Large-scale EEG neural network changes following accelerated high-definition transcranial direct current stimulation in major depressive disorder: A randomized controlled trial.

BACKGROUND: High-density transcranial direct current stimulation (HD-tDCS) shows efficacy in major depressive disorder (MDD), but underlying mechanisms remain unclear. Electroencephalogram (EEG) microstates reflect large-scale network dynamics, and MDD patients exhibit microstate abnormalities. Whether HD-tDCS modulates these states and their clinical relevance is unknown. METHODS: In a randomized controlled trial, 39 MDD patients were assigned to either drug or HD-tDCS groups. The HD-tDCS group received accelerated stimulation over the left dorsolateral prefrontal cortex, twice daily for 20 sessions across two weeks, in addition to antidepressant medication. Resting-state EEG were recorded pre- and post-treatment, and microstate dynamics were analyzed in relation to symptom change. RESULTS: Both groups identified five microstates (A-E). The HD-tDCS group showed significantly greater reductions in Hamilton Depression Rating Scale (HAMD) scores, response rates, and remission rates compared with medication group. Only HD-tDCS induced significant microstate changes: decreased coverage of A and D, reduced duration of D, and decreased occurrence of E, alongside increased coverage and occurrence of B. In the remission subgroup, D coverage decreased and E coverage increased. Reduced D coverage correlated with Hamilton Anxiety Rating Scale (HAMA) improvement, increased B occurrence with HAMD improvement, and transitions from E to B with improvements on both scales. In remitters, changes in D coverage were strongly linked to reductions in both HAMA and HAMD. CONCLUSIONS: Microstate D and B were specifically associated with anxiety and depression improvement, respectively, while E to B transitions related to both. These findings provide novel neuro-electrophysiological evidence for accelerated HD-tDCS mechanisms in MDD.