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)症状的有效方法。然而，一些研究小组报告说，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，尽管刺激继续缓解他们的震颤、动作迟钝和僵硬的症状。这些轴性症状非常致残，可能导致跌倒和严重的行动不便。最近的一些研究报道，将刺激频率从130赫兹降低到60-80赫兹，并增加刺激电压，可以改善步态的干扰。这表明，在这些患者中，经典的刺激参数不再为他们的疾病管理而优化。在优化参数时，临床医生必须考虑刺激对一系列运动功能以及对颤抖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相对迟钝的功能评估工具，而且有大量可能的刺激器设置可以测试，但不能保证所有运动功能都会以相同的方式做出反应。目前的提案计划开发一系列基于实验室的方法来测量特定的运动功能，这些方法可以用来精确量化刺激器参数变化对每个功能的影响，并确定观察到的变化在单个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群的上肢运动障碍。在一项初步研究中，将对服用和停用左旋多巴的15名帕金森病患者和一组年龄匹配的健康对照组受试者的轴向和肢体功能进行评估。这将提供广泛的基线参考数据，通过对比服药前后的反应并与UPDRS临床评级进行比较，将确定这些方法足以灵敏地反映临床变化。在第二项研究中，15名接受STN-DBS 3年或更长时间且出现步态和/或平衡问题的患者将使用新开发的基于实验室的方法进行研究。这将分三个阶段进行。在第一阶段，我们将研究6种频率的刺激，从50赫兹到150赫兹，步长为20赫兹，电压水平设置为在所有频率具有相同的能量。在第二阶段，将研究6个频率，以10 HZ的细粒度为中心，以第一阶段获得的2个最佳频率为中心，并为每个患者量身定做。在第三阶段，将根据阶段1和阶段2的结果，使用两个刺激频率来研究电压调整的效果。将在每个频率上研究三个电压，每个频率使用最高的电压，没有针对个体的不利影响，以及低于1V和2V的电压。这些数据将提供刺激频率和电压如何影响特定的轴向和附件运动功能以及最佳刺激器设置在这一组PD患者中如何变化的详细情况。

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.