Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Foivos Georgiadis, Sara Larivière, David Glahn, L. Elliot Hong, Peter Kochunov, Bryan Mowry, Carmel Loughland, Christos Pantelis, Frans A. Henskens, Melissa J. Green, Murray J. Cairns, Patricia T. Michie, Paul E. Rasser, Stanley Catts, Paul Tooney, Rodney J. Scott, Ulrich Schall, Vaughan Carr, Yann Quidé, Axel KrugFrederike Stein, Igor Nenadić, Katharina Brosch, Tilo Kircher, Raquel Gur, Ruben Gur, Theodore D. Satterthwaite, Andriana Karuk, Edith Pomarol- Clotet, Joaquim Radua, Paola Fuentes-Claramonte, Raymond Salvador, Gianfranco Spalletta, Aristotle Voineskos, Kang Sim, Benedicto Crespo-Facorro, Diana Tordesillas Gutiérrez, Stefan Ehrlich, Nicolas Crossley, Dominik Grotegerd, Jonathan Repple, Rebekka Lencer, Udo Dannlowski, Vince Calhoun, Kelly Rootes-Murdy, Caroline Demro, Ian S. Ramsay, Scott R. Sponheim, Andre Schmidt, Stefan Borgwardt, Alexander Tomyshev, Irina Lebedeva, Cyril Höschl, Filip Spaniel, Adrian Preda, Dana Nguyen, Anne Uhlmann, Dan J. Stein, Fleur Howells, Henk S. Temmingh, Ana M. Diaz Zuluaga, Carlos López Jaramillo, Felice Iasevoli, Ellen Ji, Stephanie Homan, Wolfgang Omlor, Philipp Homan, Stefan Kaiser, Erich Seifritz, Bratislav Misic, Sofie L. Valk, Paul Thompson, Theo G.M. van Erp, Jessica A. Turner, Boris Bernhardt, Matthias Kirschner

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish
JournalMolecular Psychiatry
StateAccepted/In press - 2024
Externally publishedYes


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