Stimulation location within the substantia nigra pars reticulata differentially modulates gait in hemiparkinsonian rats

Deep brain stimulation (DBS) improves the distal motor symptoms of Parkinson's disease, but long-term improvements in gait and postural disturbances are less pronounced. The effects of stimulation location, within the large nuclear region of the substantia nigra pars reticulata (SNr), and stimulation parameters on improvement in gait are unclear, and this lack of foundational knowledge hinders the application and optimization of SNr DBS. We quantified the effects of medial vs. lateral SNr DBS on methamphetamine-induced circling in hemiparkinsonian rats to test the hypothesis that stimulation location differentially modulates axial symptoms. The frequency tuning curves showed opposite trends with stimulation frequency; during high frequency stimulation, medial SNr DBS decreased ipsilateral circling, while lateral SNr DBS had no effect on circling. As well, we quantified the effects of 130 Hz SNr DBS on gait to test the hypothesis that SNr DBS location differentially modulates gait. High frequency DBS of the medial SNr, but not lateral SNr, improved the rat's ability to maintain walking speed. The therapeutic effects of medial SNr DBS appeared to improve with time on the same order as clinical studies (>10 min). These results suggest that improvement in gait depends on the location of the electrodes (medial vs. lateral SNr) with a time course for improvement reminiscent of human data and provide a rational basis for the appropriate selection of implant site and stimulation parameters for SNr DBS.