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Major depressive disorder (MDD) is a common affective disorder with complex etiologies and largely unclear pathophysiological mechanisms. The nucleus accumbens (NAc) plays a central role in reward processing, motivational regulation, and emotional integration. Neuroimaging studies suggest that structural and functional abnormalities of the NAc are key contributors to the pathogenesis of MDD. However, the alterations in structure-function coupling (SFC) of the NAc in MDD remain poorly understood. This study aims to systematically investigate abnormal functional connectivity (FC) and SFC of the NAc in patients with MDD by integrating functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) techniques.

A case-control design was adopted. Patients who met diagnostic criteria for a current depressive episode of MDD and had a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥17 were enrolled as the MDD group, while age-, sex-, and education-matched healthy controls (HCs) were included as the HC group. All participants underwent high-resolution T₁-weighted structural imaging, resting-state fMRI, and DTI scanning using a 3.0T MR system. fMRI data preprocessing was performed using SPM12 (Statistical Parametric Mapping 12) and DPARSF (Data Processing Assistant for Resting-State fMRI), while DTI preprocessing was conducted using FSL (FMRIB Software Library). Based on the Brainnetome Atlas, the cerebral cortex was parcellated into 246 regions. FC values between bilateral NAc and the whole brain and the strength of structural connectivity (sSC) derived from probabilistic tractography were calculated. SFC values of bilateral NAc were computed using region-wise Spearman correlations between sSC and FC (ρ). A multiple linear regression model was constructed using FC as the dependent variable and age, gender, years of education, and head motion parameters as covariates, and corrected FC values were extracted from the regression residuals. Group differences in corrected FC values were assessed using independent-sample t-tests with false discovery rate (FDR) correction at a significance level of P<0.1. Analysis of covariance was used to compare SFC values between groups, controlling for age, gender, and years of education (a significance level of P<0.05). FC values showing significant intergroup differences and SFC values of bilateral NAc were correlated with HAMD-17 total scores using Spearman correlation analysis.

There were no significant differences between the MDD and the HC groups in gender (χ²=0.792, P=0.373), age (t=-0.930, P=0.292), or years of education (t=0.003, P=0.059). Compared with HCs, patients with MDD exhibited significantly increased FC in the following connections: BG.L.3 (left NAc)-IPL.R.4 (right inferior parietal lobule), BG.R.3 (right NAc)-IPL.R.4, BG.R.3-Tha.R.8 (right lateral prefrontal thalamus), and BG.R.3- MFG.R.4 (right middle frontal gyrus) (all FDR-corrected P<0.1). The SFC values of bilateral NAc were significantly reduced in the MDD group compared with the HC group (left: F=11.768, P=0.001; right: F=4.386, P=0.047). Spearman correlation analyses showed no significant associations between altered FC or bilateral NAc SFC values and HAMD-17 total scores in the MDD group (all P>0.05).

Patients with MDD exhibit enhanced NAc FC, predominantly between the NAc and cognition-related regions such as the inferior parietal lobule and middle frontal gyrus, suggesting imbalance between the reward circuit and cognitive regulatory networks. Moreover, the significantly reduced SFC of bilateral NAc indicated impaired structural-functional integration in MDD. These findings provide potential neuroimaging evidence supporting the involvement of the NAc in the pathophysiological mechanisms of MDD.