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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • University of Zurich
  • McGill University Health Centre
  • Harvard University
  • University of Maryland, Baltimore
  • University of Queensland
  • University of Newcastle
  • University of Melbourne
  • University of New South Wales
  • Hunter Medical Research Institute (HMRI)
  • University of Bonn
  • University of Marburg
  • University of Pennsylvania
  • Sisters Hospitallers Research Foundation
  • August Pi i Sunyer Biomedical Research Institute
  • IRCCS Fondazione Santa Lucia - Roma
  • Singapore Institute of Mental Health
  • Hospital Universitario Virgen del Rocio
  • Hospital Universitario Marques de Valdecilla
  • University Hospital Carl Gustav Carus Dresden
  • Pontificia Universidad Católica de Chile
  • University of Münster
  • Georgia Institute of Technology
  • University of Minnesota System
  • Department of Veterans Affairs
  • University of Basel

Abstract

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.

Details

Original languageEnglish
Pages (from-to)1869-1881
Number of pages13
JournalMolecular psychiatry
Volume29
Issue number6
Early online date9 Feb 2024
Publication statusPublished - Jun 2024
Peer-reviewedYes

External IDs

PubMed 38336840
ORCID /0000-0002-1753-7811/work/173516979