Understanding the effects of deep brain stimulation on cortical processing

描述(申请人提供)：帕金森氏病(PD)的特征是整个皮质和基底节的异常放电活动。虽然许多研究都集中在基底节功能的改变上，但最近的研究表明，与帕金森病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，需要更好地了解帕金森病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)是治疗帕金森病的有效方法，但其作用机制尚不清楚。临床上有效的DBS可以通过刺激丘脑或苍白球来实现。每种类型的刺激如何调节运动皮质处理尚不清楚，但它们的作用机制可能不同。更好地从机制上了解这两种类型的DBS是如何改变皮质网络功能的，将使研究人员能够优化DBS的传递，即在哪里植入电极，以及什么刺激模式将最有效地改善运动皮质处理。在这项研究中，非人类灵长类动物将在三个可能受DBS影响最大的不同运动皮质处理区长期植入皮质内微电极记录阵列。在各种运动任务中，将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，使用神经毒素MPTP，将动物的一半身体制成中度帕金森氏症。将描述正常状态和帕金森状态之间皮质网络活动的变化。代表皮质柱的皮质微回路的详细计算模型将被用来确定在动物实验中看到的皮质活动模式变化的潜在机制。具体地说，皮质模型的输入和神经元之间的连接权重将被迭代优化，直到模拟的网络行为与在正常和帕金森综合症状态下的动物实验中看到的一致。帕金森氏症皮质微电路模型随后将扩展到包括DBS应用于丘脑底核和苍白球的输入。模型模拟将在各种新的刺激模式下应用DBS进行。将确定最有效地将皮质活动恢复到更正常状态的模拟DBS模式，并在帕金森症猴子身上进行实验测试。反过来，在DBS期间实验记录的皮质活动模式将被用于验证和进一步完善计算模型。这种实验和建模相结合的方法将促进我们对与帕金森病相关的皮质网络变化的理解，并确定不同类型的DBS可以更有效地调节这一皮质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.