Neural and Kinematic Features of Freezing of Gait for Adaptive Neurostimulation

项目摘要 帕金森病（PD）患者的步态冻结（FOG）导致不可预测的步态停止发作， 可能导致福尔斯跌倒、受伤、丧失独立生活能力，甚至死亡19。FOG的治疗不一致 使用多巴胺能药物或使用电流开环、连续高频脑深部 刺激（cDBS）15，25.使用非连续、闭环或自适应DBS（aDBS）的新兴技术， 改善FOG治疗的潜力。自适应DBS可以感测患者特定的神经和/或运动学 通过调整DBS参数发出信号并做出响应，以提供更有效的治疗，同时减少不良反应 cDBS已知的副作用。将aDBS用于FOG的关键障碍是缺乏知识 的：FOG的神经特征，可以被aDBS“感知”以触发刺激，最佳的，患者 治疗FOG的特定DBS参数，以及aDBS治疗FOG在人体中是否安全和可耐受 PD患者。在勃朗特-斯图尔特实验室，我们有技术，监管批准和研究 经验收集同步神经和定量运动信号，应用不同的DBS FOG参数，在自由移动的PD受试者中进行第一次aDBS实验。勃朗特-斯图尔特 实验室是第一个小组，斯坦福大学是美国第一个植入感知神经刺激器的地点 对于PD，Activa® PC+S（Medtronic Inc.，FDA IDE/斯坦福大学IRB批准，2013年10月）。这包括 FDA批准的神经刺激器（Activa PC®，Medtronic Inc.）通过附加软件， 通过神经刺激器本身的遥测技术发出大脑信号。我们已经植入了20名PD患者（最大 队列中的世界），从他们那里我们一直在收集同步神经和计算机化的运动 信号超过30个月，无不良事件。我们将使用这项新技术， 定量运动学和有效FOG测量方面的专业知识，开始了解神经特征 与FOG有关。此外，我们将使用FOG的定量测量来准确地确定 患者特定刺激参数对有效和一致治疗FOG的功效。没有中心 具备测试aDBS在自由移动状态下用于FOG的安全性和可行性的技术能力 PD患者。患者是否能够耐受aDBS，持续调整输出以控制时变 当患者自由行走和移动时，患者特异性神经信号是完全未知的， 在这项建议的试点研究评估。该项目预计将标志着一个新时代的开始， 精确医学：以定制的适应性方式治疗PD中FOG的可能性， 最大限度地减少不良反应，并补充PD的其他致残性运动特征的治疗 例如震颤。

PROJECT SUMMARY Freezing of gait (FOG) in Parkinson’s disease (PD) results in unpredictable episodes of gait cessation, which may lead to falls, injury, a loss of independent living, and even death19. The treatment of FOG is inconsistent with either dopaminergic medication or with current open loop, continuous high frequency deep brain stimulation (cDBS)15, 25. Emerging technology using non-continuous, closed loop or adaptive DBS (aDBS), has the potential to improve treatment for FOG. Adaptive DBS can sense patient specific neural and/or kinematic signals and respond by adjusting DBS parameters to provide more efficacious therapy while reducing adverse side effects known to occur with cDBS. The critical barriers of using aDBS for FOG are the lack of knowledge of: the neural features of FOG that could be ‘sensed’ by aDBS to trigger stimulation, the optimal, patient specific DBS parameters for the treatment of FOG, and whether aDBS for FOG is safe and tolerable in human PD patients. In the Bronte-Stewart Lab, we have the technology, the regulatory approvals and the research experience collecting synchronized neural and quantitative kinematic signals, applying different DBS parameters for FOG, performing the first aDBS experiments in freely moving PD subjects. The Bronte-Stewart Lab was the first group and Stanford was the first site in the United States to implant a sensing neurostimulator for PD, the Activa® PC+S (Medtronic Inc., FDA IDE/Stanford IRB approval, October 2013). This comprised the FDA approved neurostimulator (Activa PC®, Medtronic Inc.) with additional software that enabled recording of brain signals via telemetry from the neurostimulator itself. We have implanted twenty PD patients (largest cohort in the world), from whom we have been collecting synchronized neural and computerized kinematic signals for over thirty months without adverse events. We will use this new technology in conjunction with our expertise in quantitative kinematics and validated measure of FOG to begin understanding the neural features associated with FOG. In addition, we will use quantitative measures of FOG to accurately determine the efficacy of patient specific stimulation parameters for effective and consistent treatment of FOG. No center has had the technological capability to test the safety and feasibility of aDBS for FOG in freely moving PD patients. Whether patients can tolerate aDBS, which continually adjusts output to control a time-varying patient-specific neural signal as they are walking and moving freely is completely unknown and will be assessed in a pilot study in this proposal. This project is expected to signal the beginning of a new era of precise medicine: the possibility to treat FOG in PD in a customized, adaptive manner, while minimizing adverse effects and complementing the treatment of other disabling motor features of PD such as tremor.