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

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.

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.

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).

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.

ClinicalTrials.gov Identifier: NCT01178424.