Understanding the effects of deep brain stimulation on cortical processing

描述（由申请人提供）：帕金森病（PD）的特征是整个皮层和基底神经节的异常放电活动。虽然许多研究都集中在基底神经节功能的改变，但最近的研究表明，与PD症状相关的关键神经活动变化实际上可能来自皮质和/或由皮质驱动。因此，需要更好地了解PD如何影响皮质网络活动，以开发更有效的治疗方案。 脑深部电刺激（DBS）是一种已确立的PD治疗方法，但其治疗作用机制仍不清楚。临床有效的DBS可以通过丘脑底核或苍白球刺激来实现。每种类型的刺激如何调节运动皮层处理尚不清楚，但它们的作用机制可能不同。更好地理解这两种类型的DBS如何改变皮层网络功能的机制将使研究人员能够优化DBS输送，包括植入电极的位置以及什么样的刺激模式将最有效地改善运动皮层处理。 在这项研究中，非人类灵长类动物将长期植入皮质内微电极记录阵列在三个不同的运动皮层处理区可能是最受DBS的影响。将在各种运动任务期间记录单位尖峰和波形活动以及局部场电位，以表征正常状态下的皮质网络活动。然后，动物将使用神经毒素MPTP使其身体的一半中度帕金森病。将描述正常和帕金森病状态之间皮质网络活动的变化。 代表皮质柱的皮质微电路的详细计算模型将用于识别负责在动物实验中观察到的皮质活动模式变化的潜在机制。具体而言，皮层模型的输入和神经元间连接权重将被迭代地优化，直到模拟的网络行为与在正常和帕金森状态下的动物中实验观察到的行为相匹配。帕金森氏症皮层微电路模型，然后将扩展到包括输入DBS应用于丘脑底核和苍白球。模型模拟将在DBS应用于各种新型刺激模式的情况下运行。将识别在将皮质活动恢复到更正常状态方面最有效的模拟DBS模式，并在帕金森病猴中进行实验测试。反过来，在DBS过程中实验记录的皮层活动模式将用于验证和进一步完善计算模型。 这种结合实验和建模的方法将促进我们对与PD相关的皮层网络变化的理解，并确定不同类型的DBS可以更有效地调节这种皮层网络活动以改善运动功能的潜在机制。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized by abnormal firing activity throughout the cortex and basal ganglia. Although much research has focused on the altered function in the basal ganglia, recent studies suggest that the key neural activity changes associated with PD symptoms may actually be coming from and/or driven by cortex. Therefore, a better understanding of how PD impacts cortical network activity is needed to develop more effective treatments options. Deep brain stimulation (DBS) is an established therapy for PD but its therapeutic mechanisms of action is still unclear. Clinically-effective DBS can be achieved with either subthalamic or globus pallidus stimulation. How each type of stimulation modulates motor cortical processing is unclear, but their mechanisms of action likely differ. A better mechanistic understanding of how these two types of DBS alter cortical network function will enable researchers to optimize DBS delivery in terms of where to implant the electrodes and what stimulation patterns will most effectively improve motor cortical processing. In this study, non-human primates will be chronically implanted with intracortical microelectrode recording arrays in three different motor cortical processing areas likely to be most affected by DBS. Unit spiking and waveform activity as well as local field potentials will be recorded during various motor tasks to characterize cortical network activity in the normal state. Then the animals will be made moderately Parkinsonian on one half of their body using the neurotoxin MPTP. Changes in cortical network activity between the normal and Parkinsonian state will be characterized. Detailed computational models of the cortical microcircuit representing a cortical column will be used to identify potential mechanisms responsible for the changes in the cortical activity patterns seen experimentally in the animals. Specifically, the cortex model's inputs and inter-neuronal connectivity weights will be iteratively refined until the simulated network behavio matches what was seen experimentally in the animals in the normal and Parkinsonian states. The Parkinsonian cortical microcircuit model will then be expanded to include inputs from DBS applied to the subthalamic nucleus and to the globus pallidus. Model simulations will be run with DBS applied at a wide variety of novel stimulation patterns. Simulated DBS patterns that are most effective at returning the cortical activity to a more normal state will be identified and the be tested experimentally in the Parkinsonian monkeys. In turn, cortical activity patterns recorded experimentally during DBS will be used to validate and further refine the computational model. This combined experimental and modeling approach will advance our understanding of the cortical network changes associated with PD as well as identify potential mechanisms by which different types of DBS can more effectively modulate this cortical network activity to improve motor function.