Basal Ganglia Modulation of Cognitive Systems in Parkinson's disease

描述（由申请人提供）：这是一份名为“帕金森病认知系统的基底神经节调节”的K23指导患者导向研究职业发展奖的申请。该研究的主要目的是使用事件相关和静息状态功能性MRI（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fMRI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，并成为独立的研究者。候选人的长期职业目标是使用fMRI来阐明PD认知功能障碍的病理生理学，并开发基于fMRI的成像工具，该工具是PD认知障碍的敏感标志物和治疗反应的客观生物标志物。该提案研究了与正常对照组相比，早期PD患者（无（PD-noMCI）和（PD-MCI）轻度认知障碍）与认知功能障碍相关的体内功能变化。目的1使用功能磁共振成像任务，针对执行控制过程，需要激活基底神经节核在正常对照，以确定与PD认知障碍相关的基底神经节和皮层激活的变化。除了局部脑激活的变化，PD中的认知障碍也可能源于关键脑区之间连接的改变;因此，在目标2中，我们将使用静息状态fMRI研究基底神经节核与皮质之间的功能连接。最后，多巴胺能药物可导致认知增强和进一步损害，这取决于认知功能。因此，目标3将研究PD-noMCI组和PD-MCI组在开启药物治疗时与之前进行的关闭药物治疗研究相比基底神经节和皮质激活、纹状体-皮质连接和内在网络的变化。在这项拟议的研究中确定的与PD-MCI相关的基底神经节激活和功能连接的变化将有助于澄清基底神经节核在早期PD认知障碍中的作用，因此，对这种目前无法治疗的症状的治疗方法的发展具有影响。

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.