Neural Substrates of Switching in Parkinson's Disease

帕金森病转换的神经基质

• 批准号: 7728351
• 负责人: Elizabeth A Disbrow
• 金额: $ 61.55万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-25 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728351
• 关键词: Activities of Daily Living; Affect; Anatomy; Area; Basal Ganglia; Behavior; Behavioral; Bradykinesia; Brain; Cognitive; Consensus; Cortical Synchronization; Cues; Deterioration; Disease; Dopamine; Event; Functional Magnetic Resonance Imaging; Functional disorder; Gait; Goals; Impaired cognition; Impairment; Individual; Life; Link; Magnetoencephalography; Measures; Medical; Motor; Movement; Neurobehavioral Manifestations; Neurorehabilitation; Parkinson Disease; Parkinsonian Disorders; Patients; Pattern; Performance; Physiological; Prefrontal Cortex; Stimulus; Testing; Thinking; Walking; Work; base; behavioral impairment; clinical practice; cognitive function; design; drug development; effective therapy; motor deficit; motor disorder; neuropathology; relating to nervous system; response; standard care; therapy development

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.

本文的工作重点是确定任务转换的神经基础 帕金森病（PD）的缺陷，并将这些功能障碍与行为障碍联系起来， 日常生活虽然PD最初被认为是一种运动障碍，但认知功能缺陷 对帕金森病的标志性症状有很大影响然而，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， 以前研究和分离认知方面的挑战，如任务切换， 运动执行。任务切换是在计划中进行更改的能力（从 从一个响应选项到另一个响应选项，例如，按下一个按钮对另一个按钮）和切换可以被 基于环境刺激的外部生成，或者内部或自我生成。我们有 选择研究运动规划，特别是切换，因为它是正常运动的关键部分 行为，并与PD相关的运动缺陷密切相关。我们 假设是，这些方面的转换行为的规划依赖于单独的基础 神经节（BG）-丘脑皮层回路，受PD的影响不同。具体目标1是 测试预测，PD相关的行为缺陷，在内部产生和外部线索， 开关与个别BG-丘脑皮层电路相关，这些电路受到以下因素的不同影响： 警局具体目标2是确定帕金森病转换缺陷和相关异常是否存在于 BG-丘脑皮质活动与PD的标志性体征相关，如运动迟缓， 以及日常活动的障碍，包括语言流畅性和步态启动。我们有 设计了一个行为任务，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。我们将测量大脑皮层 与功能性磁共振成像的激活和同步， 脑磁图，分别获得互补的解剖和生理视图 帕金森病的转换功能障碍此外，我们建议提供一个异常的大脑之间的联系 PD活动和日常生活困难。意义：虽然认知能力是一个 作为正常运动行为的组成部分，我们对PD认知功能障碍的认识正在发展 尚未纳入标准临床实践。认知症状在不同的 帕金森病患者，随着疾病的进程而变化，并且可能受到以下因素的不同影响： 多巴胺替代，但患者的治疗是相似的。我们的研究结果可用于 为特定目标药物开发提供信息，指导定制认知神经康复，并评估 新兴PD治疗选择。 2.