Elucidating the relationship between white matter structure, demographic, and clinical variables in schizophrenia—a multicenter harmonized diffusion tensor imaging study

Johanna Seitz-Holland, Suheyla Cetin-Karayumak, Joanne D. Wojcik, Amanda Lyall, James Levitt, Martha E. Shenton, Ofer Pasternak, Carl Fredrik Westin, Madhura Baxi, Sinead Kelly, Raquelle Mesholam-Gately, Mark Vangel, Godfrey Pearlson, Carol A. Tamminga, John A. Sweeney, Brett A. Clementz, David Schretlen, Petra Verena Viher, Katharina Stegmayer, Sebastian WaltherJungsun Lee, Tim Crow, Anthony James, Aristotle Voineskos, Robert W. Buchanan, Philip R. Szeszko, Anil K. Malhotra, Yogesh Rathi, Matcheri Keshavan, Marek Kubicki

Research output: Contribution to journalArticlepeer-review


White matter (WM) abnormalities are repeatedly demonstrated across the schizophrenia time-course. However, our understanding of how demographic and clinical variables interact, influence, or are dependent on WM pathologies is limited. The most well-known barriers to progress are heterogeneous findings due to small sample sizes and the confounding influence of age on WM. The present study leverages access to the harmonized diffusion magnetic-resonance-imaging data and standardized clinical data from 13 international sites (597 schizophrenia patients (SCZ)). Fractional anisotropy (FA) values for all major WM structures in patients were predicted based on FA models estimated from a healthy population (n = 492). We utilized the deviations between predicted and real FA values to answer three essential questions. (1) “Which clinical variables explain WM abnormalities?”. (2) “Does the degree of WM abnormalities predict symptom severity?”. (3) “Does sex influence any of those relationships?”. Regression and mediator analyses revealed that a longer duration-of-illness is associated with more severe WM abnormalities in several tracts. In addition, they demonstrated that a higher antipsychotic medication dose is related to more severe corpus callosum abnormalities. A structural equation model revealed that patients with more WM abnormalities display higher symptom severity. Last, the results exhibited sex-specificity. Males showed a stronger association between duration-of-illness and WM abnormalities. Females presented a stronger association between WM abnormalities and symptom severity, with IQ impacting this relationship. Our findings provide clear evidence for the interaction of demographic, clinical, and behavioral variables with WM pathology in SCZ. Our results also point to the need for longitudinal studies, directly investigating the casualty and sex-specificity of these relationships, as well as the impact of cognitive resiliency on structure-function relationships.

Original languageEnglish (US)
Pages (from-to)5357-5370
Number of pages14
JournalMolecular psychiatry
Issue number9
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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