Basal Ganglia Modulation of Cognitive Systems in Parkinson's disease

描述(申请人提供)：这是一份K23指导下的以患者为导向的研究职业发展奖的申请书，题为《帕金森氏病认知系统的基底节调节》。这项研究的主要目的是利用事件相关和静息状态功能磁共振成像(FMRI)研究帕金森病(PD)患者与轻度认知障碍(MCI)相关的区域和脑网络异常。严格的教育和培训计划将增加候选人在功能磁共振成像方法学、统计分析、行为神经科学和临床研究方法方面的专业知识，从而为候选人提供必要的技能，以确保拟议研究的成功，并成为一名独立的研究人员。候选人的长期职业目标是使用功能磁共振成像来阐明帕金森病认知功能障碍的病理生理学，并开发一种基于功能磁共振成像的成像工具，该工具是帕金森病认知功能障碍的敏感标志和治疗反应的客观生物标志物。本研究旨在与正常对照组比较，研究无轻度认知损害(PD-noMCI)和轻度认知损害(PD-MCI)的早期PD患者与认知功能障碍相关的体内功能变化。目的1使用fMRI任务，针对正常对照组中需要激活基底节核团的执行控制过程，确定与帕金森病认知损害相关的基底节和皮质激活的变化。帕金森病的认知障碍除了局部脑激活的改变外，还可能源于关键脑区之间的连通性的改变；因此，在目标2中，我们将使用静息状态的fMRI来研究基底节核和皮质之间的功能连通性。最后，多巴胺能药物可以导致认知增强和进一步的损害，这取决于认知功能。因此，AIM 3将调查PD-noMCI和PD-MCI组在药物治疗期间与之前进行的非药物治疗研究相比，基底节和皮质激活、纹状体-皮质连接和内在网络的变化。本研究中发现的与PD-MCI相关的基底节激活和功能连接的变化将有助于阐明基底节核在早期PD认知损害中的作用，从而对这一目前无法治疗的症状的治疗发展具有指导意义。

DESCRIPTION (provided by applicant): This is an application for a K23 Mentored Patient-Oriented Research Career Development Award titled "Basal ganglia modulation of cognitive systems in Parkinson's disease". The primary goal of the proposed research is to investigate regional and brain network abnormalities associated with mild cognitive impairment (MCI) in Parkinson's disease (PD) patients using event-related and resting state functional MRI (fMRI). The rigorous education and training plan will increase the candidate's expertise in fMRI methodology, statistical analysis, behavioral neuroscience, and clinical research methods, thus providing the candidate the necessary skills to ensure success of the proposed research and to become an independent investigator. The candidate's long term career goal is to use fMRI to elucidate the pathophysiology of cognitive dysfunction in PD and to develop an fMRI based imaging tool that is a sensitive marker of cognitive impairment in PD and an objective biomarker of treatment response. This proposal investigates in vivo functional changes associated with cognitive dysfunction in early PD patients without (PD-noMCI) and with (PD-MCI) mild cognitive impairment, compared to normal controls. Aim 1 uses fMRI tasks targeting executive control processes that require activation of basal ganglia nuclei in normal controls to determine changes in basal ganglia and cortical activation associated with PD cognitive impairment. In addition to changes in regional brain activation, cognitive impairment in PD likely also stems from alterations in connectivity between critical brain regions; therefore in Aim 2 we will investigate functional connectivity between basal ganglia nuclei and the cortex using resting state fMRI. Finally, dopaminergic medications can lead to both cognitive enhancement and further impairment, depending on the cognitive function. Therefore, Aim 3 will investigate changes in basal ganglia and cortical activation, striato- cortical connectivity, and intrinsic networks in the PD-noMCI and PD-MCI groups while ON medications compared to the previously performed OFF medication studies. Changes in basal ganglia activation and functional connectivity associated with PD-MCI identified in this proposed research will help clarify the role of basal ganglia nuclei in early PD cognitive impairment and, thus, have implications on the development of therapies for this currently untreatable symptom.