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: 9150622
• 负责人: KINGMAN PERKINS STROHL
• 金额: $ 52.92万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150622
• 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; Health; 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 muscle; airway obstruction; autonomic reflex; base; cardiovascular risk factor; carotid sinus; cost; genioglossus muscle; heart rate variability; improved; mortality; pre-clinical; pressure; prevent; 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（由申请人提供）：阻塞性睡眠呼吸暂停 (OSA) 是一种严重的睡眠障碍，影响 2-9% 的美国人口，它是由睡眠期间上呼吸道（腭咽和口咽）反复阻塞引起的，并导致白天嗜睡。持续气道正压通气 (CPAP) 治疗可有效降低行为和心血管风险，但 40% 的中度至重度疾病患者不能或不会耐受。这种一线疗法和替代方案作为长期治疗缺乏可预测性，测试 OSA 神经刺激方法的一个障碍是缺乏可靠的工具来开发和测试技术、有效性和脱靶效应。基于兔 OSA 模型与人类上气道的解剖学相似性以及其大小、成本和性质，我们将在睡眠期间因部分鼻咽阻塞、气道拥挤而产生复发性阻塞，从而开发并验证 OSA 的临床相关性。通过在舌根注射硅胶填充物产生，并验证人类 OSA 中存在的终点，包括交感神经兴奋（心率和血压增加）和睡眠不稳定。我们将描述阻塞部位和上游的特征。 -气道的压力-流量行为将通过单侧舌下神经刺激（HNS）进行测试，并与能够激活和协调双侧上气道肌肉的颈动脉窦神经刺激（CNS）进行比较。目标 1 是开发、验证和检查麻醉下急性上呼吸道阻塞的产生，目标 2 是记录睡眠期间的选定结果及其阶段、人类 OSA 病理学的中间终点。电极将测量皮质状态相关的诱发电位和呼吸肌激活，血压和心率变异性将测定自主传出效应，我们将通过 HNS 减轻 OSA，而袖带电极将提供选择性刺激。刺激参数最初将基于经典，并转向使用不同频率和幅度的非传统范例，以激活适当的传出纤维与传入纤维。目标 1 中的可交付成果是使用使用来证明可行性和功能。 在目标 2 中，我们验证了药物诱导手术麻醉期间的刺激方法来改变上呼吸道硬度和阻力并检查呼吸控制。 我们将使用 HNS 来立即逆转 OSA，并研究其对目标腭咽和口咽部位的影响，以实现治疗目的、缓解交感神经兴奋和脱靶。对感觉或运动皮层和自主反射动作的影响该应用程序创建了一个工具，呼吸控制、上呼吸道生理学和生物医学工程领域的科学家可以通过该工具来解决模型神经治疗功效和副作用，作为普通睡眠的治疗方法。紊乱。