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

项目摘要-项目4 帕金森病（PD）与行为冲动和运动控制缺陷相关， 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。前额叶皮层及其与丘脑底核的联系 (STN)作为DBS治疗PD的主要靶点， 功能协调发展的有人提出，DBS对前额叶-小脑连接的调制可以改变反应， 抑制行为，但这种相互作用的临床研究一直相互矛盾，DBS的临床编程 器械继续专注于DBS运动结局的优化，很少关注潜在的 DBS可能导致的认知和行为变化。多巴胺能药物对 运动反应抑制也没有得到很好的理解。虽然大规模的变化，如彻底的强迫性， 虽然人们通常会意识到疾病，但行为上更微妙的变化通常不会得到承认。拟议 实验将研究PD中反应抑制异常的病理生理基础， 哪些皮层机制参与了运动抑制控制的不同方面（主动与反应; 与健康对照组相比， 脑深部电刺激对反应抑制的影响是否与前额叶的激活程度有关 皮质醇途径我们将使用侵入性和非侵入性电生理学方法，以及计算机- 理性建模我们将对患者进行纵向研究（DBS手术前、术中和术后）， 他们的表现和皮层活动，而他们执行两个反应抑制任务。我们将定义 通过不同的刺激设置，使用直接电生理和 记录（皮质下-皮质诱发电位）和最先进的计算生物物理模型。我们将 研究左旋多巴治疗后行为和潜在电生理活动的变化， 这些改变与标准临床神经心理学测试的结果有关。除了帕金森病人， 我们将研究对照受试者，以了解PD的变化在多大程度上不同于健康行为， physiology.我们假设，刺激位置和范围的刺激场产生的电刺激- DBS决定了前额叶皮质参与的程度，并影响患者抑制行为的能力。我们 我假设，通过详细了解这些变化是如何产生的，无论是在局部还是在整个 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， DBS的负面行为副作用因此，成功完成拟议的研究将通知DBS 确定目标和方案拟订战略。拟议的催化剂临床研究将与其他Udall协同作用 通过关注皮层电生理学和探索皮层-皮层下相互作用， 导致PD运动/认知功能障碍，特别是与STN-DBS相关。

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.