Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Department of child and adolescent psychiatry TU Dresden Dresden Germany

Department of Pediatric Neurology University of California Irvine Irvine CA USA

Department of Psychiatry and Behavioral Health the Ohio State University Columbus OH 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 Psychotherapy Philipps University Marburg Marburg Germany

Department of Psychiatry Harvard Medical School Boston MA USA

Department of Psychiatry Pontificia Universidad Católica de Chile Santiago Chile

Department of Psychiatry Psychotherapy and Psychosomatics Psychiatric Hospital University of Zurich Zurich Switzerland

Department of Psychiatry University of Lübeck Lübeck Germany

Department of Psychiatry University of Marburg Rudolf Bultmann Str 8 35039 Marburg Germany

Department of Radiology Marqués de Valdecilla University Hospital Valdecilla Biomedical Research Institute IDIVAL Santander Spain

Division of Adult Psychiatry Department of Psychiatry Geneva University Hospitals Geneva Switzerland

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

Faculty of Medicine University of Queensland St Lucia QLD Australia

FIDMAG Germanes Hospitalàries Research Foundation and CIBERSAM ISCIII Barcelona Spain

Forschungszentrum Jülich Jülich Germany

Hospital Universitario Virgen del Rocío IBiS CSIC Universidad de Sevilla Seville Spain

Hunter Medical Research Institute Newcastle NSW Australia

Imaging Genetics Center Stevens Institute for Neuroimaging and Informatics Keck School of Medicine University of Southern California Los Angeles CA USA

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institute for Translational Psychiatry University of Münster Münster Germany

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

Max Planck Institute for Cognitive and Brain Sciences Leipzig Germany

McGill University Montreal Neurological Institute Montreal QC Canada

Melbourne Neuropsychiatry Centre Department of Psychiatry The University of Melbourne Carlton South VIC Australia

Mental Health Research Center Moscow Russian Federation

Minneapolis VA Health Care System Minneapolis MN USA

National Institute of Mental Health Topolova 748 250 67 Klecany Czech Republic

Queensland Brain Institute The University of Queensland St Lucia QLD Australia

Research Group in Psychiatry Department of Psychiatry School of Medicine Universidad de Antioquia Medellin Colombia

Santa Lucia Foundation IRCCS Santa Lucia Rome Italy

School of Biomedical Science and Pharmacy University of Newcastle Newcastle NSW Australia

School of Clinical Medicine Discipline of Psychiatry and Mental Health UNSW Sydney Sydney NSW Australia

School of Clinical Medicine Discipline of Psychiatry UNSW Sydney Sydney NSW Australia

School of Medicine and Public Health College of Health Medicine and Wellbeing The University of Newcastle Callaghan NSW Australia

School of Medicine and Public Health University of Newcastle Newcastle NSW Australia

School of Medicine and Public Health University of Newcastle Newcastle NSW USA

School of Psychological Sciences University of Newcastle Newcastle NSW Australia

Tri Institutional Center for Translational Research in Neuroimaging and Data Science Georgia State Georgia Tech Emory Atlanta GA USA

University Hospital Bonn Department of Psychiatry and Psychotherapy Venusberg Campus 1 53127 Bonn Germany

University of Basel Department of Psychiatry Basel Switzerland

University of Minnesota Department of Psychiatry and Behavioral Sciences Minneapolis MN USA

University of Minnesota Department of Psychology Minneapolis MN USA

University of Naples Department of Neuroscience Naples Italy

University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

West Region Institute of Mental Health Singapore Singapore

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