Neural Substrates of Switching in Parkinson's Disease

拟议工作的重点是确定任务转换的潜在神经基础 帕金森氏病(PD)的缺陷并将这些功能障碍与行为障碍联系起来 日常生活。尽管帕金森病最初被认为是一种运动障碍，但认知功能障碍 对帕金森病的标志性征兆有很大贡献。然而，人们缺乏共识。 关于这些缺陷的病理生理学，主要是因为任务的多样性 以及分离认知方面的挑战，如任务切换， 从汽车行刑中。任务切换是对计划进行更改的能力(从 一种对另一种的响应选项，例如按下一个按钮而不是另一个)并且切换可以是 外部产生的，基于环境刺激，或内部或自我产生的。我们有 选择学习电机规划，特别是切换，因为它是正常电机的关键部分 并与帕金森病相关的运动缺陷密切相关。我们的 假设是，转换行为的这些方面的计划依赖于独立的基础 神经节(BG)--受帕金森病不同影响的丘脑皮质回路。具体的目标1是 测试帕金森病相关行为缺陷在内部产生和外部提示中的预测 转换与单独的BG-丘脑皮质回路相关，这些回路受到不同的 警察。特定的目的2是确定帕金森病患者的转换缺陷和相关的异常 BG-丘脑皮质活动与帕金森病的标志体征相关，如运动迟缓、AS 以及日常活动中的障碍，包括语言流利性和步态启动。我们有 设计了一项行为任务，让我们不仅可以将运动规划与执行分离， 而且还包括内部与外部产生的切换。我们将测量大脑皮质的模式 激活和同步功能磁共振成像和 脑磁图，分别获得互补的解剖和生理学观点 帕金森病患者的开关功能障碍。此外，我们建议在异常大脑之间提供联系 帕金森病的活动性和日常生活中的困难。意义：虽然认知能力是一种 正常运动行为的组成部分，我们对帕金森病认知功能障碍的逐渐认识 尚未纳入标准的临床实践。认知症状在以下方面有所不同 帕金森氏症患者，在疾病过程中发生变化，并可能受到不同程度的影响 多巴胺替代治疗，然而患者之间的治疗是相似的。我们的结果可以用来 告知特定靶点的药物开发，指导量身定制的认知神经康复，并评估 新兴的帕金森病治疗方案。 2.

The focus of the proposed work is to determine the underlying neural substrates of task switching deficits in Parkinson's disease (PD) and to link these dysfunctions with behavioral impairments in everyday life. Although PD was initially considered a motor disorder, deficits in cognitive function contribute significantly to the hallmark signs of PD. However, there is a lack of consensus regarding the pathophysiology of these deficits primarily because of the diversity of tasks previously studied and the challenge of separating the cognitive aspects, such as task switching, from motor execution. Task switching is the ability to make a change in the plan (switching from one response option to another, e.g. pressing one button vs. another) and switching can be externally generated, based on environmental stimuli, or internally or self-generated. We have chosen to study motor planning, specifically switching, because it is a critical part of normal motor behavior and is intimately intertwined with the motor deficits associated with PD. Our HYPOTHESIS is that the planning of these aspects of switching behavior relies on separate basal ganglia (BG)-thalamocortical circuits that are differentially affected by PD. SPECIFIC AIM 1 is to test the prediction that PD-related behavioral deficits in internally generated and externally cued switching are correlated with individual BG-thalamocortical circuits that are differentially affected by PD. SPECIFIC AIM 2 is to determine if parkinsonian switching deficits and related abnormalities in BG-thalamocortical activity are correlated with the hallmark signs of PD such as bradykinesia, as well as impairments in daily activities including verbal fluency and gait initiation. We have designed a behavioral task that will allow us to dissociate not only motor planning from execution, but also internally vs. externally generated switching. We will measure patterns of cortical activation and synchronization with functional magnetic resonance imaging and magnetoencephalography, respectively, to obtain complimentary anatomic and physiologic views of switching dysfunctions in PD. Further, we propose to provide a link between the abnormal brain activity of PD and difficulties in everyday life. SIGNIFICANCE: While cognitive abilities are an integral part of normal motor behavior, our developing appreciation of cognitive dysfunction in PD has not yet been incorporated into standard clinical practice. Cognitive symptoms differ among parkinsonian patients, change over the course of the disease, and may be differentially affected by dopamine replacement, yet the treatment across patients is similar. Our results can be used to inform target-specific drug development, direct tailored cognitive neuro-rehabilitation, and evaluate emerging PD treatment options. 2.