Bright light therapy influences glymphatic system function in individuals with subthreshold depression: a randomized...

Glymphatic system dysfunction is a potential early biomarker for neuropsychiatric disorders. This study aimed to evaluate the effects of bright light therapy (BLT) on the glymphatic system in individuals with subthreshold depression (StD) and its connections to brain activity, inflammatory cytokines, and depressive symptoms. A randomized placebo-controlled trial assigned adults with StD (N = 110) to 8 weeks of morning BLT (5000 lx, 30 min/day; n = 57) or placebo (inactive device; n = 53). Depression severity (primary outcome, including anhedonia), glymphatic markers (diffusion tensor image analysis along the perivascular space [DTI-ALPS] index, free water [FW], perivascular space volume), regional homogeneity (ReHo; functional MRI), and serum pro-inflammatory cytokines were assessed at baseline and post-treatment. Compared to placebo, BLT significantly relieved depressive symptoms, increased DTI-ALPS index, and decreased FW from baseline to post-treatment. BLT also increased ReHo in the left superior frontal gyrus (SFG) and decreased levels of interleukin-9 and tumor necrosis factor-β. Changes in the DTI-ALPS index correlated with ameliorated depressive symptoms, increased ReHo in the SFG, and decreased inflammatory cytokine levels. Additionally, the pairwise interaction effects between glymphatic markers, ReHo values, and serum levels of pro-inflammatory cytokines were independent predictors of improvements in depressive symptoms, particularly anhedonia. BLT may influence glymphatic function in StD, with enhanced glymphatic function correlated with reduced inflammation, enhanced prefrontal cortex activity, and symptom amelioration.