Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has rapidly emerged as an effective treatment in medically refractory Parkinson's disease (PD). However, our understanding of the effects of DBS is limited and future attempts at optimizing electrode design or stimulation parameters will depend on defining the mechanisms by which DBS achieves its therapeutic effect. The central hypothesis of the planned work is that DBS generates heterogeneous patterns of activation and inhibition in the different neuron types (local cells, fibers of passage, afferent inputs) that surround the electrode and these stimulation effects are transmitted throughout the interconnected nuclei of the basal ganglia. We further hypothesize that therapeutic and non-therapeutic stimulation result in different patterns of activation in the different neuron types and we can modulate the activation of specific neuron types via alterations in the stimulation parameters. In turn, our goal is to assess the therapeutic importance of different neural activation patterns on the behavioral and neurophysiological effects of DBS. To accomplish this goal we will develop a systems level model of DBS that will be coupled to ongoing experimental work using DBS of the parkinsonian macaque (R01-NS37019, PI: J. Vitek). The first specific aim will generate realistic field-neuron models of the electric field generated by DBS, and the different neuron types influenced by stimulation. The second and third specific aims will couple the field-neuron model to hypothesis driven research experiments with quantitative predictions of the effects of DBS as a function of the stimulation parameters. This work will provide fundamental knowledge necessary for the advancement of DBS technology for treatment of PD in the human, and may also enhance the application of DBS to other disorders such as dystonia, epilepsy, obsessive-compulsive disorder, and major depression.
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