Neural and Kinematic Features of Freezing of Gait for Adaptive Neurostimulation

项目总结 帕金森氏病(PD)患者的冻结步态(雾)会导致不可预测的步态停止发作，这 可能导致摔倒、受伤、丧失独立生活能力，甚至死亡19。雾的治疗是不一致的 使用多巴胺能药物或使用当前开环、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)的新兴技术具有 改善雾的治疗的潜力。自适应DBS可以感知患者特定的神经和/或运动学 通过调整DBS参数提供更有效的治疗信号和响应，同时减少不良反应 CDBS已知会产生副作用。在雾中使用aDBS的关键障碍是缺乏知识 特点：雾的神经特征可以被DBS‘感觉到’以触发刺激，这是最佳的患者 治疗雾的特定DBS参数，以及治疗雾的DBS对人体是否安全和耐受 帕金森病患者。在勃朗特-斯图尔特实验室，我们拥有技术、监管批准和研究 有采集同步神经和定量运动信号的经验，应用不同的DBS 在自由活动的帕金森病受试者中进行了第一次aDBS实验。勃朗特-斯图尔特 Lab是第一个小组，斯坦福大学是美国第一个植入传感神经刺激器的地点 对于PD，Activa®PC+S(美敦力公司，FDA IDE/Stanford IRB批准，2013年10月)。这包括 FDA批准的神经刺激剂(Activa PC®，Medtronic Inc.)带有支持录制的附加软件 通过遥测从神经刺激器本身发出的大脑信号。我们已经植入了20名PD患者(最大的 我们一直在从他们那里收集同步的神经和计算机化的运动学数据 信号超过30个月，没有不良事件。我们将把这项新技术与我们的 具备量化运动学专业知识和有效的雾化测量方法，以开始了解神经特征 与雾相关的。此外，我们还将使用雾的定量测量来准确确定 患者特定刺激参数的疗效，以有效和一致地治疗雾。没有中心 已经有技术能力测试ADBS在自由移动雾中的安全性和可行性 帕金森病患者。患者是否能耐受aDBS，它不断调整输出以控制时变的 当患者自由行走和活动时，患者特有的神经信号是完全未知的，也将是 在这项提案的试点研究中进行了评估。这个项目预计将标志着一个新时代的开始 精确医学：以定制的、适应性的方式治疗帕金森病患者的雾的可能性，同时 减少不良反应并补充治疗帕金森病的其他致残运动特征 比如震颤。

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.