Scalar Closed-Loop STN/GPi DBS Based on Evoked and Spontaneous Potentials

摘要 帕金森病的DBS治疗目前是帕金森病的主要手术方法， FDA在发病后4年批准。然而，这种疗法仍然局限于治疗一个子集， 运动症状（即震颤、僵硬、运动迟缓和运动障碍），需要大量的术后 临床调整以程控和维持功能。正在对DBS治疗PD进行一些改进 测试，包括刺激模式和特定目标的变化。然而，一个重要的新方法 涉及使用临床症状的替代生理标志物的内部参数调整， 确认初始电极放置、编程以及参数的长期优化。几 已经提出了研究系统，并正在测试闭环系统的开发，包括 基于记录β波段振荡的系统。涉及记录替代信号的闭环控制 与PD相关的治疗可以在几个时间尺度上改善DBS治疗，包括短期动力学（即， 分钟）、初始编程（数周至数月）和长期编程（取决于 对DBS的回应除了自发的beta波段录音，我们还实现了直接 使用刺激DBS电极记录诱发电位，需要抑制DBS诱导的 神器这些术中DBS记录在DBS植入过程中显示了复杂的诱发电位， 可能反映GPe/GPi激活的潜力，这可能提供一个出色的替代标记物。这个复杂 诱发电位在短期内随着DBS的治疗效果而变化， 这表明诱发电位可能反映了DBS对较大运动电路的影响， 动态地改变为改进的状态。我们假设，这种替代标记物（除了β 频带振荡）可以为标量、分级（比例）闭环DBS控制提供关键反馈信号， 与DBS对PD电路的影响高度相关。为了验证这一假设，我们将进行长期记录， 来自人类的这个信号（以GPe或GPi）与DBS刺激（以GPe和/或GPi）一起，使用 新型DBS记录/刺激器械（Medtronics RC+S）。 这些临床实验将侧重于一项小型的初步临床研究（n = 6例患者），以植入双侧椎间融合器+ GPe/GPi DBS电极用于符合DBS条件的帕金森病患者，使用常规立体定向定位， 连接至Medtronics RC+S IPG。患者将从普通DBS或GPi DBS刺激中受益 然后我们还将测试两个电极之间协同作用的可能性，以获得临床疗效。 此外，我们还将分析外部（使用记录和修改） 参数手动）和内部（使用自动提供参数的算法）标量，关闭 循环响应这些记录的替代标记。我们将充分利用 自发和诱发反应，以构建比例控制反馈系统，具体地说， 描述闭环系统的时间常数，以便能够定义PD的最佳阻尼控制 症状这些实验将提供一些新的结果，包括直接的，在人 比较DBS和GPe/GPi DBS的疗效，开发用于检测 使用自发和诱发生理反应的DBS疗效与临床直接比较 症状，并定义了一个最佳的，标量反馈，比例控制系统，用于治疗在不同的时间 鳞片

Abstract DBS therapy for Parkinson's disease is now the primary surgical approach for Parkinson's disease, recently FDA approved at 4 years after onset of disease. However, this therapy is still limited to treatment of a subset of motor symptoms (ie, tremor, rigidity, bradykinesia and dyskinesias) and requires considerable postoperative clinical adjustment to program and maintain function. A number of improvements to DBS for PD are being tested, including changes in patterns of stimulation and specific targets. However, a major new approach involves internal parameter adjustment using a surrogate physiological marker of clinical symptoms, useful for confirming initial electrode placement, programming, and also long-term optimization of parameters. Several research systems have been suggested and are in testing for development of closed loop systems, including systems based on recording beta-band oscillations. Closed loop control involving recording a surrogate signal relevant to PD could improve DBS therapy on several time scales, including short-term dynamics (ie, over minutes), initial programming (over weeks to months), and long-term, depending on the time course of response to STN DBS. In addition to spontaneous beta band recording we have also implemented direct evoked potential recording using the stimulating DBS electrode, requiring suppression of the DBS-induced artifact. These intraoperative DBS recordings during STN DBS implants have revealed a complex evoked potential likely reflecting GPe/GPi activation, which may provide an excellent surrogate marker. This complex evoked potential changes over a short-term time period as the treatment effect of STN DBS comes on, indicating that the evoked potential likely reflects DBS effects on a larger motor circuit as the circuit dynamically is altered to an improved state. We hypothesize that this surrogate marker (in addition to beta band oscillations) may provide a key feedback signal for scalar, graded (proportional) closed loop DBS control, highly relevant to DBS effects on PD circuitry. To test this hypothesis we will perform long-term recording of this signal from humans (in either STN or GPe/GPi) together with DBS stimulation (in STN and/or GPi), using a novel DBS recording/stimulation device (Medtronics RC+S). These clinical experiments will focus on a small, pilot clinical study (n = 6 patients) to implant bilateral STN + GPe/GPi DBS electrodes in Parkinson's patients eligible for DBS using conventional stereotactic localization, connecting to Medtronics RC+S IPGs. Patients will benefit from either ordinary STN or GPi DBS stimulation and then we will also test the possibility of synergism between the two electrodes for clinical efficacy. Additionally, we will analyze the motor efficacy of both an external (using recording and modifying the parameters manually) and internal (using an algorithm for providing parameters automatically) scalar, closed loop response to these recorded surrogate markers. We will take advantage of the graded nature of the spontaneous and evoked responses to construct a proportional control feedback system, and to specifically delineate the time constants of the closed loop system to be able to define optimally damped control of PD symptoms. These experiments will provide a number of novel outcomes, including a direct, within-person comparison of STN and GPe/GPi DBS efficacy, development of an optimal surrogate parameter for detecting DBS efficacy using spontaneous and evoked physiological responses in direct comparison to clinical symptoms, and defining an optimal, scalar feedback, proportional control system for treatment on various time scales.