Static and treatment-responsive brain biomarkers of depression relapse vulnerability following prophylactic psychotherapy: Evidence from a randomized control trial

Norman A S Farb, Philip Desormeau, Adam K Anderson, Zindel V Segal, Norman A S Farb, Philip Desormeau, Adam K Anderson, Zindel V Segal

Abstract

Background: Neural reactivity to dysphoric mood induction indexes the tendency for distress to promote cognitive reactivity and sensory avoidance. Linking these responses to illness prognosis following recovery from Major Depressive Disorder informs our understanding of depression vulnerability and provides engagement targets for prophylactic interventions.

Methods: A prospective fMRI neuroimaging design investigated the relationship between dysphoric reactivity and relapse following prophylactic intervention. Remitted depressed outpatients (N = 85) were randomized to 8 weeks of Cognitive Therapy with a Well-Being focus or Mindfulness Based Cognitive Therapy. Participants were assessed before and after therapy and followed for 2 years to assess relapse status. Neural reactivity common to both assessment points identified static biomarkers of relapse, whereas reactivity change identified dynamic biomarkers.

Results: Dysphoric mood induction evoked prefrontal activation and sensory deactivation. Controlling for past episodes, concurrent symptoms and medication status, somatosensory deactivation was associated with depression recurrence in a static pattern that was unaffected by prophylactic treatment, HR 0.04, 95% CI [0.01, 0.14], p < .001. Treatment-related prophylaxis was linked to reduced activation of the left lateral prefrontal cortex (LPFC), HR 3.73, 95% CI [1.33, 10.46], p = .013. Contralaterally, the right LPFC showed dysphoria-evoked inhibitory connectivity with the right somatosensory biomarker CONCLUSIONS: These findings support a two-factor model of depression relapse vulnerability, in which: enduring patterns of dysphoria-evoked sensory deactivation contribute to episode return, but vulnerability may be mitigated by targeting prefrontal regions responsive to clinical intervention. Emotion regulation during illness remission may be enhanced by reducing prefrontal cognitive processes in favor of sensory representation and integration.

Trial registration: ClinicalTrials.gov NCT01178424.

Keywords: Depression; Dysphoric reactivity; Mood challenge; Relapse vulnerability; Sensory deactivation; fMRI.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Study design summary. Smartphones and computers alternating within the follow-up period indicate bimonthly assessment points, which alternated between phone-based and online eSurvey assessments.
Fig. 2
Fig. 2
Study consort diagram.
Fig. 3
Fig. 3
Neural reactivity to dysphoric mood induction. A) Main Effect of Task (Sad – Neutral); B) past episodes covariate of neural reactivity, with a scatterplot of the relationship between past episodes and the peak covariate region located in the medial somatosensory cortex; C) residual symptom covariate of neural reactivity, with a scatterplot of the relationship between residual symptoms and the peak covariate region in the right somatosensory cortex and posterior insula. Scatterplots use data from both timepoints (baseline and post-intervention) and show linear fit within both the non-relapser and relapser sub-groups to illustrate the consistency of the relationship. Gray shaded areas around the fit lines are 95% confidence intervals.
Fig. 4
Fig. 4
Main effects of future relapse status on neural reactivity to dysphoric mood induction. A) Regions sensitive to future relapse status; B) Boxplot of right somatosensory reactivity at both timepoints with 95% confidence intervals; C) survival plot for participants over the follow-up period as a function of average right somatosensory reactivity (sad – neutral film clip viewing) across both time-points. Cross-hatches indicate participants censored due to relapse or being lost to follow-up. Please note that due to the context of sadness-evoked deactivation, ‘Above Median’ scores indicate less deactivation, whereas ‘Below Median’ scores indicate greater deactivation.
Fig. 5
Fig. 5
Effects of time (baseline vs. post-intervention) on neural reactivity to dysphoric mood induction within the non-relapse group. A) Regions demonstrating reduced reactivity over time; B) Boxplot of left lateral prefrontal cortex (LPFC) change scores over time with 95% confidence intervals; C) survival plot for participants over the follow-up period as a function of change in left LPFC change scores. Cross-hatches indicate participants censored due to relapse or being lost to follow-up. Please note that due to the context of reduced reactivity over time, ‘Above Median’ scores indicate a failure to reduce reactivity, whereas ‘Below Median’ scores indicate reduced reactivity.
Fig. 6
Fig. 6
Summary model of relapse risk. The Hazard Ratios for the combined Cox regression model for Relapse that includes neural biomarker activity from both the static marker of relapse (right somatosensory cortex) and the dynamic marker, wherein activity changed over the intervention period (left lateral prefrontal cortex), controlling for past episodes, concurrent depressive symptoms, and antidepressant medication status.
Fig. 7
Fig. 7
Effects of PPI analysis. A) Regions with altered connectivity to the right somatosensory cortex as a function of mood context (sad vs. neutral). Orange areas are FWE-corrected positive PPI score areas, whereas blue areas are negative scores. B) Sadness-evoked connectivity change with the right lateral prefrontal cortex (LPFC) is significantly related to future relapse status. C) Connectivity between the somatosensory cortex and right LPFC is responsive to dysphoric mood induction. D) The magnitude of sadness-evoked deactivation between right LPFC and somatosensory cortex distinguishes relapsers from non-relapsers. Interpretation of how this connectivity relates to the right somatosensory seed region may be challenging given that main effect within the somatosensory region was a deactivation; by this logic, orange areas were more negatively associated with the somatosensory cortex during sad-mood induction, whereas blue areas were more positively associated with the somatosensory cortex, sharing in the deactivation pattern. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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