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

摘要 帕金森氏病(PD)不仅损害运动，还损害认知和语言。随着PD的进展， 认知和言语症状变得越来越普遍，严重影响生活质量和 经常导致失去独立性和在养老院的安置。很少有干预措施能改善这些问题 帕金森病的非人性化方面，以及目前治疗运动症状的方法，如左旋多巴和深 脑刺激(DBS)，没有改善，甚至会恶化认知和言语。为了缓解这些问题 缺陷，更好地了解导致帕金森病认知和言语异常的基本机制 是必要的。前额叶皮质(PFC)对于时间敏感性的目标导向计划至关重要 认知和言语所必需的行为序列。在帕金森病患者中，PFC变薄，我们的 已发表的工作表明，PFC的4赫兹节律减少。此外，帕金森病还涉及到不同的 病理生理过程，如中断的多巴胺、乙酰胆碱和突触核蛋白。有一个 迫切需要了解PD是如何扰乱PFC并导致认知和语言症状的。这 知识将启发新的生物标记物和针对帕金森病非运动性症状的靶向治疗。 拟议的探索性赠款的目标是催化新的合作，这将导致Udall 卓越中心。我们将检验总体假设，即降低多巴胺依赖的PFC 4赫兹 运动损害帕金森病患者的认知和语言能力。我们将确定潜在的细胞和电路机制 临床前啮齿动物模型和人类帕金森病患者的PFC功能和功能障碍。我们会驾驭 互补和融合的尖端技术，例如特定细胞类型的双光子成像 行为动物中的PFC、人术中神经生理学、脑成像和脑 连通性。常见的研究主题集中在PFC在帕金森病认知和言语症状中的作用， 神经元振荡和神经元回路。项目之间的具体协同作用包括我们的分子- 定义的电路、共享的分析工具以及认知和语音功能的时间组织 在警局被打断了。 我们建议提供一笔探索性补助金。项目1将重点研究PFC 4赫兹的蜂窝和电路机制 啮齿动物的节律。项目2将重点放在人类手术中的PFC电路和系统 神经生理学。项目3将集中于人类PFC在认知和言语方面的多模式分析 警察。拟议的研究计划利用了我们在加州大学的世界级临床基础设施。 爱荷华州帕金森基金会卓越中心，并催化围绕认知和 言语，这是帕金森病很少被研究的方面。我们的工作将带来新的靶向治疗 那些患有帕金森病的人。

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.