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An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia.

Overview

Authors: Aoife Warren1, Laurena Holleran1, Ingrid Agartz2, Ole A. Andreassen3, Nerisa Banaj4, Dara M. Cannon1, Aiden Corvin5, Melissa Green6, Ruben Gur7, Ryota Hashimoto8, Elliot Hong9, Cyril Hoschl10, Peter Kochunov9,11, Stephen M. Lawrie12, Colm McDonald1, Derek Morris1, David Mothersill1,13, Emma Neilson12, Christos Pantelis6, Fabrizio Piras4
and 16 other authorsPaul E. Rasser14,15, David Roalf8, Theodore D. Satterthwaite7, Ulrich Schall14, Kang Sim16, Antonin Skoch10, Gianfranco Spalletta4, Filip Spaniel10, Sophia Thomopoulos17, David Tomecek10, Andrew Zalesky6, Paul M. Thompson17, Neda Jahanshad17, Jessica A. Turner18, Theo G. M. van Erp19,20, Gary Donohoe1
ORCID iDs: Ole A. Andreassen, Dara M. Cannon, Aiden Corvin, Melissa Green, Ruben Gur, Stephen M. Lawrie, Colm McDonald, Christos Pantelis, Kang Sim, Antonin Skoch, Filip Spaniel, Jessica A. Turner
20 affiliations
  1. School of Psychology, Centre for Neuroimaging, Cognition and Genomics (NICOG), & Galway Neuroscience Centre, University of Galway,Galway, Ireland
  2. NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo,Oslo, Norway
  3. Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo,Oslo, Norway
  4. Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation,Rome, Italy
  5. Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin,Dublin, Ireland
  6. Systems Lab, Departments of Psychiatry & Biomedical Engineering, University of Melbourne,Melbourne, VIC Australia
  7. Department of Psychiatry, University of Pennsylvania,Philadelphia, PA USA
  8. Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry,Kodaira, Tokyo Japan
  9. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine,Baltimore, MD USA
  10. National Institute of Mental Health,Klecany, Czechia
  11. University of Maryland Center for Brain Imaging Research, University of Maryland,Baltimore, MD USA
  12. Department of Psychiatry, University of Edinburgh,Edinburgh, UK
  13. Department of Psychology, School of Business, National College of Ireland,Dublin, Ireland
  14. Centre for Brain & Mental Health Research, The University of Newcastle,Newcastle, NSW Australia
  15. Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Callaghan,Newcastle, NSW Australia
  16. West Region, Institute of Mental Health,Singapore, Singapore
  17. Imaging Genetics Center, Keck School of Medicine, University of Southern California,Los Angeles, CA USA
  18. Department of Psychiatry & Behavioral Health, Wexner Medical Center, The Ohio State University,Columbus, OH USA
  19. Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine,Irvine, CA USA
  20. Center for the Neurobiology of Learning and Memory, University of California Irvine,Irvine, CA USA
Institutions: Ollscoil na Gaillimhe – University of Galway (Ireland); University of Oslo (Norway); Fondazione Santa Lucia (Italy); Trinity College Dublin (Ireland); The University of Melbourne (Australia); University of Pennsylvania (United States); National Center of Neurology and Psychiatry (Japan); University of Maryland, Baltimore (United States); National Institute of Mental Health (Czechia); University of Edinburgh (United Kingdom); National College of Ireland (Ireland); University of Newcastle Australia (Australia); Institute of Mental Health (Singapore); University of Southern California (United States); The Ohio State University (United States); University of California, Irvine (United States)
Journal: Schizophrenia (Heidelberg, Germany), volume 12, issue 1, article 38
Dates: received 6 August 2025; accepted 7 January 2026; published online 6 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41537-026-00728-z · PMID 41792186 · PMCID PMC13087269 · OpenAlex W7134072080
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: structural MRI / diffusion (modality), human (organism), schizophrenia / psychosis (population), clinical / translational (subfield)
Methods: Smoothing, state filtering, decompositions, Statistics, Evoked potentials, fMRI & imaging
Keywords: Schizophrenia
Topic: Advanced Neuroimaging Techniques and Applications (Radiology, Nuclear Medicine and Imaging, Medicine), according to OpenAlex
Funding: EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (677467); Science Foundation Ireland (SFI) (16/ERCS/3787); Core funding for the ENIGMA Center for Worldwide Medicine Imaging and Genomics was provided as part of the 2014 NIH Big Data to Knowledge (BD2K) Initiative under U54EB020403 (PI: Paul Thompson) to support big data analytics, management and distribution of programs
Citations: not cited yet (Europe PMC); 64 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

Code availability

The codes supporting the findings of this study are available from the first author (A.W.) upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

No dataset and no data link were found in the paper.

Data availability

The data that support the findings of this study are available from the corresponding author (G.D.) upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 36 authors, 1 keyword, 3 funders, 60 references.

Cite

This paper

Warren, A., Holleran, L., Agartz, I., Andreassen, O. A., Banaj, N., Cannon, D. M., Corvin, A., Green, M., Gur, R., Hashimoto, R., Hong, E., Hoschl, C., Kochunov, P., Lawrie, S. M., McDonald, C., Morris, D., Mothersill, D., Neilson, E., Pantelis, C., . . . Donohoe, G. (2026). An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia. Schizophrenia (Heidelberg, Germany), 12(1), 38. https://doi.org/10.1038/s41537-026-00728-z

BibTeX

@article{warren2026enigma,
author = {Warren, Aoife and Holleran, Laurena and Agartz, Ingrid and Andreassen, Ole A. and Banaj, Nerisa and Cannon, Dara M. and Corvin, Aiden and Green, Melissa and Gur, Ruben and Hashimoto, Ryota and Hong, Elliot and Hoschl, Cyril and Kochunov, Peter and Lawrie, Stephen M. and McDonald, Colm and Morris, Derek and Mothersill, David and Neilson, Emma and Pantelis, Christos and Piras, Fabrizio and Rasser, Paul E. and Roalf, David and Satterthwaite, Theodore D. and Schall, Ulrich and Sim, Kang and Skoch, Antonin and Spalletta, Gianfranco and Spaniel, Filip and Thomopoulos, Sophia and Tomecek, David and Zalesky, Andrew and Thompson, Paul M. and Jahanshad, Neda and Turner, Jessica A. and van Erp, Theo G. M. and Donohoe, Gary},
title = {{An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia}},
journal = {Schizophrenia (Heidelberg, Germany)},
year = {2026},
month = mar,
volume = {12},
number = {1},
pages = {38},
publisher = {Nature Publishing Group},
issn = {2754-6993},
doi = {10.1038/s41537-026-00728-z},
url = {https://doi.org/10.1038/s41537-026-00728-z},
pmid = {41792186},
pmcid = {PMC13087269}
}

RIS

TY - JOUR
AU - Warren, Aoife
AU - Holleran, Laurena
AU - Agartz, Ingrid
AU - Andreassen, Ole A.
AU - Banaj, Nerisa
AU - Cannon, Dara M.
AU - Corvin, Aiden
AU - Green, Melissa
AU - Gur, Ruben
AU - Hashimoto, Ryota
AU - Hong, Elliot
AU - Hoschl, Cyril
AU - Kochunov, Peter
AU - Lawrie, Stephen M.
AU - McDonald, Colm
AU - Morris, Derek
AU - Mothersill, David
AU - Neilson, Emma
AU - Pantelis, Christos
AU - Piras, Fabrizio
AU - Rasser, Paul E.
AU - Roalf, David
AU - Satterthwaite, Theodore D.
AU - Schall, Ulrich
AU - Sim, Kang
AU - Skoch, Antonin
AU - Spalletta, Gianfranco
AU - Spaniel, Filip
AU - Thomopoulos, Sophia
AU - Tomecek, David
AU - Zalesky, Andrew
AU - Thompson, Paul M.
AU - Jahanshad, Neda
AU - Turner, Jessica A.
AU - van Erp, Theo G. M.
AU - Donohoe, Gary
TI - An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia
T2 - Schizophrenia (Heidelberg, Germany)
J2 - Schizophrenia (Heidelb)
PY - 2026
DA - 2026/03/06
VL - 12
IS - 1
SP - 38
SN - 2754-6993
PB - Nature Publishing Group
DO - 10.1038/s41537-026-00728-z
UR - https://doi.org/10.1038/s41537-026-00728-z
LA - en
ER -

CSL-JSON

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