A Tool for Neurotheraputic Therapy for Sleep Disordered Breathing

 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（咽喉和口咽）的反复阻塞引起的，并产生白天嗜睡，增加心血管风险和死亡率。 持续气道正压通气（CPAP）治疗是有效的，并降低了行为和心血管风险，但40%的中度至重度疾病患者不能或不会耐受这种一线治疗，替代品作为长期治疗也不是很可预测。 测试OSA神经刺激方法的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。 该建议是在OSA的兔模型中开发和验证OSA的临床相关性，基于其与人类上呼吸道具有一般解剖学相似性，以及其大小，成本和气质。 我们将在睡眠期间通过部分鼻咽阻塞产生复发性阻塞，通过在舌根注射硅胶填充物产生气道拥挤，并验证人类OSA中存在的终点，包括交感神经兴奋（心率和血压增加）和睡眠不稳定。 我们将描述阻塞部位和气道的上游压力-流量特性。 该模型将通过单侧舌下神经刺激（HNS）进行测试，并与颈动脉窦神经刺激（CNS）进行比较，CNS具有通过脑干机制激活和协调双侧上气道肌肉激活的能力。 目的1是开发、验证和检查麻醉下急性上呼吸道阻塞的产生，目的2是记录睡眠期间的选定后果及其阶段，人类OSA病理学的中间终点。 此外，电极将调查皮层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和CNS减轻OSA。 袖带电极将提供选择性刺激。 刺激参数最初将是基于经典的，并且使用变化的频率和振幅朝向非传统范例移动，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 刺激方法，以改变上气道硬度和阻力，并检查药物诱导的外科麻醉期间的呼吸控制。 在目标2中，我们验证了 将该模型应用于人类OSA，监测睡眠（不）稳定性和自主神经结果。 我们将使用HNS立即逆转OSA，并研究其对治疗目的的靶向咽喉和口咽部位的影响，缓解交感神经兴奋，以及对感觉或运动皮层和自主反射作用的脱靶效应。 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的科学家可以将模型神经治疗功效和副作用作为常见睡眠障碍的治疗。

 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.