Reduced default mode network suppression during a working memory task in remitted major depression

Abstract

Insufficient default mode network (DMN) suppression was linked to increased rumination in symptomatic Major Depressive Disorder (MDD). Since rumination is known to predict relapse and a more severe course of MDD, we hypothesized that similar DMN alterations might also exist during full remission of MDD (rMDD), a condition known to be associated with increased relapse rates specifically in patients with adolescent onset. Within a cross-sectional functional magnetic resonance imaging study activation and functional connectivity (FC) were investigated in 120 adults comprising 78 drug-free rMDD patients with adolescent- (n = 42) and adult-onset (n = 36) as well as 42 healthy controls (HC), while performing the n-back task. Compared to HC, rMDD patients showed diminished DMN deactivation with strongest differences in the anterior-medial prefrontal cortex (amPFC), which was further linked to increased rumination response style. On a brain systems level, rMDD patients showed an increased FC between the amPFC and the dorsolateral prefrontal cortex, which constitutes a key region of the antagonistic working-memory network. Both whole-brain analyses revealed significant differences between adolescent-onset rMDD patients and HC, while adult-onset rMDD patients showed no significant effects. Results of this study demonstrate that reduced DMN suppression exists even after full recovery of depressive symptoms, which appears to be specifically pronounced in adolescent-onset MDD patients. Our results encourage the investigation of DMN suppression as a putative predictor of relapse in clinical trials, which might eventually lead to important implications for antidepressant maintenance treatment.

Keywords: Default mode network; Functional magnetic resonance imaging; Major depressive disorder; Remission; Rumination; Working memory.

Fig. 1

Activation Differences between rMDD Patients (n = 78) and HC (n = 42). Significantly decreased DMN deactivation (red) in rMDD patients compared to HC (A, C). Maximal effects are being found in the amPFC. Task activation (yellow) and deactivation (cyan) is presented as underlay of group comparison results in order to outline the DMN. Adolescent-onset rMDD patients exhibit significant and even more pronounced DMN deactivation decreases with punctum maximum in the amPFC and the PCC compared to HC (B, C). Plot (C) summarizes the significance of FWE corrected group comparisons for the amPFC and further visualizes the intermediate position of adult-onset rMDD patients compared to adolescent-onset MDD patients and HC. Abbreviations: **, highly significant (p < 0.01); *, significant (p < 0.05); 95% CI, 95% confidence interval; FWE, family-wise error rate; rMDD, remitted Major Depressive Disorder; HC, healthy controls; DMN, default-mode network; amPFC, anterior-medial prefrontal cortex; PCC, posterior cingulate cortex. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Differences in functional connectivity between adolescent-onset rMDD patients (n = 42) and HC (n = 42). The amPFC has been used as seed region (5, 46, 1) for FC analyses based on working memory paradigm data after removing task-based co-activation. The figure displays significantly increased (red) coupling of the amPFC with the dlPFC (A, C) and significantly decreased coupling (blue) with the mFG (A, D) in adolescent-onset rMDD patients compared to HC. Task activation (yellow) and deactivation (cyan) is presented as underlay of group comparison results in order to outline the DMN (A). A significant negative correlation was detected between 2B accuracy and amPFC-dlPFC coupling (B). Plots (C, D) summarize the significance of FWE corrected group comparisons for amPFC-dlPFC as well as amPFC-mFG FC and further visualize the intermediate position of adult-onset rMDD patients compared to adolescent-onset rMDD patients and HC. Abbreviations: **, highly significant (p < 0.01); *, significant (p < 0.05); 95% CI, 95% confidence interval; FWE, family-wise error rate; rMDD, remitted Major Depressive Disorder; HC, healthy controls; FC, functional connectivity; amPFC, anterior-medial prefrontal cortex; dlPFC, dorsolateral prefrontal cortex; mFG, medial frontal gyrus; DMN, default-mode network; 2B, two-back. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Post hoc response style analysis. A reduction of amPFC deactivation is significantly associated with RSQ score increases (A) in all study participants with available RSQ data (n = 39). Both rMDD subgroups show significantly higher RSQ scores than HC with more pronounced effects in adolescent-onset rMDD patients (B). Studied subgroups are depicted by symbols: adolescent-onset (square) and adult-onset rMDD patients (triangle), HC (circle). Abbreviations: **, highly significant (p < 0.01); *, significant (p < 0.05); s², estimated proportion of explained variance; rMDD, remitted Major Depressive Disorder; HC, healthy controls; amPFC, anterior-medial prefrontal cortex; RSQ, Response Style Questionnaire.