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Analyzing cortical folding may provide insight into the biological underpinnings of neurodevelopmental diseases. A neurodevelopmental subtype of bipolar disorders (BD-ND) has been characterized by the combination of early age of onset and psychotic features. We investigate potential cortical morphology differences associated with this subtype. We analyze, for the first time in bipolar disorders, the sulcal pits, the deepest points in each fold of the cerebral cortex.We extracted the sulcal pits from anatomical MRI among 512 participants gathered from 7 scanning sites. We compared the number of sulcal pits in each hemisphere as well as their regional occurrence and depth between the BD-ND subgroup (N = 184), a subgroup without neurodevelopmental features (BD, N = 77) and a group of healthy controls (HC, N = 251).In whole brain analysis, BD-ND group have a higher number of sulcal pits in comparison to the BD group. The local analysis revealed, after correction for multiple testing, a higher occurrence of sulcal pits in the left premotor cortex among the BD-ND subgroup compared to the BD and the HC groups.Our findings confirm that BD-ND is associated with a specific brain morphology revealed by the analysis of sulcal pits. These markers may help to better understand neurodevelopment in mood disorder and stratify patients according to a pathophysiological hypothesis.

The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M2-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.

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.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d= -0.42,p= 3 x 10(-5)), with weak evidence of IQ reductions among BD-FDRs (d= -0.23,p= .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. in contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment., Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1037196, 1063960, 1066177, 510135, 1176716]; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [103703, 106469, 142255]; Departament de Salut de la Generalitat de CatalunyaGeneralitat de Catalunya [SLT002/16/00331]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [1617]; Development Service Merit Review Award [I01CX000227]; Dokuz Eylul University Department of Scientific Research [2012.KB.SAG.062]; e:Med program [O1ZX1314B, O1ZX1314G]; Ege University School of Medicine Research Foundation [2009-D-00017]; Fundacio Marato TV3 [091630]; Netherlands Organisation for Health Research and DevelopmentNetherlands Organization for Health Research and Development [10-000-1002]; Generalitat de CatalunyaGeneralitat de Catalunya [2017SGR01271]; German Federal Ministry for Education and ResearchFederal Ministry of Education & Research (BMBF); Medical Research CouncilMedical Research Council UK (MRC) [G0901310]; Ministerstvo Zdravotnictvi Ceske Republiky [NR8786, NT13891]; National Alliance for Research on Schizophrenia and DepressionNARSAD [17319, 20244, 26731]; Swiss National Centre of Competence in Research Robotics [51NF40-185897]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [1S10OD017974-01, P30 NS076408, R01 MH052857, R01 MH080912, R01 MH113619, U01 MH108150, R01 MH085667]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [T32AG058507]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41 EB015922, R01 MH111671, R01 MH116147, R01 MH117601, R01MH121246, R03 MH105808, U54EB020403]; Research Council of NorwayResearch Council of Norway [223273]; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III [CPII19/00009, PI070066, PI1100683, PI1500467, PI18/00976]; Stanley Medical Research Institute; Swedish Research CouncilSwedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]; Swiss National Science FoundationSwiss National Science Foundation (SNSF) [32003B_156914]; VIDINetherlands Organization for Scientific Research (NWO) [452-11-014, 917-46-370]; Wellcome TrustWellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 064971]; ZonMwNetherlands Organization for Health Research and Development [908-02-123], Australian National Health and Medical Research Council Grants, Grant/Award Numbers: 1037196, 1063960, 1066177, 510135, 1176716; Canadian Institutes of Health Research, Grant/Award Numbers: 103703, 106469, 142255; Departament de Salut de la Generalitat de Catalunya, Grant/Award Number: SLT002/16/00331; Deutsche Forschungsgemeinschaft, Grant/Award Number: 1617; Development Service Merit Review Award, Grant/Award Number: I01CX000227; Dokuz Eylul University Department of Scientific Research Projects Funding, Grant/Award Number: 2012.KB.SAG.062; e:Med program, Grant/Award Numbers: O1ZX1314B, O1ZX1314G; Ege University School of Medicine Research Foundation, Grant/Award Number: 2009-D-00017; Fundacio Marato TV3, Grant/Award Number: 091630; Geestkracht program of the Netherlands Organisation for Health Research and Development, Grant/Award Number: 10-000-1002; Generalitat de Catalunya, Grant/Award Number: 2017SGR01271; German Federal Ministry for Education and Research; Medical Research Council, Grant/Award Number: G0901310; Ministerstvo Zdravotnictvi Ceske Republiky, Grant/Award Numbers: NR8786, NT13891; National Alliance for Research on Schizophrenia and Depression, Grant/Award Numbers: 17319, 20244, 26731; Swiss National Centre of Competence in Research Robotics, Grant/Award Number: 51NF40-185897; National Institute of Mental Health, Grant/Award Numbers: 1S10OD017974-01, P30 NS076408, R01 MH052857, R01 MH080912, R01 MH113619, U01 MH108150, R01 MH085667; National Institute on Aging, Grant/Award Number: T32AG058507; National Institutes of Health, Grant/Award Numbers: P41 EB015922, R01 MH111671, R01 MH116147, R01 MH117601, R01MH121246, R03 MH105808, U54EB020403; Research Council of Norway, Grant/Award Number: 223273; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III, Grant/Award Numbers: CPII19/00009, PI070066, PI1100683, PI1500467, PI18/00976; Stanley Medical Research Institute; Swedish Research Council, Grant/Award Numbers: K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3; Swiss National Science Foundation, Grant/Award Number: 32003B_156914; VIDI, Grant/Award Numbers: 452-11-014, 917-46-370; Wellcome Trust, Grant/Award Numbers: 085475/B/08/Z, 085475/Z/08/Z; Wellcome Trust Research Training Fellowship, Grant/Award Number: 064971; ZonMw, Grant/Award Number: 908-02-123

Aims: Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry. Methods: We obtained body mass index (BMI) and magnetic resonance imaging-derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control individuals from 14 sites within the ENIGMA-BD Working Group. We identified regionally specific profiles of cortical thickness using K-means clustering and studied clinical characteristics associated with individual cortical profiles. Results: We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the sample) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD individuals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex. Conclusions: We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in individuals with higher BMI, which was additive and similar to the BD-associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD.

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)

MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis‐driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large‐scale meta‐ and mega‐analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large‐scale, collaborative studies of mental illness., This review discusses the major challenges facing neuroimaging research of bipolar disorder and highlights the major accomplishments, ongoing challenges and future goals of the ENIGMA Bipolar Disorder Working Group.

Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR

Alcohol use in bipolar disorder (BD) is associated with mood lability and negative illness trajectory, while also impacting functional networks related to emotion, cognition, and introspection. The adverse impact of alcohol use in BD may be explained by its additive effects on these networks, thereby contributing to a poorer clinical outcome.Forty BD-I (DSM-IV-TR) and 46 psychiatrically healthy controls underwent T1 and resting state functional MRI scanning and the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) to assess alcohol use. Functional images were decomposed using spatial independent component analysis into 14 resting state networks (RSN), which were examined for effect of alcohol use and diagnosis-by-alcohol use accounting for age, sex, and diagnosis.Despite the groups consuming similar amounts of alcohol (BD: mean score ± SD 3.63 ± 3; HC 4.72 ± 3, U = 713, p = .07), for BD participants, greater alcohol use was associated with increased connectivity of the paracingulate gyrus within a default mode network (DMN) and reduced connectivity within an executive control network (ECN) relative to controls. Independently, greater alcohol use was associated with increased connectivity within an ECN and reduced connectivity within a DMN. A diagnosis of BD was associated with increased connectivity of a DMN and reduced connectivity of an ECN.Affective symptomatology in BD is suggested to arise from the aberrant functionality of networks subserving emotive, cognitive, and introspective processes. Taken together, our results suggest that during euthymic periods, alcohol can contribute to the weakening of emotional regulation and response, potentially explaining the increased lability of mood and vulnerability to relapse within the disorder.

Neuroimaging evidence implicates structural network-level abnormalities in bipolar disorder (BD); however, there remain conflicting results in the current literature hampered by sample size limitations and clinical heterogeneity. Here, we set out to perform a multisite graph theory analysis to assess the extent of neuroanatomical dysconnectivity in a large representative study of individuals with BD. This cross-sectional multicenter international study assessed structural and diffusion-weighted magnetic resonance imaging data obtained from 109 subjects with BD type 1 and 103 psychiatrically healthy volunteers. Whole-brain metrics, permutation-based statistics, and connectivity of highly connected nodes were used to compare network-level connectivity patterns in individuals with BD compared with controls. The BD group displayed longer characteristic path length, a weakly connected left frontotemporal network, and increased rich-club dysconnectivity compared with healthy controls. Our multisite findings implicate emotion and reward networks dysconnectivity in bipolar illness and may guide larger scale global efforts in understanding how human brain architecture impacts mood regulation in BD.

[Background]: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., [Methods]: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., [Results]: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., [Conclusions]: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., This work was supported by the German Research Foundation (DFG Grant Nos. HA7070/2-2, HA7070/3, HA7070/4 [to TH]) and IZKF of the medical faculty of Münster (Grants No. Dan3/012/17 [to UD] and MzH 3/020/20 [to TH]), and NHMRC projects (Grant No. 1064643 [to BJH] and 1024570 [to CGD]). The CIAM study was supported by the University of Cape Town Research Committee, South African National Research Foundation, and the South African Medical Research Council (principal investigator [PI], Fleur M. Howells) and Grant No. R01MH117601 (to NJ). This work was funded by the German Research Foundation (Grant Nos. FOR2107 JA 1890/7-1 and FOR2107 JA 1890/7-2 [to AJ]) and Swinburne University scholarship/Australian Postgraduate Award (to JK). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to JK). This work was funded by the German Research Foundation (Grant Nos. FOR2107 KI588/14-1 and FOR2107 KI588/14-2 [to TK]). The St. Göran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant Nos. ALF 20170019 and ALFGBG-716801 [to ML]). This work was supported by RFBR (Grant No. 20-013-00748 [to IL, AST]) and funded by the Health Research Board (Grant No. HRA_POR/2011/100 [to CM]). The Australian Schizophrenia Research Bank (ASRB) was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. This work was supported by Deutsche Forschungsgemeinschaft (Grant Nos. DFG NE 2254/2-1, NE 2254/3-1, NE2254/4-1 [to IN]), the University Research Priority Program “Integrative Human Physiology” at the University of Zurich (to ROT), an NHMRC Senior Principal Research Fellowship (Grant No. 1105825 [to CPa]), an NHMRC L3 Investigator Grant (Grant No. 1196508 [to CPa]), and NHMRC Program Grant (Grant No. 1150083 [to CPa]). ASRB was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (Agreement No. 798181 [to GP]). ASRB was supported by the NHMRC (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. The Imaging Genetics in Psychosis study was funded by Project Grants from the NHMRC (Grant Nos. APP630471 and APP1081603 [to YQ]) and the Macquarie University’s Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders (Grant No. CE110001021 [to YQ]). This work was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI11/01766 and CPII19/00009 [to JR]), co-financed by European Regional Development Fund funds from the European Commission (“A Way of Making Europe”). ASRB was supported by the NHMRC (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. Chief investigators for ASRB were VC, US, RSc, AJ, BM, PTM, SVC, FH, and CPa. SR was supported by an NHMRC Senior Fellowship (Grant No. GNT1154651). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to SR). This work was supported by NIHR; MRC (to KR), NIH (Grant Nos. MH-094268, MH-105660, and MH-107730 [to ASS]). The Neuroimaging of the Children's Attention Project cohort was funded by NHMRC, Australia (Grant No. 1065895). Earlier funding for the cohort as also provided by NHMRC (Grant No. 1008522) and a grant from the Collier Foundation. The ACPU cohort was funded by NHMRC, Australia (Project Grant Nos. 384419 and 569533 [to TS]). This work was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004, SIG/05028, and SIG /1103), and the Singapore Bioimaging Consortium (RP C009/2006 [to KS]), and the Ministry of Health, Czech Republic - conceptual development of research organization (“Institute for Clinical and Experimental Medicine - IKEM, IN 00023001” [to ASk]). This study was supported by the Italian Ministry of Health (Grant No. RC/17-18-19-20-21/A [to GS]) and Ministry of Health of the Czech Republic (Grant No. NU20-04-00393 [to FS]). The Drakenstein Child Health Study (DCHS) cohort is funded by the Bill and Melinda Gates Foundation (Grant No. OPP 1017641) and the South African Medical Research Council. This DCHS contribution was made possible in part by a grant from Carnegie Corporation of New York. The statements made and views expressed are solely the responsibility of the author (DJS). STRADL study was supported and funded by the Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (Grant No. 104036/Z/14/Z), and the Medical Research Council Mental Health Pathfinder Award “Leveraging routinely collected and linked research data to study the causes and consequences of common mental disorders” (MRC, Grant No. MC_PC_17209). Scottish Bipolar Family Study (SBFS) was supported by National Health Service Research Scotland, through the Scottish Mental Health Research Network (www.smhrn.org.uk), who provided assistance with subject recruitment and assessments. SBFS was conducted at the Brain Research Imaging Centre (http://www.bric.ed.ac.uk), which is supported by SINAPSE (Scottish Imaging Network, a Platform for Scientific Excellence, http://www.sinapse.ac.uk). Processing of the datasets used the resources provided by the Edinburgh Compute and Data Facility (http://www.ecdf.ed.ac.uk/) (ASt). TVR was supported by an NHMRC Early Career Fellowship (Grant No. GNT1088785). Collection of the COGSBD cohort was funded by the Jack Brockhoff Foundation, University of Melbourne, Barbara Dicker Brain Sciences Foundation, Rebecca L Cooper Foundation, and the Society of Mental Health Research (to TVR). EV was supported by the Spanish Ministry of Science and Innovation (PI18/00805) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the FEDER; the Instituto de Salud Carlos III; the CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental); by the CERCA Programme/Generalitat de Catalunya and the Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (Grant No. 2017SGR1355). This study was also supported by the Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016-2020 (Grant No. SLT006/17/00345) and the European Union Horizon 2020 research and innovation program (EU.3.1.1. Understanding health, wellbeing and disease: Grant Nos. 754907 and EU.3.1.3 [to EB]; Treating and managing disease: Grant No. 945151 [to EV]). This study was supported by the National Center for Complementary and Integrative Health (Grant Nos. R21AT009173 and R61AT009864 [to TTY]); by the National Center for Advancing Translational Sciences (CTSI), National Institutes of Health, through UCSF-CTSI (Grant No. UL1TR001872 [to TTY]); by the American Foundation for Suicide Prevention (Grant No. SRG-1-141-18 [to TTY]); by UCSF Research Evaluation and Allocation Committee (REAC) and J. Jacobson Fund (to TTY); by the NIMH (Grant No. R01MH085734 [to TTY]); and by the Brain and Behavior Research Foundation (formerly NARSAD) (to TTY). This work was supported by a personal Veni grant to MH from the Netherlands Organization for Scientific Research (NWO, Grant No. 91619115 [to MH]) and European Community’s Horizon 2020 Programme (H2020/2014 – 2020) (Grant Agreements Nos. 667302 [CoCA], 728018 [Eat2beNICE], and 847879 [PRIME] [to BF]). JBu has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes, which receive support from Innovative Medicines Initiative Joint Undertaking Grant Nos. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon 2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon 2020–supported programme CANDY (Grant No. 847818 [to JBu]). This work is supported by Grant No. NIA T32AG058507 and NIH Grant No. U54EB020403 from the Big Data to Knowledge (BD2K) Program (to CRKC). ENIGMA MDD work is supported by NIH (Grant Nos. U54 EB020403 [to PT], R01 MH116147 [to PT], and R01 MH117601 [to NJ and LS]). LS was supported by an NHMRC Career Development Fellowship (Grant No. 1140764). This work was supported by the National Center for Research Resources at the NIH (Grant Nos. NIH 1 U24 RR021992 [Function Biomedical Informatics Research Network], NIH 1 U24 RR025736-01 [Biomedical Informatics Research Network Coordinating Center; http://www.birncommunity.org]). TGMvE is supported by ENIGMA’s NIH BD2K initiative (Grant No. U54 EB020403), ENIGMA Sex Differences (Grant No. R01MH116147), and ENIGMA-COINSTAC: Advanced Worldwide Transdiagnostic Analysis of Valence System Brain Circuits (Grant No. R01MH121246). This work was supported by the NIH (Grant No. R01MH121246 [to JT, Calhoun, and TGMvE]). This work was supported in part by NIH (Grant No. U54 EB020403 [to PT]).

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

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.

Childhood trauma (CT) has been repeatedly linked to earlier onset and greater severity of bipolar disorder (BD) in adulthood. However, such knowledge is mostly based on retrospective and cross-sectional studies in adults with BD. The first objective of this selective review is to characterize the short-term effects of CT in the development of BD by focusing on studies in young people. The second objective is to describe the longer-term consequences of CT by considering studies with adult participants. This review first outlines the most prominent hypotheses linking CT exposure and the onset of BD. Then, it summarizes the psychological and biological risk factors implicated in the development of BD, followed by a discussion of original studies that investigated the role of CT in young people with early-onset BD, youths at increased risk of developing BD, or young people with BD with a focus on subclinical and clinical outcome measures. The review considers additional biological and psychological factors associated with a negative impact of CT on the long-term course of BD in later adulthood. Finally, we discuss how the integration of information of CT can improve ongoing early identification of BD and mitigate severe clinical expression in later adulthood.

The location, extent and progression of longitudinal morphometric changes after first-episode of psychosis (FEP) remains unclear. We investigated ventricular and cortico-subcortical regions over a 3-year period in FEP patients compared with healthy controls. High resolution 1.5T T1-weighted MR images were obtained at baseline from 28 FEP patients at presentation and 28 controls, and again after 3-years. The longitudinal FreeSurfer pipeline (v.5.3.0) was used for regional volumetric and cortical reconstruction image analyses. Repeated-measures ANCOVA and vertex-wise linear regression analyses compared progressive changes between groups in subcortical structures and cortical thickness respectively. Compared with controls, patients displayed progressively reduced volume of the caudate [F (1,51)=5.86, p=0.02, Hedges’ g=0.66], putamen [F (1,51)=6.06, p=0.02, g=0.67], thalamus [F (1,51)=6.99, p=0.01, g=0.72] and increased right lateral ventricular volume [F (1, 51)=4.03, p=0.05], and significantly increased rate of cortical thinning [F (1,52)=5.11, p=0.028)] at a mean difference of 0.84% [95% CI (0.10, 1.59)] in the left lateral orbitofrontal region over the 3-year period. In patients, greater reduction in putamen volume over time was associated with lower cumulative antipsychotic medication dose (r=0.49, p=0.01), and increasing lateral ventricular volume over time was associated with worsening negative symptoms (r=0.41, p=0.04) and poorer global functioning (r= −0.41, p=0.04). This study demonstrates localised progressive structural abnormalities in the cortico-striato-thalamo-cortical circuit after the onset of psychosis, with increasing ventricular volume noted as a neuroanatomical marker of poorer clinical and functional outcome.

Background: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. Methods: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. Results: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18 < d < 0.22). More (hypo)manic episodes were associated with faster cortical thinning, primarily in the prefrontal cortex. Conclusions: In the hitherto largest longitudinal MRI study on BD, we did not detect accelerated cortical thinning but noted faster ventricular enlargements in BD. However, abnormal frontocortical thinning was observed in association with frequent manic episodes. Our study yields insights into disease progression in BD and highlights the importance of mania prevention in BD treatment.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD., The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder.In the largest study of hippocampal subfields in bipolar disorder to date, from 23 sites worldwide, we report widespread reductions in nine of 12 subfields.The lack of differences between lithium users and healthy controls supports a possible protective role of lithium in bipolar disorder.

Special Issue: The ENIGMA Consortium: the first 10 years., Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia., Center for Integrated Healthcare, U.S. Department of Veterans Affairs, Grant/Award Number: I01 CX000497; Commonwealth Health Research Board, Grant/Award Number: HRA_POR/2011/100; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Numbers: 478466/2009, 480370/2009; Department of Energy, Labor and Economic Growth, Grant/Award Number: DE-FG02-99ER62764; Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Grant/Award Numbers: K2009-62X-15077-06-3, K2012-61X-15077-09-3, 523-2014-3467, 2009-7053, 2013-2838; Fundação Amazônia Paraense de Amparo à Pesquisa, Grant/Award Numbers: 2009/14891-9, 2010/18672-7, 2012/23796-2, 2013/039; Instituto de Salud Carlos III, Grant/Award Numbers: FIS 00/3095, 01/3129, PI020499, PI060507, PI10/001; National Health and Medical Research Council, Grant/Award Numbers: 1009064, 496682; National Institutes of Health, Grant/Award Numbers: 1RC1MH089257, MH 60722, MH019112, MH064045, MH085096, MH098130, MO1 RR025758, P41RR14075, P50 MH071616, R01 DA053028, R01 EB020062, R01 HD050735, R01 MH056584, R01 MH084803, R01 MH116147, R01 MH117601, R01EB005846, R01EB015611, R01MH074797, R21 MH097196, R21MH097196, R37MH43375, S10 OD023696, T32 AG058507, T32 MH073526, TR000153, U01 MH097435, U24 RR021382A, U24 RR021992, U24 RR025736, U24 RR21992, U24RR021992, U54 EB020403, U54EB020403, UL1 TR000153; National Science Foundation, Grant/Award Numbers: 1636893, 1734853; Norges Forskningsråd, Grant/Award Numbers: 213837, 217776, 223273; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359; Wellcome Trust, Grant/Award Number: 072894/2/03/Z.

Background: Increasing evidence has implicated the cholinergic system as a modulator of mood episodes, with possible involvement of nicotinic and/or muscarinic receptors. A number of randomized controlled trials (RCTs) have demonstrated a putative rapid antidepressant effect of the muscarinic antagonist scopolamine. Here, we review the clinical evidence regarding the three principal muscarinic-modulating agents administered in studies involving mood disorders: scopolamine, biperiden and physostigmine. We conduct a meta-analysis on RCTs where these agents were administered to participants experiencing a depressive episode. Methods: A systematic bibliographic search of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies utilizing the above agents was conducted between January 1970 and December 2020. A meta-analysis was subsequently performed on 9 studies which satisfied inclusion criteria, including 322 participants. Results: Administration of scopolamine significantly reduced depressive symptoms compared to placebo, as measured by objective mood rating scales with SMD of -0.95 (95% CI -1.49, -0.42, p = 0.0005). This effect increased to -1.13 (95% CI -1.61, -0.66, p

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47–67.00, ROC-AUC = 71.49%, 95% CI = 69.39–73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70–60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen’s Kappa = 0.83, 95% CI = 0.829–0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

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.

This study investigates changes on white matter microstructure and neural networks after 6 months of switching to clozapine in schizophrenia patients compared to controls, and whether any changes are related to clinical variables. T1 and diffusion-weighted MRI images were acquired at baseline before commencing clozapine and after 6 months of treatment for 22 patients with treatment-resistant schizophrenia and 23 controls. The Tract-based spatial statistics approach was used to compare changes over time between groups in fractional anisotropy (FA). Changes in structural network organisation weighted by FA and number of streamlines were assessed using graph theory. Patients displayed a significant reduction of FA over time (p

Synchronous and anti-synchronous activity between neural elements at rest reflects the physiological processes underlying complex cognitive ability. Regional and pairwise-connectivity investigations suggest perturbations in these activity patterns may relate to widespread cognitive impairments seen in bipolar disorder (BD). Here we take a network-based perspective to more meaningfully capture interactions among distributed brain regions compared to focal measurements and examine network-cognition relationships across a range of commonly affected cognitive domains in BD in relation to healthy controls. Resting-state networks were constructed as matrices of correlation coefficients between regionally averaged resting-state time series from 86 cortical/subcortical brain regions (FreeSurferv5.3.0). Cognitive performance measured using Weschler Adult Intelligence Scale, Cambridge Automated Neuropsychological Test Battery (CANTAB) and Reading the Mind in the Eyes tests was examined in relation to whole-brain connectivity measures and patterns of connectivity using a permutation-based statistical approach. Faster response times in controls (n=49) related to synchronous activity between frontal, parietal, cingulate, temporal and occipital regions while similar response times in BD (n=35) related to anti-synchronous activity between regions of this subnetwork. Across all subjects, anti-synchronous activity between frontal, parietal, temporal, occipital, cingulate, insula and amygdala regions related to improved memory performance. No resting-state subnetworks related to intelligence, executive function, short-term memory or social cognition performance in the overall sample or in a manner that would explain deficits in these facets in BD. Our results demonstrate alterations in the intrinsic connectivity patterns underlying response timing in BD that are not specific to performance or errors on the same tasks. Across all individuals, no strong effects of resting-state global topology on cognition are found, while distinct functional networks supporting episodic and spatial memory highlight intrinsic inhibitory influences present in the resting-state that facilitate memory processing.

OBJECTIVESchizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.METHODSThe meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.RESULTSMeta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).CONCLUSIONSThis study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.

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.

SummaryHuman brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genesGPR139, DACH1andAPOEare associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing.

The association of antipsychotic medication with abnormal brain morphometry in schizophrenia remains uncertain. This study investigated subcortical morphometric changes 6 months after switching treatment to clozapine in patients with treatment-resistant schizophrenia compared with healthy volunteers, and the relationships between longitudinal volume changes and clinical variables. In total, 1.5T MRI images were acquired at baseline before commencing clozapine and again after 6 months of treatment for 33 patients with treatment-resistant schizophrenia and 31 controls, and processed using the longitudinal pipeline of Freesurfer v.5.3.0. Two-way repeated MANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. Whereas no significant subcortical volume differences were found between patients and controls at baseline (F(8,52) = 1.79; p = 0.101), there was a significant interaction between time, group and structure (F(7,143) = 52.54; p