Developmental Clinical Studies - Optimising STN-DBS stimulation for late-emerging

丘脑底核脑深部电刺激（STN-DBS）是治疗帕金森病（PD）症状的强大而有效的方法。然而，许多研究小组报告称，相当大比例的患者在植入后5年内开始出现严重的轴向和步态问题，即使刺激继续缓解他们的震颤、运动不能和僵硬症状。这些轴向症状非常致残，可导致福尔斯和严重的活动问题。最近的一些研究已经报道，步态的中断可以通过将刺激频率从130 Hz降低到60-80 Hz并增加刺激电压来改善。这表明，在这些患者中，经典刺激参数不再针对其疾病管理进行优化。当优化参数时，临床医生必须考虑刺激对一系列运动功能以及对震颤和僵硬的阳性症状的影响。这是有问题的，因为临床评定量表是功能评估的相对钝的工具，并且存在大量可能的刺激器设置，其可以在不保证所有运动功能将以相同方式响应的情况下进行测试。目前的提案计划开发一系列基于实验室的方法，用于测量特定的运动功能，可用于精确量化改变刺激器参数对每个功能的影响，并确定观察到的变化在个体患者水平上是否具有统计学意义。这些方法将针对轴功能障碍，包括步态和步态冻结，平衡控制和姿势控制，以及涉及远端和近端肌肉群的上肢运动障碍。在初始研究中，将对15名接受和不接受左旋多巴研究的PD患者和一组年龄匹配的健康对照受试者的队列评估轴功能和肢体功能的测量。这将提供广泛的基线参考数据，并通过对比用药和停药的反应，并与CAFRS临床评级进行比较，将确定该方法足够敏感，可以反映临床变化。在第二项研究中，将使用新开发的基于实验室的方法对接受STN-DBS 3年或更长时间并出现步态和/或平衡问题的15名患者进行研究。这项工作将分三个阶段进行。在第一阶段，我们将研究6个频率的刺激，范围从50 Hz到150 Hz，步长为20 Hz，电压设置为在所有频率下具有等效能量的水平。在第二阶段，将研究6个频率，其中10 Hz的更细粒度集中在第一阶段获得的2个“最佳”频率上，并针对每个患者进行定制。在第三阶段中，将根据第1阶段和第2阶段的结果，使用2个刺激频率研究电压调节的影响。将在每个频率下研究三个电压，使用针对个体受试者定制的无不良影响的最高电压以及低于1V和2 V的电压。这些数据将提供刺激频率和电压如何影响特定轴向和非轴向运动功能以及最佳刺激器设置如何在该PD患者队列中变化的详细图片。

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a powerful and effective treatment for symptoms of Parkinson's disease (PD). However, a number of research groups have reported that a significant proportion of patients start to develop severe axial and gait problems within 5 years of implantation even though the stimulation continues to alleviate their symptoms of tremor, akinesia and rigidity. These axial symptoms are very disabling and can lead to falls and severe mobility problems. Some recent research has reported that the disruption of gait can be improved by lowering the stimulation frequency from 130 Hz to 60-80 Hz and increasing the stimulation voltage. This suggests that in these patients the classical stimulation parameters are no longer optimised for their disease management. When optimising parameters, the clinician has to consider the effects the stimulation has on a range of motor functions as well as on the positive symptoms of tremor and rigidity. This is problematic because clinical rating scales are relatively blunt tools of functional assessment and there are a large number of possible stimulator settings that can be tested with no guarantee that all motor functions will respond in the same way. The current proposal plans to develop a series of laboratory-based methods for measuring specific motor functions that can be used to quantify precisely the effects of changing stimulator parameters on each function and to establish whether the observed changes are statistically significant at the level of an individual patient. These methods will target the disorders of axial functions including gait and freezing of gait, balance control and posture control, as well as disorders of upper limb movements involving distal and proximal muscle groups. In an initial study the measures of axial and limb functions will be assessed on a cohort of 15 PD patients studied on and off levodopa, and a group of age-matched healthy control subjects. This will provide a broad spectrum of baseline reference data and by contrasting responses on and off medication and comparing with UPDRS clinical ratings will establish that the methods are sufficiently sensitive to reflect clinical change. In a second study a group of 15 patients who have been receiving STN-DBS for 3 years or more and with emergence of gait and/or balance problems will be studied using the newly developed laboratory-based methods. This will be done in three stages. In the first stage we will investigate 6 frequencies of stimulation ranging from 50 Hz to 150 Hz at steps of 20 Hz, with the voltage set at levels to have equivalent energy at all frequencies. In the second stage, 6 frequencies will be studied with a finer grain of 10 HZ centred on the 2 'best' frequencies obtained in the first stage and tailored to each individual patient. In the third stage, the effect of voltage adjustment will be studied using 2 frequencies of stimulation based on the results from stages 1 and 2. Three voltages will be studied at each frequency using the highest voltage without adverse effects tailored to individual subjects and 1V and 2V below. These data will provide a detailed picture of how stimulation frequency and voltage affects specific axial and appendicular motor functions and how the optimum stimulator settings vary across this cohort of PD patients.