACC) than LD. When stratified by blackout history, BDBO also had lower ACC glutamate (Glu) than LD. No group differences in MRS metabolites were observed in the parietal-occipital cortex. Lower ACC GABA and Glu remained significant after accounting for lower gray matter content in BD, however, NAA differences were no longer evident. In addition, low ACC GABA levels were associated with greater alcohol use consequences, and worse response inhibition and attention/mental flexibility in BD. CONCLUSIONS: These data indicate that binge drinking affects frontal lobe neurochemistry, more so in those who had experienced an alcohol-induced blackout. Characterization of the neurochemical profiles associated with binge alcohol consumption and blackout history may help identify unique risk factors for the later manifestation of alcohol abuse and dependence, in young individuals who are heavy, frequent drinkers, but who do not meet the criteria for alcohol abuse disorders. Language: en