Distinct and shared structural covariance reductions of the habenula in first-episode drug-naive and recurrent major depressive disorder.

Emerging evidence suggests that habenula (Hb) dysfunction plays an important role in major depressive disorder (MDD), with prior functional and structural studies implicating Hb-related networks in emotional and reward processing. However, it remains unclear whether structural covariance of Hb differs between first-episode drug-naive (FEDN) and recurrent MDD (RMDD). T1-weighted structural MRI data were obtained from the REST-meta-MDD consortium, including 839 MDD patients (346 FEDN and 261 RMDD) and 788 healthy controls. Single-subject structural covariance networks were constructed via Kullback-Leibler divergence, with bilateral Hb as seed regions. Group comparisons were conducted using linear mixed-effects models. For right Hb, FEDN group showed reduced structural covariance with the superior/inferior frontal gyrus, cerebellum, and insula, whereas RMDD group exhibited decreased structural covariance in the basal ganglia and temporoparietal junction (TPJ). Both MDD subgroups demonstrated decreased structural covariance between right Hb ventral prefrontal cortex, FEDN specifically exhibited reductions with the thalamus and ventrolateral prefrontal cortex (vlPFC), while the RMDD group specifically showed reductions with the occipital gyrus. In contrast, for left Hb, only RMDD group showed decreased structural covariance with the basal ganglia and TPJ, while no significant alterations were observed in FEDN group. Furthermore, structural covariance between the bilateral Hb and the posterior cingulate cortex was positively correlated with depressive, but not anxious, symptom severity. These findings reveal hemispheric- and subtype-specific patterns of Hb-centered single-subject structural covariance (intra-individual GMV distribution similarity) alterations in MDD, which were associated with depressive symptomatology. These findings provide hypothesis-generating evidence for Hb-centered structural covariance alterations in MDD and may inform future multimodal studies of subtype-specific pathophysiology.