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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Isabella Goodwin - , University of Melbourne (Author)
  • Kit Melissa Larsen - , University of Copenhagen (Author)
  • Arshiya Sangchooli - , University of Melbourne, Monash University (Author)
  • Robert E. Smith - , Florey Institute of Neuroscience and Mental Health, University of Melbourne (Author)
  • Tobias Banaschewski - , Heidelberg University  (Author)
  • Gareth J. Barker - , King's College London (KCL) (Author)
  • Arun L.W. Bokde - , Trinity College Dublin (Author)
  • Rüdiger Brühl - , National Metrology Institute of Germany (PTB) (Author)
  • Sylvane Desrivières - , King's College London (KCL) (Author)
  • Hugh Garavan - , University of Vermont (Author)
  • Penny Gowland - , University of Nottingham (Author)
  • Antoine Grigis - , NeuroSpin (Author)
  • Andreas Heinz - , Charité – Universitätsmedizin Berlin (Author)
  • Herve Lemaitre - , Université de Bordeaux (Author)
  • Jean Luc Martinot - , École normale supérieure Paris-Saclay (Author)
  • Marie Laure Paillère Martinot - , École normale supérieure Paris-Saclay, Public Assistance - Paris Hospitals (Author)
  • Eric Artiges - , École normale supérieure Paris-Saclay, EPS Barthélémy Durand (Author)
  • Frauke Nees - , Heidelberg University , University Hospital Schleswig-Holstein Campus Kiel (Author)
  • Dimitri Papadopoulos Orfanos - , University of Mannheim (Author)
  • Tomáš Paus - , University of Montreal, McGill University (Author)
  • Luise Poustka - , Heidelberg University  (Author)
  • Michael N. Smolka - , Department of Psychiatry and Psychotherapy (Author)
  • Nilakshi Vaidya - , Charité – Universitätsmedizin Berlin (Author)
  • Henrik Walter - , Berlin Institute of Health at Charité (Author)
  • Robert Whelan - , Trinity College Dublin (Author)
  • Gunter Schumann - , TUD Dresden University of Technology, Fudan University (Author)
  • Robert Hester - , University of Melbourne (Author)
  • Marta I. Garrido - , University of Melbourne (Author)

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.

Details

Original languageEnglish
Article numbere70414
JournalHuman brain mapping
Volume46
Issue number17
Publication statusPublished - 1 Dec 2025
Peer-reviewedYes

External IDs

PubMed 41368887
ORCID /0000-0001-5398-5569/work/203072352

Keywords

Keywords

  • diffusion-weighted imaging, fixel-based analysis, psychotic-like experiences, white matter