Structural and functional alterations of medial temporal lobe in major depressive disorder with anxious distress

Major Depressive Disorder (MDD) with anxious distress is a severe subtype. The hippocampus and parahippocampal gyrus are implicated in MDD, but findings are inconsistent. This study investigated structural and functional alterations in these regions in a clinical MDD cohort with anxious distress. We analyzed data from 78 MDD patients with anxious distress and 60 healthy controls. Structural MRI volumes and resting-state functional metrics [Amplitude of Low-Frequency Fluctuations (ALFF), fractional ALFF (fALFF), Regional Homogeneity (ReHo)] were extracted for bilateral hippocampus and parahippocampal gyrus. Clinical severity was assessed using Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) scores from medical records. Cognitive performance was evaluated via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Group comparisons were performed using analysis of covariance (ANCOVA) with appropriate covariates, and within-group partial correlations between neuroimaging measures and clinical severity were examined in the MDD group. MDD patients showed larger normalized volume of the right hippocampus (q < 0.001) but smaller bilateral parahippocampal gyral volumes (left: q = 0.002; right: q < 0.001) compared to controls. No significant group differences were observed in resting-state functional metrics. In exploratory within-group analyses, higher anxiety (HAMA) was nominally associated with smaller left parahippocampal volume and greater ReHo in the right hippocampus, but none of these correlations remained significant after false discovery rate (FDR) correction (all q > 0.05). In MDD with anxious distress, distinct structural alterations existed but were dissociated from resting-state functional metrics. The finding of right hippocampal enlargement, alongside the absence of functional group differences, underscored MDD heterogeneity and highlighted the need for symptom-focused research with rigorous statistical control.