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Subgroup-specific brain connectivity alterations in early stages of psychosis

Nature Mental Health volume 3, pages 408–420 (2025)Cite this article

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Abstract

Functional brain scans have shown that connectivity alterations are strongly associated with the first episode of psychosis, yet it is not well understood whether these alterations vary with the clinical status of patients at the time of scanning. This cross-sectional study aimed to identify brain connectivity properties that differentiate remitting and non-remitting early psychosis (EP) patients from healthy controls and to explore the mechanisms underlying these differences. To this end, we analyzed resting-state fMRI and DSI data from 88 EP patients categorized by their remission ability after the first episode of psychosis. We focused on differences between stage III remitting–relapsing (EP3R) and stage III non-remitting (EP3NR) patients. Opposing functional connectivity (FC) alterations were observed: EP3NR patients exhibited lower FC compared with controls, while EP3R patients showed higher FC, possibly reflecting compensatory mechanisms. Whole-brain network modeling revealed lower local stability affecting the ability to regulate the flow of stimuli across the network in stage III patients, particularly in EP3R, which may indicate an adaptation to impaired network conductivity. These findings highlight subgroup-specific brain alterations and underscore the importance of considering this source of heterogeneity in psychosis research.

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Fig. 1: Schematic representation of the analysis workflow, featuring clinical staging model, empirical connectivity analyses and whole-brain model fitting.
Fig. 2: Participants included at each stage of the study.
Fig. 3: Empirical functional connectivity alterations.
Fig. 4: Whole-brain model of HC.
Fig. 5: Toy model: simplified network of coupled Hopf oscillators.
Fig. 6: Whole-brain model of patient groups compared with HC.

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Data availability

The dataset used in the current study can be accessed only with a data sharing agreement with the Lausanne University Hospital and University of Lausanne (CHUV-UNIL) and is available from the corresponding author on reasonable request.

Code availability

The code used in this study is available via GitHub at https://github.com/LudoMana/NATMH-23-1084A.

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Acknowledgments

The project that gave rise to these results received the support of a fellowship from ‘la Caixa’ foundation (ID 100010434). The fellowship code is LCF/BQ/DI19/11730048) and financed L.M.’s work. In addition, G.D., M.V.-V. and L.M. were supported by the Human Brain Project Specific Grant Agreement 3 Grant agreement no. 945539 financed by the European Commission and by the Spanish Research Project ref. PID2019-105772GB-I00/AEI/10.13039/501100011033, financed by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI). This last institution also financed M.V.-V through the grant/award number PID2020-119072RA-I00/AEI/10.13039/501100011033. G.D. was supported by the project NEurological MEchanismS of Injury, and Sleep-like cellular dynamics (NEMESIS) (ref. 101071900) funded by the EU ERC Synergy Horizon Europe; by the NODYN Project PID2022-136216NBI00 funded by MICIU/AEI/10.13039/501100011033 and by ‘ERDF A way of making Europe,’ ERDF, EU; by the AGAUR research support grant (ref. 2021 SGR 00917) funded by the Department of Research and Universities of the Generalitat of Catalunya; and by the project eBRAIN-Health—Actionable Multilevel Health Data (ID 101058516), funded by the EU Horizon Europe. A.L.-G. was supported by Swiss National Science Foundation Sinergia grant no. 170873. L.A.E. was supported by a research grant of University of Lausanne, Switzerland. L.A. was supported by a fellowship of the Adrian and Simone Frutiger Foundation and from Carigest Foundation. P.K. was supported by a fellowship from the Adrian and Simone Frutiger Foundation. Y.A.-G. and P.H. were financially supported by Swiss National Science Foundation grant no. 320030-197787. None of the funders had any role in the conceptualization, design, data collection, analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Manel Vila-Vidal, Gustavo Deco.

Authors and Affiliations

  1. Center for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain

    Ludovica Mana, Ane López-González, Manel Vila-Vidal & Gustavo Deco

  2. Department of Radiology, Lausanne University Hospital and the University of Lausanne (CHUV-UNIL), Lausanne, Switzerland

    Yasser Alemán-Gómez & Patric Hagmann

  3. Service of General Psychiatry, Treatment and Early Intervention in Psychosis Program, Lausanne University Hospital (CHUV), Lausanne, Switzerland

    Philipp S. Baumann, Luis Alameda, Lilith Abrahamyan Empson & Philippe Conus

  4. Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital and the University of Lausanne, Lausanne, Switzerland

    Raoul Jenni & Paul Klauser

  5. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College of London, London, UK

    Luis Alameda

  6. Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM); Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Departamento de Psiquiatría, Universidad de Sevilla, Seville, Spain

    Luis Alameda

  7. Service of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital and the University of Lausanne, Lausanne, Switzerland

    Paul Klauser

  8. Computational Biology and Complex Systems Group, Department of Physics, Universitat Politècnica de Catalunya, Barcelona, Spain

    Manel Vila-Vidal

  9. Institució Catalana de la Recerca i Estudis Avancats (ICREA), Barcelona, Spain

    Gustavo Deco

Authors
  1. Ludovica Mana
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  2. Ane López-González
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  6. Luis Alameda
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  7. Lilith Abrahamyan Empson
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  8. Paul Klauser
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  11. Manel Vila-Vidal
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  12. Gustavo Deco
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Contributions

R.J., P.S.B., P.K., P.C., L.A. and L.A.E. collected data and performed clinical evaluation. P.S.B. and P.K. assessed the clinical staging. P.H. and Y.A.-G. collected and pre-processed the neuroimaging data. A.L.-G., L.M., M.V.-V. and G.D. designed the research. L.M., A.L.-G. and M.V.-V. analyzed the data L.M. and M.V.-V. wrote the manuscript. M.V.-V. and G.D. supervised the research. All authors contributed to the editing of the manuscript.

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Correspondence to Ludovica Mana.

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Nature Mental Health thanks Leanne Williams and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–8, Tables 1–3, Methods and Results.

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Mana, L., López-González, A., Alemán-Gómez, Y. et al. Subgroup-specific brain connectivity alterations in early stages of psychosis. Nat. Mental Health 3, 408–420 (2025). https://doi.org/10.1038/s44220-025-00394-7

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