Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.
Journal: Molecular psychiatry
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Affiliated Institutions:
Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Zurich, Switzerland. foivos.georgiadis@uzh.ch.
McGill University, Montreal Neurological Institute, Montreal, QC, Canada.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, US.
Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia.
School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, USA.
Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Carlton South, VIC, Australia.
School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.
School of Clinical Medicine, Discipline of Psychiatry and Mental Health, UNSW Sydney, Sydney, NSW, Australia.
School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
School of Psychological Sciences, University of Newcastle, Newcastle, NSW, Australia.
School of Medicine and Public Health, College of Health, Medicine, and Wellbeing, The University of Newcastle, Callaghan, NSW, Australia.
Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia.
Hunter Medical Research Institute, Newcastle, NSW, Australia.
School of Clinical Medicine, Discipline of Psychiatry, UNSW Sydney, Sydney, NSW, Australia.
University Hospital Bonn, Department of Psychiatry and Psychotherapy, Venusberg-Campus , , Bonn, Germany.
Department of Psychiatry, University of Marburg, Rudolf Bultmann Str. , , Marburg, Germany.
Department. of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
FIDMAG Germanes Hospitalàries Research Foundation & CIBERSAM, ISCIII, Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Santa Lucia Foundation IRCCS, Santa Lucia, Rome, Italy.
West Region, Institute of Mental Health, Singapore, Singapore.
Hospital Universitario Virgen del Rocío, IBiS-CSIC, Universidad de Sevilla, Seville, Spain.
Department of Radiology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute IDIVAL, Santander, Spain.
Division of Psychological & Social Medicine and Developmental Neurosciences, Technischen Universität Dresden, Faculty of Medicine, University Hospital C.G. Carus, Dresden, Germany.
Department of Psychiatry, Pontificia Universidad Católica de Chile, Santiago, Chile.
Institute for Translational Psychiatry, University of Münster, Münster, Germany.
Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State, Georgia Tech, Emory, Atlanta, GA, USA.
University of Minnesota Department of Psychology, Minneapolis, MN, USA.
University of Minnesota Department of Psychiatry & Behavioral Sciences, Minneapolis, MN, USA.
Minneapolis VA Health Care System, Minneapolis, MN, USA.
University of Basel, Department of Psychiatry, Basel, Switzerland.
Department of Psychiatry, University of Lübeck, Lübeck, Germany.
Mental Health Research Center, Moscow, Russian Federation.
National Institute of Mental Health, Topolova , , Klecany, Czech Republic.
Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
Department of Pediatric Neurology, University of California Irvine, Irvine, CA, USA.
Department of child and adolescent psychiatry, TU Dresden, Dresden, Germany.
Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
Research Group in Psychiatry, Department of Psychiatry, School of Medicine, Universidad de Antioquia, Medellin, Colombia.
University of Naples, Department of Neuroscience, Naples, Italy.
Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Zurich, Switzerland.
Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
Forschungszentrum Jülich, Jülich, Germany.
Imaging Genetics Center, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Psychiatry and Behavioral Health, the Ohio State University, Columbus, OH, USA.
Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Zurich, Switzerland. matthias.kirschner@hcuge.ch.
Abstract summary
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.
Authors & Co-authors:
Georgiadis Foivos F
Larivière Sara S
Glahn David D
Hong L Elliot LE
Kochunov Peter P
Mowry Bryan B
Loughland Carmel C
Pantelis Christos C
Henskens Frans A FA
Green Melissa J MJ
Cairns Murray J MJ
Michie Patricia T PT
Rasser Paul E PE
Catts Stanley S
Tooney Paul P
Scott Rodney J RJ
Schall Ulrich U
Carr Vaughan V
Quidé Yann Y
Krug Axel A
Stein Frederike F
Nenadić Igor I
Brosch Katharina K
Kircher Tilo T
Gur Raquel R
Gur Ruben R
Satterthwaite Theodore D TD
Karuk Andriana A
Pomarol-Clotet Edith E
Radua Joaquim J
Fuentes-Claramonte Paola P
Salvador Raymond R
Spalletta Gianfranco G
Voineskos Aristotle A
Sim Kang K
Crespo-Facorro Benedicto B
Tordesillas Gutiérrez Diana D
Ehrlich Stefan S
Crossley Nicolas N
Grotegerd Dominik D
Repple Jonathan J
Lencer Rebekka R
Dannlowski Udo U
Calhoun Vince V
Rootes-Murdy Kelly K
Demro Caroline C
Ramsay Ian S IS
Sponheim Scott R SR
Schmidt Andre A
Borgwardt Stefan S
Tomyshev Alexander A
Lebedeva Irina I
Höschl Cyril C
Spaniel Filip F
Preda Adrian A
Nguyen Dana D
Uhlmann Anne A
Stein Dan J DJ
Howells Fleur F
Temmingh Henk S HS
Diaz Zuluaga Ana M AM
López Jaramillo Carlos C
Iasevoli Felice F
Ji Ellen E
Homan Stephanie S
Omlor Wolfgang W
Homan Philipp P
Kaiser Stefan S
Seifritz Erich E
Misic Bratislav B
Valk Sofie L SL
Thompson Paul P
van Erp Theo G M TGM
Turner Jessica A JA
Bernhardt Boris B
Kirschner Matthias M
Study Outcome
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