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Data-driven, connectome-wide analysis identifies psychosis-specific brain correlates of fear and anxiety

Molecular Psychiatry (2024)Cite this article

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Abstract

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = −0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing.

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Fig. 1: Multivariate distance matrix regression (MDMR).
Fig. 2: Individuals in the early psychosis group (n = 86) had higher fear and anxiety scores than healthy controls (n = 52).
Fig. 3: Amygdala/hippocampal connectivity to broader network.
Fig. 4: Amygdala/hippocampal-insula connectivity is related to fear-affect scores in early psychosis and healthy controls.
Fig. 5: Group-specific differences in amygdala/hippocampal cluster connectivity regressed against fear-affect score.
Fig. 6: Amygdala/hippocampal-VMPFC connectivity is related to fear-affect scores in early psychosis but not in healthy controls.

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Data availability

Data presented in the present work was collected and minimally processed by the Human Connectome Project, specifically the early psychosis subgroup and sites. Statistics, analysis scripts, and figures are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors wish to thank the patients and their families for participation in this study. We also thank the Human Connectome Project for making their data accessible and assisting with database management.

Funding

This work was supported by National Institutes of Health (NIH) grants R01MH127018 to Drs. Feola and Blackford, 1R01MH120588-01 A1 to Dr. Breier, R01 MH117012 to Dr. Lewandowski, U01 MH109977 to Drs. Breier and Shenton, R01 MH116170 to Dr. Brady and KL2TR002245 and K23DA059690 to Dr. Ward.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Brandee Feola, Stephan Heckers & Heather Burrell Ward

  2. Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Adam Beermann, Karlos Manzanarez Felix & Roscoe O. Brady Jr

  3. Department of Psychiatry, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Michael Coleman & Martha E. Shenton

  4. Department of Software Engineering and Information Technology, École de technologie supérieure, Montréal, QC, Canada

    Sylvain Bouix

  5. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School Boston, Boston, MA, USA

    Daphne J. Holt

  6. McLean Hospital and Harvard Medical School, Boston, MA, USA

    Kathryn E. Lewandowski, Dost Öngür & Roscoe O. Brady Jr

  7. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    Alan Breier

  8. Department of Radiology, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Martha E. Shenton

  9. Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA

    Jennifer Urbano Blackford

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Contributions

BF, MC, SB, DH, KL, DO, AB, MS, RB, JB, and HW initiated and designed the research. BF, AB, KF, and HBW performed data analysis. BF, SH, RB, JB, and HBW interpreted the results. BF, JB, and HBW wrote the manuscript. BF and HBW prepared the figures. All authors edited the manuscript and approved the final submission.

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Correspondence to Heather Burrell Ward.

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Feola, B., Beermann, A., Manzanarez Felix, K. et al. Data-driven, connectome-wide analysis identifies psychosis-specific brain correlates of fear and anxiety. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02512-w

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