Neural Substrates of Oral Motor Dysfunction in Parkinson's Disease

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DESCRIPTION (provided by applicant): Speech and swallowing impairments occur in 90% of Parkinson's Disease (PD) patients and aspiration pneumonia is the leading cause of death. While current pharmacological and surgical interventions are effective in alleviating general motor symptoms of PD, largely controlled by corticospinal tracts, they have failed to provide significant benefit for functions controlled by corticobulbar tracts such as speech and swallowing. This suggests that oral motor and upper extremity deficits in PD are mediated by different underlying neural pathologies. Our newly developed animal model of oral motor impairment in PD suggests that striatal dopamine depletion does indeed differentially affect the neural circuits controlling lingual versus forelimb function. This has lead to the hypothesis that improvements in oral motor function in PD may require treatments different from those used to treat upper extremity function. The goal of the proposed study is to dissociate the different behavioral and neural changes mediating recovery of oral motor versus upper extremity function in PD. Specifically, this study will 1) determine the differential responses of oral motor and upper extremity function to motor rehabilitation and dopamine replacement therapy and 2) determine the differential effects of motor rehabilitation and dopamine replacement therapy on oral motor versus upper extremity movement representations within the motor cortex. This study involves first training 90 male Long Evans rats on an extensive battery of motor tasks to establish a baseline measure of upper extremity and oral motor function. Striatal dopamine will be depleted bilaterally in sixty of the animals via localized 6-Hydroxydopamine injections. One month following each injection, motor impairments will be assessed. Animals will then receive either 1) oral motor therapy; 2) oral motor therapy + levodopa; 3) upper extremity therapy; 4) upper extremity therapy + levodopa; 5) levodopa therapy; or 6) no rehabilitation for eight weeks. The impact of these treatments will be assessed on the same battery of motor tasks post treatment. Intracortical microstimulation will then be used to derive motor maps of forelimb, tongue and jaw movements and the level of striatal dopamine depletion will be determined using immunohistochemistry. This study integrates a comprehensive behavioral test battery with intracortical microstimulation to determine the specific neural substrates mediating oral motor impairment and recovery in PD. PUBLIC HEALTH RELEVANCE: The results will guide the development of neurobiologically informed therapies that specifically target oral motor impairment that can be translated to the human patient population. More effective treatment strategies of oral motor dysfunction in PD will improve patient quality of life, reduce individual health care cost and ultimately reduce PD related mortality.