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

步态损伤和步态冻结(雾)，导致摔倒、受伤(甚至死亡)、丧失独立生活能力，以及 常见于神经退行性疾病，如帕金森氏病(PD)，影响超过700万人 全世界。神经退行性疾病的发病率随着年龄的增长和人口寿命的延长而增加， 雾的社会后果将是非常显著的。步态损伤和雾气对 药物和丘脑底核(STN)开环深部脑刺激(OlDBS)，无法调整 对潜在的大脑信号或运动症状(如雾)做出反应的治疗。其中一个原因是雾可能 对不同的DBS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 不要长时间忍受60赫兹的DBS。使用感应神经刺激器和 支持蓝牙的可穿戴传感器使研究能够使用神经或自适应(A)DBS 行为控制变量。雾是间歇性的，通常发生在可预测的环境中，因此它非常适合 为《On Demand》aDBS。ADBS，对步态损害和间歇性雾的标志做出反应，随着 DBS强度或频率，可以防止雾、摔倒和受伤，同时仍然治疗PD的其他运动症状。 来自四年多的研究和监管经验，在学术和行业合作中 美敦力，我们已经为下一代aDBS设备提供了设计投入，并确定 DBS治疗震颤和运动迟缓在最大的自由活动PD队列中是安全和耐受的，植入了 美敦力研究神经刺激/感觉系统(Activa®PC S-Nexus D/D3/E)。我们发现 使用同步神经和运动学记录的步态损害和雾的神经和行为标志 在引起雾气的步态任务中。我们的研究成果和嵌入在 美敦力Summit®RC S-系统现在支持下一步：第一项偏侧化、独立、 受试者特定神经(目标1)或行为驱动的PD中雾的双边STN aDBS控制算法 (目标2)控制变量，以及对药物的反应(目标3)。这个项目将在长凳上逐步翻译 到床边的方式，在就地踏步(SIP)任务期间测试aDBS，其中受试者戴着马具和 双力板上的台阶就位。然后在前行转弯和障碍物的过程中进行aDBS测试 当然，它模拟了已知在现实世界中触发雾的环境，然后是DBS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 下一步-在受试者家中测试aDBS的步态损害和雾气的安全性和可行性 环境，以及他们正常的药物治疗。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，间歇性冰冻情节(FE)的数量和持续时间 (I)olDBS将为未来的设备和适用于NaDBS或KaDBS的步态新算法提供输入 其他神经系统疾病中的损害和雾。

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.