Disease Duration Differentiates Freezing of Gait Response to Subthalamic and Nigral Stimulation for Parkinson's Disease in an Exploratory Multicenter Controlled Trial

BACKGROUND: Freezing of gait (FoG) belongs to most pressing unmet symptoms in the treatment of Parkinson's disease. OBJECTIVES: To explore whether combined subthalamic and nigral (STN + SNr) deep brain stimulation improves FoG compared with optimized STN stimulation alone; to identify clinical variables associated with therapeutic response. METHODS: In this exploratory multicenter randomized controlled double-blind trial, we recruited patients from our existing cohorts and randomized them 1:1 to STN or STN + SNr. After baseline, patients were followed with close interim visits (visits 1-5) for 90 days (visit 6). The Freezing of Gait Assessment Course (FoG-AC) was the primary endpoint and was evaluated at P < 0.2 with exploratory intent. Secondary endpoints assessed responder rates, treatment dynamics, predictors of response, and patient preferences. RESULTS: At V6, STN (n = 23) and STN + SNr (n = 22) FoG-AC outcomes did not differ significantly. We identified responders with clinically meaningful FoG improvement in both the STN (n = 7) and STN + SNr (n = 8) groups. In STN + SNr responders, mean disease duration was ~12 years, which was ~4.5 years shorter than in non-responders, but there were no differences in motor and cognitive functions. Treatment dynamics suggested that FoG responders improved slowly and gradually. The STN + SNr responder group showed numerically stronger FoG improvement compared with STN responders. Additionally, 15 STN compared to 10 STN + SNr patients wished to change treatment after the RCT phase and before unblinding. Both STN and STN + SNr treatment was safe. CONCLUSIONS: Future trials evaluating adjunctive STN + SNr stimulation should stratify patients by disease duration to optimize outcomes.