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Temporal interactions between neural proxies for memory recall, negative affect, and emotion regulation in major depression

Molecular Psychiatry volume 30, pages 4039–4046 (2025)Cite this article

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Abstract

Dysfunction in emotion regulation (ER) and autobiographical memory are components of major depressive disorder (MDD). However, little is known about how they mechanistically interact with mood disturbances in real time. Using machine learning-based neural signatures, we can quantify negative affect (NA), ER, and memory continuously to evaluate how these processes dynamically interact in MDD. Unmedicated individuals with MDD (N = 45) and healthy volunteers (HV; N = 38) completed a negative autobiographical memory functional magnetic resonance imaging task wherein they recalled, distanced from (an ER strategy), and immersed into memories. We used a negative affect signature (PINES) and an emotion regulation signature (ERS) to quantify moment-to-moment NA and ER. We then examined whether memory engagement, indexed by hippocampal activity, predicted subsequent change in PINES and ERS over time. During memory recall and immersion, greater hippocampal activity predicted increased PINES across groups. During distancing, greater hippocampal activity in HVs predicted increased ERS but not PINES. In MDD, greater hippocampal activity predicted increased PINES but not ERS. Findings suggest abnormalities in the real-time relationship between memory, NA, and ER in MDD. During distancing, as predicted, HVs showed an attenuation of the linkage between memory engagement and NA, and they had subsequent increases in ER following memory reactivation. In contrast, MDD was characterized by continued linkage between memory engagement and NA, without subsequent increases in ER. Deficits in engagement of ER and ineffective modulation of NA following negative memory recall may contribute to the mood disturbances in MDD and are potential targets for clinical intervention.

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Fig. 1: Negative autobiographical memories task.
Fig. 2: Self-report ratings for negative affect and vividness.
Fig. 3: Temporal relationship between hippocampal activity and subsequent negative affect signature (PINES) expression.
Fig. 4: Temporal relationship between hippocampal activity and subsequent emotion regulation signature (ERS) expression during the distance condition.
Fig. 5: Greater reduction in hippocampal activity when instructed to distance following memory recall in depressed individuals vs. healthy volunteers.

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Data availability

Deidentified data is available from the corresponding author upon request.

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Acknowledgements

This work was support by the National Institute of Mental Health P50 MH090964 (PI: J. Mann) and 5T32MH015144-46 (PI: D. Leonardo).

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Author notes

  1. These authors contributed equally: Lila Davachi, Noam Schneck.

Authors and Affiliations

  1. Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA

    Christina A. Michel, Mike Schmidt, J. John Mann, Sarah Herzog & Noam Schneck

  2. Department of Psychiatry, Columbia University, New York, NY, USA

    Christina A. Michel, Mike Schmidt, J. John Mann, Sarah Herzog & Noam Schneck

  3. Department of Radiology, Columbia University, New York, NY, USA

    J. John Mann

  4. Department of Psychology, Columbia University in the City of New York, New York, NY, USA

    Kevin N. Ochsner & Lila Davachi

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  1. Christina A. Michel
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Contributions

CAM: project conception, design, data analysis, and writing of the manuscript. NS, LD: project design and data analysis, comments on manuscript. JJM, KNO: grant design and funding, comments on manuscript. MS: preprocessing, assistance with data analysis & figure design, comments on manuscript. SH: comments on manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Christina A. Michel.

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Competing interests

JJM receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. CAM, MS, SH, KNO, LD, and NS have no conflicts to report.

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Michel, C.A., Schmidt, M., Mann, J.J. et al. Temporal interactions between neural proxies for memory recall, negative affect, and emotion regulation in major depression. Mol Psychiatry 30, 4039–4046 (2025). https://doi.org/10.1038/s41380-025-02982-6

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