Meta-Analysis

. 2025 Apr 1;182(4):373-388.

doi: 10.1176/appi.ajp.20230806. Epub 2025 Feb 26.

Estimating Multimodal Structural Brain Variability in Schizophrenia Spectrum Disorders: A Worldwide ENIGMA Study

Wolfgang Omlor¹, Finn Rabe¹, Simon Fuchs¹, Werner Surbeck¹, Giacomo Cecere¹, Gao-Yang Huang¹, Stephanie Homan¹, Nils Kallen¹, Foivos Georgiadis¹, Tobias Spiller¹, Erich Seifritz¹, Thomas Weickert¹, Jason Bruggemann¹, Cynthia Weickert¹, Steven Potkin¹, Ryota Hashimoto¹, Kang Sim¹, Kelly Rootes-Murdy¹, Yann Quide¹, Josselin Houenou¹, Nerisa Banaj¹, Daniela Vecchio¹, Fabrizio Piras¹, Federica Piras¹, Gianfranco Spalletta¹, Raymond Salvador¹, Andriana Karuk¹, Edith Pomarol-Clotet¹, Amanda Rodrigue¹, Godfrey Pearlson¹, David Glahn¹, David Tomecek¹, Filip Spaniel¹, Antonin Skoch¹, Matthias Kirschner¹, Stefan Kaiser¹, Peter Kochunov¹, Feng-Mei Fan¹, Ole A Andreassen¹, Lars T Westlye¹, Pierre Berthet¹, Vince D Calhoun¹, Fleur Howells¹, Anne Uhlmann¹, Freda Scheffler¹, Dan Stein¹, Felice Iasevoli¹, Murray J Cairns¹, Vaughan J Carr¹, Stanley V Catts¹, Maria A Di Biase¹, Assen Jablensky¹, Melissa J Green¹, Frans A Henskens¹, Paul Klauser¹, Carmel Loughland¹, Patricia T Michie¹, Bryan Mowry¹, Christos Pantelis¹, Paul E Rasser¹, Ulrich Schall¹, Rodney Scott¹, Andrew Zalesky¹, Andrea de Bartolomeis¹, Annarita Barone¹, Mariateresa Ciccarelli¹, Arturo Brunetti¹, Sirio Cocozza¹, Giuseppe Pontillo¹, Mario Tranfa¹, Annabella Di Giorgio¹, Sophia I Thomopoulos¹, Neda Jahanshad¹, Paul M Thompson¹, Theo van Erp¹, Jessica Turner¹, Philipp Homan¹

Affiliations

Affiliation

¹ Psychiatric Hospital, University of Zurich, Zurich (Omlor, Rabe, Fuchs, Surbeck, Cecere, Huang, S. Homan, Kallen, Georgiadis, Spiller, Seifritz, Kirschner, P. Homan); Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich (Huang, P. Homan); Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY (T. Weickert, C. Weickert); Edith Collins Centre, Sydney Local Health District, Sydney (Bruggemann); Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior (Potkin, van Erp), and Center for the Neurobiology of Learning and Memory (van Erp), University of California Irvine, Irvine; Department of Pathology of Mental Diseases, National Center of Neurology and Psychiatry, National Institute of Mental Health, Tokyo (Hashimoto); Institute of Mental Health, Singapore (Sim); Psychology Department and Neuroscience Institute, Georgia State University, Atlanta (Rootes-Murdy); School of Psychology, University of New South Wales, Sydney (Quide); Hopitaux Universitaires Henri Mondor, Crétail, France (Houenou); Neuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS, Rome (Banaj, Vecchio, Fabrizio Piras, Federica Piras, Spalletta); FIDMAG Sisters Hospitallers Research Foundation, Barcelona, Spain (Salvador, Karuk, Pomarol-Clotet); Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston (Rodrigue, Glahn); Department of Psychiatry, Yale University, New Haven, CT, and Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT (Pearlson); National Institute of Mental Health, Klecany, Czech Republic (Tomecek, Spaniel, Skoch); Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva (Kirschner, Kaiser); Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore (Kochunov); Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing (Fan); NORMENT Center, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, and K.G. Jebsen Center for Neurodevelopment, University of Oslo, Oslo (Andreassen, Westlye, Berthet); Neuroscience Institute (Howells) and Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa (Howells, Uhlmann); Department of Child and Adolescent Psychiatry, Technische Universität Dresden, Dresden, Germany (Uhlmann); SA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Neuroscience Institute, University of Cape Town, Cape Town, South Africa (Scheffler, Stein); Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Reproductive and Odontostomatological Sciences, Department of Neuroscience, University of Naples Federico II, Naples (Iasevoli); Neuroscience Research Australia, Sydney (T. Weickert, C. Weickert, Bruggemann, Quide); School of Psychiatry, University of New South Wales, Sydney (T. Weickert, C. Weickert, Bruggemann); Specialty of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney (Bruggemann); Department of Psychiatry and Behavioral Health, Wexner Medical Center, Ohio State University, Columbus (Turner); Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta (Calhoun); School of Biomedical Sciences and Pharmacy (Cairns, Scott), Centre for Brain and Mental Health Research (Cairns, Loughland, Schall), School of Medicine and Public Health, College of Health, Medicine, and Wellbeing (Henskens, Rasser), Priority Research Centre for Health Behaviour (Henskens), and School of Psychological Sciences (Michie), University of Newcastle, Callaghan, Australia; Hunter Medical Research Institute, New Lambton Heights, Australia (Cairns, Loughland, Schall); School of Clinical Medicine, Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney (Carr, Green); Neuroscience Research Australia, Randwick (Carr, Green); Department of Psychiatry, Monash University, Clayton, Australia (Carr); School of Medicine, University of Queensland, Brisbane, Australia (Catts); Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Carlton South, Australia (Di Biase, Klauser, Pantelis, Zalesky); Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston (Di Biase); University of Western Australia, Perth (Jablensky); Hunter Medical Research Institute, Newcastle, Australia (Henskens, Michie); Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, Australia (Klauser); Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (Klauser); Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Australia (Mowry); Florey Institute of Neuroscience and Mental Health, Parkville, Australia (Pantelis); Melbourne School of Engineering, University of Melbourne, Parkville, Australia (Zalesky); Section of Psychiatry, Department of Neuroscience (de Bartolomeis, Barone, Ciccarelli), Department of Advanced Biomedical Sciences (Brunetti, Cocozza, Pontillo, Tranfa), and Department of Electrical Engineering and Information Technology (Pontillo), University Federico II, Naples; ASST Papa Giovanni XXIII, Mental Health Department, Bergamo, Italy (Di Giorgio); Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles (Thomopoulos, Jahanshad, Thompson).

PMID: 40007253
PMCID: PMC13022572
DOI: 10.1176/appi.ajp.20230806

Meta-Analysis

Estimating Multimodal Structural Brain Variability in Schizophrenia Spectrum Disorders: A Worldwide ENIGMA Study

Wolfgang Omlor et al. Am J Psychiatry. 2025.

. 2025 Apr 1;182(4):373-388.

doi: 10.1176/appi.ajp.20230806. Epub 2025 Feb 26.

Authors

Affiliation

¹ Psychiatric Hospital, University of Zurich, Zurich (Omlor, Rabe, Fuchs, Surbeck, Cecere, Huang, S. Homan, Kallen, Georgiadis, Spiller, Seifritz, Kirschner, P. Homan); Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, Zurich (Huang, P. Homan); Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY (T. Weickert, C. Weickert); Edith Collins Centre, Sydney Local Health District, Sydney (Bruggemann); Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior (Potkin, van Erp), and Center for the Neurobiology of Learning and Memory (van Erp), University of California Irvine, Irvine; Department of Pathology of Mental Diseases, National Center of Neurology and Psychiatry, National Institute of Mental Health, Tokyo (Hashimoto); Institute of Mental Health, Singapore (Sim); Psychology Department and Neuroscience Institute, Georgia State University, Atlanta (Rootes-Murdy); School of Psychology, University of New South Wales, Sydney (Quide); Hopitaux Universitaires Henri Mondor, Crétail, France (Houenou); Neuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, Santa Lucia Foundation IRCCS, Rome (Banaj, Vecchio, Fabrizio Piras, Federica Piras, Spalletta); FIDMAG Sisters Hospitallers Research Foundation, Barcelona, Spain (Salvador, Karuk, Pomarol-Clotet); Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston (Rodrigue, Glahn); Department of Psychiatry, Yale University, New Haven, CT, and Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT (Pearlson); National Institute of Mental Health, Klecany, Czech Republic (Tomecek, Spaniel, Skoch); Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva (Kirschner, Kaiser); Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore (Kochunov); Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing (Fan); NORMENT Center, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, and K.G. Jebsen Center for Neurodevelopment, University of Oslo, Oslo (Andreassen, Westlye, Berthet); Neuroscience Institute (Howells) and Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa (Howells, Uhlmann); Department of Child and Adolescent Psychiatry, Technische Universität Dresden, Dresden, Germany (Uhlmann); SA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Neuroscience Institute, University of Cape Town, Cape Town, South Africa (Scheffler, Stein); Laboratory of Molecular and Translational Psychiatry and Unit of Treatment Resistant Psychosis, Section of Psychiatry, Reproductive and Odontostomatological Sciences, Department of Neuroscience, University of Naples Federico II, Naples (Iasevoli); Neuroscience Research Australia, Sydney (T. Weickert, C. Weickert, Bruggemann, Quide); School of Psychiatry, University of New South Wales, Sydney (T. Weickert, C. Weickert, Bruggemann); Specialty of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney (Bruggemann); Department of Psychiatry and Behavioral Health, Wexner Medical Center, Ohio State University, Columbus (Turner); Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta (Calhoun); School of Biomedical Sciences and Pharmacy (Cairns, Scott), Centre for Brain and Mental Health Research (Cairns, Loughland, Schall), School of Medicine and Public Health, College of Health, Medicine, and Wellbeing (Henskens, Rasser), Priority Research Centre for Health Behaviour (Henskens), and School of Psychological Sciences (Michie), University of Newcastle, Callaghan, Australia; Hunter Medical Research Institute, New Lambton Heights, Australia (Cairns, Loughland, Schall); School of Clinical Medicine, Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney (Carr, Green); Neuroscience Research Australia, Randwick (Carr, Green); Department of Psychiatry, Monash University, Clayton, Australia (Carr); School of Medicine, University of Queensland, Brisbane, Australia (Catts); Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Carlton South, Australia (Di Biase, Klauser, Pantelis, Zalesky); Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston (Di Biase); University of Western Australia, Perth (Jablensky); Hunter Medical Research Institute, Newcastle, Australia (Henskens, Michie); Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, Australia (Klauser); Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (Klauser); Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Australia (Mowry); Florey Institute of Neuroscience and Mental Health, Parkville, Australia (Pantelis); Melbourne School of Engineering, University of Melbourne, Parkville, Australia (Zalesky); Section of Psychiatry, Department of Neuroscience (de Bartolomeis, Barone, Ciccarelli), Department of Advanced Biomedical Sciences (Brunetti, Cocozza, Pontillo, Tranfa), and Department of Electrical Engineering and Information Technology (Pontillo), University Federico II, Naples; ASST Papa Giovanni XXIII, Mental Health Department, Bergamo, Italy (Di Giorgio); Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles (Thomopoulos, Jahanshad, Thompson).

PMID: 40007253
PMCID: PMC13022572
DOI: 10.1176/appi.ajp.20230806

Abstract

Objective: The clinical diversity of schizophrenia is reflected by structural brain variability. It remains unclear how this variability manifests across different gray and white matter features. In this meta- and mega-analysis, the authors investigated how brain heterogeneity in schizophrenia is distributed across multimodal structural indicators.

Methods: The authors used the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6,037 individuals for a given brain measure. Variability and mean values of cortical thickness, cortical surface area, cortical folding index, subcortical volume, and fractional anisotropy were examined in individuals with schizophrenia and healthy control subjects.

Results: Individuals with schizophrenia showed greater variability in cortical thickness, cortical surface area, subcortical volume, and fractional anisotropy within the frontotemporal and subcortical network. This increased structural variability was mainly associated with psychopathological symptom domains, and the schizophrenia group frequently displayed lower mean values in the respective structural measures. Unexpectedly, folding patterns were more uniform in individuals with schizophrenia, particularly in the right caudal anterior cingulate region. The mean folding values of the right caudal anterior cingulate region did not differ between the schizophrenia and healthy control groups, and folding patterns in this region were not associated with disease-related parameters.

Conclusions: In patients with schizophrenia, uniform folding patterns in the right caudal anterior cingulate region contrasted with the multimodal variability in the frontotemporal and subcortical network. While variability in the frontotemporal and subcortical network was associated with disease-related diversity, uniform folding may indicate a less flexible interplay between genetic and environmental factors during neurodevelopment.

Keywords: Neuroimaging; Neuroscience; Schizophrenia Spectrum and Other Psychotic Disorders.

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Conflict of interest statement

Dr. Andreassen has served as a consultant for Cortechs.ai and has received speakers honoraria from Janssen, Lundbeck, and Sunovion. Dr. Seifritz has served as an adviser and provided educational lectures for Angelini, Janssen, Lundbeck, Mepha Pharma, Otsuka, Recordati, Sunovion, and Schwabe. Dr. P. Homan has received grants and honoraria from Boehringer Ingelheim, Janssen, Lundbeck, Mepha, Neurolite, and Novartis. The other authors report no financial relationships with commercial interests.

Figures

**Figure 1:. Variability ratio of cortical thickness.**
Lower panel: Variability ratio (VR) effect sizes for schizophrenia patients (SZ) vs. healthy controls (HC) are shown for different cortical regions and on a linear scale, statistically controlling for age and gender. Upper panel: VR effect sizes are projected onto the brain surface and color-coded as z-values. In these cortical maps, areas with higher VRs in patients appear in gradients of red, and areas with higher VRs in controls appear in gradients of blue. CI: Confidence Interval. Independent of the applied variability measure (variability ratio vs. coefficient of variation ratio), higher heterogeneity in schizophrenia was observed for the following regions: Bilateral superior, middle and inferior temporal region, bilateral superior frontal region, left supramarginal and fusiform region as well as right pars orbitalis and precentral region.

**Figure 2:. Variability ratio for cortical surface area.**
Same conventions as for Fig. 1. Higher heterogeneity in schizophrenia was observed for the following regions, irrespective of the deployed variability measure: Bilateral superiorfrontal and transverse temporal regions, cortical areas around the right superior temporal sulcus, right superiortemporal region, right supramarginal region, left postcentral region, right medialorbitofrontal region, left superiorparietal region, left precuneus, right middle temporal region and right lingual region.

**Figure 3:. Variability ratio for cortical folding index.**
Same conventions as for Fig. 1. Irrespective of the applied variability measure, schizophrenia patients exhibited higher heterogeneity in the right inferiortemporal region, but lower heterogeneity in the left parahippocampal area.

**Figure 4:. Variability ratio for subcortical volume.**
Same conventions as for Fig. 1. Lower panel: Variability ratio (VR) effect sizes are shown for subcortical volumes. Upper panel: VR effect sizes are projected onto respective subcortical structures and color-coded as z-values. In these subcortical maps, areas with higher VRs in patients appear in gradients of red, and areas with higher VRs in controls appear in gradients of blue. Independent of the applied variability measure, schizophrenia patients showed higher heterogeneity for lateral ventricles, left nucleus accumbens, left caudate and right hippocampus.

**Figure 5:. Variability ratio for fractional anisotropy.**
Same conventions as for Fig. 1. Lower panel: Variability ratio (VR) effect sizes are shown for fractional anisotropy (FA) of white matter structures. Upper panel: VR effect sizes are projected onto respective white matter structures and color-coded as z-values. In these maps, areas with higher VRs in patients appear in gradients of red, and areas with higher VRs in controls appear in gradients of blue. Irrespective of the deployed variability measure, higher homogeneity in schizophrenia was observed for the superior fronto-occipital fasciculus in both hemispheres.

**Figure 6:. PBSI analysis.**
PBSI for cortical thickness (CT), cortical surface area (SA), cortical folding Index (FI), subcortical volume (SV) and fractional anisotropy (FA).

See this image and copyright information in PMC

Update of

Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.
Omlor W, Rabe F, Fuchs S, Cecere G, Homan S, Surbeck W, Kallen N, Georgiadis F, Spiller T, Seifritz E, Weickert T, Bruggemann J, Weickert C, Potkin S, Hashimoto R, Sim K, Rootes-Murdy K, Quide Y, Houenou J, Banaj N, Vecchio D, Piras F, Piras F, Spalletta G, Salvador R, Karuk A, Pomarol-Clotet E, Rodrigue A, Pearlson G, Glahn D, Tomecek D, Spaniel F, Skoch A, Kirschner M, Kaiser S, Kochunov P, Fan FM, Andreassen OA, Westlye LT, Berthet P, Calhoun VD, Howells F, Uhlmann A, Scheffler F, Stein D, Iasevoli F, Cairns MJ, Carr VJ, Catts SV, Di Biase MA, Jablensky A, Green MJ, Henskens FA, Klauser P, Loughland C, Michie PT, Mowry B, Pantelis C, Rasser PE, Schall U, Scott R, Zalesky A, de Bartolomeis A, Barone A, Ciccarelli M, Brunetti A, Cocozza S, Pontillo G, Tranfa M, Di Giorgio A, Thomopoulos SI, Jahanshad N, Thompson PM, van Erp T, Turner J, Homan P. Omlor W, et al. bioRxiv [Preprint]. 2023 Nov 2:2023.09.22.559032. doi: 10.1101/2023.09.22.559032. bioRxiv. 2023. Update in: Am J Psychiatry. 2025 Apr 01;182(4):373-388. doi: 10.1176/appi.ajp.20230806. PMID: 37961617 Free PMC article. Updated. Preprint.

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Estimating Multimodal Structural Brain Variability in Schizophrenia Spectrum Disorders: A Worldwide ENIGMA Study

Affiliation

Estimating Multimodal Structural Brain Variability in Schizophrenia Spectrum Disorders: A Worldwide ENIGMA Study

Authors

Affiliation

Abstract

Conflict of interest statement

Figures

Update of

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous