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

描述（由申请人提供）：在帕金森病（PD）的晚期，缺乏自发的意志运动（运动障碍）往往成为该疾病最衰弱的方面。在一部分患者中，肌动症表现为步态启动（开始犹豫）与步态冻结（FOG）的发作性损伤。随着疾病的进展，运动障碍、开始犹豫和FOG通常对左旋多巴和深部脑刺激等当前治疗变得难以治愈。目前对这些症状没有有效的治疗方法。然而，PD的一个悖论是，在某些情况下，提供外部线索可以显着促进运动启动，即使是在那些处于停药状态的深度运动障碍患者中。这一观察结果表明，PD患者保留了启动运动的能力，但由于尚不清楚的原因，无法可靠地访问这些通路，特别是在自我启动（无提示）的情况下。尽管外界提示可以促进PD患者的运动启动，但在家庭环境中使用外部提示的临床试验结果令人失望。我们认为，在临床和家庭环境中使用外部线索的效用目前受到限制，因为我们缺乏对可靠地促进线索启动所需的条件和介导运动释放的机制的理解。该项目的第一个具体目标是研究提示方式（声音、视觉或体感）和提示时间对开始犹豫患者步态准备和开始的影响。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协议。具体目标2将使用高分辨率脑电图记录和功能性磁共振成像（fMRI）来检查通过外部线索介导运动准备和释放的皮层和皮层下结构。特异性目标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作用，额叶皮质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。这些实验将提供机制和途径，使外部线索能够规避PD患者自主运动的受损启动，如开始犹豫，并将为开发促进这些途径的新型治疗干预提供经验依据。

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. PUBLIC HEALTH RELEVANCE: In a large subset of patients with Parkinson's disease, one of the most disabling aspect of their disorder is a syndrome characterized by episodic impairments in the initiation of gait (termed start hesitation) in conjunction with freezing of gait (FOG). Currently there are no effective treatments for these symptoms. Yet, it is well known that under certain contexts, the provision of external cues can markedly facilitate gait initiation. This project will investigate the optimal strategies for cueing movement initiation to improve the efficacy and reliability of cueing in clinical and home settings and to develop standardized cueing protocols for portable devices. In addition, we will examine the mechanisms and pathways that enable external cues to circumvent impaired gait initiation with the goal to develop novel therapeutic interventions that facilitate these pathways.