Altered right amygdala-prefrontal connectivity is associated with symptom severity in major depressive disorder: An exploratory analysis of anxiety subgroups.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent and often complicated by anxiety symptoms, yet the neurobiological features associated with anxious depression remain incompletely characterized. The amygdala-prefrontal cortex (PFC) circuit, central to affect regulation, has been implicated in anxious depressive symptoms. METHODS: We recruited 40 MDD patients and 69 healthy controls (HCs) from Tianjin Anding Hospital. All participants underwent resting-state functional magnetic resonance imaging(fMRI) and clinical assessments. Seed-based functional connectivity (FC) analyses were performed using the bilateral amygdala based on the Automated Anatomical Labeling (AAL) atlas. Group comparisons, partial correlations, and regression analyses tested associations between amygdala-based FC and HDRS-17 symptom dimensions, with subgroup analyses distinguishing MDD patients with and without anxiety. RESULTS: Compared with HCs, MDD patients exhibited reduced FC between the right amygdala and prefrontal cortex, including the right middle frontal gyrus (MFG) and the left inferior frontal gyrus, triangular part (IFGtri) (GRF: voxel-level p < 0.001, cluster-level p < 0.05). Within the MDD group, higher right amygdala-MFG FC values were associated with HDRS-17 symptoms, including total scores and depressive and somatic symptom dimensions (r = 0.393, p = 0.020; r = 0.360, p = 0.033; r = 0.351, p = 0.039, uncorrected p). In exploratory subgroup analyses, right amygdala-MFG FC showed a positive association with HDRS-17 scores in MDD patients with anxiety (R2 = 0.280, F = 8.957, p = 0.006, Beta = 0.529, t = 2.993, p = 0.006); however, the FC × anxiety subgroup interaction did not reach statistical significance. CONCLUSION: Our findings identify disrupted right amygdala-MFG connectivity as a potential neural correlate of symptom heterogeneity in MDD, particularly in patients with anxiety symptoms.