Right caudal hippocampal structural-functional coupling alterations in major depressive disorder: an exploratory...

Major depressive disorder (MDD) often emerges during adolescence and young adulthood, a period marked by ongoing maturation of executive function. In MDD, childhood trauma is frequently reported and may compromise this developing cognitive domain, yet its neural link to executive performance remains unclear. Structural-functional (SC-FC) coupling captures correspondence between structural connectivity and functional organization, offering a metric for detecting trauma-related neural mismatch. This study examined SC-FC coupling alterations and their associations with childhood trauma and executive performance in MDD.

We included 67 first-episode, drug-naïve adolescents and young adults with MDD and 44 healthy controls. Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ), and executive function using the Digit Symbol Substitution Test (DSST) and Stroop Color and Word Test (SCWT). Regional SC-FC coupling was estimated using a principal component analysis-based predictive model. Group differences, brain-behavior associations, group interactions, and exploratory mediation were examined.

Nineteen regions showed significant SC-FC coupling differences, involving limbic, default mode, frontoparietal, salience, visual, and somatomotor systems. In MDD, thalamic coupling was associated with trauma scores, whereas left precuneus, right anterior temporal, and right caudal hippocampal coupling was associated with executive performance. Only the trauma-related right rostral hippocampal coupling interaction survived correction. Exploratory mediation showed a conditional indirect association between trauma and SCWT reaction time via right caudal hippocampal coupling at lower depressive severity.

First-episode, drug-naïve MDD showed widespread SC-FC coupling alterations. Hippocampal coupling may preliminarily link childhood trauma and executive performance.