Imaging the motor system in Parkinson's disease: identifying network deficits with isolated vs. coordinated movements of the upper and lower limbs

项目摘要/摘要 帕金森氏病(PD)是一种使人衰弱的运动障碍，它显著改变了数百万人的生活 世界各地的人们。传统观点认为，这种疾病是由选择性地失去多巴胺引起的。 在黑质产生神经元和随后的纹状体多巴胺缺乏，导致进行性 自愿行动的恶化。到目前为止，功能神经成像在识别 多巴胺耗竭后与帕金森病相关的神经异常，但重要的是要注意到，我们的大多数 了解与疾病相关的大脑变化是基于对上肢功能的研究。尽管多产的 迄今为止在帕金森病中开展的影像研究的数量，我们仍然没有清楚地了解到 控制下肢运动的大脑网络会受到这种疾病的影响。此外，当大脑发生变化时 与孤立肢体控制相关的研究一直都在进行，但同时进行的研究并非如此 四肢的运动对我们的许多日常行为都很关键，包括走路。我们建议解决这个问题 通过使用强大的功能成像协议(依赖于量化)对PD变化敏感来实现知识差距 等长肌肉收缩时的血氧水平依赖(BOLD)MRI反应。我们将使用 研究孤立肢体运动过程中大脑活动差异的强迫产生任务 帕金森病患者与健康受试者的同侧协调运动。值得一提的是，我们预计 协调任务将进一步阐明小脑在疾病病理生理学中的作用，这在很大程度上是 帕金森州未开发且知之甚少的地区。为了实现我们的目标，我们提出了两个目标。首先，确定 下肢/上肢力量产生过程中的脑活动模式和决定是否与足部相关的缺陷 在跨越两个皮质下-皮质运动神经回路的关键大脑区域中，躯体定位区域与 与手相关的缺陷。其次，我们将确定同时运动时大脑活动的差异。 帕金森病患者与健康对照组的肢体不同。我们假设PD有以下变化： 基础神经节和小脑-丘脑-皮质运动回路的大脑活动广泛减少 单独的肢体运动和高级运动区(小脑半球、辅助运动区、 运动前皮质)在肢体间协调时，体位组织的变化，运动回路的特异性 可穿戴设备的功能性脑活动与运动特征的相关性 技术通过建立特定任务的神经活动模式，我们的目标是开发一种非侵入性测试 该平台将：1)允许未来评估疾病进展和对干预措施的反应， 2)指导未来寻找新的治疗神经靶点的研究；3)为分型提供客观标准 PD，并与非典型帕金森综合征相鉴别。

Project Summary/Abstract Parkinson's disease (PD) is a debilitating movement disorder that significantly changes the lives of millions of people worldwide. The conventional viewpoint is that the disease is caused by a selective loss of dopamine- producing neurons in the substantia nigra and subsequent striatal dopamine deficiency, leading to a progressive deterioration of voluntary movements. Thus far, functional neuroimaging has been instrumental in identifying PD-related neural abnormalities following dopamine depletion, but it is important to note that most of our understanding of disease-related brain changes is based on studies of upper limb function. Despite the prolific amount of imaging research carried out to date in PD, we still do not have a clear understanding of the extent to which the brain network controlling lower limb movements is affected by the disease. Also, while brain changes associated with isolated limb control have been consistently investigated, the same is not true for simultaneous movements of limbs which are key to many of our daily behaviors including walking. We propose to address this knowledge gap by using a robust functional imaging protocol sensitive to PD changes that relies on quantifying the blood-oxygen-level dependent (BOLD) MRI response during isometric muscle contraction. We will use a force production task to investigate differences in brain activity during performance of isolated limb movements and ipsilateral coordinated movements between PD and healthy subjects. Of note, we anticipate that an interlimb coordination task will further clarify the role of the cerebellum in the pathophysiology of the disease, a largely unexplored and poorly understood area in PD. To accomplish our goals, we propose two aims. First, determine the patterns of brain activity during lower/upper limb force production and determine whether foot-related deficits in key brain regions across the two subcortical-cortical motor circuits are in a different somatotopic region than hand-related deficits. Second, we will determine differences in brain activity during simultaneous movements of non-homologous limbs between PD and healthy controls. We hypothesize the following changes in PD: extensive reduction in brain activity across the basal ganglia- and cerebello-thalamo-cortical motor circuits during isolated limb movements and in higher-order motor areas (cerebellar hemispheres, supplementary motor area, premotor cortex) during interlimb coordination, changes in somatotopic organization, motor circuit specific correlations between functional brain activity and characteristics of movements derived from wearable technology. By establishing task-specific neural activity patterns, we aim to develop a non-invasive testing platform that would: 1) allow for future assessment of disease progression and responsiveness to interventions, 2) guide future research in identifying new neural targets for therapy, 3) provide objective criteria for subtyping PD, and distinguishing it from atypical parkinsonian syndromes.