Time Course of Parkinson's Symptoms in Response to Deep Brain Stimulation

描述（由申请人提供）：脑深部电刺激（DBS）治疗帕金森病（PD）的主要症状，包括运动迟缓、僵硬和震颤，DBS的疗效在很大程度上取决于找到刺激参数（频率、脉冲宽度、电压），这些参数可最大限度地减轻症状，而不会引起副作用。然而，目前很少有指导方针来告知程序员关于刺激参数的选择。因此，器械程控是一个特殊过程，存在时间、费用和患者不适等困难，患者通常无法获得刺激的最佳益处。开发用于PD的脑深部电刺激参数编程的合理方法的主要障碍是缺乏对运动症状响应对刺激条件变化的时间演变的理解。虽然震颤立即响应，但运动迟缓和僵硬对刺激变化的反应延迟。延迟响应导致程控期间的遗留效应，并使有效刺激参数的选择复杂化。本研究的长期目标是开发用于编程最佳刺激参数的自动化方法。本提案的直接目标是量化DBS打开或关闭时症状的时间变化，并制定适当的方案来测量刺激参数变化对运动症状的影响。在目标1中，将在人类受试者志愿者中打开和关闭DBS后定期量化运动症状。在目标2中，运动症状反应数据将与数学模型拟合，以量化症状变化的时间常数并确定时间变化是否取决于刺激持续时间和/或参数。目标1和目标2的结果将用于目标3，以设计一个方案，在刺激打开后的短时间内测量对刺激的稳态反应。结果将是了解刺激打开和关闭后症状如何随时间变化。这将使编程方法的设计，最大限度地减少结转效应和最佳DBS参数的选择。最佳刺激参数将最大限度地缓解症状，允许患者减少多巴胺能药物，最大限度地延长电池寿命，并最大限度地减少电气和药物相关副作用。 公共卫生相关性：使用脑深部电刺激成功治疗帕金森病的致残性运动症状取决于刺激参数的正确选择。这项研究的结果将是了解帕金森病的运动症状如何随着时间的推移对深部脑刺激做出反应。需要了解症状如何随时间变化，以开发选择最佳脑深部电刺激参数的方法。

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) treats the cardinal symptoms of Parkinson's disease (PD) including bradykinesia, rigidity, and tremor, and the efficacy of DBS is strongly dependent on finding stimulation parameters (frequency, pulse width, voltage) that maximize symptom reduction without causing side effects. However, there are presently few guidelines to inform programmers regarding selection of stimulation parameters. Thus, device programming is an ad-hoc process, with difficulties of time, expense, and patient discomfort, and patients are often deprived of the optimal benefits of stimulation. A major obstacle to developing rational methods of programming deep brain stimulation parameters for PD is the lack of understanding of the temporal evolution of the motor symptom response to changes in stimulation condition. While tremor responds immediately, bradykinesia and rigidity have delayed responses to changes in stimulation. The delayed responses result in carry-over effects during programming and complicate selection of effective stimulation parameters. The long-term goal of this research is to develop automated methods for programming optimal stimulation parameters. The immediate goals of this proposal are to quantify the temporal changes in symptoms when DBS is turned ON or OFF, and develop an appropriate protocol to measure the effects of stimulation parameter variations on motor symptoms. In aim 1, motor symptoms will be quantified at regular intervals after DBS is turned ON and OFF in human subject volunteers. In aim 2, the motor symptom response data will be fit with mathematical models to quantify the time constants of symptom change and to determine whether the temporal changes depend on the stimulation duration and/or parameters. The results of aims 1 and 2 will be used in aim 3 to design a protocol to measure the steady-state response to stimulation at short times after stimulation is turned ON. The outcome will be an understanding of how the symptoms change over time after stimulation is turned ON and OFF. This will enable the design of programming methods which minimize carry-over effects and the selection of optimal DBS parameters. Optimal stimulation parameters will maximize symptom relief, allow patients to reduce their dopaminergic medications, maximize battery life, and minimize both electrical and drug- related side effects. PUBLIC HEALTH RELEVANCE: Successful treatment of the disabling motor symptoms of Parkinson's disease with deep brain stimulation depends on the proper selection of stimulation parameters. The outcome of this research will be an understanding of how the motor symptoms of Parkinson's disease respond over time to deep brain stimulation. Understanding how the symptoms change over time is required to develop methods to select optimal deep brain stimulation parameters.