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.

3rd Faculty of Medicine Charles University Prague Czech Republic

Beijing Huilongguan Hospital Beijing China

Brain and Mental Health Laboratory Monash Institute of Cognitive and Clinical Neurosciences School of Psychological Sciences and Monash Biomedical Imaging Monash University Clayton VIC Australia

Brain and Mind Centre University of Sydney Sydney NSW Australia

Center for Addiction and Mental Health Toronto ON Canada

Centre for Neural Engineering Department of Electrical and Electronic Engineering University of Melbourne Parkville VIC Australia

Centre for Neuroimaging and Cognitive Genomics Clinical Neuroimaging Laboratory NCBES Galway Neuroscience Centre National University of Ireland Galway Galway Ireland

Child and Adolescent Psychiatry Department Hospital General Universitario Gregorio Marañón School of Medicine Universidad Complutense IiSGM CIBERSAM Madrid Spain

Chongqing Three Gorges Central Hospital Chongqing China

CIBERSAM Centro Investigación Biomédica en Red Salud Mental Santander Spain

Department NESMOS Faculty of Medicine and Psychology University 'Sapienza' of Rome Rome Italy

Department of Clinical Neuroscience Centre for Psychiatry Research Karolinska Institutet Stockholm Sweden

Department of Computer Science and Electrical Engineering University of Maryland Baltimore MD USA

Department of Computer Science and Engineering The Ohio State University Columbus OH USA

Department of General Practice The University of Melbourne Parkville VIC Australia

Department of Neurology and Psychiatry Sapienza University of Rome Rome Italy

Department of Psychiatric Research Diakonhjemmet Hospital Oslo Norway

Department of Psychiatry and Biobehavioral Sciences University of California Los Angeles Los Angeles CA USA

Department of Psychiatry and Human Behavior University of California Irvine Irvine CA USA

Department of Psychiatry and Mental Health University of Cape Town Cape Town South Africa

Department of Psychiatry and MRC Unit on Anxiety and Stress Disorders University of Cape Town Cape Town South Africa

Department of Psychiatry and Neuropsychiatric Genetics Research Group Institute of Molecular Medicine Trinity College Dublin Dublin Ireland

Department of Psychiatry Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

Department of Psychiatry Brigham and Women's Hospital Harvard Medical School Boston MA USA

Department of Psychiatry Lausanne University Hospital University of Lausanne Lausanne Switzerland

Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston MA USA

Department of Psychiatry Osaka University Graduate School of Medicine Osaka Japan

Department of Psychiatry School of Clinical Sciences Monash University and Monash Health Clayton VIC Australia

Department of Psychiatry Seoul National University College of Medicine Seoul Republic of Korea

Department of Psychiatry Trinity College Dublin Dublin Ireland

Department of Psychiatry University of Iowa Iowa City IA USA

Department of Psychiatry University of Minnesota Minneapolis MN USA

Department of Psychiatry University of Pennsylvania Philadelphia PA USA

Department of Psychiatry Yale University School of Medicine New Haven CT USA

Department of Psychology University of Oslo Oslo Norway

Departments of Psychiatry and Radiology Brigham and Women's Hospital Harvard Medical School Boston MA USA

Departments of Psychiatry and Radiology Massachusetts General Hospital Harvard Medical School Boston MA USA

Discipline of Psychiatry School of Medicine University of Queensland Herston QLD Australia

Division of Cerebral Integration National Institute for Physiological Sciences Aichi Japan

Division of Neuropsychiatry Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Houston TX USA

Division of Psychological and Social Medicine and Developmental Neurosciences Technische Universität Dresden Faculty of Medicine University Hospital C G Carus Dresden Germany

Erasmus University Medical Center Rotterdam The Netherlands

Florey Institute of Neuroscience and Mental Health Parkville VIC Australia

Harvard Medical School and Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center Boston MA USA

Harvard Medical School Boston MA USA

Health Behaviour Research Group University of Newcastle Callaghan NSW Australia

Hunter Medical Research Institute Newcastle NSW Australia

Imaging Genetics Center Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Marina del Rey CA USA

Instituto de Alta Tecnología Médica Medellín Colombia

Kimel Family Translational Imaging Genetics Research Laboratory Campbell Family Mental Health Research Institute CAMH Department of Psychiatry University of Toronto Toronto ON Canada

Laboratory for Neuroimaging Department of Psychiatry Psychosomatic Medicine and Psychotherapy Goethe University Frankfurt Main Germany

Laboratory of Neuropsychiatry Department of Clinical and Behavioral Neurology IRCCS Santa Lucia Foundation Rome Italy

Luoyang 5th People's Hospital Henan Province China

Maryland Psychiatric Research Center Department of Psychiatry University of Maryland School of Medicine Baltimore MD USA

Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne and Melbourne Health Carlton South VIC Australia

Molecular Research Center for Children's Mental Development United Graduate School of Child Development Osaka University Osaka Japan

Murdoch Childrens Research Institute The Royal Children's Hospital Parkville VIC Australia

National Institute of Mental Health Klecany Czech Republic

Neuroimaging Unit Technological Facilities Valdecilla Biomedical Research Institute IDIVAL Santander Spain

Neuropsychiatry Unit Royal Melbourne Hospital Parkville VIC Australia

Neuroscience Research Australia and School of Psychiatry University of New South Wales Sydney NSW Australia

Neuroscience Research Australia Sydney NSW Australia

NORMENT KG Jebsen Centre for Psychosis Research Division of Mental Health and Addiction Oslo University Hospital and Institute of Clinical Medicine University of Oslo Oslo Norway

Olin Neuropsychiatric Research Center Institute of Living Hartford Hospital and Department of Psychiatry Yale University School of Medicine New Haven CT USA

Priority Centre for Brain and Mental Health Research The University of Newcastle Newcastle NSW Australia

Psychology Department and Neuroscience Institute Georgia State University Atlanta GA USA

Queensland Brain Institute The University of Queensland Brisbane QLD Australia and Queensland Centre for Mental Health Research Brisbane and Queensland Centre for Mental Health Research Brisbane QLD Australia

Research Group in Psychiatry Department of Psychiatry Faculty of Medicine Universidad de Antioquia Medellín Colombia

Research Group in Psychiatry Department of Psychiatry Faculty of Medicine Universidad de Antioquia Mood Disorder Program Hospital Universitario San Vicente Fundación Medellín Colombia

Santa Lucia Foundation Rome Italy

Schizophrenia Research Institute Sydney NSW Australia

School of Biomedical Sciences Faculty of Health the University of Newcastle Callaghan NSW Australia

School of Electrical Engineering and Computer Science University of Newcastle Callaghan NSW Australia

School of Psychiatry University of New South Wales Sydney NSW Australia

School of Psychology Shaanxi Normal University and Key Laboratory for Behavior and Cognitive Neuroscience of Shaanxi Province Xi'an Shaanxi China

SU UCT MRC Unit on Anxiety and Stress Disorders Department of Psychiatry Stellenbosch University Stellenbosch South Africa

Sunshine Coast Mind and Neuroscience Institute University of the Sunshine Coast QLD Australia Brain and Mind Centre University of Sydney Sydney NSW Australia

Swinburne University of Technology Melbourne VIC Australia

The Department of Electrical and Computer Engineering University of New Mexico Albuquerque NM USA

The Florey Institute of Neuroscience and Mental Health University of Melbourne Melbourne VIC Australia

The Mind Research Network Albuquerque NM USA

The University of Newcastle Newcastle NSW Australia

The University of Queensland Queensland Brain Institute and Centre for Advanced Imaging Brisbane QLD Australia

The University of Texas Health Science Center at Houston Houston TX USA

University Hospital Marqués de Valdecilla IDIVAL Department of Medicine and Psychiatry School of Medicine University of Cantabria Santander Spain

University of California VAMC San Francisco CA USA

University of Edinburgh Edinburgh UK

University of Iowa Iowa City IA USA

University of New Mexico Albuquerque NM USA

University of New South Wales School of Psychiatry Sydney NSW Australia

University of Oslo Oslo Norway

University of Western Australia Perth WA Australia

VA Boston Healthcare System Boston MA USA

VABHS Harvard Medical School Boston MA USA

Worldwide Research and Development Pfizer Cambridge MA USA

Zhumadian Psychiatry Hospital Henan Province China

Zobrazit více v PubMed

Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011; 21: 655–679. PubMed

Friston KJ. Dysfunctional connectivity in schizophrenia. World Psychiatry 2002; 1: 66–71. PubMed PMC

Kanaan RAA, Kim J-SS, Kaufmann WE, Pearlson GD, Barker GJ, McGuire PK. Diffusion tensor imaging in schizophrenia. Biol Psychiatry 2005; 58: 921–929. PubMed

Konrad A, Winterer G. Disturbed structural connectivity in schizophrenia primary factor in pathology or epiphenomenon? Schizophr Bull 2008; 34: 72–92. PubMed PMC

Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 2009; 108: 3–10. PubMed

Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001; 98: 4746–4751. PubMed PMC

Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR et al. White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 2003; 60: 443–456. PubMed

Bohlken MM, Brouwer RM, Mandl RCC, Kahn RSS, Hulshoff Pol HE. Genetic variation in schizophrenia liability is shared with intellectual ability and brain structure. Schizophr Bull 2016; 42: 1167–1175. PubMed PMC

Kubicki M, Shenton ME. Diffusion tensor imaging findings and their implications in schizophrenia. Curr Opin Psychiatry 2014; 27: 179–184. PubMed

Samartzis L, Dima D, Fusar-Poli P, Kyriakopoulos M. White matter alterations in early stages of schizophrenia: a systematic review of diffusion tensor imaging studies. J Neuroimaging 2014; 24: 101–110. PubMed

Wheeler AL, Voineskos AN. A review of structural neuroimaging in schizophrenia: from connectivity to connectomics. Front Hum Neurosci 2014; 8: 653. PubMed PMC

Pettersson-Yeo W, Allen P, Benetti S, McGuire P, Mechelli A. Dysconnectivity in schizophrenia: where are we now? Neurosci Biobehav Rev 2011; 35: 1110–1124. PubMed

Kubicki M, McCarley R, Westin C-F, Park H-J, Maier S, Kikinis R et al. A review of diffusion tensor imaging studies in schizophrenia. J Psychiatr Res 2005; 41: 15–30. PubMed PMC

Zalesky A, Fornito A, Seal M, Cocchi L, Westin C-F, Bullmore E et al. Disrupted axonal fiber connectivity in schizophrenia. Biol Psychiatry 2011; 69: 80–89. PubMed PMC

Hubl D, Koenig T, Strik W, Federspiel A, Kreis R, Boesch C et al. Pathways that make voices: white matter changes in auditory hallucinations. Arch Gen Psychiatry 2004; 61: 658–668. PubMed

Klauser P, Baker S, Cropley V, Bousman C, Fornito A, Cocchi L et al. White matter disruptions in schizophrenia are spatially widespread and topologically converge on brain network hubs. Schizophr Bull 2016; 43: 425–435. PubMed PMC

Melicher T, Horacek J, Hlinka J, Spaniel F, Tintera J, Ibrahim I et al. White matter changes in first episode psychosis and their relation to the size of sample studied: a DTI study. Schizophr Res 2015; 162: 22–28. PubMed

Jahanshad N, Kochunov P, Sprooten E, Mandl R, Nichols T, Almasy L et al. Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA–DTI working group. Neuroimage 2013; 81: 455–469. PubMed PMC

Kochunov P, Jahanshad N, Sprooten E, Nichols T, Mandl R, Almasy L et al. Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: comparing meta and megaanalytical approaches for data pooling. Neuroimage 2014; 95: 136–150. PubMed PMC

Kochunov P, Jahanshad N, Marcus D, Winkler A, Sprooten E, Nichols T et al. Heritability of fractional anisotropy in human white matter: a comparison of Human Connectome Project and ENIGMA-DTI data. Neuroimage 2015; 111: 300–311. PubMed PMC

van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA et al. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry 2015; 21: 585–585. PubMed PMC

Kochunov P, Williamson DE, Lancaster J, Fox P, Cornell J, Blangero J et al. Fractional anisotropy of water diffusion in cerebral white matter across the lifespan. Neurobiol Aging 2012; 33: 9–20. PubMed PMC

Hibar DP, Westlye LT, van Erp TG, Rasmussen J, Leonardo CD, Faskowitz J et al. Subcortical volumetric abnormalities in bipolar disorder. Mol Psychiatry 2016; 21: 1710–1716. PubMed PMC

Schmaal L, Veltman D, Erp T, Sämann P, Frodl T, Jahanshad N et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. Mol Psychiatry 2015; 21: 806–812. PubMed PMC

Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry 2016; 22: 900–909. PubMed PMC

Cohen J. CHAPTER 1. The concepts of power analysis. Statistical power analysis for the behavioral sciences. Lawrence Erlbaum: Hillsdale, NJ, 1977.

Van den Heuvel M, Sporns O, Collin G, Scheewe T, Mandl R, Cahn W et al. Abnormal rich club organization and functional brain dynamics in schizophrenia. JAMA Psychiatry 2013; 70: 783–792. PubMed

Aydin K, Ucok A, Guler J. Altered metabolic integrity of corpus callosum among individuals at ultra high risk of schizophrenia and first-episode patients. Biol Psychiatry 2008; 64: 750–757. PubMed

Rotarska-Jagiela A, Schönmeyer R, Oertel V, Haenschel C, Vogeley K, Linden D. The corpus callosum in schizophrenia-volume and connectivity changes affect specific regions. Neuroimage 2008; 39: 1522–1532. PubMed

Walterfang M, Wood A, Reutens D, Wood S, Chen J, Velakoulis D et al. Corpus callosum size and shape in first-episode affective and schizophrenia-spectrum psychosis. Psychiatry Res 2009; 173: 77–82. PubMed

Bora E, Fornito A, Radua J, Walterfang M, Seal M, Wood S et al. Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophr Res 2011; 127: 46–57. PubMed

Levitt J, Alvarado J, Nestor P, Rosow L, Pelavin P, McCarley R et al. Fractional anisotropy and radial diffusivity: diffusion measures of white matter abnormalities in the anterior limb of the internal capsule in schizophrenia. Schizophr Res 2012; 136: 55–62. PubMed

Rosenberger G, Nestor P, Oh J, Levitt J, Kindleman G, Bouix S et al. Anterior limb of the internal capsule in schizophrenia: a diffusion tensor tractography study. Brain Imaging Behav 2012; 6: 417–425. PubMed PMC

Ćurčić-Blake B, Nanetti L, van der Meer L, Cerliani L, Renken R, Pijnenborg G et al. Not on speaking terms: hallucinations and structural network disconnectivity in schizophrenia. Brain Struct Funct 2015; 220: 407–418. PubMed

Nestor P, Kubicki M, Kuroki N, Gurrera R, Niznikiewicz M, Shenton M et al. Episodic memory and neuroimaging of hippocampus and fornix in chronic schizophrenia. Psychiatry Res 2007; 155: 21–28. PubMed

Prakash KN, Nowinski W. Morphologic relationship among the corpus callosum, fornix, anterior commissure, and posterior commissure MRI-based variability study. Acad Radiol 2006; 13: 24–35. PubMed

Pai D, Soltanian-Zadeh H, Hua J. Evaluation of fiber bundles across subjects through brain mapping and registration of diffusion tensor data. Neuroimage 2011; 54: S165–S175. PubMed

Alba-Ferrara LM, de Erausquin GA. What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia. Front Integr Neurosci 2013; 7: 9. PubMed PMC

Highley R, Esiri M, McDonald B, Cortina-Borja M, Herron B, Crow T. The size and fibre composition of the corpus callosum with respect to gender and schizophrenia: a post-mortem study. Brain 1999; 122: 99–110. PubMed

Highley JR, Esiri M, McDonald B, Roberts H, Walker M, Crow T. The size and fiber composition of the anterior commissure with respect to gender and schizophrenia. Biol Psychiatry 1999; 45: 1120–1127. PubMed

Rametti G, Junqué C, Falcón C, Bargalló N, Catalán R, Penadés R et al. A voxel-based diffusion tensor imaging study of temporal white matter in patients with schizophrenia. Psychiatry Res 2009; 171: 166–176. PubMed

Chiapponi C, Piras F, Fagioli S, Piras F, Caltagirone C, Spalletta G. Age-related brain trajectories in schizophrenia: a systematic review of structural MRI studies. Psychiatry Res 2013; 214: 83–93. PubMed

Kochunov P, Ganjgahi H, Winkler A, Kelly S, Shukla D, Du X et al. Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia. Hum Brain Mapp 2016; 37: 4673–4688. PubMed PMC

Whitford T, Kubicki M, Schneiderman J, O’Donnell L, King R, Alvarado J et al. Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia. Biol Psychiatry 2010; 68: 70–77. PubMed PMC

Mamah D, Conturo T, Harms M, Akbudak E, Wang L, McMichael A et al. Anterior thalamic radiation integrity in schizophrenia: a diffusion-tensor imaging study. Psychiatry Res Neuroimaging 2010; 183: 144–150. PubMed PMC

Knöchel C, O’Dwyer L, Alves G, Reinke B, Magerkurth J, Rotarska-Jagiela A et al. Association between white matter fiber integrity and subclinical psychotic symptoms in schizophrenia patients and unaffected relatives. Schizophr Res 2012; 140: 129–135. PubMed

Kyriakopoulos M, Samartzis L, Dima D, Hayes D, Corrigall R, Barker G et al. P03-111 - Does antipsychotic medication affect white matter in schizophrenia and bipolar disorder? A review of diffusion tensor imaging literature. Eur Psychiatry 2011; 26: 1280.

Franke B, Stein JL, Ripke S, Anttila V, Hibar DP, van Hulzen KJE et al. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat Neurosci 2016; 19: 420–431. PubMed PMC

Cassoli JS, Guest PC, Malchow B, Schmitt A, Falkai P, Martins-de-Souza D. Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules. NPJ Schizophr 2015; 1: 15034. PubMed PMC

Cropley VL, Klauser P, Lenroot RK, Bruggemann J, Sundram S, Bousman C et al. Accelerated gray and white matter deterioration with age in schizophrenia. Am J Psychiatry 2016; 174: 286–295. PubMed

Pasternak O, Westin CF, Bouix S, Seidman L, Goldstein JM, Woo TU et al. Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. J Neurosci 2012; 32: 17365–17372. PubMed PMC

Pasternak O, Westin CF, Dahlben B, Bouix S, Kubicki M. The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia. Schizophr Res 2015; 161: 113–118. PubMed PMC

Acheson A, Wijtenburg SA, Rowland RM, Winkler A, Mathias CW, Hong LE et al. Redroducibility of tract-based white matter microstructural measures using the ENIGMA-DTI protocol. Brain Behav 2017; 7: e00615. PubMed PMC

Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 2006; 31: 1487–1505. PubMed

Zalesky A. Moderating registration misalignment in voxelwise comparisons of DTI data: a performance evaluation of skeleton projection. Magn Reson Imaging 2011; 29: 111–125. PubMed

Schwarz CG, Reid RI, Gunter JL, Senjem ML, Przybelski SA, Zuk SM et al. Improved DTI registration allows voxel-based analysis that outperforms tract-based spatial statistics. Neuroimage 2014; 94: 65–78. PubMed PMC

Bach M, Laun FB, Leemans A, Tax CMW, Biessels GJ, Stieltjes B et al. Methodological considerations on tract-based spatial statistics (TBSS). Neuroimage 2014; 100: 358–369. PubMed

Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group

On the Role of Bilateral Brain Hypofunction and Abnormal Lateralization of Cortical Information Flow as Neural Underpinnings of Conventional Metaphor Processing Impairment in Schizophrenia: An fMRI and EEG Study

The Relationship Between White Matter Microstructure and General Cognitive Ability in Patients With Schizophrenia and Healthy Participants in the ENIGMA Consortium

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?