Study Rationale: Gait deficits in Parkinson’s disease (PD) are not well controlled with existing therapeutic strategies. Episodic gait deficits such as freezing of gait are particularly debilitating and can lead to serious injuries from falls. Although deep brain stimulation (DBS) of the upper brainstem has been proposed for the treatment of gait deficits, the outcome has been disappointing. Using sophisticated tools available to basic research, we have gained unprecedented knowledge about the brainstem circuits involved in gait and determined the reasons for this lack of therapeutic benefit. We propose to translate this knowledge into an approach that enhances the efficacy of DBS.
Hypothesis: We hypothesize that different neuronal populations within a brainstem structure called the pedunculopontine nucleus (PPN) respond differently to electrical stimulation and need to be targeted individually. By establishing electrical stimulation protocols that have different effects on different cell types, we will identify and target the neurons responsible for gait.
Study Design: We will stimulate the PPN in preclinical rodent models of PD and record the neuronal activity of different neuronal cell types in response to this treatment. Using this knowledge, we will establish stimulation protocols that will allow us to differentially modulate the neuronal activity of different cell types at the same time. The stimulation protocols will be adapted in accordance with the pathological changes these neuronal subtypes display after the loss of dopamine-producing neurons. These protocols will then be tested in freely moving mice, with the aim of rescuing deficits in their motor symptoms.
Impact on Diagnosis/Treatment of Parkinson’s disease: Managing gait disorders remains a pressing, unmet need for many people with PD. Developing stimulation protocols that target the motor circuits of the PPN can lead to immediate use in the clinic and offer a real treatment option for patients with gait deficits.
Next Steps for Development: DBS is a clinically safe therapy, and the PPN has been an investigational target for almost two decades. Because implantation protocols, targeting strategies and safety profiles have already been developed, the results of this study can be taken directly to the clinic and tested, including in patients with DBS implants.