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

项目概要/摘要 帕金森病 (PD) 是一种使人衰弱的运动障碍，显着改变了数百万人的生活 世界各地的人们。传统观点认为，这种疾病是由多巴胺选择性丧失引起的 在黑质中产生神经元并随后导致纹状体多巴胺缺乏，导致进行性 随意运动恶化。到目前为止，功能性神经影像学在识别 多巴胺耗竭后与 PD 相关的神经异常，但值得注意的是，我们大多数人 对与疾病相关的大脑变化的理解是基于对上肢功能的研究。尽管硕果累累 尽管迄今为止在 PD 方面进行了大量的影像学研究，但我们仍然对 PD 的程度没有清楚的了解。 控制下肢运动的大脑网络受到疾病的影响。另外，当大脑发生变化时 与孤立肢体控制相关的研究已经得到了一致的研究，但对于同步控制来说情况并非如此 肢体运动是我们许多日常行为（包括行走）的关键。我们建议解决这个问题 通过使用对 PD 变化敏感的强大功能成像协议（依赖于量化）来弥补知识差距 等长肌肉收缩过程中血氧水平依赖 (BOLD) MRI 反应。我们将使用一个 力产生任务，用于研究孤立肢体运动执行过程中大脑活动的差异 PD 和健康受试者之间的同侧协调运动。值得注意的是，我们预计肢体间 协调任务将进一步阐明小脑在疾病病理生理学中的作用，很大程度上是 PD 中未经探索且知之甚少的领域。为了实现我们的目标，我们提出两个目标。首先，确定 下肢/上肢力量产生期间的大脑活动模式，并确定是否与足部相关的缺陷 两个皮质下-皮质运动回路的关键大脑区域位于不同的躯体区域 与手相关的缺陷。其次，我们将确定同时运动期间大脑活动的差异 PD 和健康对照之间的非同源肢体。我们假设 PD 发生以下变化： 基底神经节和小脑丘脑皮质运动回路的大脑活动大幅减少 孤立的肢体运动和高阶运动区（小脑半球、辅助运动区、 前运动皮层）在肢体间协调过程中，躯体组织的变化，运动回路特异性 功能性大脑活动与可穿戴设备运动特征之间的相关性 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 平台将：1）允许未来评估疾病进展和对干预措施的反应， 2) 指导未来研究确定新的神经治疗靶点，3) 提供亚型分型的客观标准 PD，并将其与非典型帕金森综合征区分开来。

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.