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Robust and replicable functional brain signatures of 22q11.2 deletion syndrome and associated psychosis: a deep neural network-based multi-cohort study

Molecular Psychiatry (2024)Cite this article

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Abstract

A major genetic risk factor for psychosis is 22q11.2 deletion (22q11.2DS). However, robust and replicable functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis remain elusive due to small sample sizes and a focus on small single-site cohorts. Here, we identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis, and their links with idiopathic early psychosis, using one of the largest multi-cohort data to date. We obtained multi-cohort clinical phenotypic and task-free fMRI data from 856 participants (101 22q11.2DS, 120 idiopathic early psychosis, 101 idiopathic autism, 123 idiopathic ADHD, and 411 healthy controls) in a case-control design. A novel spatiotemporal deep neural network (stDNN)-based analysis was applied to the multi-cohort data to identify functional brain signatures of 22q11.2DS and 22q11.2DS-associated psychosis. Next, stDNN was used to test the hypothesis that the functional brain signatures of 22q11.2DS-associated psychosis overlap with idiopathic early psychosis but not with autism and ADHD. stDNN-derived brain signatures distinguished 22q11.2DS from controls, and 22q11.2DS-associated psychosis with very high accuracies (86–94%) in the primary cohort and two fully independent cohorts without additional training. Robust distinguishing features of 22q11.2DS-associated psychosis emerged in the anterior insula node of the salience network and the striatum node of the dopaminergic reward pathway. These features also distinguished individuals with idiopathic early psychosis from controls, but not idiopathic autism or ADHD. Our results reveal that individuals with 22q11.2DS exhibit a highly distinct functional brain organization compared to controls. Additionally, the brain signatures of 22q11.2DS-associated psychosis overlap with those of idiopathic early psychosis in the salience network and dopaminergic reward pathway, providing substantial empirical support for the theoretical aberrant salience-based model of psychosis. Collectively, our findings, replicated across multiple independent cohorts, advance the understanding of 22q11.2DS and associated psychosis, underscoring the value of 22q11.2DS as a genetic model for probing the neurobiological underpinnings of psychosis and its progression.

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Fig. 1: Study overview.
Fig. 2: Group-level functional brain signatures (feature attribution maps) of 22q11.2DS.
Fig. 3: Individual functional brain signatures (feature attribution maps) of 22q11.2DS and their distinctiveness.
Fig. 4: Group-level functional brain signatures (feature attribution maps) of 22q11.2DS with psychosis.
Fig. 5: Individual functional brain signatures (feature attribution maps) of 22q11.2DS with psychosis spectrum symptoms (22q-PS+) and their distinctiveness.

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Data availability

The processed fMRI regional time-series data along with demographic information will be made available upon reasonable request.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Kaustubh Supekar, Carlo de los Angeles, Srikanth Ryali & Vinod Menon

  2. Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA

    Kaustubh Supekar & Vinod Menon

  3. Department of Psychiatry and Behavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA

    Leila Kushan & Carrie E. Bearden

  4. Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA

    Leila Kushan, Charlie Schleifer & Carrie E. Bearden

  5. Center for Genetics and Genomics, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile

    Gabriela Repetto

  6. Department of Psychiatry, Pontificia Universidad Católica de Chile, Santiago, Chile

    Nicolas A. Crossley

  7. Department of Psychiatry, University of Oxford, Oxford, UK

    Nicolas A. Crossley

  8. Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA, USA

    Tony Simon

  9. MIND Institute, University of California, Davis, Sacramento, CA, USA

    Tony Simon

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KS designed and conceptualized the study, contributed methods, performed investigation, wrote the original draft of the manuscript and reviewed and edited it. CDLA helped in data analysis. SR contributed to the development of the deep neural network model. LK, CS, GR, NC, and TS supervised and contributed to data collection. CB supervised data collection and reviewed and edited the manuscript. VM designed and conceptualized the study, and reviewed and edited the manuscript.

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Correspondence to Kaustubh Supekar or Vinod Menon.

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Supekar, K., de los Angeles, C., Ryali, S. et al. Robust and replicable functional brain signatures of 22q11.2 deletion syndrome and associated psychosis: a deep neural network-based multi-cohort study. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02495-8

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  • DOI: https://doi.org/10.1038/s41380-024-02495-8

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