Parkinson's Disease (PD) is characterized by the degeneration of dopamine producing cells in the substantia nigra. Although the neurochemical lesion is mainly localized to the nigrostriatal dopamine system, the effects of dopamine loss are widespread and affect non-dopaminoceptive neurons in brain regions constituting crucial elements of motor control and other pathways. These systems, which are still incompletely delineated, play a critical role in mediating the prominent motor and cognitive impairments of PD. We have previously used positron emission tomography (PET) to begin to identify the functional alterations in these pathways in PD. We propose to utilize recent advances in functional imaging, network analysis, motor control physiology, and stereotaxic neurosurgery to explore mechanisms of clinical disability in PD. We will endeavor to elucidate the neurological basis for impaired motor performance in this disorder by implementing a novel set of behavioral paradigms with concurrent psychophysical measurements. We will determine how functional brain networks are specifically altered in treated and untreated parkinsonism, and in normal aging where motor and cognitive impairments similar in nature may also occur. We intend to analyze in a quantitative fashion the functional interactions of the basal ganglia, thalamus and motor cortices in untreated PD patients. To this end, we will use 18F-fluorodeoxyglucose (FDG) as a PET tracer to assess brain metabolism in individual regions, and apply these data in a comprehensive network modeling approach to define regional patterns of regional covariation characteristic of disease. We will also use 15-O-labeled water (15-O-H2O) and PET to assess dynamic changes in brain function as measured by regional changes in cerebral blood flow in the course of movement. These activation experiments will allow us to determine how regional brain work differs in motor task performance in PD and normal aging, and how these measurements vary with subject differences in the psychophysics of movement. We also intend to examine the functional brain mechanisms underlying successful dopaminergic pharmacotherapy for PD. We will use PET to study PD patients before and during levodopa infusion. We will use network modeling to assess whether the expression of PD-related regional covariance patterns is altered by treatment, and whether these alterations correlate with clinical therapeutic responses. Changes in brain function with medical therapy will be contrasted with those occurring following stereotaxic surgery: We propose to examine changes in regional brain function in a population of patients before and after ventral pallidotomy performed because of unsatisfactory responses to levodopa. We will use 15-O-H2O and PET to study the effects of pallidal ablation on regional brain function during motor execution and learning. By delineating the functional brain changes that are associated with clinical improvement following medical and surgical interventions, we hope to develop quantitative imaging markers for the objective assessment of therapeutic responses. This approach may have great utility in evaluating new therapies for PD and related disorders.
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