In a double-blind, sham-controlled RCT of 60 Parkinson's patients (H&Y 1–3), twice-daily high-intensity tACS added to multidisciplinary intensive rehabilitation produced significantly greater and durable improvements in PDQ-39 quality-of-life scores and reductions in depression and apathy up to 24…

This trial delivers clinically actionable evidence that noninvasive high-intensity tACS can be a scalable, low-risk adjunct to rehabilitation to improve long-term QoL and non-motor symptoms in PD, making it a promising candidate for translation and for follow-up mechanistic and biomarker-driven…

AIMS: In this randomized, double-blind, sham-controlled trial, we explored whether high-intensity transcranial alternating current stimulation (Hi-tACS), as an add-on to multidisciplinary intensive rehabilitation therapy (MIRT), could yield more durable quality of life (QoL) improvements than MIRT alone. METHODS: Sixty patients with Parkinson's disease (PwP) (Hoehn and Yahr stages 1-3, aged 45-70) were assigned (1:1) to receive 10 days of MIRT with either twice-daily Hi-tACS (15 mA, 77.5 Hz, 40 min/session) or sham stimulation. The primary outcome was the longitudinal change in the 39-item Parkinson's Disease Questionnaire (PDQ-39) total score from baseline to 4, 12, and 24 weeks after intervention. Secondary outcomes included changes in motor and non-motor symptom scales. Adverse events were monitored throughout the intervention period. RESULTS: Generalized estimating equation analysis revealed a significant group-by-time interaction for PDQ-39 total scores (Pgroup × time = 0.008). The Hi-tACS+MIRT group demonstrated significantly greater reductions in PDQ-39 scores than the sham-Hi-tACS+MIRT group at 4 weeks (T2: effect size = 0.68, 95% CI: 0.14-1.21; PFDR = 0.009), 12 weeks (T3: effect size = 1.43, 95% CI: 0.80-2.05; PFDR = 0.003), and 24 weeks (T4: effect size = 1.26, 95% CI: 0.65-1.85; PFDR < 0.001). In addition, the Hi-tACS+MIRT group exhibited superior improvements in depression and apathy. Adverse events were mild and infrequent, with no serious adverse events reported. CONCLUSIONS: This trial demonstrated that the Hi-tACS add-on to MIRT could maintain long-term improvements in QoL and improve non-motor symptoms for PwP, providing a new strategy for PwP rehabilitation.