History of childhood trauma enhances the detrimental effects of recent stressors on brain structure and function in major depressive disorder.

Stressful life events are major precipitants of depressive episodes, yet their effects vary across individuals. Childhood trauma is a well-established vulnerability factor that may increase sensitivity to subsequent stress. However, the neural correlates of this interaction in major depressive disorder (MDD) remain poorly characterized. This study investigated whether childhood trauma moderates the association between recent stress exposure and brain structure and functional connectivity in MDD. Structural magnetic resonance imaging (MRI) data were obtained from 130 inpatients with MDD; resting-state functional MRI data were available for a subsample (n = 97). Whole-brain cortical thickness and surface-based functional connectivity measures, including global correlation (GCOR) and local correlation (LCOR), were examined to test interaction effects between childhood trauma and recent stress exposure. A significant interaction between childhood trauma and recent stress was observed in medial prefrontal regions, including the anterior cingulate cortex, where greater stress exposure was associated with reduced cortical thickness at higher levels of early adversity. Convergent interaction effects were also observed at the functional level, with greater recent stress associated with lower LCOR in the left superior frontal gyrus and precuneus at higher levels of childhood trauma. No interaction effects were observed for GCOR. Analyses of specific trauma dimensions indicated partially distinct effects of abuse and neglect. Childhood trauma moderated the association between recent stress exposure and structural and functional brain measures in MDD, particularly within prefrontal regulatory regions. These multimodal findings are consistent with stress sensitization models and suggest that early adversity may contribute to heterogeneity in neural correlates of stress in depression.