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，我们介绍了新的技术相结合的硬膜下皮质电图（ECoG）与基底节记录和刺激的人接受神经外科治疗。从ECoG电位中，我们可以提取有关低频节律（如运动β节律）或群体尖峰活动（从高频宽带活动）的信息。我们之前在急性术中记录方面的工作表明：1）帕金森病（PD）运动皮层的一个主要异常是群体尖峰与运动β节律的过度耦合; 2）急性治疗性脑深部电刺激（DBS）可逆性地消除了这种过度同步模式。这些发现为理解运动受损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，关键的问题仍然是，不能很容易地在术中环境中进行研究：慢性治疗刺激的机制是否不同于急性刺激？刺激机制和左旋多巴相比如何？运动障碍背后的网络特征是什么？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， 输送DBS和治疗，并感测/存储ECoG或局部场电位（目标1和2）。我们记录和下载基底神经节和皮层电位在我们的门诊在明确的行为条件下，由运动障碍神经学家的运动功能的专家表征定期。2013年11月，我们在医生赞助的协议下，在帕金森病患者体内植入了第一个用于多部位（皮层和基底神经节）记录的此类设备。 通过ECoG记录具有优异的信号：噪声特性和极好的空间和时间分辨率的优点，但鉴于其侵入性，不适合正常对照。因此，在目标3中，我们使用互补的非侵入性技术头皮脑电图（EEG）来解决类似的问题，这是基于我们最近的发现，即PD特有的皮质群体同步性的测量可通过EEG检测，并通过口服左旋多巴和DBS进行调制。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PD中异常网络同步的更详细的理解，为比过去模型更好地结合皮质功能的新模型提供信息。2)提供治疗性DBS对皮质功能影响的机制理解。3)为闭环脑深部电刺激的开发奠定基础，该刺激可以利用临床实用的皮层信号自动控制刺激参数。在这项研究中阐明的机制可能适用于其他网络脑疾病，其中皮层下刺激显示出治疗前景。

 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.