Prefrontal Cortex, Cognition, and Speech Symptoms in PD (PRECIS-PD)

PD 中的前额皮质、认知和言语症状 (PRECIS-PD)

• 批准号: 10283241
• 负责人: Nandakumar Narayanan
• 金额: $ 46.38万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283241
• 关键词: Acetylcholine; Animals; Applications Grants; Behavior; Behavioral; Biological Markers; Brain; Brain imaging; Calcium; Cells; Cognition; Cognitive; Collaborations; Data; Deep Brain Stimulation; Dehumanization; Diffusion Magnetic Resonance Imaging; Dopamine; Dopamine Receptor; Electroencephalography; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Genetic; Goals; Grant; Human; Image; Impaired cognition; Impairment; Intervention; Iowa; Knowledge; Levodopa; Link; Magnetic Resonance Imaging; Molecular; Morbidity - disease rate; Movement; Mus; Neurons; Nursing Homes; Operative Surgical Procedures; Parkinson Disease; Participant; Patients; Prefrontal Cortex; Process; Publishing; Quality of life; Research; Rodent; Rodent Model; Speech; Structure; Structure of subthalamic nucleus; Symptoms; System; Techniques; Testing; Thinness; Tissue Sample; Universities; Work; analytical tool; awake; cell cortex; cell type; clinical infrastructure; functional electrical stimulation; improved; mortality; motor symptom; multimodality; neuronal circuitry; neurophysiology; neuroregulation; new therapeutic target; non-motor symptom; novel; pre-clinical; recruit; synergism; synuclein; two-photon

Abstract Parkinson’s disease (PD) impairs not only movement, but also cognition and speech. As PD progresses, cognitive and speech symptoms become increasingly prevalent, heavily compromising quality of life and often leading to loss of independence and placement in nursing homes. Few interventions improve these dehumanizing aspects of PD, and current therapies for motor symptoms, such as levodopa and deep brain stimulation (DBS), do not improve, and can even worsen cognition and speech. To mitigate these deficits, a better understanding of the basic mechanisms leading to abnormal cognition and speech in PD is needed. The prefrontal cortex (PFC) is critical for goal-directed planning of temporally sensitive behavioral sequences essential for cognition and speech. In PD patients, the PFC is thinned, and our published work demonstrates that PFC 4 Hz rhythms are decreased. Furthermore, PD involves diverse pathophysiological processes such as disrupted dopamine, acetylcholine, and synuclein. There is a critical need to understand how PD disrupts the PFC and leads to cognitive and speech symptoms. This knowledge will inspire new biomarkers and targeted treatments for non-motor symptoms of PD. The goal of the proposed Exploratory Grant is to catalyze novel collaborations that will lead to an Udall Center of Excellence. We will test the overall hypothesis that decreased dopamine-dependent PFC 4 Hz activity impairs cognition and speech in PD. We will identify cellular and circuit mechanisms underlying PFC function and dysfunction in preclinical rodent models and in human PD patients. We will harness complementary and convergent cutting-edge techniques, such as cell-type-specific 2-photon imaging of the PFC in behaving animals, human intraoperative neurophysiology, brain imaging, and brain connectivity. Common research themes focus on the PFC in cognitive and speech symptoms of PD, neuronal oscillations, and neuronal circuits. Specific synergies among projects include our molecularly- defined circuits, shared analytic tools, and the temporal organization of cognitive and speech functions disrupted in PD. We propose an Exploratory Grant. Project 1 will focus on cellular and circuit mechanisms of PFC 4 Hz rhythms in rodents. Project 2 will focus on PFC circuits and systems in human intraoperative neurophysiology. Project 3 will focus on Multi-modal analysis of human PFC in cognition and speech in PD. The proposed research plan leverages our world-class clinical infrastructure at The University of Iowa Parkinson’s Foundation Center of Excellence and catalyzes new synergies around cognition and speech, which are greatly understudied facets of PD. Our work will lead to new targeted therapies for those suffering from PD.

抽象的 帕金森氏病（PD）不仅会损害运动，而且会损害认知和言语。随着PD的进展 认知和言语症状变得越来越普遍，严重折衷的生活质量和 通常导致在护士之家失去独立和安置。很少有干预措施改善这些 PD的非人性化方面以及当前的运动症状疗法，例如Levodopa和Deep 脑刺激（DB），不要改善，甚至可以担心认知和言语。减轻这些 缺陷，更好地理解导致PD异常认知和语音的基本机制 需要。前额叶皮层（PFC）对于暂时敏感的目标规划至关重要 行为序列对于认知和言语必不可少。在PD患者中，PFC变薄，我们 已发表的工作表明PFC 4 Hz节奏减少。此外，PD涉及多样 病理生理过程，例如破坏多巴胺，乙酰胆碱和综合蛋白。有一个 了解PD如何破坏PFC并导致认知和语音症状。这 知识将激发新的生物标志物和针对PD非运动症状的目标治疗方法。 拟议的探索性赠款的目标是催化新颖的合作，这将导致Udall 卓越中心。我们将测试改善多巴胺依赖性PFC 4 Hz的总体假设 活动会损害PD中的认知和语音。我们将确定基础的细胞和电路机制 临床前啮齿动物模型和人类PD患者的PFC功能和功能障碍。我们会利用的 完整的收敛性尖端技术，例如细胞型特异性2-Photon成像 行为动物的PFC，人类术中神经生理学，脑成像和大脑 连接性。普通研究主题侧重于PD认知和语音症状的PFC， 神经元振荡和神经元电路。项目之间的特定协同作用包括我们的分子 定义的电路，共享分析工具以及认知和语音功能的临时组织 在PD中破坏。 我们提出了探索性赠款。项目1将重点关注PFC 4 Hz的蜂窝和电路机制 啮齿动物的节奏。项目2将重点关注人类术中的PFC电路和系统 神经生理学。项目3将重点介绍人类PFC在认知和语音中的多模式分析 PD。拟议的研究计划利用我们的世界一流的临床基础设施在大学 爱荷华州帕金森基金会的卓越基金中心，并促进围绕认知和的新协同作用 语音，这是PD的广泛理解的。我们的工作将导致新的目标疗法 那些患有PD的人。