The Effect of Low Frequency STN DBS on Sleep and Vigilance in PD Patients

描述(由申请人提供)：睡眠障碍是一种致残的非运动症状，对帕金森氏病(PD)患者的生活质量产生不利影响(1-4)。睡眠障碍很常见，影响74-98%的帕金森病患者(1，5)。丘脑深部电刺激(DBS)丘脑下核(STN)能有效控制晚期帕金森病(6-8)患者的运动症状。研究(9-15)表明，STN DBS使用针对运动功能进行优化的设置，也可以改善这些患者的睡眠。然而，DBS参数和睡眠之间的关系还没有报道，也不知道最有效的刺激器设置来优化睡眠结构。由于睡眠障碍对PD患者的生活质量有负面影响，了解DBS的运动和睡眠效应之间的关系非常重要，以便优化目前可用于这种常见的非运动症状的治疗方案。这项拟议的研究将检验这一中心假设，即低频(60赫兹)单侧STN DBS比传统的高频(？130赫兹)刺激更有效地改善帕金森病患者的睡眠。这一假说是基于这样一种观点，即低频率的STN DBS调节脑干活动，如对睡眠调节至关重要的桥脚核。为了解决这一假设，PI将使用受试者内交叉设计，在实验室环境中评估低频率和高频设置下的多导睡眠图睡眠参数。在每项研究之后的第二天早上，受试者将被评估睡眠时间低频刺激(目标1)是否有任何残留的不良运动影响。此外，PI将确定低频STN DBS是否引起睡眠效率的变化(如在AIM 1中测量的 通过使用虚拟现实过街模拟器测量的帕金森病新的警戒终点，与白天警戒的变化相关联(AIM 2)。这将为研究的睡眠参数的“真实世界”后果提供重要的生态学有效数据。最后，这些发现将被转化到家庭环境中，对一个月以上的睡眠时间低频率STN DBS进行更长持续时间的随机评估(目标3)。如果该项目成功，下一步将是对睡眠时间低频刺激进行更大规模的多中心研究。这最终可能改变传统的DBS编程方法，使用不同的睡眠和唤醒时间设置，以提高患者的生活质量和安全性。独立调查组处于有利地位，能够实施拟议的研究，并发展成为独立的调查员。在攻读医学博士学位的过程中，她培养了对如何批判性地处理研究问题的理解，通过出版3篇第一作者手稿(16-18)证明了她的成功。她随后接受的神经学临床住院医师培训以及运动障碍和睡眠医学方面的研究员培训为这项提议和她的职业生涯提供了一个框架。通过接受同行评审的外部资助和该领域的出版物，候选人对该研究领域作出贡献的潜力已得到确认(15，19)。到目前为止，PI的培训表明了她对临床科学和以患者为导向的研究事业的奉献精神。阿拉巴马大学伯明翰分校是这项拟议研究的理想环境。UAB在NIH资金方面排名第20位，拥有全国最大的运动障碍部门之一。这项建议的主要导师大卫·标准医学博士是帕金森氏症研究领域的领先者。共同导师苏珊·哈丁，医学博士，是公认的睡眠医学专家。指导团队的其他成员包括埃默里大学运动障碍和睡眠医学专家David Rye，医学博士，以及生物统计学和临床试验设计专家Gary Cutter博士。实施所需的资源 这项试验的部分可在UAB获得，包括大量患有DBS的患者(&gt；700) 哪些研究参与者可以被抽出？此外，UAB睡眠/唤醒障碍中心每年进行2000多项睡眠研究，并有2张床位专门用于研究。此外，虚拟现实过街模拟器是由UAB的博士David Scheele开发的，已经安装了必要的基础设施。UAB有生物统计学、试验设计和研究伦理方面的课程。最后，UAB是NIH临床和翻译科学奖(CTSA)计划的获得者，通过UAB临床和翻译服务中心为研究、合作、教育和培训提供资源。这项试验的成功资助和实施将使PI能够追求她的长期职业目标：1)作为运动障碍和睡眠医学重叠领域的专家获得认可，同时帮助塑造这些领域的临床和研究轨迹；2)确定睡眠障碍及其治疗对PD患者运动症状的影响；3)作为一名独立的内科科学家获得一致的R01资助。为了实现这些长期目标，更近期的目标包括：1)进一步了解生物统计学和临床试验设计；2)获得有关脑深部刺激器编程和DBS机制的额外培训；3)开发和利用虚拟现实作为与帕金森病患者睡眠功能障碍相关的安全结果的衡量标准。这些短期目标将通过正式的课程作业、导师指导下的阅读和讨论以及在试验实施期间的实践经验来实现。候选人的背景和目标、研究和指导环境以及拟议研究的设计(涉及NIH帕金森氏病研究计划中概述的多个目标)将PI定位为K23机制的理想候选人。

DESCRIPTION (provided by applicant): Sleep dysfunction is a disabling non-motor symptom that adversely affects quality of life in patients with Parkinson's disease (PD) (1-4). Sleep disorders are common, affecting 74-98% of PD patients (1, 5). Deep brain stimulation (DBS) of the sub thalamic nucleus (STN) effectively controls motor symptoms in advanced PD (6-8). Studies (9-15) show that STN DBS, using settings optimized for motor function, also improves sleep in these patients. However, the relationship between DBS parameters and sleep has not been reported, and the most effective stimulator settings for optimizing sleep architecture are not known. Since sleep dysfunction negatively Impacts quality of life in PD patients, it is important to understand the relationship between motor and sleep effects of DBS in order to optimize currently available treatment options for this common non-motor symptom. The proposed research will test the central hypothesis that LOW frequency (60 Hz) unilateral STN DBS improves sleep more effectively than conventional HIGH frequency (¿130 Hz) stimulation in PD patients. This hypothesis is based on the idea that LOW frequency STN DBS modulates brainstem activity at locations such as the pedunculopontine nucleus that are important for sleep regulation. To address this hypothesis, the PI will use a within-subject cross-over design evaluating polysomnographic sleep parameters at LOW and HIGH frequency settings in the laboratory setting. The morning following each study, subjects will be assessed for any residual adverse motor effects from sleep-time LOW frequency stimulation (Aim 1). Additionally, the PI will determine if changes in sleep efficiency (as measured in Aim 1) induced by LOW frequency STN DBS Correlate with changes in daytime vigilance through use of a novel endpoint of vigilance in PD, measured by a virtual reality street-crossing simulator (Aim 2). This will provide important ecologically valid data on the "real world" consequences of the sleep parameters examined. Finally, these findings will be translated to the home environment with a longer duration randomized evaluation of sleep-time LOW frequency STN DBS over one month (Aim 3). If this project is successful, the next step would be a larger-scale, multicenter study of sleep time LOW frequency stimulation. This could ultimately alter conventional methods of DBS programming, with different sleep and wake-time settings, to improve patient quality of life and safety. The PI is well positioned to implement the proposed studies and develop into an independent investigator. During pursuit of combined MD and PhD degrees, she developed an understanding of how to critically approach a research question, demonstrating success through publication of 3 first-author manuscripts (16-18). Her subsequent clinical residency training in neurology and fellowship training in both Movement Disorders and Sleep Medicine provide a framework upon which this proposal and her career can grow. The candidate's potential for contribution to this field of study has been recognized through receipt of peer-reviewed extramural funding and through publications in this area (15, 19). The PI's training to date demonstrates her dedication to a career in clinical science and patient-oriented research. The University of Alabama at Birmingham is the ideal environment for this proposed research. UAB ranks 20th for NIH funding and has one of the largest Divisions of Movement Disorders in the nation. The primary mentor for this proposal, David Standard, MD, PhD, is a leader in the field of Parkinson's disease research. The co-mentor, Susan Harding, MD, is a recognized expert in Sleep Medicine. Additional members of the mentoring team include David Rye, MD, PhD, an expert in Movement Disorders and Sleep Medicine at Emory University, and Gary Cutter, PhD, a specialist in biostatistics and clinical trial design. The necessary resources for implementation of this trial are available at UAB, including a large pool of patients (>700) with DBS from Which research participants can be drawn? Additionally, the UAB Sleep/Wake Disorders Center performs more than 2000 sleep studies per year and has 2 beds that are dedicated to research. Also, the virtual reality street crossing simulator was developed by David Scheele, PhD at UAB, and has the necessary infrastructure in place. UAB has coursework in biostatistics, trial design, and research ethics. Finally, UAB is a recipient of the NIH Clinical and Translational Science Award (CTSA) Program, providing resources for research, collaboration, education, and training through the UAB Center for Clinical and Translational Services. Successful funding and implementation of this trial will allow the PI to pursue her long-term career goals: 1) To gain recognition as an expert in the overlapping fields of Movement Disorders and Sleep Medicine, while helping to shape the clinical and research trajectory of these fields, 2) To determine the effects of sleep dysfunction and its treatment on motor symptoms in PD patients, and 3) To obtain consistent R01 funding as an independent physician scientist. In order to achieve these long-term goals, more immediate goals include: 1) To further develop an understanding of biostatistics and clinical trial design, 2) To obtain additional training in deep brain stimulator programming and the mechanisms of DBS, and 3) To develop and utilize virtual reality as a measure of safety outcomes related to sleep dysfunction in patients with PD. These short-term goals will be achieved through formal coursework, mentor-guided readings and discussions, and hands-on experience during implementation of the trial. The candidate's background and goals, the research and mentoring environment, and the design of the proposed study, which addresses multiple goals outlined in the NIH Parkinson's Disease Research Plan, positions the PI as an ideal candidate for the K23 mechanism.