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Longitudinal inference of multiscale markers in psychosis: from hippocampal centrality to functional outcome

Molecular Psychiatry (2024)Cite this article

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Abstract

Multiscale neuroscience conceptualizes mental illness as arising from aberrant interactions across and within multiple biopsychosocial scales. We leverage this framework to propose a multiscale disease progression model of psychosis, in which hippocampal-cortical dysconnectivity precedes impairments in episodic memory and social cognition, which lead to more severe negative symptoms and lower functional outcome. As psychosis represents a heterogeneous collection of biological and behavioral alterations that evolve over time, we further predict this disease progression for a subtype of the patient sample, with other patients showing normal-range performance on all variables. We sampled data from two cross-sectional datasets of first- and multi-episode psychosis, resulting in a sample of 163 patients and 119 non-clinical controls. To address our proposed disease progression model and evaluate potential heterogeneity, we applied a machine-learning algorithm, SuStaIn, to the patient data. SuStaIn uniquely integrates clustering and disease progression modeling and identified three patient subtypes. Subtype 0 showed normal-range performance on all variables. In comparison, Subtype 1 showed lower episodic memory, social cognition, functional outcome, and higher negative symptoms, while Subtype 2 showed lower hippocampal-cortical connectivity and episodic memory. Subtype 1 deteriorated from episodic memory to social cognition, negative symptoms, functional outcome to bilateral hippocampal-cortical dysconnectivity, while Subtype 2 deteriorated from bilateral hippocampal-cortical dysconnectivity to episodic memory and social cognition, functional outcome to negative symptoms. This first application of SuStaIn in a multiscale psychiatric model provides distinct disease trajectories of hippocampal-cortical connectivity, which might underlie the heterogeneous behavioral manifestations of psychosis.

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Fig. 1: Methods workflow.
Fig. 2: Subtype differences and disease progression.
Fig. 3: Subtype and stage inference.
Fig. 4: FEP and MEP along low and high negative symptoms.

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Data availability

The datasets generated during and/or analysed during the current study are not publicly available due to containing sensitive patient information but are available from the corresponding author on reasonable request.

Code availability

The code for the steps of data preparation and SuStaIn has been made publicly available on GitHub (https://github.com/janatotzek/2023-multiscale-markers-psychosis).

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Acknowledgements

We would like to thank all participants who took part in the two studies which contributed to our project. We would also like to thank PEPP-Montréal and the CRISP Research Lab of the Douglas Research Centre for participant recruitment and data collection. We would also like to thank Caroline Dakoure and Joshua Unrau for their support with data preparation and Karyne Anselmo for her help with reconstructing the SOFAS. A special thank you also goes to Alan C. Evans for early methodological guidance. We used the high-performance computing resources available via the Digital Research Alliance of Canada (https://alliancecan.ca/en).

Funding

Funding Study 1 was funded by the Canadian Institutes of Health Research in collaboration with the Otsuka Lundbeck Alliance (#141636), while Study 2 was funded by the Canadian Institutes of Health Research (#106434) and the Otsuka/Lundbeck Alliance (#20135257). This research was undertaken thanks in part to funding from the Canada First Research Excellence Fund and Fonds de recherche du Québec, awarded to the Healthy Brains, Healthy Lives initiative at McGill University. The funding agencies did not influence the study design, data collection or writing of the manuscript.

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Author notes

  1. These authors contributed equally: Martin Lepage, Katie M. Lavigne.

Authors and Affiliations

  1. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Jana F. Totzek, M. Mallar Chakravarty, Ridha Joober, Ashok Malla, Jai L. Shah, Delphine Raucher-Chéné, Martin Lepage & Katie M. Lavigne

  2. Douglas Research Centre, Montreal, QC, Canada

    Jana F. Totzek, M. Mallar Chakravarty, Ridha Joober, Ashok Malla, Jai L. Shah, Delphine Raucher-Chéné, Martin Lepage & Katie M. Lavigne

  3. Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands

    Jana F. Totzek

  4. Department of Biological and Biomedical Engineering, McGill University, Montreal, QC, Canada

    M. Mallar Chakravarty

  5. Department of Computer Science, University College London, London, United Kingdom

    Alexandra L. Young

  6. Department of Psychiatry & Neuropsychology, School for Mental Health and NeuroScience MHeNS, Maastricht University, Maastricht, The Netherlands

    Dennis Hernaus

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Contributions

Conceptualization: ML, KML, JFT. Supervision: ML, KML, DH. Writing—Original Draft: JFT. Formal analysis: JFT. Writing—Review & Editing: JFT, KML, RJ, AM, JLS, ML, DH, ALY, DR. Software: JFT, KML, ALY, MMC. Methodology: JFT, KML, ALY. Visualization: JFT. Funding Acquisition: ML, MMC, RJ, AM, JLS.

Corresponding author

Correspondence to Katie M. Lavigne.

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Competing interests

ML holds salary awards through the James McGill Professorship and reports grants from Otsuka Lundbeck Alliance, Hoffman-La Roche, personal fees from Lundbeck Canada, personal fees from Otsuka Canada, personal fees from Boehringer-Ingelheim, grants and personal fees from Janssen outside the submitted work. KML reports personal fees from Otsuka Canada, Lundbeck Canada, and Boehringer Ingelheim. DH has received financial compensation as a consultant for P1vitalProducts Ltd. These activities were unrelated to the work presented in this manuscript. JLS holds a salary award from the Fonds de recherche du Québec—Santé. AM reports receipt of grants, fees or honoraria from Lundbeck and Otsuka and salary awards by the Canada Research Chairs program. MMC holds salary awards from the Fonds de Recherche du Québec—Santé and reports funding from the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Weston Brain Institute, Healthy Brains Healthy Lives, and the Fonds de Recherche du Québec—Santé. RJ served as member of advisory board committees and speaker for Bristol Myers Squibb, Pfizer, Sunovian, Janssen, Myelin and Associates, Lundbeck, Otsuka, Shire, and Perdue, and received grants from Janssen, Otsuka, Lundbeck, Bristol Myers Squibb, Astra Zeneca, and HLS Therapeutics Inc. ALY was supported by a Skills Development Fellowship (MR/T027800/1) from the Medical Research Council and a Career Development Award from the Wellcome Trust [227341/Z/23/Z]. This research was funded in whole, or in part, by the Wellcome Trust [227341/Z/23/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. JFT reports receipt of the Healthy Brains Healthy Lives Graduate Student Fellowship. All of these disclosures are unrelated to the present study.

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Totzek, J.F., Chakravarty, M.M., Joober, R. et al. Longitudinal inference of multiscale markers in psychosis: from hippocampal centrality to functional outcome. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02549-x

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