Disrupted resting-state functional connectivity of the amygdala subregion and its clinical correlates in major depressive disorder with anxious distress specifier

The anxious distress specifier (ADS) identifies a subtype of major depressive disorder (MDD) characterized by heightened anxiety and poorer outcomes. However, the neurobiological mechanisms underlying ADS remain poorly understood. This study investigated alterations in amygdala subregional resting-state functional connectivity (rsFC) in ADS and explored their associations with clinical symptoms. A total of 119 unmedicated patients with MDD and 65 healthy controls (HC) were included in the analysis. Based on DSM-5 criteria, patients were categorized into ADS ( n = 68) and non-ADS ( n = 51) subgroups. Group differences in rsFC of six amygdala subregions were examined. Multivariate correlation analyses were conducted to assess associations between rsFC strength and clinical symptoms. Moderation analyses were tested to determine whether anxious distress moderated the relationship between rsFC and clinical symptoms. Compared with non-ADS patients and HC, ADS patients exhibited significantly reduced rsFC between the left superficial amygdala (SFA) and the right middle occipital gyrus (MOG). In the ADS group, the left SFA–right MOG rsFC strength was positively correlated with early morning awakening, whereas in the non-ADS group, it was negatively correlated with difficulty falling asleep. Moderation analysis revealed a significant rsFC × group interaction, indicating that anxious distress significantly moderated the relationship between SFA–MOG connectivity and sleep disturbance. Our findings suggest that disrupted SFA–MOG connectivity might represent a neurobiological feature specific to the ADS subtype of MDD and may underlie sleep-related pathophysiology. These results highlight the importance of amygdala subregional analyses in elucidating neurobiological heterogeneity in MDD and warrant further validation in larger and independent cohorts.