Mechanisms of Movement Facilitation and Release by Cueing in Parkinson's disease

描述(申请人提供)：在帕金森氏病(PD)的晚期，缺乏自发的意志运动(运动障碍)通常成为疾病最虚弱的方面。在一组患者中，行动不便表现为步态启动(开始犹豫)和步态冻结(雾)的间歇性损害。随着疾病的发展，行动不便、开始犹豫和雾气往往对目前的治疗方法如左旋多巴和脑深部刺激变得难以奏效。目前还没有针对这些症状的有效治疗方法。然而，帕金森病的一个悖论是，在某些情况下，提供外部线索可以显著促进运动的启动，即使在那些处于停药状态的严重失动症的人中也是如此。这一观察结果表明，帕金森病患者仍有启动运动的能力，但由于不明原因，他们无法可靠地进入这些通路，特别是在自我启动(非提示)的情况下。尽管人们一致认为外部线索可以促进帕金森病患者的运动启动，但检验在家庭环境中使用外部线索的有效性的临床试验一直令人失望。我们认为，在临床和家庭环境中使用外部线索的有效性目前受到限制，因为我们缺乏对可靠地促进线索启动所需的条件的了解，以及调节运动释放的机制。本项目的第一个具体目标将检验提示通道(声学、视觉或体感)和提示时机对启动迟缓患者步态准备和启动的影响。从这些实验中获得的信息可用于建立可在临床或家庭环境中或通过便携式设备实施的刺激呈现方案。特定目标2将使用高分辨率脑电记录和功能磁共振成像(FMRI)来检查皮质和皮质下结构，这些结构介导外部线索对运动的准备和释放。具体目标3将使用经颅直流电刺激(Tdcs)来检查额叶皮质结构的瞬时抑制或促进的效果，这些结构被认为在步态和上肢运动的计划、准备和启动中发挥作用。这些实验将提供对机制和途径的洞察，使外部线索能够绕过帕金森病患者自愿运动的受损启动，如启动犹豫，并将为开发促进这些途径的新型治疗干预提供经验基础。

DESCRIPTION (provided by applicant): In advanced stages of Parkinson's disease (PD), the absence of spontaneous volitional movements (akinesia) often becomes the most debilitating aspect of the disease. In a subset of patients, akinesia manifests as an episodic impairment in the initiation of gait (start hesitation) in conjunction with freezing of gait (FOG). With disease progression, akinesia, start hesitation and FOG often becomes refractory to current treatments such as levodopa and deep brain stimulation. Currently there are no effective treatments for these symptoms. Yet, one of the paradoxes of PD is it that, under certain contexts, the provision of external cues can markedly facilitate movement initiation, even in those with profound akinesia in the off medication state. This observation demonstrates that patients with PD retain the capacity to initiate movement, but for reasons that are not understood, are unable to reliably access these pathways, particularly in self-initiated (non-cued) conditions. Despite the consensus that external cues can facilitate movement initiation in PD, clinical trials examining the efficacy of using external cues in the home environment have been disappointing. We propose that the utility of using external cues in clinical and home environments is currently limited by our lack of understanding of the conditions required to reliably facilitate initiation with cues and the mechanisms mediating the release of movement. The first Specific Aim of this project will examine the effects of cueing modality (acoustic, visual or somatosensory) and cue timing on the preparation and initiation of gait in patients with start hesitation. Information derived from these experiments can be used to establish stimulus presentation protocols that can be implemented in the clinical or home environments or via portable devices. Specific Aim 2 will use high- resolution EEG recordings and functional magnetic resonance imaging (fMRI) to examine the cortical and subcortical structures that mediate the preparation and release of movements by external cues. Specific Aim 3 will use transcranial direct current stimulation (tDCS) to examine the effects of transient suppression or facilitation of frontal cortical structures that are considered to a play role in the planning, preparation and initiation of gait and upper limb movements. These experiments will provide insight into the mechanisms and pathways that enable external cues to circumvent the impaired initiation of voluntary movements in patients with PD, such as start hesitation, and will provide an empirical rationale for the development of novel therapeutic interventions that facilitate these pathways.