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 帕金森氏病（PD）是一种使人衰弱的运动障碍，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，这种疾病是由多巴胺的选择性丢失引起的- 在黑质产生神经元，随后纹状体多巴胺缺乏，导致进行性 自愿运动的恶化。到目前为止，功能性神经成像已经在识别 多巴胺耗竭后PD相关的神经异常，但重要的是要注意，我们的大多数患者， 对疾病相关的大脑变化的理解是基于对上肢功能的研究。尽管多产的 尽管迄今为止在PD中进行了大量的成像研究，但我们仍然没有清楚地了解PD的程度， 控制下肢运动的大脑网络受到疾病的影响。同时，当大脑改变 与孤立肢体控制相关的研究一直在进行，但对于同时控制， 四肢的运动是我们日常行为的关键，包括走路。我们建议解决这个问题 通过使用对PD变化敏感的稳健功能成像方案， 血氧水平依赖（BOLD）MRI反应在等长肌肉收缩。我们将使用一个 力产生任务，以研究在执行孤立的肢体运动过程中大脑活动的差异 PD与健康受试者之间的同侧协调运动。值得注意的是，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，在很大程度上 在PD中未探索和了解不多的领域。为了实现我们的目标，我们提出了两个目标。一是确定 在下肢/上肢力量产生过程中的大脑活动模式，并确定是否与足部相关的缺陷 在关键的大脑区域，两个皮层下-皮层运动回路位于不同的躯体位置区域， 与手有关的缺陷其次，我们将确定在同时运动的大脑活动的差异， 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： 大脑活动在基底神经节和小脑-丘脑-皮质运动回路中的广泛减少， 孤立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，改变躯体组织，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的测试， 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)指导未来的研究，以确定新的神经靶点的治疗，3）提供客观标准的亚型 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.