Bilateral Closed Loop Deep Brain Stimulation for Freezing of Gait using Neural and Kinematic Feedback

步态障碍和步态冻结（FOG）导致福尔斯跌倒、受伤（甚至死亡）、丧失独立生活能力， 常见于神经退行性疾病，如帕金森病（PD），影响超过700万人 国际吧神经退行性疾病的发病率随着年龄的增长而增加，随着人口寿命的延长， FOG的社会后果将非常严重。步态障碍和FOG有部分反应， 药物治疗和丘脑底核（ODBS）开环脑深部电刺激（ODBS）， 治疗响应潜在的大脑信号或运动症状，如FOG。一个原因是FOG可能 对DBS的不同参数作出反应，例如频率低于震颤和大多数患者所需的频率 不能长时间忍受60 Hz DBS。使用传感神经刺激器的新兴技术， 支持蓝牙的可穿戴传感器已经允许研究闭环或自适应（a）使用神经或 行为控制变量FOG是偶发性的，通常发生在可预测的环境中，因此非常适合 “按需”的DBS。ADBS，对步态障碍和间歇性FOG的标志物有反应， DBS的强度或频率，然后可以防止FOG，福尔斯和损伤，同时仍然治疗PD的其他运动体征。 凭借四年多的研究和监管经验， Medtronic，我们已经为下一代aDBS器械提供了设计输入，并确定 在最大的植入aDBS的自由移动PD队列中，aDBS治疗震颤和运动迟缓是安全和可耐受的。 Medtronic研究性神经刺激/感知系统（Activa® PC+S-Nexus D/D3/E）。我们已经发现 使用同步神经和运动记录的步态障碍和FOG的神经和行为标记 引起FOG的步态任务。我们的研究成果和技术进步嵌入 美敦力Summit® RC+ S系统现在可以实现下一步：第一项单侧、独立、 用于PD中FOG的双边AMBADBS控制算法，由受试者特定神经（Aim 1）或行为驱动 (Aim 2）控制变量，并对药物进行响应（目的3）。该项目将逐步翻译在一个'板凳 以床边的方式，在原地踏步（SIP）任务期间测试aDBS，其中受试者穿着背带， 双测力板上的台阶就位。然后，在向前行走、转弯和障碍期间测试aDBS 当然，它模仿了真实的世界中已知的触发FOG的环境，然后aDBS如何响应 受试者特定剂量的药物，同时自由移动。这些实验的结果将提供关键的 在受试者家中测试aDBS的步态障碍和FOG的安全性和可行性的后续步骤 环境和正常的药物。患者安全性、耐受性、不良反应、步态参数和 在无DBS、olDBS、aDBS和对照期间，间歇性冻结发作（FE）的次数和持续时间 （i）olDBS将为未来的设备和适用于NaDBS或KaDBS步态的新算法提供输入 其他神经系统疾病中的损伤和FOG。

Gait impairment and Freezing of gait (FOG), lead to falls, injury (even death), loss of independent living, and are common in neurodegenerative diseases such as Parkinson’s Disease (PD), affecting over 7 million people worldwide. The incidence of neurodegenerative diseases increases with age and as the population lives longer, the societal consequences of FOG, will be very significant. Gait impairment and FOG have a partial response to medication and subthalamic nucleus (STN) open loop deep brain stimulation (olDBS), which cannot adjust therapy in response to underlying brain signals or motor symptoms such as FOG. One reason is that FOG may respond to different parameters of DBS, such as lower frequency, than that needed for tremor and most patients do not tolerate 60 Hz DBS for long periods of time. Emerging technology using sensing neurostimulators and Bluetooth enabled wearable sensors has allowed research into closed loop or adaptive (a)DBS using neural or behavioral control variables. FOG is episodic and usually occurs in predictable environments, so it is well suited for ‘on demand’ aDBS. ADBS, responding to markers of gait impairment and intermittent FOG, with changes in DBS intensity or frequency, could then prevent FOG, falls and injury, while still treating other motor signs of PD. From over four years of research and regulatory experience in an academic-industry collaboration with Medtronic, we have provided design inputs for the next generation aDBS devices, and have determined that aDBS for tremor and bradykinesia is safe and tolerable in the largest freely-moving PD cohort implanted with a Medtronic investigative neurostimulation/sensing system (Activa® PC+S-Nexus D/D3/E). We have discovered neural and behavioral markers of gait impairment and FOG using synchronized neural and kinematic recordings during gait tasks that elicit FOG. Our research findings and the technological advances embedded in the Medtronic Summit® RC+S-system now enable the next step: the first clinical studies of lateralized, independent, bilateral STN aDBS control algorithms for FOG in PD, driven by subject-specific neural (Aim 1) or behavioral (Aim 2) control variables, and in response to medication (Aim 3). The project will translate stepwise in a ‘bench to bedside’ manner, testing aDBS during the stepping in place (SIP) task, where the subject is in a harness and steps in place on dual force-plates. Then aDBS will be tested during the forward walking Turning and Barrier Course, which mimics environments known to trigger FOG in the real world, and then how aDBS responds to subject-specific doses of medication, while freely moving. The outcome of these experiments will provide critical next-steps for safety and feasibility of testing aDBS for gait impairment and FOG in the subject’s home environment, and on their normal medication. Patient safety, tolerability, adverse effects, gait parameters, and the number and duration of freezing episodes (FEs), during no DBS, olDBS, aDBS and a control, intermittent (i)olDBS will provide inputs for future devices and novel algorithms applicable to NaDBS or KaDBS for gait impairment and FOG in other neurological diseases.