Investigating Inhibitory Control Networks in Parkinson's Disease

项目摘要：这个项目的总体目标是提供申请人J.妮可本特利，医学博士适当 资源和指导，以发展技能，从而在以下领域实现研究独立 用于认知障碍的神经调节这项建议的重点是背外侧前额叶皮层的作用 （DLPFC）在帕金森病（PD）患者中的认知改变， 清醒脑深部电刺激（DBS）手术期间的皮层下记录。认知障碍是一种常见的 帕金森病（PD）的非运动症状，影响四分之一的新诊断患者，以及更多 超过80%的患者在病程中。尽管其流行，但治疗选择很少。 不幸的是，PD运动症状的主要治疗方法，如多巴胺能药物和高- 频率脑深部电刺激（DBS）不会改善，在某些情况下甚至会恶化认知功能 症状最近的证据表明，在帕金森病患者减少前额叶θ频率振荡活动， 与认知受损有关，特别是在抑制控制领域。鉴于其密集的 连接到基底神经节和前运动区，DLPFC-基底神经节网络的神经调节可以 增强PD中认知功能障碍的要素。我们新的初步数据显示，DLPFC和皮质下 术中Simon任务中功率调制和相位振幅耦合测量抑制性 控制，并且猝发θ频率DBS调制DLPFC θ功率。在这里，我们建议研究（1） PD患者DLPFC和GPi局部场电位同步记录 在Simon任务期间，以及（2）对比来自DBS电极的连续和间歇θ刺激， GPi以确定对行为和电生理测量的影响。鉴于越来越多的流行病 由于认知障碍和缺乏可用的治疗方法，迫切需要促进发展 临床神经科学家们对此感兴趣。作为一名神经调节专业的神经外科医生， Bentley是担任此职位的理想人选。她组建了一个多学科、多机构的 专家导师团队将为科学和职业发展提供指导和支持 这一提议的目的。她和她的导师们设计了一个职业发展计划， 神经科学、计算神经科学和信号处理技术。这些培训目标将是 结合大量的三级运动障碍功能神经外科实践， 伯明翰亚拉巴马大学。凭借该机构在研究计算、生物统计学、 工程学和神经生理学，这一建议将确保本特利博士做好充分准备， 研究独立完成这个奖项。

Project Summary: The overall goal of this project is to provide applicant J. Nicole Bentley, MD appropriate resources and mentorship to develop skills allowing a path to research independence in the field of neuromodulation for cognitive disorders. This proposal focuses on the role of dorsolateral prefrontal cortex (DLPFC) in altered cognition in Parkinson’s disease (PD) patients with simultaneous intracranial cortical and subcortical recordings during awake deep brain stimulation (DBS) surgery. Cognitive impairment is a common non-motor symptom of Parkinson’s disease (PD), affecting one-quarter of newly diagnosed patients, and more than 80% of patients over the course of the disease. Despite its prevalence, very few treatment options exist. Unfortunately, mainstay treatments for motor symptoms of PD such as dopaminergic medications and high- frequency deep brain stimulation (DBS) do not improve and in some instances can even worsen cognitive symptoms. Recent evidence in PD patients suggests that reduced prefrontal theta frequency oscillatory activity is associated with impaired cognition, specifically evident in the domain of inhibitory control. Given its dense connections to basal ganglia and pre-motor areas, neuromodulation of the DLPFC-basal ganglia network could enhance elements of cognitive dysfunction in PD. Our novel preliminary data shows DLPFC and subcortical power modulation and phase-amplitude coupling during an intraoperative Simon task measuring inhibitory control, and that bursting theta-frequency DBS modulates DLPFC theta power. Here we propose studies to (1) simultaneously record DLPFC and globus pallidus interna (GPi) local field potentials (LFPs) in awake PD patients during the Simon task, and (2) contrast continuous and intermittent theta stimulation from the DBS electrode at the GPi to determine the effect on behavioral and electrophysiologic measures. Given the increasing prevalence of cognitive impairment and the dearth of available treatments, there is an urgent need to foster the development of clinician-neuroscientists with this interest. As a neurosurgeon with specialization in neuromodulation, Dr. Bentley is an ideal candidate to serve in this role. She has assembled a multi-disciplinary and multi-institutional team of expert mentors who will provide guidance and support towards the scientific and career development aims of this proposal. She and her mentors have designed a career development plan consisting of cognitive neuroscience, computational neuroscience, and signal processing techniques. These training aims will be combined with the high volume of a tertiary movement disorders functional neurosurgery practice at the University of Alabama, Birmingham. With the institution’s robust resources in research computing, biostatistics, engineering, and neurophysiology, this proposal will ensure that Dr. Bentley is well-prepared for progressing to research independence by the completion of this award.