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

低频 STN DBS 对 PD 患者睡眠和警觉性的影响

• 批准号: 8704745
• 负责人: Amy Willis Amara
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704745
• 关键词: Address; Affect; Alabama; Area; Award; Beds; Biometry; Brain Stem; Cell Nucleus; Clinical; Clinical Research; Clinical Sciences; Clinical Trials Design; Collaborations; Crossover Design; Data; Dedications; Deep Brain Stimulation; Disease; Doctor of Philosophy; Energy Metabolism; Environment; Environment Design; Evaluation; Extramural Activities; Fellowship; Frequencies; Functional disorder; Funding; Goals; High Prevalence; Home environment; Intervention; Laboratories; Lead; Location; Manuscripts; Measures; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Motor; Movement Disorders; Multicenter Studies; Neurology; Operative Surgical Procedures; Outcome; Parkinson Disease; Participant; Patients; Peer Review; Phase; Physicians; Polysomnography; Positioning Attribute; Publications; Quality of life; Randomized; Reading; Reporting; Research; Research Ethics; Research Infrastructure; Research Personnel; Residencies; Residual state; Resources; Rye cereal; Safety; Scientist; Services; Severities; Shapes; Sleep; Sleep Architecture; Sleep Disorders; Specialist; Structure of subthalamic nucleus; Study Subject; Symptoms; Testing; Thalamic Nuclei; Therapeutic; Time; Training; Training and Education; Translating; Translational Research; Treatment Efficacy; United States National Institutes of Health; Universities; base; career; deep brain stimulator; design; efficacy testing; experience; field study; group intervention; implementation trial; improved; member; motor control; non-motor symptom; novel; patient oriented research; programs; sleep regulation; success; vigilance; virtual reality

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.

描述（由申请人提供）：睡眠功能障碍是一种致残性非运动症状，对帕金森病（PD）患者的生活质量产生不利影响（1-4）。睡眠障碍是常见的，影响74-98%的PD患者（1，5）。丘脑底核（DBS）的脑深部电刺激（DBS）可有效控制晚期PD的运动症状（6-8）。研究（9-15）表明，使用针对运动功能优化的设置的DBS还可以改善这些患者的睡眠。然而，DBS参数和睡眠之间的关系尚未报道，并且用于优化睡眠结构的最有效的刺激器设置尚不清楚。由于睡眠功能障碍会对PD患者的生活质量产生负面影响，因此了解DBS的运动和睡眠效应之间的关系非常重要，以便优化这种常见非运动症状的当前可用治疗方案。拟议的研究将测试中心假设，即低频（60 Hz）单侧DBS比常规高频（<$130 Hz）刺激更有效地改善PD患者的睡眠。这一假说是基于这样的想法，即低频DBS调制脑干活动的位置，如脚桥核是重要的睡眠调节。为了解决这一假设，PI将使用受试者内交叉设计，在实验室环境中评价低频和高频设置下的多导睡眠图睡眠参数。每次研究后的早晨，将评估受试者睡眠时间低频刺激的任何残留不良运动影响（目标1）。此外，PI将确定低频DBS是否会引起睡眠效率的变化（如目标1中所测量的） 通过使用一种新的PD警戒终点（通过虚拟现实过街模拟器测量），与日间警戒变化相关（Aim 2）。这将提供重要的生态有效数据的“真实的世界”的后果的睡眠参数检查。最后，这些发现将被转化为家庭环境，对睡眠时间低频DBS进行为期一个月的更长时间的随机评价（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。这可能最终改变DBS编程的传统方法，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。PI能够很好地实施拟定的研究并发展成为独立研究者。在攻读医学博士和博士学位的过程中，她了解了如何批判性地对待一个研究问题，并通过发表3篇第一作者手稿（16-18）展示了成功。她随后的神经病学临床住院医师培训和运动障碍和睡眠医学的奖学金培训提供了一个框架，在此基础上，这一建议和她的职业生涯可以成长。候选人对这一研究领域的贡献潜力已经通过收到同行评审的校外资金和通过在这一领域的出版物（15，19）得到了认可。PI迄今为止的培训证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。位于伯明翰的亚拉巴马大学是这项研究的理想环境。UAB在NIH资助中排名第20位，拥有全国最大的运动障碍部门之一。该提案的主要导师大卫标准，医学博士，博士，是帕金森病研究领域的领导者。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大卫拉伊，医学博士，以及生物统计学和临床试验设计专家加里卡特博士。执行所需资源 UAB提供了这项试验的所有数据，包括来自以下地区的大量DBS患者（>700） 可以抽取哪些研究参与者？此外，UAB睡眠/觉醒障碍中心每年进行2000多项睡眠研究，并有2张床专门用于研究。此外，虚拟现实过街模拟器是由UAB的大卫舍勒博士开发的，并具有必要的基础设施。UAB有生物统计学，试验设计和研究伦理学的课程。最后，UAB是NIH临床和转化科学奖（CTSA）计划的获得者，通过UAB临床和转化服务中心提供研究，合作，教育和培训资源。本试验的成功资助和实施将使PI能够追求其长期职业目标：1）获得运动障碍和睡眠医学重叠领域专家的认可，同时帮助塑造这些领域的临床和研究轨迹，2）确定睡眠功能障碍及其治疗对PD患者运动症状的影响，和3）获得一致的R 01资金作为一个独立的医生科学家。为了实现这些长期目标，更直接的目标包括：1）进一步了解生物统计学和临床试验设计，2）获得深部脑刺激器编程和DBS机制的额外培训，3）开发和利用虚拟现实作为PD患者睡眠功能障碍相关安全性结局的衡量标准。这些短期目标将通过正式的课程作业，导师指导的阅读和讨论，以及在试验实施过程中的实践经验来实现。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，解决了NIH帕金森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。