Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

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Significance

Schizophrenia has been proposed to involve altered left-hemispheric dominance for language in the brain, but research in limited sample sizes has not clarified whether structural asymmetry differs in this condition. In MRI data from 5,080 affected individuals and 6,015 controls, we found altered asymmetry of two brain regions driven by thinner left-hemisphere cortex in schizophrenia: the rostral anterior cingulate and middle temporal gyrus. The latter is a core region of the left-hemisphere language network. Effects were very small in terms of macroanatomical asymmetry, but might be compatible with altered lateralized function. Across all brain regions considered together, 7% of variance in asymmetry was linked to case–control status, indicating a more diffuse pattern of subtly altered anatomical asymmetry.

Abstract

Left–right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case–control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case–control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case–control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case–control status. Subtle case–control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

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FreeSurfer is a suite of tools for the analysis of neuroimaging data that provides an array of algorithms to quantify the functional, connectional and structural properties of the human brain. It has evolved from a package primarily aimed at generating surface representations of the cerebral cortex into one that automatically creates models of most macroscopically visible structures in the human brain given any reasonable T1-weighted input image. It is freely available, runs on a wide variety of hardware and software platforms, and is open source. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Clyde Francks:

ORCID: https://orcid.org/0000-0002-9098-890X

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Electronic, pub): 28 March 2023

Publication date (Print, pub): 4 April 2023

Publication date PMC-release: 28 March 2023

Volume: 120

Issue: 14

Electronic Location Identifier: e2213880120

Affiliations

[1] ^aLanguage & Genetics Department, Max Planck Institute for Psycholinguistics , Nijmegen 6525 XD, The Netherlands

[2] ^bDepartment of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam 1081 HZ, The Netherlands

[3] ^cDivision of Cerebral Integration , National Institute for Physiological Sciences , Okazaki 444-8585, Japan

[4] ^dDepartment of Pathology of Mental Diseases, National Center of Neurology and Psychiatry, National Institute of Mental Health , Tokyo 187-8551, Japan

[5] ^eDepartment of Psychiatry, University Medical Center Utrecht Brain Center, University Medical Center Utrecht , Utrecht University , Utrecht 3584 CG, The Netherlands

[6] ^fDepartment of Child and Adolescent Psychiatry/Psychology , Erasmus University Medical Center Sophia Children's Hospital , Rotterdam 3015 CN, The Netherlands

[7] ^gDepartment of Psychiatry , Icahn School of Medicine at Mount Sinai , New York, NY 10029

[8] ^hThe Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center , New York, NY 10468

[9] ⁱDepartment of Psychiatry, Instituto de Investigación Marqués de Valdecilla, University Hospital Marqués de Valdecilla , Santander 39008, Spain

[10] ^jCentro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III , Madrid 28029, Spain

[11] ^kDepartment of Medicine and Psychiatry, School of Medicine, University of Cantabria , Santander 39011, Spain

[12] ^lDepartment of Psychiatry, Marqués de Valdecilla University Hospital, Instituto de Investigación Sanitaria Valdecilla, School of Medicine, University of Cantabria , Santander 39011, Spain

[13] ^mDepartment of Radiology, Instituto de Investigación Marqués de Valdecilla, Marqués de Valdecilla University Hospital , Santander 39011, Spain

[14] ⁿAdvanced Computing and e-Science, Instituto de Física de Cantabria, Universidad de Cantabria - Consejo Superior de Investigaciones Científicas , Santander 39005, Spain

[15] ^oDepartment of Psychiatry, School of Medicine, University of Sevilla, University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas - Instituto de Biomedicina de Sevilla , Sevilla 41013, Spain

[16] ^pNorwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo , Oslo 0450, Norway

[17] ^qDepartment of Psychology, University of Oslo , Oslo 0373, Norway

[18] ^rBjørknes College , Oslo 0456, Norway

[19] ^sDivision of Mental Health and Addiction, Oslo University Hospital , Oslo 0372, Norway

[20] ^tKG Jebsen Center for Neurodevelopmental Disorders, University of Oslo , Oslo 0450, Norway

[21] ^uDepartment of Psychiatric Research, Diakonhjemmet Hospital , Oslo 0373, Norway

[22] ^vCentre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm , Stockholm 113 64, Sweden

[23] ^wDepartment of Psychiatry, University of Maryland School of Medicine , Baltimore, MD 21201

[24] ^xSchool of Psychiatry, University of New South Wales , Sydney 2033, Australia

[25] ^yNeuroscience Research Australia , Sydney 2031, Australia

[26] ^zEdith Collins Centre (Translational Research in Alcohol, Drugs & Toxicology), Sydney Local Health District , Sydney 2050, Australia

[27] ^aaSpecialty of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney , Sydney 2006, Australia

[28] ^bbSchool of Medicine, The University of Queensland , Brisbane 4006, Australia

[29] ^ccSchool of Psychological Sciences, University of Newcastle , Newcastle 2308, Australia

[30] ^ddQueensland Brain Institute, The University of Queensland , Brisbane 4072, Australia

[31] ^eeQueensland Centre for Mental Health Research, The University of Queensland, Brisbane 4076, Australia

[32] ^ffCentre for Brain and Mental Health Research, University of Newcastle , Newcastle 2308, Australia

[33] ^ggPriority Research Centre for Stroke and Brain Injury, University of Newcastle , Newcastle 2308, Australia

[34] ^hhHunter Medical Research Institute , Newcastle 2305, Australia

[35] ⁱⁱSchool of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle , Newcastle 2308, Australia

[36] ^jjSchool of Medicine and Public Health, University of Newcastle , Newcastle 2308, Australia

[37] ^kkPRC for Health Behaviour, Hunter Medical Research Institute , Newcastle 2305, Australia

[38] ^llHunter New England Mental Health Service , Newcastle 2305, Australia

[39] ^mmMelbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne , Melbourne 3053, Australia

[40] ⁿⁿDepartment of Neuroscience and Physiology, Upstate Medical University , Syracuse, NY 13210

[41] ^ooEarly Psychosis Department, Department of Psychiatry, Amsterdam UMC (location AMC) , Amsterdam 1105 AZ, The Netherlands

[42] ^ppArkin Institute for Mental Health , Amsterdam 1033 NN, The Netherlands

[43] ^qqDepartment of Psychiatry and Psychotherapy, Philipps-Universität Marburg , Marburg 35039, Germany

[44] ^rrCenter for Mind, Brain and Behavior , Marburg 35032, Germany

[45] ^ssCore-Facility Brainimaging, Faculty of Medicine, Philipps-Universität Marburg , Marburg 35032, Germany

[46] ^ttDepartment of General Psychiatry, Section for Experimental Psychopathology and Neuroimaging, Heidelberg University , Heidelberg 69115, Germany

[47] ^uuDepartment of Psychiatry, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104

[48] ^vvLifespan Brain Institute, University of Pennsylvania & Children's Hospital of Philadelphia , Philadelphia, PA 19104

[49] ^wwCenter for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104

[50] ^xxDepartment of Psychiatry and Neuroscience, University of New Mexico , Albuquerque, NM 87106

[51] ^yyDepartment of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences, University of California , San Francisco, CA 94143

[52] ^zzMental Health Service, Veterans Affairs San Francisco Healthcare System , San Francisco, CA 94121

[53] ^aaaDepartment of Psychiatry and Human Behavior, University of California Irvine , Irvine, CA 92697

[54] ^bbbPsychology Department and Neuroscience Institute, Georgia State University , Atlanta, GA 30303

[55] ^cccTri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology and Emory University , Atlanta, GA 30303

[56] ^dddSan Francisco VA Medical Center, University of California , San Francisco, CA 94121

[57] ^eeeLong Beach VA Health Care System , Long Beach, CA 90822

[58] ^fffBeijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School , Beijing 100096, P.R. China

[59] ^gggChongqing University Three Gorges Hospital , Chongqing 404188, P.R. China

[60] ^hhhDivision of Psychological and Social Medicine and Developmental Neurosciences, Translational Developmental Neuroscience Section, Technische Universität Dresden, University Hospital C.G. Carus , Dresden 01307, Germany

[61] ⁱⁱⁱDepartment of Child and Adolescent Psychiatry, Eating Disorder Treatment and Research Center, Technische Universität Dresden, Faculty of Medicine, University Hospital C.G. Carus , Dresden 01307, Germany

[62] ^jjjFIDMAG Germanes Hospitalàries Research Foundation , Barcelona 08035, Spain

[63] ^kkkMental Health Research Networking Center (Ciber del Área de Salud Mental) , Madrid 28029, Spain

[64] ^lllBenito Menni Complex Assistencial en Salut Mental , Barcelona 08830, Spain

[65] ^mmmLaboratory of Neuropsychiatry, Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation , Rome 00179, Italy

[66] ⁿⁿⁿMenninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine , Houston, TX 77030

[67] ^oooDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht University , Maastricht 6229 ER, The Netherlands

[68] ^pppCampbell Family Mental Health Institute, Centre for Addiction and Mental Health , Toronto M5S 2S1, Canada

[69] ^qqqDepartment of Psychiatry, University of Toronto , Toronto M5T 1R8, Canada

[70] ^rrrWest Region, Institute of Mental Health , Singapore 539747, Singapore

[71] ^sssYong Loo Lin School of Medicine, National University of Singapore , Singapore 119228, Singapore

[72] ^tttDepartment of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London , London SE5 8AF, United Kingdom

[73] ^uuuDepartment of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London , London SE5 8AF, United Kingdom

[74] ^vvvDepartment of Psychiatry, Jeonbuk National University Medical School , Jeonju 54896, Republic of Korea

[75] ^wwwResearch Institute of Clinical Medicine, Jeonbuk National University-Biomedical Research Institute, Jeonbuk National University Hospital , Jeonju 54896, Republic of Korea

[76] ^xxxDepartment of Psychiatry, University Psychiatric Clinics (Universitäre Psychiatrische Kliniken), University of Basel , Basel 4002, Switzerland

[77] ^yyyDepartment of Psychiatry and Psychotherapy, University of Lübeck , Lübeck 23562, Germany

[78] ^zzzDivision of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB, United Kingdom

[79] ^aaaaDepartment of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University , Stellenbosch 7505, South Africa

[80] ^bbbbStellenbosch University Genomics of Brain Disorders Research Unit, South African Medical Research Council , Cape Town 7505, South Africa

[81] ^ccccDepartment of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town , Cape Town 7935, South Africa

[82] ^ddddNeuroscience Institute, University of Cape Town , Cape Town 7935, South Africa

[83] ^eeeeInstitute for Translational Psychiatry, Westfälische Wilhelms-Universität Münster , Münster 48149, Germany

[84] ^ffffThe Mind Research Network , Albuquerque, NM 87106

[85] ^ggggDepartment of Education, Psychology, Communication, University of Bari Aldo Moro , Bari 70121, Italy

[86] ^hhhhDepartment of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro , Bari 70121, Italy

[87] ⁱⁱⁱⁱPsychiatry Unit, Bari University Hospital , Bari 70121, Italy

[88] ^jjjjDepartment of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón , Madrid 28009, Spain

[89] ^kkkkCiber del Área de Salud Mental, Instituto de Salud Carlos III , Madrid 28029, Spain

[90] ^llllInstituto de Investigación Sanitaria Gregorio Marañón , Madrid 28009, Spain

[91] ^mmmmSchool of Medicine, Universidad Complutense , Madrid 28040, Spain

[92] ⁿⁿⁿⁿLaboratory of Neuroimaging and Multimodal Analysis, Mental Health Research Center , Moscow 115522, Russian Federation

[93] ^ooooDepartment of Medical Sciences, Psychiatry, Uppsala University , Uppsala 751 85, Sweden

[94] ^ppppDepartment of Physiology and Pharmacology, Karolinska Institutet , Stockholm 171 65, Sweden

[95] ^qqqqDepartment of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich (PUK) , Zurich 8008, Switzerland

[96] ^rrrrMontreal Neurological Institute, McGill University , Montreal H3A 2B4, Canada

[97] ^ssssDepartment of Psychiatry, Division of Adult Psychiatry, Geneva University Hospitals , Geneva 1202, Switzerland

[98] ^ttttNational Institute of Mental Health , Klecany 250 67, Czech Republic

[99] ^uuuuDepartment of Psychiatry, Dalhousie University , Halifax B3H 2E2, Canada

[100] ^vvvvMR Unit, Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine , Prague 140 21, Czech Republic

[101] ^wwwwDepartment of Neuropsychiatry, Seoul National University Hospital , Seoul 08826, Republic of Korea

[102] ^xxxxDepartment of Psychiatry, Seoul National University College of Medicine , Seoul 08826, Republic of Korea

[103] ^yyyyDepartment of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences , Seoul 08826, Republic of Korea

[104] ^zzzzDepartment of Psychiatry, University of Oxford , Oxford OX3 7JX, United Kingdom

[105] ^aaaaaDepartment of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt , Frankfurt am Main 60528, Germany

[106] ^bbbbbDepartment of Child and Adolescent Psychiatry, Technische Universität Dresden , Dresden 01187, Germany

[107] ^cccccSA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town , Cape Town 7505, South Africa

[108] ^dddddDepartment of Psychiatry, Research Group in Psychiatry (GIPSI), Faculty of Medicine, Universidad de Antioquia , Medellín 050010, Colombia

[109] ^eeeeeExperimental Psychopathology and Psychotherapy, Department of Psychology, University of Zurich , Zurich 8050, Switzerland

[110] ^fffffCenter for Psychiatric Neuroscience, Feinstein Institute for Medical Research , Manhasset, NY 11030

[111] ^gggggDivision of Psychiatry Research, Zucker Hillside Hospital, Northwell Health , New York, NY 11004

[112] ^hhhhhDepartment of Psychiatry, Zucker School of Medicine at Northwell/Hofstra , New York, NY 11549

[113] ⁱⁱⁱⁱⁱDonders Institute for Brain, Cognition and Behaviour, Radboud University , Nijmegen 6500 HB, The Netherlands

[114] ^jjjjjDepartment of Human Genetics, Radboud University Medical Center , Nijmegen 6525 GA, The Netherlands

[115] ^kkkkkDepartment of Psychiatry, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands

[116] ^lllllDepartment of Psychiatry, Boston Children's Hospital and Harvard Medical School , Boston, MA 02115

[117] ^mmmmmOlin Neuropsychiatry Research Center, Institute of Living , Hartford, CT 06102

[118] ⁿⁿⁿⁿⁿDepartment of Radiology, Perelman School of Medicine , Philadelphia, PA 19104

[119] ^oooooDepartment of Neurology, Perelman School of Medicine , Philadelphia, PA 19104

[120] ^pppppImaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California , Los Angeles, CA 90033

[121] ^qqqqqSchool of Psychology, University of Auckland , Auckland 1010, New Zealand

[122] ^rrrrrDepartment of Women’s and Children’s Health, Uppsala University , Uppsala 752 37, Sweden

[123] ^sssssLaboratory of Neuro Imaging, School of Medicine, University of Southern California , Los Angeles, CA 90033

[124] ^tttttPsychiatric Genetics, QIMR Berghofer Medical Research Institute , Brisbane 4006, Australia

[125] ^uuuuuClinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine , Irvine, CA 92697

[126] ^vvvvvCenter for the Neurobiology of Learning and Memory, University of California Irvine , Irvine, CA 92697