Motor Learning in Parkinson's Disease

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DESCRIPTION (provided by applicant): The specific aims of the original proposal were: 1. To determine the effect of Parkinson's disease (PD) on the learning of spatial and temporal features of motor learning tasks, compared to a normally aging population. 2. To test the hypothesis that the deficits in motor learning in PD result from the altered function of specific cortical and subcortical networks whose expression correlates with task performance in age-matched controls. 3. To assess the effect on motor learning of new therapies, such as pallidal ablation and pallidal stimulation. Over the past two and a half year, we have made extensive progress in accomplishing these aims, as described in Progress Report and in the publication track record. In this competing continuation application, we plan to complete the initial research and educational aims and to extend our work. Specifically, we will pursue the following aims: 1. To study the effects of DBS and levodopa administration on motor learning in PD. We have shown that aspects of motor learning are defective in the earliest stages of PD and are associated with abnormal brain organization. Preliminary data indicate that these abnormalities are not rectified by levodopa, but, GPi DBS can improve sequence learning and increase activity in brain regions normally involved in this process. Here we ask if STN DBS (which drives GPi and other structures mediating simple and complex motor behavior) can improve performance in PD by modulating the brain circuits involved in sequence learning, similarly to GPi DBS. PET recordings during motor tasks will be conducted in a group of PD patients with STN DBS, a group with GPi DBS, and a group treated with levodopa infusion in on and off conditions. Brain network expression and performance will be compared across groups and conditions. 2. To characterize the progression of motor and cognitive dysfunction in PD. We found that PD patients in stage I and 11 require longer time and need to recruit more brain areas to learn a motor sequence. Here we ask how performance and brain network activation change in relation to disease progression. In this longitudinal study, we will also evaluate changes in acquisition of motor skills other than sequence learning, such as adaptation to new reference frames or novel inertial configuration. We will use tasks we have recently developed and tested in a population of young normal subjects. We will ask the following questions: Which are the normal brain networks involved in the different types of learning? Are they independent or share some common bases? Does their expression change in PD patients in early stages? Does brain network expression in PD change with disease progression? These studies psychophysical and imaging studies will be conducted in the group of PD patients and age-matched controls we have tested in the previous grant period. 3. To study motor learning and execution in hyperkinetic basal ganglia disorders. Studies with "F-fluoro-deoxyglucose (FDG) and PET have demonstrated an abnormal metabolic network in clinically non-manifesting carriers of Idiopathic Torsion Dystonia (ITD) DYT I gene. In preliminary studies, we have found that motor sequence learning may be impaired in these same gene carriers. We plan to complete the psychophysical studies in non-manifesting DYTI carriers and to assess the effect of GPiDBS on rcbf in affected DYTI patients. Specifically, we will ask the following questions: Will non-manifesting DYTI carriers show motor learning and network activation abnormalities that parallel their resting metabolic abnormalities? Will non-manifesting DYT I carriers and dystonic patients show differences in motor learning and network activation? By comparing rcbf before and during pallidal stimulation, we will determine how altering pallidal function affects the expression of activation patterns subserving motor learning in ITD. Overall, these studies will provide the bases for a comprehensive understanding of basal ganglia and related cicuitry in motor learning and execution, as well as for the development of new therapeutical strategies for basal ganglia disorders.