HD-tACS at 40 Hz improves consciousness and brain connectivity in prolonged disorders of consciousness: a randomized sham-controlled clinical trial

Background Frequency-specific high-definition transcranial alternating current stimulation (HD-tACS) may facilitate recovery in patients with prolonged disorders of consciousness (pDoC), but predictive biomarkers and mechanistic insights are limited.Objective To investigate the therapeutic efficacy of 40 Hz or 4 Hz HD-tACS in pDoC.Methods Sixty pDoC patients were randomized into four groups receiving 40 Hz or 4 Hz HD-tACS, each with a corresponding sham condition. Behavioral recovery was assessed via Coma Recovery Scale-Revised (CRS-R), network connectivity was analyzed with electroencephalography (EEG), and baseline 40 Hz auditory steady-state response (ASSR) was explored as a predictive biomarker.Results Five days of 40 Hz HD-tACS yielded greater improvements of total CRS-R scores than 4 Hz or sham, particularly in visual and arousal subscales. EEG revealed strengthened short- and long-range connectivity quantified by phase-locking value (PLV), correlating with behavioral gains. At six months, 37.5% of 40 Hz patients got a good outcome with Glasgow Outcome Scale-Extended (GOS-E) score ≥ 4, which was significantly higher than that observed in the sham group (P = 0.019). Higher baseline ASSR predicted stronger network enhancement and clinical improvement.Conclusions 40 Hz HD-tACS promotes recovery and network reorganization in pDoC. Baseline ASSR may provide complementary information for understanding individual variability in responses to frequency-specific neuromodulation.