Deep brain stimulation (DBS), the chronic delivery of high frequency electrical stimulation to the brain, effectively improves the distal motor symptoms of Parkinson's disease (PD), but improvements in gait and postural disturbances are less reliable in the long-term. Due to the substantial impact of gait and postural instability on qualiy of life, alternative targets for DBS are under investigation. Among these, stimulation of the Substantia Nigra pars reticulata (SNr), an output structure of the basal ganglia involved in locomotion, appears to improve preferentially gait symptoms. The effects of stimulation location and stimulation parameters on improvement in gait and postural instability, as well as the neuroanatomic substrates involved, are unclear and this lack of foundational knowledge hinders the application and optimization of SNr DBS. We propose to characterize the effects of SNr DBS location, amplitude and frequency on gait and postural instability, and determine the neural pathways involved, using a preclinical rat model of PD. We will first test the hypothesis that the effectiveness of SNr DBS on improving gait and postural instability depends on the specific region stimulated within the SNr as well as the amplitude and frequency. The results of this aim will contribute to our understanding of which stimulation zone(s) within the SNr and which stimulation parameters are effective at treating gait and postural instability. Next, we will test the hypothesis that the activity and plasticity of neurons in regions downstream of the SNr depends on the location within SNr where DBS is applied. The results of this aim will provide insight into which neural regions are modulated by therapeutically effective SNr DBS. The outcome of the proposed project will provide a rational basis for the appropriate selection of implant site and stimulation parameters for SNr DBS for subsequent translational studies and make an important impact on the PD community.
The clinical benefits of deep brain stimulation to treat the distal motor symptoms of Parkinson's disease are well established, but gait and postural disturbances can worsen with progression of the disease. The outcome of the proposed project will determine the effects of location and parameters of deep brain stimulation of the Substantia Nigra pars reticulata on relief of gait and postural instability and neuronal activity to enable th full development and optimization of this promising treatment.