Abstract
Symptom severity in schizophrenia has been repeatedly associated with thinner cortical gray matter. While global and regional white matter microstructure alterations in schizophrenia are well-documented, their association with clinical symptom severity remains unclear. As this is likely due to methodological heterogeneity across studies, we tested whether symptom severity in schizophrenia was associated with regional and global white matter alterations using standardized methods. We hypothesized that positive symptom severity would be associated with temporal white matter changes and that negative symptom severity would be associated with alterations in frontal white matter. Using a standardized fractional anisotropy (FA) analysis pipeline developed by the ENIGMA consortium, we conducted a meta-analysis of the association between white matter microstructure and symptom severity in n = 1025 (ages 16–68 years; 369 women/656 men) across 19 ENIGMA sites. Where significant heterogeneity was detected across sites, we examined whether variation in association strength between white matter microstructure and symptom severity was explained by duration of illness and/or current antipsychotic use. Positive symptom severity was significantly associated with white matter microstructure as measured using temporal lobe FA and global FA. Negative symptom severity showed no significant association with white matter microstructure as measured using frontal lobe FA or global FA. Significant heterogeneity across sites was observed for the negative symptom analysis, explained partly by duration of illness. Post-hoc exploratory analyses identified one site as disproportionately contributing to this heterogeneity, and when removed, negative symptom severity was significantly associated with both global and frontal FA. These findings support the view of schizophrenia as a disorder of brain connectivity, in a manner relevant to understanding variation in clinical symptom severity.
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Data availability
The data that support the findings of this study are available from the corresponding author (G.D.) upon reasonable request.
Code availability
The codes supporting the findings of this study are available from the first author (A.W.) upon reasonable request.
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Funding
This research was generously supported by grants from the European Research Council (grant no. 677467), Science Foundation Ireland (16/ERCS/3787), and the Health Research Board (RL-2020-007) to G.D., and by the Ministry of Health of the Czech Republic (grant no. NU22-04-00143) to F.S. The ENIGMA Schizophrenia Working Group gratefully acknowledges support from the NIH BD2K award, U54EB020403.
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All authors are members of the ENIGMA Schizophrenia Working Group and contributed data following established protocols (https://doi.org/10.1038/mp.2017.170; https://doi.org/10.1176/appi.ajp.2019.19030225). Each participating site performed site-specific preliminary analyses to assess associations between white matter tract microstructure and symptom severity, accounting for scanner and acquisition differences. G.D. supervised the study. A.W. and L.H. carried out the pooled data analysis, with guidance from G.D. A.W. and G.D. wrote the manuscript. T.v.E. and J.T. currently lead the ENIGMA Schizophrenia Working Group. All authors contributed to manuscript review and editing and approved the final version.
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The authors declare no conflicts of interest related to this work. N.J. and P.T. received a research grant from Biogen, Inc., for research unrelated to this manuscript. O.A.A. is a consultant for HealthLytix.
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Warren, A., Holleran, L., Agartz, I. et al. An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia. Schizophr (2026). https://doi.org/10.1038/s41537-026-00728-z
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DOI: https://doi.org/10.1038/s41537-026-00728-z
