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Lifetime depression and mania/hypomania risk predicted by neural markers in three independent young adult samples during working memory and emotional regulation

Molecular Psychiatry volume 30, pages 870–880 (2025)Cite this article

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Abstract

Objective markers of pathophysiological processes underlying lifetime depression and mania/hypomania risk can provide biologically informed targets for novel interventions to help prevent the onset of affective disorders in individuals with subsyndromal symptoms. Greater activity within and functional connectivity (FC) between the central executive network (CEN), supporting emotional regulation (ER) subcomponent processes such as working memory (WM), the default mode network (DMN), supporting self-related information processing, and the salience network (SN), is thought to interfere with cognitive functioning and predispose to depressive disorders. Using an emotional n-back paradigm designed to examine WM and ER capacity, we examined in young adults: (1) relationships among activity and FC in these networks and lifetime depression and mania/hypomania risk; (2) the extent to which these relationships were specific to lifetime depression risk versus lifetime mania/hypomania risk; (3) whether findings in a first, Discovery sample n = 101, 63 female, age = 23.85 (2.9) could be replicated in a two independent Test samples of young adults: Test sample 1: n = 90, 60 female, age = 21.7 (2.0); Test sample 2: n = 96, 65 female, age = 21.6 (2.1). The Mood Spectrum Self-Report (MOODS-SR-L) assessed lifetime mania/hypomania risk and depression risk. We showed significant clusters of activity to each contrast in similar locations in the anatomic mask in each Test sample as in the Discovery sample, and, using extracted mean BOLD signal from these clusters as IVs, we showed similar patterns of IV-DV relationships in each Test sample as in the Discovery sample. Specifically, in the Discovery sample, greater DMN activity during WM was associated with greater lifetime depression risk. This finding was specific to depression and replicated in both independent samples (all ps<0.05 qFDR). Greater CEN activity during ER was associated with increased lifetime depression risk and lifetime mania/hypomania risk in all three samples (all ps< 0.05 qFDR). These replicated findings provide promising objective, neural markers to better identify, and guide and monitor early interventions for, depression and mania/hypomania risk in young adults.

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Fig. 1: Activity and functional connectivity related to working memory and emotional regulation.
Fig. 2: Associations between working memory and lifetime depression risk.
Fig. 3: Associations between emotional regulation and lifetime depression risk.
Fig. 4: Associations between emotional regulation and lifetime mania/hypomania risk.

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Data availability

The dataset is available per request. Please request access by contacting the corresponding author Yvette Afriyie-Agyemang.

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Funding

This study was supported by R01MH100041 and R37MH100041 (PI: M.L.P.) from the National Institute of Mental Health, the Pittsburgh Foundation (PI: M.L.P.), and the Brain and Behavior Research Foundation (PI: M.A.B.). This research was supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. The funding agency was not involved in the conduct, analysis, or reporting of this work.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Yvette Afriyie-Agyemang, Michele A. Bertocci, Richelle S. Stiffler, Lisa K. Bonar, Haris A. Aslam, Simona Graur, Genna Bebko, Alexander S. Skeba, Tyler J. Brady, Osasumwen Benjamin, Yiming Wang, Henry W. Chase & Mary L. Phillips

  2. Department of Statistics, University of Pittsburgh School of Arts and Sciences, Pittsburgh, PA, USA

    Satish Iyengar

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  1. Yvette Afriyie-Agyemang
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Contributions

YA-A, MAB and MLP conceived of and wrote the manuscript. YA-A completed the analyses. YA-A, MAB, SI, and MLP conceived of and interpreted the statistical analysis. RS, LB, HAA, SG, GB, OB and YW contributed substantially to the acquisition of the data. AS, TY and HC contributed substantially to the processing of the data. All authors approved the final version of the manuscript.

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Correspondence to Yvette Afriyie-Agyemang.

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Competing interests

Afriyie-Agyemang, Bertocci, Iyengar, Stiffler, Bonar, Aslam, Graur, Bebko, Skeba, Brady, Benjamin, Wang Chase, Phillips have no financial interests or potential conflicts of interest.

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All methods were performed in accordance with the Declaration of Helsinki. The University of Pittsburgh Institutional Review Board approved this study (IRB no: 18110024, 19040176). All participants gave written informed consent.

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Afriyie-Agyemang, Y., Bertocci, M.A., Iyengar, S. et al. Lifetime depression and mania/hypomania risk predicted by neural markers in three independent young adult samples during working memory and emotional regulation. Mol Psychiatry 30, 870–880 (2025). https://doi.org/10.1038/s41380-024-02702-6

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