Idiopathic torsion dystonia (ITD) and Huntington's disease (HD) are common hereditary hyperkinetic movement disorders affecting the basal ganglia. However, neuronal loss in the basal ganglia may result in widespread disease-specific alterations in brain function. New advances in functional brain imaging with positron emission tomography (PET) and network analysis have allowed us to identify and quantitate spatially distributed changes in brain organization associated with neurodegenerative processes. We have previously used these methods to delineate the specific abnormalities in motor control networks which mediate the akinetic-rigid manifestations of parkinsonism. We now propose to extend this approach to characterize the functional network basis for the hyperkinetic manifestations of ITD and HD. Because HD and many types of ITD are genetically mediated, these disorders provide the unique possibility of quantitatively assessing complex inter- relationships between genotype, brain organization and behavior. In this proposal we intend to integrate recent advances in functional brain imaging technology, network analysis, motor control physiology and human genetics to explore the neural mechanics of clinical disability in the hyperkinetic disorders. We will implement several novel experimental approaches to delineate the abnormal brain circuitry underlying ITD and HD. (1) We will limit our PET studies of hyperkinesia to genetically homogeneous populations, specifically DYT-1 and HD gene carriers. (2) We will focus our brain imaging studies on non-manifesting carriers of these mutations. (3) We will also scan affected hyperkinetic patients in sleep in order to eliminate confounding abnormal movements. We will also pursue novel experiments focused on the experimental therapeutics of these hyperkinetic movement disorders. Firstly, we will extend our functional brain imaging study to include DYT-1 dystonia patients undergoing deep brain stimulation (DBS). By quantifying and contrasting brain network expression under different stimulation conditions, we will assess the changes in functional brain organization that are associated with clinical improvement under DBS. Similarly, we propose to extend our baseline functional imaging studies in preclinical and symptomatic improvement under DBS. Similary, we propose to extend our baseline functional imaging studies in preclinical and symptomatic HD gene carriers by carring out longitudianl follow-up studies of brain-behavior interactions in these individuals. These studies will allow us to trace the temporal evolution of the manifestation of pathological brain networks in HD and to assess their relationship with motor performance. Knowledge of the rate of progression of behavioral and functional impairment before and following clinical onset is relevant for the future treatment of HD gene carriers with neuroprotective drugs or striatal cell implantation techniques. By delineating the functional brain changes that are associated with clinical improvement and with the natural progression of illness, we hope to develop functional imaging markers for the objective assessment of therapeutic responses. This approach may have great utility in evaluating new interventions for the treatment of the hyperkinetic movement disorders.
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