Voltage imaging analysis of striatal network dynamics related to movement, Parkinson's disease and deep brain stimulation

帕金森病患者纹状体网络运动相关动力学的电压成像分析 和脑深部刺激 摘要 脑深部刺激(DBS)通过慢性方式提供高频电流刺激 植入电极。DBS已被FDA批准用于治疗包括帕金森氏症在内的几种脑部疾病 疾病(PD)、癫痫、特发性震颤和强迫症。然而，治疗性的 星展银行的机制在很大程度上仍不清楚。有许多耐人寻味的假设，但实验证据 都是有限的。在过去20年中，PD越来越多地使用DBS，这为以下方面提供了一个独特的机会 从患者的各种基底节脑结构中记录，并积累的证据表明 皮质-基底节病理性局部场电位(LFP)β振荡(~10-30赫兹) 电路是帕金森病的特征。使用STN中记录的夸大的LFPβ振荡作为目标特征， 最近的研究表明，闭环式DBS可以更有效地缓解灵长类帕金森病模型的运动障碍， 强调了使用病理性β振荡作为帕金森病生物标记物的潜力。 帕金森病的特征是投射到纹状体的SNPC多巴胺神经元变性。事实是， DBS在管理运动病理方面有效强调帕金森病涉及神经回路缺陷 通过电刺激改变以达到治疗效果。这项建议的中心目标是研究 使用一种新的单电池电压，与帕金森病相关的神经电路动力学和DBS的治疗机制 韩博士的实验室最近开发的成像技术。具体地说，我们将研究个人如何 纹状体神经元阈值下膜电压和棘波模式与纹状体整体LFP振荡有关 在健康和多巴胺耗竭的帕金森病条件下进行自愿运动，以及DBS如何改变这些 互动。这样的理解将为了解单个神经元之间的关系提供重要的见解 阈值下膜电压动态(突触输入的测量)和尖峰输出，并提供直接的 将病理性LFP振荡与单个神经元生物物理学联系起来的实验证据，以及DBS如何影响 这些关系。我们相信，这样的见解将有助于建立基于振荡的脑生物标记物 障碍，并促进未来的星展银行设计。

Title: Voltage imaging analysis of striatal network dynamics related to movement, Parkinson’s disease and deep brain stimulation Summary Deep brain stimulation (DBS) delivers high frequency electrical current stimulation through chronically implanted electrodes. DBS has been FDA approved for managing several brain disorders, including Parkinson’s disease (PD), epilepsy, essential tremor, and obsessive compulsive disorders. However, the therapeutic mechanisms of DBS remain largely unknown. There are many intriguing hypothesis, but experimental evidence has been limited. The increasing use of DBS for PD over the past 20 years has offered a unique opportunity to record from various basal ganglia brain structures in patients, and accumulating evidence suggests that exaggerated pathological local field potential (LFP) beta oscillations (~10-30Hz) in the cortical-basal ganglia circuit are a signature of PD. Using exaggerated LFP beta oscillations recorded in STN as a target feature, a recent study showed that closed-loop DBS could be more effective in alleviating akinesia in primate PD models, highlighting the potential of using pathological beta oscillations as a biomarker for PD. PD is characterized by degeneration of SNpc dopamine neurons that project to the striatum. The fact that DBS is effective at managing motor pathologies highlights that PD involves neural circuit deficits that can be altered by electrical stimulation to achieve therapeutic effects. The central goal of this proposal is to study the neural circuit dynamics related to PD, and the therapeutic mechanisms of DBS, using a novel single cell voltage imaging technique that was recently developed in Dr. Han’s lab. Specifically, we will examine how individual striatal neurons’ subthreshold membrane voltage and spiking patterns relate to bulk striatal LFP oscillations during voluntary movement in healthy and dopamine-depleted PD conditions, and how DBS alters these interactions. Such understanding will provide important insights into the relationship between individual neurons subthreshold membrane voltage dynamics (a measure of synaptic inputs) and spiking outputs, and provide direct experimental evidence linking pathological LFP oscillations with single neuron biophysics, and how DBS affects these relationships. We believe that such insights will help establish oscillation based biomarkers for brain disorders, and facilitate future DBS designs.