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

摘要 高达80%的帕金森病（PD）患者会出现认知症状，包括 注意力、计划、推理和工作记忆以及幻觉、视觉空间障碍 功能障碍和妄想症这些损伤导致轻度认知障碍（PD-MCI）， 痴呆症（PDD）。PD的认知症状与我们社会的巨大成本有关。 PD-MCI/PDD没有明确的生物标志物，有效的治疗方法也很少。因为帕金森病的风险 随着年龄的增长，这个问题会急剧增加，随着我们人口的老龄化，这个问题会急剧增加。的机制 导致PD-MCI/PDD的原因尚不清楚。我们的小组发现，低频（1 - 8赫兹;或 δ/θ波）脑节律可能有助于诊断PD的认知功能障碍。这 δ/θ活动起源于内侧额叶皮层的区域，例如前扣带回， 前额中部头皮脑电图电极可以检测到。我们发现额叶中部的δ/θ脑节律 当健康的个体发现新鲜事物、错误和冲突，或做出决定时，他们会参与其中。这些 PD患者的心律减弱。我们的工作模型是PD患者表现出不同的神经元 和网络缺陷，损害中额叶三角洲/θ活动，导致参与认知失败， 控制这些异常导致PD-MCI和PDD。在本提案中，我们将联合收割机"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 研究额叶中部δ/θ节律在PD中的作用。我们将检验总体假设， 额叶中部δ/θ损伤是PD中认知功能障碍的机制。在目标1中， 确定额叶中部δ/θ活动是否预测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 丘脑底核中的神经元，这是电流靶向的功能会聚的关键部位 深部脑刺激治疗帕金森病值得注意的是，丘脑底核是一个紧凑的结构， 来自认知和运动皮层区域的高度重叠的输入，使得我们的记录可能会 捕捉这个核心中的认知过程。最后，在目标3中，我们将确定丘脑底核是否 以δ/θ频率进行的核深部脑刺激改善了PD患者的认知控制。 由于这些实验涉及多个PD患者人群的记录（目标1）， 单个丘脑底神经元（目标2）和脑刺激（目标3），这些目标中的每一个都将提供 独立的机制洞察认知功能障碍的PD。PD是一种复杂的疾病，但如果皮质 脑电图异常是一个一致的主题，它可能会激发新的诊断工具或新的大脑刺激 帕金森病认知功能障碍的治疗。这项建议的结果对其他国家也很重要。 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.