Systems Level Model of Deep Brain Stimulation

描述（由申请人提供）：丘脑底核（DBS）的脑深部电刺激（DBS）已迅速成为医学难治性帕金森病（PD）的有效治疗方法。然而，我们对DBS效果的理解是有限的，未来优化电极设计或刺激参数的尝试将取决于定义DBS实现其治疗效果的机制。计划工作的中心假设是，DBS在电极周围的不同神经元类型（局部细胞、通道纤维、传入输入）中产生不同的激活和抑制模式，这些刺激效应通过基底神经节的互连核传递。我们进一步假设，治疗性和非治疗性刺激导致不同神经元类型的不同激活模式，并且我们可以通过改变刺激参数来调节特定神经元类型的激活。反过来，我们的目标是评估不同的神经激活模式对DBS的行为和神经生理效应的治疗重要性。为了实现这一目标，我们将开发一个DBS的系统级模型，该模型将与正在进行的使用帕金森病猕猴DBS的实验工作相结合（R 01-NS 37019，PI：J. Vitek）。第一个具体目标将生成DBS产生的电场的真实场神经元模型，以及受刺激影响的不同神经元类型。第二个和第三个具体目标将耦合场神经元模型的假设驱动的研究实验与DBS的刺激参数的函数的影响的定量预测。这项工作将为DBS技术在人类PD治疗中的进步提供必要的基础知识，也可能增强DBS在肌张力障碍、癫痫、强迫症和重度抑郁症等其他疾病中的应用。

DESCRIPTION (provided by applicant): 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.