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ObjectiveNeurobiological correlates of resilience to stress or trauma have not been investigated extensively. Studies on white matter connectivity in resilience, in particular, have been few and far between. This explorative study included 12,516 participants from the UK Biobank to investigate white matter connectivity in resilience in 13 selected regions of interest (ROIs).MethodsThe data for this cross-sectional cohort study were retrieved from UK Biobank, a large-scale biomedical database and research resource. The study included 40-69-year-old participants divided into three groups: a trauma-exposed, healthy (resilient) group, a trauma-exposed, mentally ill (vulnerable) group and a nonexposed, healthy (control) group. The primary outcome measures consisted of mean fractional anisotropy values in the following ROIs: cingulate gyrus, cingulum hippocampus, superior fronto-occipital fasciculus, uncinate fasciculus, corpus callosum body, genu, splenium, and tapetum. Group differences in fractional anisotropy were assessed using a one-way ANOVA.ResultsThis study did not find correlates of resilience in the investigated ROIs.ConclusionsThe results indicate that there is no association between resilience and white matter connectivity in the selected ROIs in this large population sample, which is in contrast with previous studies on morphometric and functional correlates of resilience. To corroborate this finding, the authors recommend collection of longitudinal data and utilization of voxelwise analysis, if possible, to improve sensitivity. The authors also suggest a whole-brain analysis in a similar study population to investigate other white matter tracts that might be implicated in resilience.

BackgroundCurrent clinical assessments of Posttraumatic stress disorder (PTSD) rely solely on subjective symptoms and experiences reported by the patient, rather than objective biomarkers of the illness. Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. Here we aimed to classify individuals with PTSD versus controls using heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.MethodsWe analyzed brain MRI data from 3,527 structural-MRI; 2,502 resting state-fMRI; and 1,953 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls (TEHC and HC) using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.ResultsWe found lower performance in classifying PTSD vs. controls with data from over 20 sites (60% test AUC for s-MRI, 59% for rs-fMRI and 56% for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history across all three modalities (75% AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance.ConclusionOur findings highlight the promise offered by machine learning methods for the diagnosis of patients with PTSD. The utility of brain biomarkers across three MRI modalities and the contribution of DVAE models for improving generalizability offers new insights into neural mechanisms involved in PTSD.Significance⍰Classifying PTSD from trauma-unexposed healthy controls (HC) using three imaging modalities performed well (∼75% AUC), but performance suffered markedly when classifying PTSD from trauma-exposed healthy controls (TEHC) using three imaging modalities (∼60% AUC).⍰Using deep learning for feature reduction (denoising variational auto-encoder; DVAE) dramatically reduced the number of features with no concomitant performance degradation.⍰Utilizing denoising variational autoencoder (DVAE) models improves generalizability across heterogeneous multi-site data compared with the traditional machine learning frameworks

Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

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.

Cross-sectional Diffusion Tensor Imaging (DTI) studies have reported alterations in white matter (WM) microstructure in adolescents with internalizing psychopathology. Yet, longitudinal studies investigating the course of WM microstructure are lacking. This study explored WM alterations and its relation to clinical symptoms over time in adolescents with internalizing disorders. DTI scans were acquired at baseline and after three months in 22 adolescents with clinical depression and comorbid anxiety (INT), and 21 healthy peers (HC) (age: 12-18). Tract-based spatial statistics was used for three voxelwise analyses: i) changes in WM microstructure between and within the INT and HC group; ii) associations between changes in symptom severity and changes in WM microstructure within youths with INT; and iii) associations between baseline WM parameters with changes in symptom severity within youths with INT. Data did not reveal changes in WM microstructure between or within groups over three months' time nor associations between changes in WM microstructure and changes in self-reported symptoms (analyses corrected for age, gender and puberty stage). Lower baseline levels of fractional anisotropy (FA) in the right posterior corona radiata (PCR) and right cingulum were associated with a higher decrease of depressive symptoms within the INT group. Post hoc analysis of additional WM parameters in the significant FA clusters showed that higher levels of baseline mean diffusivity and radial diffusivity in the PCR were associated with a lower decrease in depressive symptoms. Baseline WM microstructure characteristics were associated with a higher decrease in depressive symptoms over time. These findings increase our understanding of neurobiological mechanisms underlying the course of internalizing disorders in adolescents.

ObjectiveIdentifying brain differences associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and generating effective approaches to early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth.MethodsFirst, we examined associations among regional brain structure and STBs, which were assessed in six samples of youth with mood disorders, using the Columbia Suicide Severity Rating Scale (C-SSRS;N=577). Second, we combined this sample with a larger sample (total 21 sites) in which STBs were assessed using various instruments. MRI metrics were compared among healthy controls without STBs (HC;N=688), clinical controls without STBs (CC;N=648), and young people with psychiatric diagnoses and current suicidal ideation (N=406). In separate analyses, MRI metrics were compared among HCs (N=335), CCs (N=768), and suicide attempters (N=254).ResultsIn the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and history of actual suicide attempts (N=163) than those without (N=394; FDR-pd=.334). When expanding to more clinically heterogeneous samples, we also found lower surface area of the frontal pole in those with a history of suicide attempts (Cohen’sd=.22).ConclusionsLower frontal pole surface area may represent a vulnerability for a suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site- specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,343 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,067 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM were more sensitive to the detection of significant case-control differences in regional cortical thickness (X2(3) = 34.339, p < 0.001), and case-control differences in age-related cortical thinning (X2(3) = 15.128, p = 0.002). Specifically, ComBat-GAM led to larger effect size estimates of cortical thickness reductions (corrected p-values < 0.001), smaller age-appropriate declines (corrected p-values < 0.001), and lower female to male contrast (corrected p-values < 0.001) in cases compared to controls relative to other harmonization methods. Harmonization with ComBat-GAM also led to greater estimates of age-related declines in cortical thickness (corrected p-values < 0.001) in both cases and controls compared to other harmonization methods. Our results support the use of ComBat-GAM for harmonizing cortical thickness data aggregated from multiple sites and scanners to minimize confounds and increase statistical power.

Highlights • Microstructure of white matter tracts is altered in social anxiety disorder. • Endophenotypes could be used to investigate neurobiological vulnerability to SAD • Altered microstructure of the SLF is a promising candidate endophenotype for SAD. SAD, Background Social anxiety disorder (SAD) is a mental illness with a complex, partially genetic background. Differences in characteristics of white matter (WM) microstructure have been reported in patients with SAD compared to healthy controls. Also, WM characteristics are moderately to highly heritable. Endophenotypes are measurable characteristics on the road from genotype to phenotype, putatively reflective of genetically based disease mechanisms. In search of candidate endophenotypes of SAD we used a unique sample of SAD patients and their family members of two generations to explore microstructure of WM tracts as candidate endophenotypes. We focused on two endophenotype criteria: co-segregation with social anxiety within the families, and heritability. Methods Participants (n = 94 from 8 families genetically vulnerable for SAD) took part in the Leiden Family Lab Study on Social Anxiety Disorder (LFLSAD). We employed tract-based spatial statistics to examine structural WM characteristics, being fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD) and radial diffusivity (RD), in three a-priori defined tracts of interest: uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF). Associations with social anxiety symptoms and heritability were estimated. Results Increased FA in the left and right SLF co-segregated with symptoms of social anxiety. These findings were coupled with decreased RD and MD. All characteristics of WM microstructure were estimated to be at least moderately heritable. Conclusion These findings suggest that alterations in WM microstructure in the SLF could be candidate endophenotypes of SAD, as they co-segregated within families genetically vulnerable for SAD and are heritable. These findings further elucidate the genetic susceptibility to SAD and improve our understanding of the overall etiology.

SUMMARYBackgroundSuicidal behavior is highly heterogeneous and complex. A better understanding of its biological substrates and mechanisms could inform the design of more effective suicide prevention and intervention strategies. Neuroimaging studies of suicidality have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD working group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior.MethodsHere, we pool data from eighteen international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy controls and 6,448 people with depression, of whom 694 had attempted suicide). We compare regional cortical thickness and surface area, and measures of subcortical, lateral ventricular and intracranial volumes between suicide attempters, clinical controls (non-attempters with depression) and healthy controls.FindingsWe identified 25 regions of interest with statistically significant (FDRPost-hoc examinations identified neuroimaging markers associated with suicide attempt over and above the effects of depression, including smaller volumes of the left and right thalamus and the right pallidum, and lower surface area of the left inferior parietal lobe.InterpretationThis study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt, and further demonstrates the need for well-powered samples and collaborative efforts to avoid reaching biased or misleading conclusions. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidality may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk.

Previous neuroimaging studies on resilience have generally compared resilience and psychopathology after stress exposure, which does not allow for conclusions regarding correlates specific to resilience. The aim of the present study was to investigate resilience‐specific correlates in cortical thickness and/or cortical surface area and their correlations with psychometric measurements, using a three‐group design that included a non–trauma‐exposed control group in order to disentangle effects related to resilience from those related to psychopathology. Structural magnetic resonance imaging scans were acquired from 82 Dutch police officers. Participants were categorized into resilient (n = 31; trauma exposure, no psychopathology), vulnerable (n = 32; trauma exposure, psychopathology), and control groups (n = 19; no trauma exposure, no psychopathology). Specific regions of interest (ROIs) were identified based on previous studies that found the rostral and caudal anterior cingulate cortex (ACC) to be implicated in trauma‐related psychopathology. Cortical thickness and surface area of the ROIs—the rostral and caudal ACC—and of the whole brain were examined. No significant differences in cortical thickness or surface area were found between the resilient group and other groups in the ROI and whole‐brain analyses. Thus, the results of the present study provide no evidence of an association between resilience to traumatic stress and measures of thickness and surface area in cortical regions of the brain in a sample of Dutch police officers.

Exposure to childhood adverse events is associated with severe consequences for general health and structural and functional changes in the brain of its survivors. In order to unravel and in the end influence the pathway linking adversity and pathology, neuroimaging research is crucial. Up till now studies in minors are scarce and differ in type of adversity or methodology. Almost all studies report lower cortical thickness, but in a broad variety of regions. In this study we investigated cortical thickness measures and clinical data in a well circumscribed group of adolescents with PTSD related to childhood sexual abuse (CSA) (N = 21) and a healthy non-traumatised control group (N = 21). The ventromedial PFC (vmPFC), ACC, insula, and middle/superior temporal gyrus were chosen as ROI’s due to their respective roles in emotion and information processing. No significant effect of group was found for cortical thickness, surface area or volume in any of the ROIs. This is in line with the results of research in adult women with sexual abuse related PTSD, suggesting that this may be specific to this group, independent of age. Recent research points to differential biological and pathological consequences of different types of childhood adversity.

Context Signs and symptoms of Cushing’s syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications. Objective The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis. Data Sources A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included. Study Selection Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question. Data Extraction Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included. Data Synthesis Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age ( Conclusions Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.

Altres ajuts: The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT) and NIH grant R01 MH116147 (PMT). LS is supported by an NHMRC MRFF Career Development Fellowship (APP1140764). We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. M-JvT was supported by a VENI grant (NWO grant number 016.156.077). UCSF: This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) to TTY; the National Institute of Mental Health (R01MH085734 to TTY; K01MH117442 to TCH) and by the American Foundation for Suicide Prevention (PDF-1-064-13) to TCH. Stanford: This work was supported by NIMH Grants R01MH59259 and R37101495 to IHG. MS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). Marburg: This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; KI 588/ 14-1, KI 588/14-2 to TK; KR 3822/7-1, KR 3822/7-2 to AK; JA 1890/ 7-1, JA 1890/7-2 to AJ). IMH-MDD: This work was supported by the National Healthcare Group Research Grant (SIG/15012) awarded to KS. Barcelona: This study was funded by two grants of the Fondo de Investigación Sanitaria from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The author is funded through 'Miguel Servet' research contract (CP16-0020), co-financed by the European Regional Development Fund (ERDF) (2016-2019). QTIM: We thank the twins and singleton siblings who gave generously of their time to participate in the QTIM study. We also thank the many research assistants, radiographers, and IT support staff for data acquisition and DNA sample preparation. This study was funded by White matter disturbances in major depressive disorder: a coordinated analysis across 20 international. . . 1521 the National Institute of Child Health & Human Development (RO1 HD050735); National Institute of Biomedical Imaging and Bioengineering (Award 1U54EB020403-01, Subaward 56929223); National Health and Medical Research Council, Australia (Project Grants 496682, 1009064). NIH ENIGMA-BD2K U54 EB020403 (Thompson); R01 MH117601 (Jahanshad/Schmaal). Magdeburg: M.L. and M.W. are funded by SFB 779. Bipolar Family Study: This study has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award (104036/Z/14/Z). Minnesota Adolescent Depression Study: The study was funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women's Health Seed Grant, University of Minnesota. Dublin: This study was supported by Science Foundation Ireland through a Stokes Professorhip grant to TF. MPIP: The MPIP Sample comprises patients included in the Recurrent Unipolar Depression (RUD) Case-Control study at the clinic of the Max Planck Institute of Psychiatry, Munich, German. The RUD study was supported by GlaxoSmithKline. Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T-1-weighted MRI data were processedwith a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1.Results: The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Contains fulltext : 204838.pdf (Publisher’s version ) (Open Access) The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions.

Alongside various physical symptoms, patients with Cushing's disease and Cushing's syndrome display a wide variety of neuropsychiatric and cognitive symptoms, which are indicative of involvement of the central nervous system. The aim of this review is to provide an overview of the structural brain abnormalities that are associated with Cushing's disease and Cushing's syndrome and their relation to behavioral and cognitive symptomatology.In this review, we discuss the gray matter structural abnormalities found in patients with active Cushing's disease and Cushing's syndrome, the reversibility and persistence of these changes and the white matter structural changes related to Cushing's syndrome. Recent findings are of particular interest because they provide more detailed information on localization of the structural changes as well as possible insights into the underlying biological processes.Active Cushing's disease and Cushing's syndrome is related to volume reductions of the hippocampus and in a prefrontal region involving the anterior cingulate cortex (ACC) and medial frontal gyrus (MFG). Whilst there are indications that the reductions in hippocampal volume are partially reversible, the changes in the ACC and MFG appear to be more persistent. In contrast to the volumetric findings, changes in white matter connectivity are typically widespread involving multiple tracts.

Objective Neurobiological research has traditionally focused on vulnerability rather than on resilience to severe stress. So far, only a few neuroimaging studies examining resilience have used designs that allow disentangling of the neural correlates of resilience from those related to psychopathology or trauma-exposure. The aim of this study was to identify structural brain correlates of resilience, and their correlations with behavioral measures. Method MRI scanning was performed in three groups of police officers: (1) a resilient group (N = 29; trauma-exposed, no psychopathology), (2) a vulnerable group (N = 33; trauma-exposed, psychopathology), and (3) a control group (N = 19; no trauma, no psychopathology). Using whole brain and region-of-interest approaches, we examined gray matter volume and shapes, and white matter integrity using software tools from the FSL-library. Results We did not find patterns of gray matter volumes or shape specific for the resilient group. In resilient police officers, we found an increase in structural connectivity in the corticopontine tract. White matter integrity in this location correlated with a coping style of positive reappraisal. Conclusions Resilient police officers show a specific pattern of increased structural connectivity, which is associated to the use of higher order emotion regulation strategies. Given this finding in an area that has not been implicated in stress-related disorders before, as well as the null findings in areas repeatedly shown to be involved in stress-related disorders, the current study indicates that resilience is not simply the opposite of having psychiatric symptoms, but rather an independent construct.

Beneficial effects of attentional bias modification have been claimed for a number of anxiety disorders, but study results are variable. A recent trial in patients with posttraumatic stress disorder (PTSD) showed no therapeutic effects. The use of personally relevant and verbal stimuli might increase the efficacy of attentional bias modification. In an A-B case series design, we hypothesized that individualized attentional bias modification would lead to reduction of attentional bias and a decrease in PTSD symptoms. Six Dutch male war veterans (mean age 39.33 years) who had developed PTSD after peacekeeping missions underwent the treatment. No therapeutic effects were observed. Inter- and intraindividual attentional bias scores varied widely and did not respond to attentional bias modification as hypothesized. This study provides no evidence that individualized attentional bias modification is an effective treatment for PTSD.

ObjectivePatients with long-term remission of Cushing's disease (CD) have persistent psychological and cognitive impairments. It is unknown whether, and to what extent, these impairments are accompanied by structural abnormalities in the brain. We aim to investigate structural changes in the brain in patients with predominantly long-term remission of CD and to examine whether these changes are associated with psychological and cognitive dysfunction and clinical severity.DesignA cross-sectional, case–control study.MethodsIn 25 patients with predominantly long-term remission of CD and 25 matched healthy controls, grey matter volumes in the regions of interest (hippocampus, amygdala, and anterior cingulate cortex (ACC)) and in the whole brain were examined, using 3T magnetic resonance imaging and a voxel-based morphometry approach. Psychological and cognitive functioning were assessed using validated questionnaires and clinical severity was assessed using the Cushing's syndrome severity index.ResultsCompared with controls, patients had smaller grey matter volumes of areas in the ACC (on average 14%, PPP=0.005), more anxiety (P=0.003), more social phobia (P=0.034), more apathy (P=0.002), and more cognitive failure (P=0.023) compared with controls, but the differences in grey matter volumes were not associated with psychological or cognitive measures, nor with clinical severity.ConclusionPatients with predominantly long-term remission of CD showed specific structural brain abnormalities, in the presence of psychological dysfunction. Our data form a basis for future work aimed at elucidating the relation of the structural brain abnormalities and the sustained psychological deficits after long-term exposure to high cortisol levels.

Models of the neuroanatomy of panic disorder (PD) have relied on both animal work on fear and on clinical data from neuroimaging. Early work hypothesised a network of brain regions involved in fear processing (e.g. the amygdala), but more recent work has also pointed to the involvement of other cortical areas and other brain circuitry (e.g. the insula and anterior cingulate cortex). Studies investigating functional and structural brain connectivity in PD may ultimately shed light on the extent to which the neuroanatomy of PD is localised versus distributed, and on how current treatments alter this neuroanatomy.

Resilience is defined as a dynamic, multidimensional process encompassing positive adaptation within the context of significant adversity. The complex nature of this construct makes it a difficult topic to study in neuroimaging research; however, in this article, we propose ways to operationalize resilience. The limited amount of structural and functional neuroimaging studies specifically designed to examine resilience have mainly focused on investigating alterations in regions of the brain involved in emotion and stress regulation circuitry. In the future, neuroimaging of resilience is expected to benefit from functional and structural connectivity approaches and the use of novel imaging task paradigms. Copyright © 2013 John Wiley & Sons, Ltd.

The experience of childhood maltreatment is related to an increased risk of developing a variety of psychiatric disorders, as well as a change in the structure of the brain. However, not much is known about the neurobiological basis of resilience to childhood maltreatment. This study aims to identify resting-state functional connectivity (RSFC) patterns specific for resilience to childhood maltreatment, focusing on the default mode and salience network and networks seeded from the amygdala and left dorsomedial prefrontal cortex. Resting-state functional MRI scans were obtained in 33 individuals. Seeds in the bilateral amygdala, the dorsal anterior cingulate cortex (dACC), the posterior cingulate cortex and the left dorsomedial prefrontal cortex were defined and used to examine whether resilient individuals differed from vulnerable individuals and healthy controls in RSFC with other brain regions. Within the salience network, the resilient group was associated with increased RSFC between the left dACC and a region containing the bilateral lingual gyrus and the occipital fusiform gyrus compared to both the vulnerable group and the healthy controls. In this study, we found RSFC patterns specific for resilient individuals. Regions that are implicated are related on a functional level to declarative memory and the processing of emotional stimuli. (C) 2013 Elsevier Ltd. All rights reserved.

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

Glucocorticoid disturbance can be a cause of psychiatric symptoms. Cushing's disease represents a unique model for examining the effects of prolonged exposure to high levels of endogenous cortisol on the human brain as well as for examining the relation between these effects and psychiatric symptomatology. This study aimed to investigate resting-state functional connectivity (RSFC) of the limbic network, the default mode network (DMN), and the executive control network in patients with long-term remission of Cushing's disease. RSFC of these three networks of interest was compared between patients in remission of Cushing's disease (n=24; 4 male, mean age=44.96 years) and matched healthy controls (n=24; 4 male, mean age=46.5 years), using probabilistic independent component analysis to extract the networks and a dual regression method to compare both groups. Psychological and cognitive functioning was assessed with validated questionnaires and interviews. In comparison with controls, patients with remission of Cushing's disease showed an increased RSFC between the limbic network and the subgenual subregion of the anterior cingulate cortex (ACC) as well as an increased RSFC of the DMN in the left lateral occipital cortex. However, these findings were not associated with psychiatric symptoms in the patient group. Our data indicate that previous exposure to hypercortisolism is related to persisting changes in brain function.

Extensive evidence exists for an association between attentional bias (AB; attentional vigilance or avoidance) and anxiety. Recent studies in healthy participants suggest that attentional control (AC) may facilitate inhibition of automatic attentional processes associated with anxiety. To investigate relationships among AC, trauma-related AB, symptom severity and trait anxiety in patients with Posttraumatic Stress Disorder (PTSD), participants (N = 91) completed self-report measures of AC, posttraumatic stress symptoms (PTSS) and trait anxiety. AB was measured with a pictorial version of the Dot Probe Test. AC moderated the relationship between PTSS and AB (threat avoidance). Patients high in PTSS and low in AC showed attentional avoidance. No association between PTSS and AB in patients with medium or high levels of AC was found. A similar pattern of results was observed for the relationship between trait anxiety, AC and AB. These results suggest that a low ability to control attention is a risk factor for AB in PTSD. This first clinical study corroborates the accumulating evidence from analog studies that individual differences in top-down attentional control are of considerable importance in the expression of AB in anxious psychopathology.

Adolescent depression is associated with increased risk for suicidality, social and educational impairment, smoking, substance use, obesity, and depression in adulthood. It is of relevance to further our insight in the neurobiological mechanisms underlying this disorder in the developing brain, as this may be essential to optimize treatment and prevention of adolescent depression and its negative clinical trajectories. The equivocal findings of the limited number of studies on neural abnormalities in depressed youth stress the need for further neurobiological investigation of adolescent depression. We therefore performed a voxel-based morphometry study of the hippocampus, amygdala, superior temporal gyrus, and anterior cingulate cortex (ACC) in 26 treatment-naïve, clinically depressed adolescents and 26 pair-wise matched healthy controls. Additionally, an exploratory whole-brain analysis was performed. Clinically depressed adolescents showed a volume reduction of the bilateral dorsal ACC compared to healthy controls. However, no association was found between gray matter volume of the ACC and clinical severity scores for depression or anxiety. Our finding of a smaller ACC in clinically depressed adolescents is consistent with literature on depressed adults. Future research is needed to investigate if gray matter abnormalities precede or follow clinical depression in adolescents., Highlights • Voxel-based morphometry ROI and exploratory whole-brain analyses were performed • Depressed adolescents showed a smaller anterior cingulate cortex compared to healthy controls • No association found between gray matter volume of the effect and clinical scores for depression

The neurobiology of social anxiety disorder (SAD) is not yet fully understood. Structural and functional neuroimaging studies in SAD have identified abnormalities in various brain areas, particularly the amygdala and elements of the salience network. This study is the first to examine resting-state functional brain connectivity in a drug-naive sample of SAD patients without psychiatric comorbidity and healthy controls, using seed regions of interest in bilateral amygdala, in bilateral dorsal anterior cingulate cortex for the salience network, and in bilateral posterior cingulate cortex for the default mode network. Twelve drug-naive SAD patients and pair-wise matched healthy controls, all drawn from the Netherlands Study of Depression and Anxiety sample, underwent resting-state fMRI. Group differences were assessed with voxel-wise gray matter density as nuisance regressor. All results were cluster corrected for multiple comparisons (Z>2.3, p

Power density-ratios of fast and slow frequency spectrum-bands can be calculated from resting-state electroencephalography (EEG) recordings. A well-established phenomenon is that slow wave/fast wave ratios (SW/FW) are increased in attention-deficit/hyperactivity disorder. Several researchers have also begun to study relationships between SW/FW and affect. This work suggests that increased SW/FW may reflect reduced frontal cortical control over subcortical affective approach drive. The present study (n=28) aimed to further examine this notion by testing several predictions derived from it. In line with these predictions, SW/FW was found to correlate negatively with fearful modulation of response inhibition in an emotional go/no-go task and with self-reported attentional control. Results also suggested a positive relation between SW/FW and trait approach motivation and a negative relation to anxiety, as predicted. These results are consistent with previous studies and support the notion that SW/FW may provide a useful tool in the study of affect and emotion regulation. Language: en

Background: Panic disorder (PD) is a prevalent and debilitating disorder but its neurobiology is still poorly understood. We investigated resting-state functional connectivity (RSFC) in PD without comorbidity in three networks that have been linked to PD before. This could provide new insights in how functional integration of brain regions involved in fear and panic might relate to the symptomatology of PD.Methods: Eleven PD patients without comorbidity and eleven pair-wise matched healthy controls underwent resting-state fMRI. We used seed regions-of-interest in the bilateral amygdala (limbic network), the bilateral dorsal anterior cingulate cortex (dACC) (salience network), and the bilateral posterior cingulate cortex (default mode network). RSFC of these areas was assessed using seed-based correlations. All results were cluster corrected for multiple comparisons (Z > 2.3, p Results: Abnormalities were identified in the limbic network with increased RSFC between the right amygdala and the bilateral precuneus in PD patients. In the salience network the dACC demonstrated altered connectivity with frontal, parietal and occipital areas.Limitations: The small sample size and hypothesis-driven approach could restrict finding additional group differences that may exist. Other caveats are reflected in the use of medication by two participants and the acquisition of the resting-state scan at the end of a fixed imaging protocol.Conclusion: We found altered RSFC in PD between areas involved in emotion regulation and emotional and somatosensory stimulus processing, as well as an area engaged in self-referential processing, not implicated in models for PD before. These findings extend existing functional neuroanatomical models of PD, as the altered RSFC may underlie increased sensitivity for bodily symptoms. (C) 2012 Elsevier B.V. All rights reserved.

This study seeks to determine whether white matter integrity in the brain differs between adolescents with post-traumatic stress disorder (PTSD) due to child- hood sexual abuse (CSA) and matched healthy adolescents and whether there is a relationship between white matter integrity and symptom severity in the patient group. Using 3T diffusion tensor imaging, we examined fractional ani- sotropy (FA) in a group of adolescents with CSA-related PTSD (n = 20) and matched healthy controls (n = 20), in a region of interest consisting of the bilateral uncinate fas- ciculus (UF), the genu, splenium and body of the corpus callosum (CC), and the bilateral cingulum. In addition, we performed an exploratory whole brain analysis. Trauma symptomatology was measured with the Trauma Symp- tom Checklist for Children (TSCC) to enable correlational analyses between FA differences and trauma symptomatol- ogy. The PTSD group had significantly lower FA values in the genu, midbody and splenium of the CC in comparison with controls (p < 0.05, tfce corrected). Post hoc analyses of the eigenvalues of the DTI scan showed increased radial and mean diffusivity in the patient group. In addition, we found a significant negative correlation between scores on the anger subscale of the TSCC and FA values in the left body of the CC in patients (p < 0.05). Adolescents with CSA-related PTSD show decreased FA in the CC, with abnormalities in the integrity of the left body of the CC being related to anger symptoms. These findings suggest that early trauma exposure affects the development of the CC, which may play a role in the pathophysiology of PTSD in adolescents.

Background Hypercortisolism leads to various physical, psychological and cognitive symptoms, which may partly persist after the treatment of Cushing's disease. The aim of the present study was to investigate abnormalities in white matter integrity in patients with long-term remission of Cushing's disease, and their relation with psychological symptoms, cognitive impairment and clinical characteristics. Methods In patients with long-term remission of Cushing's disease (n = 22) and matched healthy controls (n = 22) we examined fractional anisotropy (FA) values of white matter in a region-of-interest (ROI; bilateral cingulate cingulum, bilateral hippocampal cingulum, bilateral uncinate fasciculus and corpus callosum) and the whole brain, using 3 T diffusion tensor imaging (DTI) and a tract-based spatial statistics (TBSS) approach. Psychological and cognitive functioning were assessed with validated questionnaires and clinical severity was assessed using the Cushing's syndrome Severity Index. Results The ROI analysis showed FA reductions in all of the hypothesized regions, with the exception of the bilateral hippocampal cingulum, in patients when compared to controls. The exploratory whole brain analysis showed multiple regions with lower FA values throughout the brain. Patients reported more apathy (p = .003) and more depressive symptoms (p, Highlights • We study white matter integrity in patients in remission of Cushing's disease. • The patients were compared to matched controls on fractional anisotropy (FA) values. • We found widespread reductions of FA after exposure to hypercortisolism. • Depression severity was related to FA in the left uncinate fasciculus in patients.