Disrupted functional connectivity of the emotion regulation network in major depressive disorder and its association with symptom improvement: A multisite resting-state functional MRI study

Abstract

Background: The emotion regulation network (ERN) in the brain provides a framework for understanding the neuropathology of affective disorders. Although previous neuroimaging studies have investigated the neurobiological correlates of the ERN in major depressive disorder (MDD), whether patients with MDD exhibit abnormal functional connectivity (FC) patterns in the ERN and whether the abnormal FC in the ERN can serve as a therapeutic response signature remain unclear.

Methods: A large functional magnetic resonance imaging dataset comprising 709 patients with MDD and 725 healthy controls (HCs) recruited across five sites was analyzed. Using a seed-based FC approach, we first investigated the group differences in whole-brain resting-state FC of the 14 ERN seeds between participants with and without MDD. Furthermore, an independent sample (45 MDD patients) was used to evaluate the relationship between the aforementioned abnormal FC in the ERN and symptom improvement after 8 weeks of antidepressant monotherapy.

Results: Compared to the HCs, patients with MDD exhibited aberrant FC between 7 ERN seeds and several cortical and subcortical areas, including the bilateral middle temporal gyrus, bilateral occipital gyrus, right thalamus, calcarine cortex, middle frontal gyrus, and the bilateral superior temporal gyrus. In an independent sample, these aberrant FCs in the ERN were negatively correlated with the reduction rate of the HAMD₁₇ score among MDD patients.

Conclusions: These results might extend our understanding of the neurobiological underpinnings underlying unadaptable or inflexible emotional processing in MDD patients and help to elucidate the mechanisms of therapeutic response.

Keywords: Antidepressant; Emotion regulation network; Functional connectivity; Major depressive disorder; RS-fMRI; Symptom improvement.

Figure 1.

Between-group comparisons of seed-based functional connectivity in the ERN between the MDD and HC groups (A-G). The first column shows the seed regions. The brain regions (MOG, IOG, MTG, STG, MFG, THA, ACC, CAL, and MCC) that exhibited abnormal functional connectivity with the seed regions in patients with MDD compared with HCs are shown in the brain maps. L, left side; R, right side; AG, angular gyrus; MTG, middle temporal gyrus; MOG, middle occipital gyrus; IOG, inferior occipital gyrus; MFG, middle frontal gyrus; STG, superior temporal gyrus; Amy, amygdala; sgACC, subgenual anterior cingulate cortex; THA, thalamus; vlPFC, ventrolateral prefrontal cortex; ACC, anterior cingulate cortex; CAL, calcarine; MCC, middle cingulate cortex. All clusters were corrected for multiple comparisons with a voxel p < 0.001 and cluster p < 0.05/14 according to Gaussian random field theory and Bonferroni correction.

Figure 2.

Relationships between the functional connectivity aberrations in the ERN and the reduction rate of the HAMD₁₇ score in patients with MDD. The scatter maps show that the aberrant functional connectivity in the ERN was significantly correlated with the reduction rate of the HAMD₁₇ score in the MDD group. HAMD₁₇, 17-item Hamilton Rating Scale for Depression; AG, angular gyrus; MTG, middle temporal gyrus; STG, superior temporal gyrus; Amy, amygdala; sgACC, subgenual anterior cingulate cortex; ACC, anterior cingulate cortex; CAL, calcarine.