Functional brain biomarkers of self-referential bias in remitted depressed outpatients: a randomized controlled trial.

Overview

1. Department of Psychology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada
2. Graduate Department of Psychological Clinical Science, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada

Abstract

Background: Negative self-referential bias (NSB) is a hallmark of depression, yet its neural signature and link to relapse vulnerability remain unclear. We investigated whether NSB and its associated neural activity predict relapse and depressive symptoms following prophylactic psychotherapy.

Methods: This is a two-year prospective neuroimaging study nested within a randomized controlled trial of Mindfulness-Based Cognitive Therapy and Cognitive Behavior Therapy with a Well-Being focus. Remitted depressed outpatients (N = 81) completed the Self-Referential Encoding Task during fMRI pre- and post-treatment and were followed bi-monthly. Study preregistration: https://osf.io/s4n8j.

Results: NSB predicted higher depressive symptoms (b = 0.10; 95% CI, 0.06 to 0.14; p ≤0.001) but not relapse. Greater NSB neural activity within frontal DMN and SN was associated with relapse status (DMN: b = 0.32; 95% CI, 0.09 to 0.55; SN: b = 0.36, 95% CI, 0.09 to 0.63), whereas DMN–SN connectivity was not. Static whole brain relapse biomarkers included elevated prefrontal activation and somatosensory deactivation. In non-relapsers, treatment-related attenuation of somatosensory deactivation predicted lower risk. Subgenual reactivity was the best prefrontal relapse indicator (Hazard Ratio = 1.84, 95% CI, 1.23 to 2.77), but somatosensory deactivation was the best overall relapse indicator (Hazard Ratio = 0.16; 95% CI, 0.05 to 0.52).

Conclusions: Relapse vulnerability reflects not only heightened prefrontal negative self-processing but also insufficient recruitment of somatosensory systems supporting embodied self-experience, providing a more comprehensive model of depression relapse vulnerability.

Trial registration: ClinicalTrials.gov Identifier: NCT01178424

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• osf:s4n8j, at OSF; found in “Data sharing statement”

Data availability

Data will be made available on request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Data sharing statement

Deidentified behavioral task and clinical data are publicly available on the Open Science Framework (https://osf.io/s4n8j). The authors are happy to provide deidentified fMRI-derived data upon request. Access to raw fMRI data requires execution of a material transfer agreement and approval by the originating institution.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 4 authors, 6 keywords, 15 MeSH terms, 1 funder, 74 references.

Cite

This paper

Wu, L. C., Livingston, J. L., Segal, Z. V., & Farb, N. A. (2026). Functional brain biomarkers of self-referential bias in remitted depressed outpatients: a randomized controlled trial. NeuroImage. Clinical, 51, 104025. https://doi.org/10.1016/j.nicl.2026.104025

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