An Integrated Biomarker Approach to Personalized, Adaptive Deep Brain Stimulation in Parkinson Disease

帕金森病个性化、适应性深部脑刺激的综合生物标志物方法

• 批准号: 10571952
• 负责人: DENNIS Alan TURNER
• 金额: $ 97.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571952
• 关键词: Accelerometer; Accounting; Affect; Algorithms; Architecture; Bilateral; Biological Markers; Bradykinesia; Brain; Clinic; Clinical; Clinical Research; Clinical Trials; Complex; Coupling; Data; Deep Brain Stimulation; Devices; Disease Outcome; Dose; Dyskinetic syndrome; Electrodes; FDA approved; Feedback; Frequencies; Funding; Globus Pallidus; Goals; Guidelines; Home; Human; Implant; Institutional Review Boards; Measurement; Measures; Medical Device; Noise; Operative Surgical Procedures; Outcome; Parkinson Disease; Patient-Focused Outcomes; Patients; Pattern; Persons; Pharmaceutical Preparations; Phase; Physicians; Physiologic pulse; Physiological; Policies; Postoperative Period; Procedures; Prospective cohort; Public Health; Research; Signal Transduction; Site; Sleep; Structure of subthalamic nucleus; Surrogate Markers; Symptoms; System; Technology; Testing; Time; Tremor; Update; Walking; biomarker selection; clinical outcome measures; cohort; comparative; comparative efficacy; energy efficiency; experimental study; flexibility; implantation; improved; innovation; internal control; machine learning model; motor symptom; neural; novel; novel strategies; programs; reduce symptoms; response; sensor; smart watch; success; symposium; symptom management; symptom treatment; synergism; wearable device; wearable sensor technology

DBS therapy for Parkinson Disease [PD], the primary, FDA-approved surgical approach, has proven efficacious in clinical trials. However, this continuous stimulation therapy is limited to treatment of a subset of motor symptoms (i.e., tremor, rigidity, bradykinesia and dyskinesias) and requires considerable postoperative clinical adjustment to treat symptoms. Improvements to DBS for PD are being tested, including changes in patterns of stimulation, additional targets, and multiple electrodes. However, a critical new approach involves autonomous parameter adjustment [adaptive DBS] using surrogate physiological biomarkers relevant to clinical symptoms. These biomarkers and autonomous control may be useful for dynamic adjustment, subsequent programming, and long-term optimization of parameters. Adaptive DBS involves recording surrogate signals and developing a control policy that relates these signals to activity through parameter adjustments. This approach could improve DBS therapy across multiple time scales, including short-term dynamics (i.e., over minutes), initial programming (over weeks to months), and long-term, depending on the time course of response to DBS. However, which biomarkers are useful at these various time scales and appropriate, multi- layered control policy, will require testing in comparison to continuous DBS for relative efficacy and efficiency. We hypothesize that integrating multiple biomarkers (in addition to beta band oscillations) across multiple time scales will provide more efficacious adaptive DBS control. To test this hypothesis we will perform long-term recordings of multiple, relevant biomarkers from humans with implanted, advanced implantable pulse generators [IPGs], comparing internal control modes to highly complex external control modes. These clinical experiments will focus on a small, pilot clinical study (n = 6 PD patients) who have undergone implantation of bilateral subthalamic nucleus [STN] and globus pallidus [GP] DBS electrodes, with all 4 electrodes connected to a single Medtronic Summit RC+S recording and stimulating IPG. We have formally analyzed this cohort for efficacy at 1 year, showing that combined STN + GP stimulation is both preferred and better compared to either site alone. We will analyze the comparative efficacy of internal (embedded, available within the IPG) simple adaptive DBS to external (distributed) adaptive DBS, which allows both integrating multiple biomarkers and using a complex, multiple time scale control policy. We will further develop a proportional control feedback program, which specifically integrates the time multiple time constants of PD symptoms, to optimally control PD symptom. These clinical experiments in a unique cohort of research patients will lead to multiple novel outcomes, continuing a direct, within-person comparison of STN, GP, and combined DBS efficacy, analyzing an optimal mix of surrogate biomarkers for enhancing DBS efficacy, and defining an optimal, scalar feedback, proportional control system for treatment on various time scales.

DBS治疗帕金森病[PD]是FDA批准的主要手术方法，已在临床试验中证明有效。然而，这种连续刺激疗法限于治疗运动症状的子集（即，震颤、僵硬、运动迟缓和运动障碍），并且需要相当大的术后临床调整来治疗症状。正在测试对DBS治疗PD的改进，包括刺激模式、额外靶点和多个电极的变化。然而，一种关键的新方法涉及使用与临床症状相关的替代生理生物标志物的自主参数调整[自适应DBS]。这些生物标志物和自主控制可用于参数的动态调整、后续编程和长期优化。自适应DBS涉及记录替代信号并开发通过参数调整将这些信号与活动相关联的控制策略。这种方法可以在多个时间尺度上改善DBS治疗，包括短期动力学（即，几分钟）、初始编程（几周到几个月）和长期编程，取决于DBS响应的时间过程。然而，在这些不同的时间尺度和适当的多层控制策略下，哪些生物标志物是有用的，将需要与连续DBS相比测试相对功效和效率。我们假设，在多个时间尺度上整合多个生物标志物（除了β带振荡）将提供更有效的适应性DBS控制。为了检验这一假设，我们将对植入高级植入式脉冲发生器[IPG]的人体的多种相关生物标志物进行长期记录，并将内部控制模式与高度复杂的外部控制模式进行比较。这些临床实验将侧重于一项小型的初步临床研究（n = 6例PD患者），这些患者已植入双侧丘脑底核[DBS]和苍白球[GP] DBS电极，所有4个电极均连接到单个Medtronic Summit RC+S记录和刺激IPG。我们已经正式分析了该队列的1年疗效，表明与单独使用任何一个部位相比，联合使用丙泊酚+ GP刺激是首选和更好的。我们将分析内部（嵌入式，可在IPG内使用）简单自适应DBS与外部（分布式）自适应DBS的比较疗效，后者允许整合多种生物标志物并使用复杂的多时间尺度控制策略。我们将进一步发展一个比例控制回馈程式，特别是整合时间多重时间常数的局部放电症状，以最佳控制局部放电症状。在一个独特的研究患者队列中进行的这些临床实验将产生多种新的结局，继续直接的人内比较DBS、GP和组合DBS的疗效，分析用于增强DBS疗效的替代生物标志物的最佳组合，并定义用于各种时间尺度治疗的最佳标量反馈比例控制系统。