Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study
Authors: Georgiadis Foivos , Larivière Sara , Glahn David , Hong L. Elliot , Kochunov Peter , Mowry Bryan , Loughland Carmel , Pantelis Christos , Henskens Frans A. , Green Melissa J. , Cairns Murray J. , Michie Patricia T , Rasser Paul E. , Tooney Paul , Scott Rodney J. , Catts Stanley , Schall Ulrich , Carr Vaughan , Quidé Yann , Krug Axel , Stein Frederike , Nenadić Igor , Brosch Katharina , Kircher Tilo , Gur Raquel , Gur Ruben , Satterthwaite Theodore D. , Karuk Andriana , Clotet Edith Pomarol- , Radua Joaquim , Fuentes-Claramonte Paola , Salvador Raymond , Spalletta Gianfranco , Voineskos Aristotle , Sim Kang , Crespo-Facorro Benedicto , Gutiérrez Diana Tordesillas , Ehrlich Stefan , Crossley Nicolas , Grotegerd Dominik , Repple Jonathan , Lencer Rebekka , Dannlowski Udo , Calhoun Vince , Demro Caroline , Ramsay Ian S. , Sponheim Scott R. , Schmidt Andre , Borgwardt Stefan , Tomyshev Alexander S. , Lebedeva Irina , Hoschl Cyril , Spaniel Filip , Preda Adrian , Nguyen Dana , Uhlmann Anne , Stein Dan J , Howells Fleur M , Temmingh Henk S. , Diaz Zuluaga Ana M. , Jaramillo Carlos López , Iasevoli Felice , Ji Ellen , Homan Stephanie , Omlor Wolfgang , Homan Philipp , Kaiser Stefan , Seifritz Erich , Misic Bratislav , Valk Sofie L. , Thompson Paul , van Erp Theo G.M. , Turner Jessica , Bernhardt Boris , Kirschner Matthias 
Published: February 2023

While schizophrenia is considered a prototypical network disorder characterized by widespread brain-morphological alterations, it still remains unclear whether distributed structural alterations robustly reflect underlying network layout. Here, 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 2,439 adults with schizophrenia and 2,867 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 identify 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. Schizophrenia-related structural alterations co-localized with interconnected functional and structural hubs and harbored temporo-paralimbic and frontal epicenters. Findings were robust across sites and related to individual symptom profiles. We observed localized unique epicenters for first-episode psychosis and early stages, and transmodal epicenters that were shared across first-episode to chronic stages. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, yielding insights in 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 contributes to recognizing potentially common pathways to better understand macroscale structural alterations, and inter-individual variability in schizophrenia.