Cerebellar Deep Brain Stimulation

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PROJECT SUMMARY/ABSTRACT Neurological and neuropsychiatric diseases are a growing concern worldwide as the consequences are often lethal, or at best they leave patients incapacitated. Unfortunately, most patients with these diseases do not respond to the current medications, and in the few cases that do work, they too can eventually develop drug resistance. Deep brain stimulation (DBS), a neurosurgical approach, has become an effective treatment when traditional medicines are not an option. However, even DBS has its limitations, as a large number of people do not respond to the treatment. Research using humans and animal models suggests that the current brain locations into which DBS is directed are not always adequate. As a first step towards identifying better targets for brain repair, we designed a genetic toolkit in mice that provides a versatile method for generating mouse models for severe motor disease. The toolkit is based on controlling the function of neural circuits in a brain region called the cerebellum, a structure involved in motor and cognitive function and a susceptibility site in a growing list of brain diseases. In Aim1, we will use a combination of these genetic models, high-resolution anatomy and in vivo electrophysiology conducted in behaving mice to define neural signatures for different motor diseases. In Aim2, we will use these neural signatures as biomarkers to test the feasibility of providing targeted close-loop cerebellar DBS to eliminate motor deficits with fast moment-to-moment precision. The ultimate goal of this work is to reverse the behavioral outcomes of disease by correcting brain function and restoring mobility. The availability of additional treatment options for incurable neurological and neuropsychiatric diseases will provide alternate healthcare considerations for reducing the impact of disease and improving the quality of life of affected patients.