The basal ganglia are part of larger circuits that also involve thalamus and cortex. Cortical inputs reach striatum and subthalamic nucleus (STN), and are transmitted via external and internal pallidal segments (GPe, GPi, resp.) and substantia nigra pars reticulata 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 abnormalities in their firing patterns. One of the most salient abnormalities is the appearance of synchronized oscillatory activity. The synchrony of ensembles of basal ganglia neurons can be measured with local field potential (LFP) recordings. Studies in humans, using implanted deep brain stimulation (DBS) electrodes to record LFPs, have suggested that high-amplitude, low frequency oscillations develop in parkinsonism which can be ameliorated by systemic dopaminergic medications. Uncertainties persist, however, regarding the temporal and causal relationship between circuit synchrony and parkinsonism, as well as the location at which dopamine loss exerts its synchronizing effects. We propose to study the development and long-term stability of LFP characteristics of parkinsonism in MPTP-treated primates, using multiple chronically implanted LFP electrodes throughout striatum, GPe, GPi and STN, combined with pharmacologic manipulation of dopaminergic transmission (aim 1). We will also study the local effects of dopaminergic drugs on neuronal synchrony in these nuclei, using a microdialysis/LFP recording probe which allows us to assess the effects of drugs, applied locally via reverse microdialysis, on LFPs in the vicinity of the probe. These studies will be done to assess drug-effects on spontaneous LFP production (aim 2), and on event-related LFP fluctuations in motor tasks (aim 3). These experiments will help us to better understand the origin(s) and functional significance of neuronal ensemble activity in parkinsonism. This knowledge will also be useful in the development of antiparkinsonian treatments targeting synchronous basal ganglia activity, and may help us to develop criteria to detect the presence of parkinsonism in LFP signals from the basal ganglia. Conceivably, such criteria could be used in the next generation of DBS devices to trigger 'on-demand' stimulation. ? ? ?
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