Psychotic‐Like Experiences and White Matter Microstructure: A Fixel‐Based Analysis Approach With Robust Replication Across Two Cohorts

Structural deficits in white matter fibre have been linked to psychosis. However, it remains unclear whether these aberrations are present in individuals that experience non-clinical psychotic-like experiences, predating illness onset. While previous research demonstrates that alterations in white matter in schizotypy are consistent with those in clinical psychosis, these studies often dichotomise healthy samples into high and low schizotypy, which may reduce statistical sensitivity. Previous research is also confounded by the investigation of diffusion MRI parameters that fail to account for complex crossing fibre populations. In this work, we treat psychotic-like experiences as a continuous variable, and applied Fixel-Based Analysis (FBA), a framework for investigating microstructural and morphological effects in brain white matter using diffusion-weighted imaging data. Across two independent cohorts of healthy participants with varied psychotic-like experiences including data from the IMAGEN consortium (Study 1 n = 41; Study 2 n = 1098), we hypothesized that greater psychotic-like experiences would be associated with FBA metrics sensitive to microstructural fibre density and/or cross-sectional morphological effects. Contrary to our hypothesis, we did not find significant correlations between psychotic-like experiences and FBA metrics across either dataset (FWE p < 0.05). Bayesian analysis of tract-aggregated data showed substantial evidence of no association (Bayes factor < 1/3) between psychotic-like experiences and fibre density, nor cross-sectional morphology, across several white matter tracts of interest, pre-defined from prior neuroimaging literature. These findings suggest that the relationship between non-clinical psychotic-like experiences and white matter microstructure may not be as robust as previously thought. This raises the possibility that white matter alterations across the psychosis spectrum echo clinical diagnostic thresholding, with observable effects in clinical but not sub-clinical presentations. Our findings show no association between whole-brain fibre-specific properties of white matter microstructure and sub-clinical psychotic-like experiences. Further, we show evidence for the lack of an association within tract-aggregated fibre-specific metrics. Future research should integrate longitudinal designs to explore whether fibre-specific white matter attributes provide clinically meaningful insight into the risk of psychosis onset.

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Journal
Human Brain Mapping
Published
2025-12-01
DOI
https://doi.org/10.1002/hbm.70414
Primary Topic
Advanced Neuroimaging Techniques and Applications
Type
article
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0.00

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article

Psychotic‐Like Experiences and White Matter Microstructure: A Fixel‐Based Analysis Approach With Robust Replication Across Two Cohorts

Sylvane Desrivières, Tomáš Paus, Tobias Banaschewski, Jean‐Luc Martinot et al.
Human Brain Mapping
Advanced Neuroimaging Techniques and Applications
article

Psychotic‐Like Experiences and White Matter Microstructure: A Fixel‐Based Analysis Approach With Robust Replication Across Two Cohorts

Sylvane Desrivières, Tomáš Paus, Tobias Banaschewski, Jean‐Luc Martinot, Marie‐Laure Paillère Martinot, Arun L.W. Bokde, Andreas Heinz, Isabella Goodwin, Antoine Grigis, Hervé Lemaître, Michael N. Smolka, Dimitri Papadopoulos Orfanos, Marta I. Garrido, Kit Melissa Larsen, Frauke Nees, Gareth J. Barker, Eric Artiges A, Robert Hester, Arshiya Sangchooli, Günter Schumann, Robert E. Smith, Hugh Garavan, Henrik Walter, Nilakshi Vaidya, Luise Poustka, Robert Whelan, Penny Gowland, Rüdiger Brühl
article en

Abstract

Structural deficits in white matter fibre have been linked to psychosis. However, it remains unclear whether these aberrations are present in individuals that experience non-clinical psychotic-like experiences, predating illness onset. While previous research demonstrates that alterations in white matter in schizotypy are consistent with those in clinical psychosis, these studies often dichotomise healthy samples into high and low schizotypy, which may reduce statistical sensitivity. Previous research is also confounded by the investigation of diffusion MRI parameters that fail to account for complex crossing fibre populations. In this work, we treat psychotic-like experiences as a continuous variable, and applied Fixel-Based Analysis (FBA), a framework for investigating microstructural and morphological effects in brain white matter using diffusion-weighted imaging data. Across two independent cohorts of healthy participants with varied psychotic-like experiences including data from the IMAGEN consortium (Study 1 n = 41; Study 2 n = 1098), we hypothesized that greater psychotic-like experiences would be associated with FBA metrics sensitive to microstructural fibre density and/or cross-sectional morphological effects. Contrary to our hypothesis, we did not find significant correlations between psychotic-like experiences and FBA metrics across either dataset (FWE p < 0.05). Bayesian analysis of tract-aggregated data showed substantial evidence of no association (Bayes factor < 1/3) between psychotic-like experiences and fibre density, nor cross-sectional morphology, across several white matter tracts of interest, pre-defined from prior neuroimaging literature. These findings suggest that the relationship between non-clinical psychotic-like experiences and white matter microstructure may not be as robust as previously thought. This raises the possibility that white matter alterations across the psychosis spectrum echo clinical diagnostic thresholding, with observable effects in clinical but not sub-clinical presentations. Our findings show no association between whole-brain fibre-specific properties of white matter microstructure and sub-clinical psychotic-like experiences. Further, we show evidence for the lack of an association within tract-aggregated fibre-specific metrics. Future research should integrate longitudinal designs to explore whether fibre-specific white matter attributes provide clinically meaningful insight into the risk of psychosis onset.

Human Brain MappingVol. 46(17)
University of Vermont (US), Technische Hochschule Mannheim (DE), Physikalisch-Technische Bundesanstalt (DE), Centre National de la Recherche Scientifique (FR), University of Nottingham (GB), Université de Bordeaux (FR), Inserm (FR), Wellcome Centre for Human Neuroimaging (GB), The University of Melbourne (AU), University of Mannheim (DE), King's College London (GB), Trinity College Dublin (IE), Heidelberg University (DE), Florey Institute of Neuroscience and Mental Health (AU), Fudan University (CN), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University Hospital Heidelberg (DE), Centre Hospitalier Universitaire Sainte-Justine (CA), Copenhagen University Hospital (DK), Hochschule für Angewandte Wissenschaften Kiel (DE), Christian-Albrechts-Universität zu Kiel (DE), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Institut des Maladies Neurodégénératives (FR), Central Institute of Mental Health (DE), University Hospital Schleswig-Holstein (DE), Pitié-Salpêtrière Hospital (FR), CEA Paris-Saclay (FR), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Laboratoire de Biologie et Pharmacologie Appliquée (FR), Einstein Center for Neurosciences Berlin (DE), Shanghai Center for Brain Science and Brain-Inspired Technology (CN), McGill University (CA), Monash University (AU), Australian Psychological Society (AU), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE), University of Lübeck (DE)
Fondation de l'Avenir pour la Recherche Médicale Appliquée, UK Research and Innovation, Australian Government, National Imaging Facility, European Commission, Science Foundation Ireland, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, Lundbeckfonden, Fondation de France, Fédération pour la Recherche sur le Cerveau, Mission Interministérielle de Lutte Contre les Drogues et les Conduites Addictives, H. Lundbeck A/S, National Institutes of Health, HORIZON EUROPE Framework Programme, Medical Research Council, Centre of Excellence for Integrative Brain Function, Australian Research Council
Openalex Percentile: Top 46%
Advanced Neuroimaging Techniques and Applications
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