A Tool for Neurotheraputic Therapy for Sleep Disordered Breathing

睡眠呼吸障碍的神经治疗工具

• 批准号: 9054568
• 负责人: KINGMAN PERKINS STROHL
• 金额: $ 28.51万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054568
• 关键词: Address; Adverse effects; Affect; Alternative Therapies; Anatomy; Anesthesia procedures; Animal Model; Apnea; Behavior; Behavioral; Bilateral; Biological Assay; Biomedical Engineering; Bionics; Blood Pressure; Brain Stem; Carotid Body; Central Sleep Apnea; Chronic; Clinical; Continuous Positive Airway Pressure; Crowding; Custom; Devices; Dilator; Disease; Disease remission; Effectiveness; Electrodes; Environmental air flow; Evoked Potentials; Fiber; Filler; Frequencies; Grant; Heart Diseases; Heart Rate; Human; Human Pathology; Hypoglossal nerve structure; Implant; Individual; Injection of therapeutic agent; Measures; Mechanics; Medical; Modeling; Motor Cortex; Muscle; Nerve; Obstruction; Obstructive Sleep Apnea; Operative Surgical Procedures; Oral; Oropharyngeal; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharyngeal structure; Physiology; Polysomnography; Population; Production; Recurrence; Reflex action; Research Personnel; Resistance; Respiration; Respiratory Diaphragm; Respiratory Muscles; Respiratory physiology; Scientist; Silicones; Site; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Soft Palate; Staging; Stimulus; Surveys; System; Technology; Temperament; Testing; Therapeutic; Therapeutic Intervention; Variant; Work; airway obstruction; autonomic reflex; base; cardiovascular risk factor; carotid sinus; cost; heart rate variability; improved; mortality; pre-clinical; pressure; prevent; public health relevance; relating to nervous system; respiratory; sensory cortex; success; therapy outcome; tongue root; tool; tool development; treatment effect

 DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) is a serious sleep disorder affecting 2-9% of the US population. It is caused by recurrent obstruction of the upper airway (velopharynx and oropharynx) during sleep and produces daytime sleepiness, and increases cardiovascular risk and mortality. Treatment with continuous positive airway pressure (CPAP) is effective and reduces behavioral and cardiovascular risk, but 40% of patients with moderate to severe disease cannot or will not tolerate this first line therapy, and alternatives no very predictable as long-term treatment. A barrier to testing neurostimulation approaches for OSA is the lack of a reliable tool for development and testing of technology, effectiveness, and off-target effects. The proposal is to develop and verify clinical correlates of OSA in a rabbit model of OSA, based on it having general anatomic similarity to the human upper airway, and its size, cost, and temperament. We will produce recurrent obstruction during sleep by partial nasopharyngeal obstruction, airway crowding produced by injection of a silicone filler in the base of the tongue, and verify the endpoints present in human OSA, including sympathetic excitation (increasing heart rate and blood pressure) and sleep instability. We will characterize site(s) of obstruction and the upstream-pressure-flow behavior of the airway. The model will be tested by unilateral hypoglossal nerve stimulation (HNS), and compared to carotid sinus nerve stimulation (CNS) which has an ability to activate and coordinate bilateral upper airway muscle activation through brainstem mechanisms. Aim 1 is to develop, verify, and examine the production of upper airway obstruction acutely under anesthesia and Aim 2 is to record selected consequences during sleep and its stages, intermediate endpoints in the pathology of human OSA. In addition, electrodes will survey cortical state-related evoked potentials and respiratory muscle activation, and blood pressure and heart rate variability will assay autonomic efferent effects. We will mitigate OSA by HNS and CNS. Cuff electrodes will provide selective stimulation. Stimulus parameters will initially be classically-based, and move towards non-traditional paradigms using varying frequency and amplitude, to activate appropriate efferent vs. the afferent fibers. The deliverables in Aim 1 are to demonstrate feasibility and functions, using stimulation approaches to alter upper airway stiffness and resistance and examine respiratory control during drug-induced surgical anesthesia. In Aim 2, we verify the stability and fidelity of the model to human OSA, monitoring sleep (in)stability and autonomic outcomes. We will use HNS to immediately reverse OSA, and study its effects on on-target velopharyngeal and oropharyngeal sites for therapeutic intent, mitigation of sympathetic excitation, and off-target effects on the sensory or motor cortex and autonomic reflex actions. This application creates a tool where scientists in respiratory control, upper airway physiology, and biomedical engineering can address model neurotherapeutic efficacy and side effects as treatment for a common sleep disorder.

 描述（由适用提供）：阻塞性睡眠呼吸暂停（OSA）是一种严重的睡眠障碍，影响了美国人群的2-9％。这是由于睡眠期间的上呼吸道（速咽和口咽）反复反对引起的，并产生白天的嗜睡，并增加心血管风险和死亡率。连续气道压力（CPAP）的治疗是有效的，可以降低行为和心血管风险，但是40％的中度至重度疾病患者不能或不会容忍这种第一线治疗，并且替代方案没有可预测的长期治疗。 OSA测试神经刺激方法的障碍是缺乏用于开发和测试技术，有效性和非目标效应的可靠工具。该提议是在OSA的兔模型中开发和验证OSA的临床相关性，基于它与人类上呼吸道具有一般的解剖相似性及其大小，成本和温度。我们将通过部分鼻咽反对，在睡眠期间产生反复反对，这是通过在舌底部注射硅酮填充剂而产生的气道拥挤，并验证人类OSA中存在的终点，包括交感神经兴奋（心脏速度和血压增加）和睡眠不稳定性。我们将表征反对的部位和气道的上游压力流动行为。该模型将通过单侧降压神经刺激（HNS）进行测试，并与颈动脉窦神经刺激（CNS）进行比较，该神经刺激（CNS）具有通过脑干机制激活和协调双侧双边气道肌肉激活的能力。目的1是在麻醉和目标2下急性呼吸道目标的产生，验证和检查上呼吸道目标的产生，是在人类OSA病理学中记录睡眠及其阶段中所选的后果。此外，电极将调查皮质状态相关的诱发潜力和呼吸肌的激活，血压和心率变异性将主张自主有效的效果。我们将通过HNS和CNS减轻OSA。袖口电极将提供选择性刺激。刺激参数最初将基于经典，并使用变化的频率和放大器朝着非传统范式转向非传统范式，以激活适当的有效性与传入纤维。 AIM 1中的可交付成果是使用可行性和功能 刺激方法改变了上呼吸道刚度和抗性，并检查药物引起的手术麻醉期间的呼吸控制方法。在AIM 2中，我们验证了 人类OSA的模型，监测睡眠（以）稳定性和自主性结果。我们将使用HN立即反向OSA，并研究其对靶向脂咽上和口咽位点的影响，以进行热意图，减轻交感神经兴奋以及对感觉或运动皮层和自主反射动作的脱靶影响。该应用程序创建了一种工具，其中具有呼吸道控制，上空气道生理学和生物医学工程的科学家可以解决神经治疗效率的模型，并作为对常见睡眠障碍的治疗方法的副作用。