Direct Substantia Nigra Deep Brain Stimulation in Parkinson's Disease: Efficacy, Safety, and the Frequency-Response Relationship.
BACKGROUND The substantia nigra (SN) is an emerging deep brain stimulation (DBS) target for Parkinson's disease (PD). However, its independent therapeutic profile remains obscured by concurrent subthalamic nucleus (STN) stimulation in clinical practice. We systematically evaluated the frequency-dependent efficacy, longitudinal feasibility, and clinical boundaries of direct SN DBS to optimize both targeted nigral modulation and STN-SN combined stimulation. METHODS Phase 1 comprised an acute randomized crossover assessment in which 30 participants underwent both SN stimulation at 10, 30, and 130 Hz and standard STN stimulation at 130 Hz. Outcomes included the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III), objective gait kinematics, and episodic memory. Phase 2 was an exploratory, non-randomized 3-month feasibility cohort. Seven participants initiated chronic SN stimulation; two discontinued because of treatment-limiting adverse events, and longitudinal outcomes were available for five treatment-tolerant completers, with descriptive comparison to five STN-DBS comparator participants. RESULTS SN-DBS produced clear, frequency-dependent acute motor improvements. High-frequency (130 Hz) stimulation yielded the most pronounced clinical benefits, including a 43.6% reduction in MDS-UPDRS III and a 13.5% increase in stride length. The motor and spatial gait effects at 130 Hz were of similar magnitude to those observed with standard STN-DBS, while episodic memory performance remained stable across stimulation conditions. Patient-specific VTA mapping identified an outcome-associated region predominantly within the dorsal SN, and greater spatial overlap was associated with greater motor improvement. In Phase 2, chronic SN stimulation was maintained for 3 months in five of seven participants; two discontinued because of treatment-limiting adverse events. CONCLUSION Direct SN stimulation produced a clear frequency-dependent acute response in PD, with 130 Hz yielding the strongest motor and spatial gait benefits among the tested frequencies and effects of similar magnitude to standard STN stimulation. VTA mapping localized the strongest response-associated region predominantly within the dorsal SN, and the 3-month observations provided a basis for further development of anatomically precise and individualized SN neuromodulation.