“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有关，这会导致 无法取消计划的行动或停止正在进行的行动。这些行为受到大脑深部的影响 刺激(DBS)和左旋多巴治疗。前额叶皮质及其与丘脑底核的联系 DBS治疗帕金森病的主要靶点(STN)参与了这些“反应抑制”的控制。 功能。已经提出，DBS对前额叶-STN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的临床规划 设备继续专注于优化DBS的运动结果，而对潜在的关注很少 DBS可能导致的认知和行为的改变。多巴胺能药物对血管紧张素转换酶的影响 运动反应抑制也没有得到很好的理解。而大规模的变化，如彻底的强迫 障碍通常是被认识到的，而行为中更微妙的变化通常不被认识。建议数 实验将研究帕金森病反应抑制异常的病理生理基础 哪些大脑皮层机制参与运动抑制控制的不同方面(主动性与反应性； 与健康对照组相比，停用左旋多巴治疗和接受左旋多巴治疗的患者中的离散和连续)，并进行检查 STN DBS对反应抑制的影响是否与前额叶激活程度有关 皮质-STN通路。我们将使用有创和非侵入性电生理学方法，以及计算- 传统造型。我们将对患者进行纵向研究(在DBS手术前、中和之后)并测量 当他们执行两个反应抑制任务时，他们的表现和皮质活动。我们将定义学位 不同刺激环境对前额叶皮质-STN通路激活的影响 记录(皮质下诱发电位)和最先进的计算生物物理模型。我们会 也要研究左旋多巴治疗后行为和潜在电生理活动如何改变，以及如何改变。 这些改变与标准临床神经心理测试的结果有关。除了帕金森病患者， 我们将对对照受试者进行研究，以了解帕金森病的变化与健康行为和 生理学。我们假设STN产生的刺激位置和刺激场的范围- DBS决定前额叶皮质参与的程度，并影响患者抑制行为的能力。我们 假设通过详细了解这些变化是如何发生的，无论是局部的还是整个的 在认知和运动网络中，我们可以设计刺激策略，使运动受益最大化，同时最小化 星展银行的负面行为副作用。因此，成功完成拟议的研究将通知星展银行 目标和规划战略。拟议的Catalyst临床研究将与另一项Udall协同 通过专注于皮质电生理学和探索皮质-皮质下相互作用 导致帕金森病患者的运动/认知功能障碍，特别是与STN-DBS有关。

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.