The basal ganglia are part of larger circuit that involves thalamus and cortex. Cortical inputs reach striatum and subthalamic nucleus (STN), and are transmitted via internal pallidal segment (GPi) and substantia nigra pars reticulata (SNr) to influence the activity of thalamocortical neurons. The function of this circuitry is disturbed in Parkinson's disease because of loss of dopamine in the basal ganglia. Besides changes in discharge rates, basal ganglia neurons also develop significant abnormalities in their discharge patterns in parkinsonism. One of the most salient abnormalities is the appearance of synchronized oscillatory discharge in STN, the external pallidum (GPe), GPi/SNr, and frontal cortex (detected by EEG). Available data suggest that this may result from altered activity along the cortex-STN-GPi/SNrthalamocortical route. With a combination of extracellular basal ganglia recordings and EEG, the proposed primate experiments explore the relationship between oscillatory activity in cortex and basal ganglia and will test the hypothesis that oscillatory discharge in the cortex-basal ganglia circuitry contributes to parkinsonism. The correlation studies under specific aim (S.A.) 1 assess the link between neuronal discharge in the basal ganglia (GPe, STN GPi, SNr) and EEG with simultaneous recordings in both brain regions. The importance of striatal or extrastriatal dopamine loss for the development of oscillatory discharge in parkinsonism will be tested under S.A. 2 by studying changes in oscillatory activity in basal ganglia and cortex induced by microinjections of the dopamine receptor agonist apomorphine at striatal and extrastriatal basal ganglia sites in parkinsonian animals. The experiments under S.A. 3 will test whether blockade of glutamate receptors in STN (blocking corticosubthalamic inputs) reduces oscillatory activity in basal ganglia and cortex. Finally (S.A. 4), the hypothesis will be tested that synchronized oscillatory discharge in the basal ganglia, induced by electrical stimulation of STN with bursts of stimulation pulses at burst rates between 2 and 30 Hz, disrupts motor performance and induces parkinsonian motor abnormalities in normal monkeys. These studies will help to understand the significance of oscillatory discharge in the basal ganglia and cortex in parkinsonism. This may provide guidance in the development of drug treatments directed at normalizing abnormal discharge patterns, and may help to understand the mechanism of action of existing treatments for Parkinson's disease, including dopamine receptor agonists, glutamate receptor antagonists, and deep brain stimulators.
