Increased glymphatic system activity and thalamic vulnerability in drug-naive somatic depression: Evidenced by DTI-ALPS index

Major depressive disorder (MDD) is a significant contributor to global disease burden, with somatic symptoms frequently complicating its diagnosis and treatment. Recent advances in neuroimaging have provided insights into the neurobiological underpinnings of MDD, yet the role of the glymphatic system remains largely unexplored. This study aimed to assess glymphatic function in drug-naïve somatic depression (SMD) patients using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. A total of 272 participants, including somatic depression patients (SMD), pure depression (PMD), and healthy controls (HC), were enrolled. We collected T1-weighted (T1w) and DTI (diffusion tensor image) scans and clinical data of all participants. The DTI-ALPS indices were calculated and compared among three groups. Gray matter regions associated with the DTI-ALPS index were identified by voxel-based morphometry analysis (VBM), revealing a cluster located in the thalamus. Then, we performed partial correlation analyses to further investigate the relationships between the DTI-ALPS index, thalamic volume, and clinical data. The DTI-ALPS index was significantly higher in the MDD group compared to the HC group, particularly in the SMD group. Furthermore, a significant positive correlation was observed between the DTI-ALPS index and thalamic volume, with lower DTI-ALPS values associated with reduced thalamic volumes, especially in the SMD group. Our findings suggest heightened glymphatic activity in MDD patients, especially SMD patients, and a potential link between glymphatic function and thalamic vulnerability. Therefore, the thalamus' vulnerability to glymphatic system function may play a role in the pathophysiology of depression, particularly somatic depression, suggesting that both the glymphatic system and the thalamus could serve as potential therapeutic or intervention targets for future treatments.