“Cortical electrophysiology of response inhibition and implications for DBS therapy in patients

Ø 反应抑制的皮层电生理学及其对患者 DBS 治疗的影响

• 批准号: 10495230
• 负责人: Svjetlana Miocinovic
• 金额: $ 38.72万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10495230
• 关键词: Affect; Age; Area; Attention; Basal Ganglia; Behavior; Behavioral; Behavioral inhibition; Biophysics; Brain; Characteristics; Clinical; Clinical Research; Cognition; Cognitive; Computer Models; Conflict (Psychology); Cues; Data; Deep Brain Stimulation; Devices; Disease; Electrocorticogram; Electrodes; Electroencephalography; Electrophysiology (science); Emergency Situation; Evaluation; Evoked Potentials; Frequencies; Functional disorder; Gait; Impairment; Implant; Implantation procedure; Impulsivity; Knowledge; Lateral; Lead; Levodopa; Location; Maps; Measurement; Measures; Methods; Motor; Movement; Neuropsychological Tests; Neuropsychology; Operative Surgical Procedures; Outcome; Parkinson Disease; Pathway interactions; Patients; Performance; Persons; Pharmaceutical Preparations; Physiology; Postoperative Period; Prefrontal Cortex; Proactive Inhibition; Procedures; Process; Reactive Inhibition; Research; Resolution; Role; STN stimulation; Sampling; Scalp structure; Signal Transduction; Structure of subthalamic nucleus; Task Performances; Testing; Universities; base; behavior measurement; behavioral outcome; behavioral study; biophysical model; catalyst; cognitive impairment in Parkinson' s; design; dopamine replacement therapy; electric field; executive function; experimental study; frontal lobe; implantation; member; motor control; motor deficit; motor symptom; novel; patient oriented; patient subsets; predictive modeling; recruit; response; sex; side effect

Project Summary – Project 4 Parkinson’s disease (PD) is associated with behavioral impulsivity and deficits in motor control which result in an inability to cancel planned actions or stop ongoing movements. These behaviors are affected by deep brain stimulation (DBS) and levodopa treatment. The prefrontal cortex and its connections to the subthalamic nucleus (STN), the main target of DBS therapy for PD, have been implicated in the control of these ‘response inhibition’ functions. It has been proposed that modulation of prefrontal-STN connections by DBS can change response inhibition behavior, but clinical studies of this interaction have been conflicting, and clinical programming of DBS devices continues to focus on the optimization of the motoric outcome of DBS, with little attention to the potential changes in cognition and behavior which may result from DBS. The effects of dopaminergic medications on motor response inhibition are also not well understood. While large-scale changes such as outright compulsive disorders are often recognized, more subtle shifts in behavior are not usually acknowledged. The proposed experiments will study the pathophysiologic underpinning of response inhibition abnormalities in PD, asking which cortical mechanisms are engaged in different aspects of motor inhibitory control (proactive vs reactive; discrete vs continuous) in patients off and on levodopa therapy, compared to healthy controls, and examine whether the effects of STN DBS on response inhibition correlates with the degree of activation of the prefrontal cortico-STN pathway. We will use invasive and non-invasive electrophysiology methods, as well as computa- tional modeling. We will study patients longitudinally (before, during and after DBS procedures) and measure their performance and cortical activity while they perform two response inhibition tasks. We will define the degree of prefrontal cortico-STN pathway activation by different stimulation settings, using both direct electrophysiologic recordings (subcortico-cortical evoked potentials) and state-of-the-art computational biophysical models. We will also study how behavior and the underlying electrophysiologic activity change with levodopa treatment, and how these alterations relate to the results of standard clinical neuropsychological tests. In addition to the PD patients, we will study control subjects to understand to what extent changes in PD differ from healthy behavior and physiology. We hypothesize that the stimulation location and the extent of stimulation field produced by STN- DBS determine the degree of prefrontal cortex engagement and impact the patient’s ability to inhibit actions. We postulate that by developing a detailed understanding of how these changes arise, both locally and throughout the cognitive and motor networks, we can design stimulation strategies that maximize motor benefit and minimize negative behavioral side effects of DBS. Successful completion of the proposed studies will thus inform DBS targeting and programming strategies. The proposed Catalyst clinical study will synergize with the other Udall Center components by focusing on cortical electrophysiology and exploring cortical-subcortical interactions that lead to motor/cognitive dysfunction in PD, specifically as it relates to STN-DBS.

项目总结 – 项目 4 帕金森病 (PD) 与行为冲动和运动控制缺陷有关，从而导致 无法取消计划的行动或停止正在进行的运动，这些行为受到大脑深层的影响。 刺激（DBS）和左旋多巴治疗前额皮质及其与底丘脑核的连接。 (STN) 是 DBS 治疗 PD 的主要靶点，与这些“反应抑制”的控制有关 有人提出，DBS 调节前额叶-STN 连接可以改变反应。 抑制行为，但这种相互作用的临床研究一直相互矛盾，并且 DBS 的临床规划 设备继续关注 DBS 运动结果的优化，而很少关注潜在的 DBS 可能导致认知和行为的变化 多巴胺能药物对患者的影响。 运动反应抑制也尚未得到很好的理解，而大规模的变化，例如彻底的强迫性。 疾病通常会被识别，但行为上更微妙的变化通常不会被识别。 实验将研究 PD 反应抑制异常的病理生理学基础，询问 哪些皮质机制参与运动抑制控制的不同方面（主动与反应； 离散与连续）在停止和接受左旋多巴治疗的患者中与健康对照进行比较，并检查 STN DBS 对反应抑制的影响是否与前额叶的激活程度相关 我们将使用侵入性和非侵入性电生理学方法以及计算方法。 我们将纵向研究患者（DBS 手术之前、期间和之后）并进行测量。 当他们执行两项反应抑制任务时，他们的表现和皮质活动我们将定义其程度。 通过不同的刺激设置，使用直接电生理学方法激活前额皮质-STN 通路 我们将记录（皮质下诱发电位）和最先进的计算生物物理模型。 还研究左旋多巴治疗如何改变行为和潜在的电生理活动，以及如何 这些改变与标准临床神经心理学测试的结果有关。 我们将研究对照受试者，以了解 PD 的变化与健康行为有多大不同， 我们追求的是STN-产生的刺激位置和刺激场的范围。 DBS 确定前额皮质参与程度并影响患者抑制行为的能力。 假设通过详细了解这些变化是如何在当地和整个地区发生的 通过认知和运动网络，我们可以设计刺激策略，最大限度地提高运动效益并最大限度地减少运动效益 星展银行的负面行为副作用因此，成功完成拟议的研究将为星展银行提供信息。 拟议的 Catalyst 临床研究将与其他 Udall 协同作用。 通过关注皮质电生理学并探索皮质-皮质下相互作用来中心组件 导致 PD 运动/认知功能障碍，特别是因为它与 STN-DBS 相关。