Neurophysiological mechanisms underlying parkinsonian motor signs

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DESCRIPTION (provided by applicant): The goal of this study is to identify the specific neurophysiological changes in the basal ganglia thalamic network that underlie the development and severity of bradykinesia, rigidity and tremor, the three cardinal motor signs of Parkinson's disease (PD). This will be done by comparing single neuron activity during normal, mild, moderate and severe parkinsonian symptoms in the same monkeys using sequential low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Structures that will be examined include the internal and external segments of the globus pallidus (GPi and GPe, respectively), the subthalamic nucleus (STN), and the motor thalamus including ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis. Specific aims 1 and 2 will determine the characteristics of neuronal activity at these nodal points within the basal ganglia network that underlie the development of bradykinesia, rigidity and tremor and characterize the evolution of changes in neuronal activity that occur with increasing severity of these motor signs. Specific aim 2 will also determine the relative effect of fiber sparing lesions of each thalamic subnucleus on individual motor signs. Specific aim 3 will assess the causal role of the particular changes in neurophysiological activity found to occur in specific aims 1 and 2. This will be done by reproducing these neurophysiological changes in the STN and GPi in normal monkeys and augmenting them in mildly parkinsonian monkeys using externally programmed implanted stimulators at these nodal points. By examining the neurophysiological changes that occur at different stages of PD and relating them to the occurrence and severity of individual motor symptoms, we will be able to clarify the neuronal basis underlying the development and severity of motor signs associated with PD. This will in turn provide the rationale from which to base the development of promising new therapies such as deep brain stimulation and gene therapy that are directed at modulating neuronal activity in the basal ganglia thalamic circuit. The goal of this study is to identify the specific changes in the activity of brain cells in the basal ganglia that cause the movement problems in Parkinson's disease (PD). People with PD develop specific problems with movement manifested as slowness (bradykinesia), stiffness (rigidity), and uncontrollable rhythmic movements in the extremities and face (tremor). This study will identify the specific changes in brain activity that cause each motor symptom and determine how they are related to increasing severity of each symptom. The results of this study will provide the understanding necessary for the refinement of current and development of future therapies, e.g., deep brain stimulation and gene therapy, directed at modulating the neuronal activity in the basal ganglia thalamic circuit responsible for the development of PD motor symptoms.