Mid-frontal delta/theta rhythms and cognitive control in PD

摘要 高达80%的帕金森氏症(PD)患者将出现认知症状，包括 注意力、计划、推理和工作记忆受损，以及幻觉、视觉空间 功能障碍和妄想症。这些损害会导致轻度认知障碍(PD-MCI)和 帕金森病中的痴呆(PDD)。帕金森病的认知症状与我们的社会付出了巨大的代价。 目前对PD-MCI/PDD尚无明确的生物标志物，也缺乏有效的治疗方法。因为帕金森病的风险 随着年龄的增长，这个问题将会随着我们的人口老龄化而激增。其作用机制 导致PD-MCI/PDD的因素尚不清楚。我们小组发现，低频(1-8赫兹；或 脑节律)可能有助于诊断帕金森病患者的认知功能障碍。这 Delta/theta活动起源于内侧额叶皮质区域，如前扣带回， 可通过正中头皮脑电电极检测到。我们已经发现额叶中段的Delta/theta脑节律 当健康的人发现新奇、错误和冲突，或做出决定时，就会参与进来。这些 帕金森病患者的节律减弱。我们的工作模型是帕金森病患者表现出不同的神经元 和网络缺陷，损害额叶中段的Delta/theta活动，导致认知参与失败 控制力。这些异常导致PD-MCI和PDD。在这个提案中，我们结合了大数据 机器学习工具、人类术中神经生理学和新的脑刺激范例 探讨额叶中段Delta/theta节律在帕金森病中的作用。我们将检验总体假设 额叶中段δ/theta损害是帕金森病患者认知功能障碍的一种机制。在目标1中，我们将 确定额叶中段Delta/theta活动是否可预测PD-MCI/PDD。在目标2中，我们将使用Unique 术中记录以确定内侧额叶皮质内的Delta/theta活动如何影响 丘脑底核的神经元，这是电流的靶点，是功能会聚的关键部位 脑深部刺激治疗帕金森病。值得注意的是，丘脑底核是一种紧凑的结构，它接收 来自认知和运动皮质区域的高度重叠的输入，使得我们的录音很可能 捕捉这个核团内的认知过程。最后，在目标3中，我们将确定丘脑下部 脑深部核刺激以Delta/theta频率改善帕金森病患者的认知控制。 因为这些实验涉及几个PD患者群体的录音(目标1)，来自 单个丘脑底核神经元(目标2)和脑刺激(目标3)，这些目标中的每一个都将提供 对帕金森病患者认知功能障碍的独立机制洞察。帕金森病是一种复杂的疾病，但如果皮质 脑电异常是一个始终如一的主题，它可能会启发新的诊断工具或新的大脑刺激 帕金森病患者认知功能障碍的治疗。这项提案的结果也可能对其他 神经退行性疾病，如路易体痴呆和阿尔茨海默病。

Abstract Up to 80% of patients with Parkinson's disease (PD) will suffer from cognitive symptoms, including impaired attention, planning, reasoning and working memory as well as hallucinations, visuospatial dysfunction, and delusions. These impairments lead to mild cognitive impairment (PD-MCI) and dementia (PDD) in PD. Cognitive symptoms of PD are associated with enormous cost to our society. There are no clear biomarkers and few effective treatments for PD-MCI/PDD. Because risk for PD increases dramatically with age, this problem will surge as our population grows older. The mechanisms contributing to PD-MCI/PDD are unknown. Our group has found that low-frequency (1-8 Hz; or delta/theta bands) brain rhythms might be helpful in diagnosing cognitive dysfunction in PD. This delta/theta activity originates from areas of medial frontal cortex such as the anterior cingulate, and is detectable by mid-frontal scalp EEG electrodes. We have found that mid-frontal delta/theta brain rhythms are engaged when healthy individuals detect novelty, errors, and conflict, or make decisions. These rhythms are attenuated in PD patients. Our working model is that PD patients manifest diverse neuronal and network deficits that impair mid-frontal delta/theta activity, leading to failures in engaging cognitive control. These abnormalities contribute to PD-MCI and PDD. In this proposal we combine `big-data' machine learning tools, intraoperative neurophysiology in humans, and new brain-stimulation paradigms to investigate the role of mid-frontal delta/theta rhythms in PD. We will test the overall hypothesis that mid-frontal delta/theta impairments are a mechanism of cognitive dysfunction in PD. In Aim 1 we will determine if mid-frontal delta/theta activity predicts PD-MCI/PDD. In Aim 2 we will use unique intraoperative recordings to determine how delta/theta activity within medial frontal cortex influences neurons in the subthalamic nucleus, a key site of functional convergence that is targeted by current deep-brain stimulation for PD. Notably, the subthalamic nucleus is a compact structure that receives highly overlapping input from cognitive and motor cortical regions, making it likely that our recordings will capture cognitive processing within this nucleus. Finally, in Aim 3 we will determine if subthalamic nucleus deep-brain stimulation at delta/theta frequencies improves cognitive control in PD patients. Because these experiments involve recordings across several PD patient populations (Aim 1), from single subthalamic neurons (Aim 2), and brain stimulation (Aim 3), each of these aims will provide independent mechanistic insight into cognitive dysfunction in PD. PD is a complex disease, but if cortical EEG abnormalities are a consistent theme it might inspire new diagnostic tools or new brain-stimulation therapies for cognitive dysfunction in PD. Results from this proposal could also be important for other neurodegenerative diseases such as dementia with Lewy bodies and Alzheimer's disease.