The motor network in Parkinson's disease: mechanisms of therapy

 描述(由申请人提供)：我们的目标是在非常快的时间尺度上了解运动障碍中的运动网络和人类治疗干预的机制。在过去的五年中，我们介绍了在接受神经外科治疗的患者中，将硬膜下皮质脑电图(ECoG)与基底节记录和刺激相结合的新技术。从ECoG电位中，我们可以提取关于低频节律(如运动β节律)的信息，或关于群体尖峰活动的信息(从高频宽带活动中)。我们先前在急性术中记录中所做的工作表明：1)帕金森病(PD)运动皮质的一个主要异常是人群与运动β节律的过度耦合；以及2)急性治疗性脑深部刺激(DBS)可逆地缓解这种过度同步的模式。这些发现为理解运动障碍的皮质基础和抗帕金森病治疗的网络机制提供了新的基础。然而，关键问题仍然存在，这些问题在术中环境下不容易研究：慢性治疗性刺激的机制与急性刺激的机制是否不同？刺激机制与左旋多巴相比如何？运动障碍的潜在网络特征是什么？在这里，我们使用一种新颖的、完全可植入的双向神经接口来解决这些问题 提供DBS和治疗，并感知/存储ECoG或局部场电位(目标1和2)。我们在门诊定期记录和下载基底节和皮质电位，在明确定义的行为条件下，由运动障碍神经病学家对运动功能进行专家表征。2013年11月，我们在医生赞助的方案下，在一名帕金森病患者身上植入了第一个用于多部位(皮质和基底节)记录的设备。通过ECoG记录具有良好的信号：噪声特性和卓越的时空分辨率的优势，但考虑到其侵入性，不服从正常控制。因此，在目标3中，我们使用一种补充的、非侵入性的技术，头皮脑电图仪(EEG)来解决类似的问题，基于我们最近的发现，PD特有的皮质种群同步性的测量可以通过EEG检测到，并受到口服左旋多巴和DBS的调节。这种方法使我们能够研究大量的受试者，并包括正常对照。这些研究的影响将是：1)提供对帕金森病异常网络同步的更详细的理解，为比过去的模型更好地结合皮质功能的新模型提供信息。2)从机制上理解治疗性DBS对皮质功能的影响。3)为闭环式脑深部刺激的发展奠定了基础，它可以利用临床上实用的皮质信号来自动控制刺激参数。这项研究阐明的机制可能适用于其他皮质下刺激显示出治疗前景的网络性大脑疾病。

 DESCRIPTION (provided by applicant): Our goal is to understand the motor network in movement disorders and the mechanism of therapeutic interventions in humans, at very fast time scales. Over the past five years we introduced the novel technique of combining subdural electrocorticography (ECoG) with basal ganglia recording and stimulation in persons undergoing neurosurgical treatment. From ECoG potentials, we can extract information about low frequency rhythms (such as the motor beta rhythm), or about population spiking activity (from high frequency broadband activity). Our prior work in acute intraoperative recording showed that: 1) a major abnormality of the motor cortex in Parkinson's disease (PD) is the excessive coupling of population spiking to the motor beta rhythm; and 2) acute therapeutic deep brain stimulation (DBS) reversibly alleviates this pattern of excessive synchrony. These findings provide a new foundation for understanding the cortical basis for impaired movement and the network mechanisms of antiparkinsonian therapies. However, critical questions remain that cannot readily be studied in the intraoperative setting: Does the mechanism of chronic therapeutic stimulation differ from that of acute stimulation? How do mechanisms of stimulation and levodopa compare? What are the network characteristics underlying dyskinesias? Here, we address these questions using a novel, totally implantable bidirectional neural interface that both delivers DBS and therapy and senses/stores ECoG or local field potentials (Aims 1 and 2). We record and download basal ganglia and cortical potentials at regular intervals in our outpatient clinic under well-defined behavioral conditions with expert characterization of motor function by movement disorders neurologists. In November 2013, we implanted the first such device for multisite (cortex and basal ganglia) recording in a Parkinson's disease patient, under a physician-sponsored protocol. Recording via ECoG has the advantage of excellent signal:noise characteristics and superb spatial and temporal resolution, but given its invasiveness is not amenable to normal controls. Therefore, in Aim 3 we address similar questions using a complementary, noninvasive technique, scalp electroencephalograph (EEG), based on our recent finding that measures of cortical population synchrony unique to PD are detectable by EEG and modulated by both oral levodopa and DBS. This approach allows us to study a large number of subjects and to include normal controls. The impact of these studies will be to: 1) Provide a more detailed understanding of abnormal network synchronization in PD, informing new models that better incorporate cortical function than past models. 2) Provide a mechanistic understanding of the effects of therapeutic DBS on cortical function. 3) Create a foundation for the development of closed loop deep brain stimulation, which could utilize a clinically practical cortical signal for automated control of stimulation parameters. Mechanisms elucidated in this study may be applicable to other network brain disorders where subcortical stimulation shows therapeutic promise.