Disentangling white matter correlates of symptom severity and general impairment in early psychosis

White matter (WM) alterations are well documented in individuals at clinical high-risk for psychosis (CHR-P) and with recent-onset psychosis (ROP), yet it remains unclear whether they reflect vulnerability, psychosis-related symptom severity, or general impairments shared with other disorders such as depression. To disentangle these correlates, we analyzed diffusion MRI data from 882 individuals (457 females) of the multisite Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, including 183 CHR-P, 206 ROP, 298 healthy controls, and 195 individuals with depression who were assessed as a clinical comparison group of observed associations. Fractional anisotropy (FA) was extracted from 25 WM regions. Analyses of covariance tested group differences across CHR-P, ROP, and healthy controls. Canonical correlation analysis then identified multivariate correlation components between FA and a broad set of twelve clinical, two cognitive, and two risk-related measures in CHR-P and ROP, restricted to regions with group effects. To identify if these findings are not specific to psychosis, we additionally tested whether the correlation components were expressed in the depression comparison group. Group differences emerged in 17 of 25 regions. Canonical correlation analysis identified two significant correlation components. Component 1 linked widespread lower FA with impaired cognition and functioning, representing general impairment. Component 2 linked focal lower FA with more severe psychosis-related symptoms and absence of familial risk. Component 1, but not Component 2, showed also a significant association in the depression group emphasizing its relevance for general impairment. Disentangling general impairment from psychosis-related symptom severity suggests potentially different underlying processes. Developing imaging biomarkers accounting for these processes may guide early detection strategies and targeted interventions.

Authors

Institutions

Publication Details

Journal
Molecular Psychiatry
Published
2026-08-20
DOI
https://doi.org/10.1038/s41380-026-03832-9
Primary Topic
Advanced Neuroimaging Techniques and Applications
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Disentangling white matter correlates of symptom severity and general impairment in early psychosis

Stephan Ruhrmann, Nora Penzel, Christos Pantelis, Marlene Rosen et al.
Molecular Psychiatry
Advanced Neuroimaging Techniques and Applications
article

Disentangling white matter correlates of symptom severity and general impairment in early psychosis

Stephan Ruhrmann, Nora Penzel, Christos Pantelis, Marlene Rosen, Suheyla Cetin‐Karayumak, Lana Kambeitz‐Ilankovic, Stephen James Wood, Dominic Dwyer, Anne Ruef, Giuseppe Cabras, Linda T. Betz, Ofer Pasternak, Ulrich Ettinger, Frauke Schultze‐Lutter, Shalaila S. Haas, Paolo Brambilla, Peter Falkai, Johanna Seitz‐Holland, Stefan Borgwardt, Martha E. Shenton, Grace R. Jacobs, Joseph Kambeitz, Nikolaos Koutsouleris, Rebekka Lencer, Kang Ik K. Cho, Pedro Costa Klein, Maria F. Urquijo Castro, Fan Zhang, Giulio Pergola, Linda A. Antonucci, Alessandro Bertolino, Raimo R. K. Salokangas, Theresa Lichtenstein, Rachel Upthegrove, Eva Meisenzahl
article en

Abstract

White matter (WM) alterations are well documented in individuals at clinical high-risk for psychosis (CHR-P) and with recent-onset psychosis (ROP), yet it remains unclear whether they reflect vulnerability, psychosis-related symptom severity, or general impairments shared with other disorders such as depression. To disentangle these correlates, we analyzed diffusion MRI data from 882 individuals (457 females) of the multisite Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, including 183 CHR-P, 206 ROP, 298 healthy controls, and 195 individuals with depression who were assessed as a clinical comparison group of observed associations. Fractional anisotropy (FA) was extracted from 25 WM regions. Analyses of covariance tested group differences across CHR-P, ROP, and healthy controls. Canonical correlation analysis then identified multivariate correlation components between FA and a broad set of twelve clinical, two cognitive, and two risk-related measures in CHR-P and ROP, restricted to regions with group effects. To identify if these findings are not specific to psychosis, we additionally tested whether the correlation components were expressed in the depression comparison group. Group differences emerged in 17 of 25 regions. Canonical correlation analysis identified two significant correlation components. Component 1 linked widespread lower FA with impaired cognition and functioning, representing general impairment. Component 2 linked focal lower FA with more severe psychosis-related symptoms and absence of familial risk. Component 1, but not Component 2, showed also a significant association in the depression group emphasizing its relevance for general impairment. Disentangling general impairment from psychosis-related symptom severity suggests potentially different underlying processes. Developing imaging biomarkers accounting for these processes may guide early detection strategies and targeted interventions.

Molecular Psychiatry
University of Bern (CH), University of Udine (IT), University of Bonn (DE), Harvard University (US), Johns Hopkins University (US), University of Turku (FI), The University of Melbourne (AU), University of Cologne (DE), King's College London (GB), University of Basel (CH), University of Milan (IT), Universitas Airlangga (ID), University of Münster (DE), Johns Hopkins Medicine (US), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), LMU Klinikum (DE), University of Oxford (GB), Düsseldorf University Hospital (DE), Max Planck Institute for Metabolism Research (DE), Orygen (AU), Western Health (AU), Sunshine Hospital (AU), GAIA (Germany) (DE), Max Planck Institute of Psychiatry (DE), Lieber Institute for Brain Development (US), University Hospital Cologne (DE), Heinrich Heine University Düsseldorf (DE), Mass General Brigham (US), University of Bari Aldo Moro (IT), Monash University (AU), University of Birmingham (GB), Ludwig-Maximilians-Universität München (DE), University of Lübeck (DE), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 10%
Advanced Neuroimaging Techniques and Applications
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.