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Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Contains fulltext : 248376.pdf (Publisher’s version ) (Open Access) For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development. This paper reports activation patterns for fMRI tasks assessing response inhibition, working memory and reward processing obtained at baseline in the longitudinal ABCD Study, providing a reference for research into adolescent brain development.

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.

Significance As the prevalence of pediatric obesity continues to rise, determining neurobiological mechanisms underlying longitudinal childhood weight gain is critically important for informing early intervention and prevention strategies. We use an MRI technique to probe nucleus accumbens (NAcc) tissue microstructure and predict waist circumference after 1 y. We find that increased cell density in the NAcc is strongly associated with obesity in a large cohort of children and predicts future weight gain independent of waist circumference at baseline. These results extend animal studies showing a vicious cycle in which diet-induced neuroinflammation leads to disruption of the brain’s reward circuitry and subsequently promotes further unhealthy eating and weight gain., The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life. Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens [NAcc]) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear. Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity. Here, we leverage a diffusion MRI technique, restriction spectrum imaging, to probe the microstructure (cellular density) of subcortical brain regions. More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain. In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y. These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.

Author(s): Elman, Jeremy A; Puckett, Olivia K; Beck, Asad; Fennema-Notestine, Christine; Cross, Latonya K; Dale, Anders M; Eglit, Graham ML; Eyler, Lisa T; Gillespie, Nathan A; Granholm, Eric L; Gustavson, Daniel E; Hagler, Donald J; Hatton, Sean N; Hauger, Richard; Jak, Amy J; Logue, Mark W; McEvoy, Linda K; McKenzie, Ruth E; Neale, Michael C; Panizzon, Matthew S; Reynolds, Chandra A; Sanderson-Cimino, Mark; Toomey, Rosemary; Tu, Xin M; Whitsel, Nathan; Williams, McKenna E; Xian, Hong; Lyons, Michael J; Franz, Carol E; Kremen, William S | Abstract: IntroductionThe locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.MethodsParticipants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.ResultsHeritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.DiscussionReduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Temporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter pathology in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity, and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

Special Issue: The ENIGMA Consortium: the first 10 years.-- Karolinska Schizophrenia Project (KaSP)., Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., National Institute of Mental Health, Grant/Award Numbers: MH104284, MH116147, R01MH113619, R01 MH090553, R01MH117014, R01MH042191; Karolinska Institutet; Stockholm County Council; Southern and Eastern Norway Regional Health Authority; German Centre for Cardiovascular Research; DZHK; Siemens Healthineers; University of Queensland; US National Institute of Child Health and Human Development, Grant/Award Number: RO1HD050735; Australian National Health and Medical Research Council; Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Institute on Drug Abuse, Grant/Award Numbers: UL1 TR000153, 1 U24 RR025736-01, 1 U24 RR021992; Brain Injury Fund Research Grant Program; Indiana State Department of Health Spinal Cord; Parents Against Childhood Epilepsy; Epilepsy Therapy Project, Fight Against Childhood Epilepsy and Seizures; Epilepsy Foundation; American Epilepsy Society; Knut and Alice Wallenberg Foundation; European Community's Horizon 2020 Programme; Vici Innovation Program; NWO Brain & Cognition Excellence Program; Netherlands Organization for Scientific Research; Hersenstichting Nederland; Netherlands Organization for Health Research and Development; Geestkracht Programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; Universiteit Utrecht; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; National Center for Advancing Translational Sciences; National Institutes of Health; National Center for Research Resources; Consortium grant, Grant/Award Number: U54 EB020403; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Number: G0500092; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; the Research Council, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Swedish Research Council; European Community's Seventh Framework Programme, Grant/Award Number: 602450; King's College London; South London and Maudsley NHS Foundation Trust; Biomedical Research Centre; National Institute for Health Research.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

Brain atrophy in human epilepsy syndromes is explainable by network architecture and strongest in hub regions., Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.

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.

Delineating age-related cortical trajectories in healthy individuals is critical given the association of cortical thickness with cognition and behaviour. Previous research has shown that deriving robust estimates of age-related brain morphometric changes requires large-scale studies. In response, we conducted a large-scale analysis of cortical thickness in 17,075 individuals aged 3-90 years by pooling data through the Lifespan Working group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium. We used fractional polynomial (FP) regression to characterize age-related trajectories in cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma (LMS) method. Inter-individual variability was estimated using meta-analysis and one-way analysis of variance. Overall, cortical thickness peaked in childhood and had a steep decrease during the first 2-3 decades of life; thereafter, it showed a gradual monotonic decrease which was steeper in men than in women particularly in middle-life. Notable exceptions to this general pattern were entorhinal, temporopolar and anterior cingulate cortices. Inter-individual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results reconcile uncertainties about age-related trajectories of cortical thickness; the centile values provide estimates of normative variance in cortical thickness, and may assist in detecting abnormal deviations in cortical thickness, and associated behavioural, cognitive and clinical outcomes.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalised on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine the age-related morphometric trajectories of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum early in life; the volume of the basal ganglia showed a gradual monotonic decline thereafter while the volumes of the thalamus, amygdala and the hippocampus remained largely stable (with some degree of decline in thalamus) until the sixth decade of life followed by a steep decline thereafter. The lateral ventricles showed a trajectory of continuous enlargement throughout the lifespan. Significant age-related increase in inter-individual variability was found for the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to derive risk predictions for the early identification of diverse clinical phenotypes.

SUMMARYEpilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided novel insights into the macroscale features that shape the pathophysiology of common epilepsies.

BackgroundChildhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.MethodsWithin the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.ResultsCM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.ConclusionsSeverity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research. ENIGMA MDD work is supported by NIH grants U54 EB020403 (Thompson), R01 MH116147 (Thompson), and R01 MH117601 (Jahanshad & Schmaal). LS was supported by an NHMRC Career Development Fellowship (1140764). AFFDIS cohort: this study was funded by the University Medical Center Goettingen (UMG Startfoerderung) and the research team is supported by German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung, BMBF: 01 ZX 1507, “PreNeSt - e:Med”). Barcelona cohort: MJP is funded by the Ministerio de Ciencia e Innovación of the Spanish Government and by the Instituto de Salud Carlos III through a ‘Miguel Servet’ research contract (CP16–0020); National Research Plan (Plan Estatal de I + D + I 2016–2019); and co-financed by the European Regional Development Fund (ERDF). BRC DeCC cohort: CHYF is supported by NIHR BRC. Calgary cohort: supported by Canadian Institutes for Health Research, Branch Out Neurological Foundation. Cardiff cohort: supported by the Medical Research Council (grant G 1100629) and the National Center for Mental Health (NCMH), funded by Health Research Wales (HS/14/20). CLING cohort: this study was partially supported by the Deutsche Forschungsgemeinschaft (DFG) via grants to OG (GR1950/5–1 and GR1950/10–1). CODE cohort: Henrik Walter is supported by a grant of the Deutsche Forschungsgemeinschaft (WA 1539/4–1). The CODE cohort was collected from studies funded by Lundbeck and the German Research Foundation (WA 1539/4–1, SCHN 1205/3–1, SCHR443/11–1). DIP-Groningen cohort: this study was supported by the Gratama Foundation, the Netherlands (2012/35 to NG). Edinburgh cohort: The research leading to these results was supported by IMAGEMEND, which received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602450. 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. FOR2107-Marburg cohort: funded by the German Research Foundation (DFG, grant FOR2107 KR 3822/7–2 to AK; FOR2107 KI 588/14–2 to TK and FOR2107 JA 1890/7–2 to AJ). Houston cohorts: supported in part by NIMH grant R01 085667 and the Dunn Research Foundation. JCS is supported by the Pat Rutherford, Jr. Endowed Chair in Psychiatry. IMH Study cohort: supported by funding from NHG (SIG/15012) and NMRC CISSP (2018). Melbourne cohort: funded by National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (Principal Investigator BJH) and 1024570 (Principal Investigator CGD). Minnesota cohort: the study was funded by the National Institute of Mental Health (K23MH090421; Dr. Cullen) and Biotechnology Research Center (P41 RR008079; Center for Magnetic Resonance Research), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, and the Minnesota Medical Foundation. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. Münster cohort: funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5–1 and DA1151/5–2 to UD; 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). NESDA cohort: 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. Pharmo cohort: supported by ERA-NET PRIOMEDCHILD FP 6 (EU) grant 11.32050.26. PSYABM-NORMENT: supported by the Research Council of Norway (project number 229135). The South East Norway Health Authority Research Funding (project number 2015052). The Department of Psychology, University of Oslo, Norway. San Francisco cohort: supported by NIH/NCCIH 1R61AT009864–01A1. NIMH R01MH085734. SHIP and SHIP-trend cohorts: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Stanford cohorts: this work was supported by NIH grant R37 MH101495. The BiDirect Study was supported by grants from the German Federal Ministry of Education and Research (BMBF; grants FKZ-01ER0816 and FKZ-01ER1506). MDS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. TCH is supported by NIMH grant 5K01MH117442. EJWVS, JL, and TFB are supported by European Research Council grant no. ERC-ADG-2014–671084 INSOMNIA. TFB is supported by a VU University Amsterdam University Research Fellowship 2016–2017. JL is supported by a VU University Amsterdam University Research Fellowship 2017–2018.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p“all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P

Early identification of younger, non-demented adults at elevated risk for Alzheimer's disease (AD) is crucial because the pathological process begins decades before dementia onset. Toward that end, we showed that an AD polygenic risk score (PRS) could identify mild cognitive impairment (MCI) in adults who were only in their 50s. Participants were 1176 white, non-Hispanic community-dwelling men of European ancestry in the Vietnam Era Twin Study of Aging (VETSA): 7% with amnestic MCI (aMCI); 4% with non-amnestic MCI (naMCI). Mean age was 56 years, with 89%

Importance Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings. Objectives To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended. Design, setting, and participants This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020. Main outcomes and measures Percentage of children with IFs in each category and prevalence of specific IFs. Results A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387). Conclusions and relevance Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

Childhood maltreatment (CM) is associated with enhanced risk of psychiatric illness and reduced subcortical grey matter in adulthood. The hippocampus and amygdala, due to their involvement in stress and emotion circuitries, have been subject to extensive investigations regarding the effect of CM. However, the complex relationship between CM, subcortical grey matter and mental illness remains poorly understood partially due to a lack of longitudinal studies. Here we used segmentation and linear mixed effect modelling to examine the impact of CM on hippocampal and amygdala development in young people with emerging mental illness. A total of 215 structural magnetic resonance imaging (MRI) scans were acquired from 123 individuals (age: 14-28 years, 79 female), 52 of whom were scanned twice or more. Hippocampal and amygdala volumes increased linearly with age, and their developmental trajectories were not moderated by symptom severity. However, exposure to CM was associated with significantly stunted right hippocampal growth. This finding bridges the gap between child and adult research in the field and provides novel evidence that CM is associated with disrupted hippocampal development in youth. Although CM was associated with worse symptom severity, we did not find evidence that CM-induced structural abnormalities directly underpin psychopathology. This study has important implications for the psychiatric treatment of individuals with CM since they are clinically and neurobiologically distinct from their peers who were not maltreated.

Childhood abuse has an enduring impact on the brain's stress system. Whether the effects of childhood abuse and adulthood stress are additive (cumulative stress hypothesis) or interactive (mismatch hypothesis) is widely disputed, however. The primary aim of this study was to test the utility of the cumulative stress and mismatch hypotheses in understanding brain and behaviour. We recruited 64 individuals (aged 14-26) from a specialised clinic for assessment and early intervention of mental health problems in young people. A T1-weighted MRI, a resting state fMRI and clinical assessment were acquired from each participant. Grey matter estimates and resting state functional connectivity (rsFC) of the hippocampus, amygdala and anterior cingulate cortex (ACC) were determined using segmentation and seed-to-voxel rsFC analyses. We explored the effects of childhood abuse and recent stress on the structure and function of the regions of interest within general linear models. Worse psychiatric symptoms were significantly related to higher levels of life time stress. Individuals with mismatched childhood and recent stress levels had reduced left hippocampal volume, reduced ACC-ventrolateral prefrontal cortex rsFC and greater ACC-hippocampus rsFC, compared to individuals with matched childhood and recent stress levels. These results show specific utility of the cumulative stress hypothesis in understanding psychiatric symptomatology and of the mismatch hypothesis in modelling hippocampal grey matter, prefrontal rsFC, and prefrontal-hippocampal rsFC. We provide novel evidence for the enduring impact of childhood abuse on stress reactivity in a clinical population, and demonstrate the distinct effects of stress in different systems. Hum Brain Mapp 38:2709-2721, 2017. © 2017 Wiley Periodicals, Inc.

The extinction of a conditioned fear response is of great interest in the search for a means of ameliorating adverse neurobiological changes resulting from stress. The discovery that endocannibinoid (EC) levels are inversely related to the extent of such stress, and that the amygdala is a primary site mediating stress, suggests that ECs in this brain region might play a major role in extinction. Supporting this are the observations that the basolateral complex of the amygdala shows an increase in ECs only during extinction and that early clinical trials indicate that cannabinoid-like agents, when taken orally by patients suffering from post traumatic stress disorder (PTSD), reduce insomnia and nightmares. In order to optimize the potential of these agents to ameliorate symptoms of PTSD four important questions need to be answered: first, what is the identity of the cells that release ECs in the amygdala during extinction; second, what are their sites of action; third, what roles do the ECs play in the alleviation of long- depression (LTD), a process central to extinction; and finally, to what extent does brain derived neurotrophic factor (BDNF) facilitate the release of ECs? A review of the relevant literature is presented in an attempt to answer these questions. It is suggested that the principal cell involved in EC synthesis and release during extinction is the so-called excitatory extinction neuron in the basal nucleus of the amygdala. Furthermore that the main site of action of the ECs is the adjacent calcitonin gene-related peptide inhibitory interneurons, whose normal role of blocking the excitatory neurons is greatly diminished. The molecular pathways leading (during extinction trials) to the synthesis and release of ECs from synaptic spines of extinction neurons, that is potentiated by BDNF, are also delineated in this review. Finally, consideration is given to how the autocrine action of BDNF, linked to the release of ECs, can lead to the sustained release of these, so maintaining extinction over long times.

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle-aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56-66 years old. Using an atlas-based registration approach to delineate individual white matter tracts, we investigated mean DTI-based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%-80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community-based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026-2036, 2017. © 2017 Wiley Periodicals, Inc.

Affective disorders in young people have been associated with disruptions in circadian rhythms, including abnormalities in secretion of the pineal hormone melatonin. Previous research reports relationships between pineal gland volumes, melatonin secretion, and sleep-wake cycles, but the relationship between these factors has not been explored in affective disorders. This study aimed to characterize these factors and explore associations with mood symptoms and functioning in a sample of young people with affective disorders. Pineal volume from magnetic resonance imaging and melatonin assay from evening dim-light saliva collection were evaluated in 50 individuals (15-30 years old; 72 % female) with bipolar, depressive, or anxiety disorders. Actigraphy monitoring was also conducted for approximately two weeks to derive sleep-wake measures. Pineal volume was associated with melatonin secretion across the evening, replicating previous findings in psychiatrically healthy individuals. Pineal volume was smaller in participants in which melatonin onset was not detected. Timing of melatonin secretion was related to sleep timing, but amount of melatonin and pineal volume were not related to any sleep-wake measures. A shorter phase angle between onset of melatonin secretion and sleep onset was associated with longer total sleep time. Lower melatonin levels were associated with poorer social and occupational functioning. Although pineal volume is not directly related to sleep disturbances or symptoms, melatonin may influence both sleep-wake cycles and functioning in the early stages of affective disorder. Causal links remain to be established, however, treatments that target circadian rhythms may be useful in improving functioning in young people with affective disorders.

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.

ObjectiveWe previously identified 4 empirically derived mild cognitive impairment (MCI) subtypes via cluster analysis within the Alzheimer's Disease Neuroimaging Initiative (ADNI) and demonstrated high correspondence between patterns of cortical thinning at baseline and each cognitive subtype. We aimed to determine whether our MCI subtypes demonstrate unique longitudinal atrophy patterns.MethodsADNI participants (295 with MCI and 134 cognitively normal [CN]) underwent annual structural MRI and neuropsychological assessments. General linear modeling compared vertex-wise differences in cortical atrophy rates between each MCI subtype and the CN group. Linear mixed models examined trajectories of cortical atrophy over 3 years within lobar regions of interest.ResultsCompared to the CN group, those with amnestic MCI (memory deficit) initially demonstrated greater atrophy rates within medial temporal lobe regions that became more widespread over time. Those with dysnomic/amnestic MCI (naming/memory deficits) showed greater atrophy rates largely localized to temporal lobe regions. The mixed MCI (impairment in all cognitive domains) group showed greater atrophy rates in widespread regions at all time points. The cluster-derived normal group, who had intact neuropsychological performance and normal cortical thickness at baseline despite their MCI diagnosis via conventional diagnostic criteria, continued to show normal cognition and minimal cortical atrophy over 3 years.ConclusionsADNI's purported amnestic MCI sample produced more refined cognitive subtypes with unique longitudinal cortical atrophy rates. These novel MCI subtypes reliably reflect underlying atrophy, reduce false-positive diagnostic errors, and improve prediction of clinical course. Such improvements have implications for the selection of participants for clinical trials and for providing more precise risk assessment for individuals diagnosed with MCI.

Posttraumatic stress disorder (PTSD) is known to persist, eliciting early medical co-morbidity, and accelerated aging. Although PTSD diagnosis has been found to be associated with smaller volume in multiple brain regions, posttraumatic stress (PTS) symptoms and their associations with brain morphometry are rarely assessed over long periods of time. We predicted that persistent PTS symptoms across ~24 years would be inversely associated with hippocampal, amygdala, anterior cingulate volumes, and hippocampal occupancy (HOC = hippocampal volume/[hippocampal volume + inferior lateral ventricle volume]) in late middle age. Exploratory analyses examined prefrontal regions. We assessed PTS symptoms in 247 men at average ages 38 (time 1) and 62 (time 2). All were trauma-exposed prior to time 1. Brain volumes were assessed at time 2 using 3 T structural magnetic resonance imaging. Symptoms were correlated over time (r = 0.46 p

BackgroundLarge-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach.ObjectiveWe aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups.MethodsPubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences.ResultsQualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50.1% and 62.5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38.4% and 47.0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging.

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The ABCD Study is a collaborative effort, including a Coordinating Center, 21 data acquisition sites across the United States, and a Data Analysis and Informatics Center (DAIC). The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data will provide a resource of unprecedented scale and depth for studying typical and atypical development. Here, we describe the baseline neuroimaging processing and subject-level analysis methods used by the ABCD DAIC in the centralized processing and extraction of neuroanatomical and functional imaging phenotypes. Neuroimaging processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI.HighlightsAn overview of the MRI processing pipeline for the ABCD StudyA discussion on the challenges of large, multisite population studiesA methodological reference for users of publicly shared data from the ABCD Study

The present study investigated differences in white matter (WM) integrity between 96 young people with affective and/or psychotic symptoms classified at an early stage of mental disorder (i.e. 'attenuated syndrome'; stage 1b), 85 young people classified at a more advanced stage of mental disorder (i.e. 'discrete disorder'; stage 2), and 81 demographically matched healthy controls using diffusion tensor imaging. The relationship between WM integrity (indexed by fractional anisotropy; FA) across the tracts and neuropsychological functioning was also investigated. A significant reduction in FA was identified in those with more advanced disorder in the body of the corpus callosum. Clinical stage groups were associated with significant neuropsychological impairment, which was significantly greater in those with discrete disorders. Compared to those in the earlier stage of disorder, participants at the later clinical stage showed decreased FA in the body of the corpus callosum that was associated with worse performance in attentional set formation maintenance, shifting and flexibility. These results provide further support for clinical staging of mental disorder and highlight the potential for utilising neuroanatomical biomarkers to support the classification of stages of mental disorder in the future.

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9–10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.

Negative fateful life events (FLEs) such as interpersonal conflict, death in the family, financial hardship, and serious medical emergencies can act as allostatic stressors that accelerate biological aging. However, the relationship between FLEs and neuroanatomical aging is not well understood. We examined 359 men (mean age 62years) participating in the Vietnam Era twin study of aging (VETSA) to determine whether negative midlife FLEs are associated with advanced brain aging after controlling for physical, psychological, and lifestyle factors. At two different time points, participants were assessed for negative FLEs, health and well-being, general cognitive ability, socioeconomic status, depression, and ethnicity. Participants underwent a magnetic resonance imaging examination, and T1-weighted images were processed with FreeSurfer. Subsequent neuroanatomical measurements were entered into the Brain-Age Regression Analysis and Computation Utility software (BARACUS) to predict brain age. Having more midlife FLEs, particularly relating to interpersonal relationships, was associated with advanced predicted brain aging (i.e., higher predicted brain age relative to chronological age). This association remained after controlling for the significant covariates of alcohol consumption, cardiovascular risk, adult socioeconomic status, and ethnicity.

Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD.

Diffusion tensor imaging (DTI) has been utilized to index white matter (WM) integrity in the major psychiatric disorders. However, the findings within and across such disorders have been mixed. Given this, transdiagnostic sampling with data-driven statistical approaches may lead to new and better insights about the clinical and functional factors associated with WM abnormalities. Thus, we undertook a cross-sectional DTI study of 401 young adult (18-30 years old) outpatients with a major psychiatric (depressive, bipolar, psychotic, or anxiety) disorder and 61 healthy controls. Participants also completed self-report questionnaires and underwent neuropsychological assessment. Fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity was determined via a whole brain voxel-wise approach (tract-based spatial statistics). Hierarchical cluster analysis was performed on FA scores in patients only, obtained from 20 major WM tracts (that is, association, projection and commissural fibers). The three cluster groups derived were distinguished by having consistently increased or decreased FA scores across all tracts. Compared to controls, the largest cluster (N = 177) showed significantly increased FA in 55% of tracts, the second cluster (N = 169) demonstrated decreased FA (in 90% of tracts) and the final cluster (N = 55) exhibited the most increased FA (in 95% of tracts). Importantly, the distribution of primary diagnosis did not significantly differ among the three clusters. Furthermore, the clusters showed comparable functional, clinical and neuropsychological measures, with the exception of alcohol use, medication status and verbal fluency. Overall, this study provides evidence that among young adults with a major psychiatric disorder there are subgroups with either abnormally high or low FA and that either pattern is associated with suboptimal functioning. Importantly, these neuroimaging-based subgroups appear despite diagnostic and clinical factors, suggesting differential treatment strategies are warranted.

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56–66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9–28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage., Highlights • In middle-aged men brain white matter metrics differed by amount of alcohol intake. • Fractional anisotropy (FA) was highest among moderate drinkers. • FA decreased with heavier drinking (>2 drinks/day, on average). • Never drinkers and heavy drinkers had highest white matter lesion burden. • Light to moderate drinking is associated with indices of better white matter health.

Background and Objectives Childhood socioeconomic status (cSES) is found to predict later-life cognitive abilities, yet the mechanisms underlying these associations remain unclear. The objective of this longitudinal study was to examine the direct and indirect paths through which cSES influences late midlife cognitive outcomes. Research Design and Methods Participants were 1,009 male twins in the Vietnam Era Twin Study of Aging (VETSA). At mean ages 20 and 62, participants completed a standardized test for general cognitive ability (GCA). The age 62 cognitive assessment also included in-person tests of processing speed, episodic memory, abstract reasoning, working memory, verbal fluency, visual-spatial ability, and executive functions. At mean age 56, participants were interviewed regarding their own and their parents’ education and occupation, and completed questionnaires about cognitive leisure activities and sociodemographic information. Multiple mediation analyses were conducted to examine the direct path effects and indirect path effects of cSES through age 20 GCA, adult SES, and cognitive leisure activities on seven cognitive outcomes at age 62, adjusting for age, ethnicity, and non-independence of observations. Results Total (direct plus indirect) effects were significant for all measures with the exception of executive functions. Men from lower cSES backgrounds had poorer cognitive functioning in late midlife. The direct effect of cSES was partially mediated for abstract reasoning, and was fully mediated for the remaining six cognitive outcomes. Total indirect effects accounted for at least half of the total effects in each model, with paths through age 20 GCA explaining most of the total indirect effects. Discussion and Implications cSES predicted cognitive functioning in late middle age Using multiple mediation models, we show that lower cSES predicts poorer cognition in late midlife primarily through young adult cognitive ability and to a lesser extent through SES in adulthood and engagement in cognitively stimulating activities.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n = 3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N = 451) vs healthy controls (N = 1996) or MDD patients with no suicidal symptoms (N = 650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P = 4.12 × 10 - 3) or a 2.87% smaller volume compared with controls (Cohen's d = - 0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P = 0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression. (C) 2016 Published by Elsevier Ltd.

The aim of this study was to investigate differences in subcortical and hippocampal volumes between healthy controls, young people at an early stage of affective and psychotic disorders and those in more advanced stages, to identify markers associated with functional outcomes and illness severity. Young people presenting to youth mental health services with admixtures of depressive, manic and psychotic symptoms (n = 141), and healthy counterparts (n = 49), aged 18-25 were recruited. Participants underwent magnetic resonance imaging, clinical assessments and were rated as to their current clinical stage. Eighty-four patients were classified at the attenuated syndrome stage (Stage 1b) and 57 were classified as having discrete and persistent disorders (Stage 2+). Automated segmentation was performed using NeuroQuant® to determine volumes of subcortical and hippocampus structures which were compared between groups and correlated with clinical and functional outcomes. Compared to healthy controls, Stage 2+ patients showed significantly reduced right amygdala volumes. Whereas Stage 1b patients showed significantly reduced left caudate volumes compared to healthy controls. Smaller left caudate volume correlated with greater psychological distress and impaired functioning. This study shows a clinical application for an automated program to identify and track subcortical changes evident in young people with emerging psychopathology.

Contains fulltext : 193179.pdf (Publisher’s version ) (Open Access) The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Aim Continence is dependent on anorectal-brain interactions. Consequently, aberrations of the brain-gut axis may be important in the pathophysiology of faecal incontinence (FI) in certain patients. The aim of this study was to assess the feasibility of recording brain responses to rectal mechanical stimulation in patients with FI using functional magnetic resonance imaging (fMRI). Method A prospective, cohort pilot study was performed to assess brain responses during rectal stimulation in 14 patients [four men, mean (SD) age 62 (15) years]. Blood oxygen level dependent (BOLD) signals were measured by fMRI during rest and mechanical distension, involving random repetitions of isobaric phasic rectal distensions at fixed (15 and 45 mmHg) and variable (10% above sensory perception threshold) pressures. Results Increases in BOLD signals in response to high pressure rectal distension (45 mmHg) and maximum toleration were observed in the cingulate gyrus, thalamus, insular cortex, inferior frontal gyrus, cerebellum, caudate nucleus, supramarginal gyrus, putamen and amygdala. Additionally, activation of the supplementary motor cortex and caudate nucleus with inconsistent activity in the frontal lobe was observed. Conclusions This study has demonstrated the feasibility of recording brain responses to rectal mechanical stimulation using fMRI in patients with FI, revealing activity in widespread areas of the brain involved in visceral sensory processing. The observed activity in the supplementary motor cortex and caudate nucleus, with relative paucity of activity in the frontal lobes, warrants investigation in future studies to determine whether aberrations in cerebral processing of rectal stimuli play a role in the pathogenesis of FI.

Fronto-limbic connectivity is compromised in mood disorders, as reflected by impairments in white matter (WM) integrity revealed by diffusion tensor imaging. Although the underlying mechanisms remain unclear, disruption to normal myelination due to oxidative stress is thought to play a key role. We aimed to determine whether fronto-limbic WM integrity is compromised, and associated with in vivo antioxidant levels (indexed by glutathione; GSH), in young adults with unipolar depression (DEP) and bipolar (BD) disorders. Ninety-four patients with DEP, 76 with BD and 59 healthy controls (18–30 years) underwent diffusion tensor and proton magnetic resonance spectroscopy imaging. Fractional anisotropy (FA) was calculated from the cingulum bundle (cingulate, hippocampus), fornix, stria terminalis (ST) and uncinate fasciculus tracts. GSH concentration was measured in anterior cingulate cortex (ACC) and hippocampus (HIPP). Compared to controls, DEP showed significantly reduced FA in ST, whereas BD did not significantly differ in FA across the five tracts. There were significant positive correlations between ST-FA and HIPP-GSH across groups. Regression analysis revealed that having DEP or BD and reduced HIPP-GSH were significantly associated with reduced ST-FA. Similarly, decreased ST-FA was associated with poorer neuropsychological performance in conjunction with having DEP. Our findings suggest a structural disconnectivity specific to the limbic region of young adults with DEP. Decreased WM integrity was associated with depleted levels of hippocampal GSH suggesting that this particular disruption may be linked to oxidative stress at early stages of illness. Young adults with BD do not have the same degree of impairment.