Over the last decade, the outlook for patients with advanced parkinsonism and other movement disorders has been revolutionized by the introduction of deep brain stimulation (DBS) in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) as a highly effective treatment modality. According to recent estimates over 2000 patients with PD have undergone implantation of DBS electrodes for the treatment of PD and over 15,000 patients per year may be candidates for this procedure. This number will increase, as the use of DBS as treatment of brain disorders becomes more widespread. Despite their widespread use, very little is known about the physiologic effects of DBS. Given the somewhat similar effect of lesions and stimulation in STN, GPI and thalamus on parkinsonian motor signs, it has been speculated that stimulation may act similar to lesioning, by blocking neuronal activity. Several studies have supported this view reporting suppression of neuronal activity in the site of stimulation. Our preliminary results, as well as the results of other groups have suggested that stimulation may, in fact increase output from the stimulated structure, demonstrating that stimulation in the STN increases neuronal activity in the GPi, while GPi stimulation suppresses neuronal activity in the thalamus. Additional support for this hypothesis is derived from microdialysis studies that found increased levels of glutamate in the entopeduncular nucleus (the rodent equivalent of GPi in primates) during STN stimulation. Conceivably, stimulation of basal ganglia activity may improve parkinsonism simply by regularizing pallidal discharge patterns. Both activation and inactivation could, in fact, be invoked during stimulation, because electrical stimulation may inhibit neuronal activity, while activating fibers in the stimulated area. For further optimization of current DBS protocols, and to minimize risks and side-effects of DBS implantation, it is mandatory that a solid understanding of the mechanism of action of this intervention is developed. This study will determine the mechanism underlying the effects of DBS of STN and GPi by examining in the MPTP monkey model of PD: 1) the effect of stimulation in the STN and GPi on neuronal activity and on neurotransmitter release in different portions of the basal ganglia-thalamocortical circuit, 2) the role of GPe in mediating the effect of stimulation in the STN and GPI, in mediating the development of parkinsonian motor signs and as an alternative site for stimulation for the treatment of PD and 3) determine the effect of stimulation in the STN and GPI on cortical function. The experiments will use a combination of single cell recording, microdialysis, and 18F-fluoro-deoxy-glucose (FDG) PET studies. DBS will be accomplished by implantation of a downscaled version of DBS leads used in humans.
Showing the most recent 10 out of 32 publications
