A Tool for Neurotheraputic Therapy for Sleep Disordered Breathing

 描述(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，会导致白天嗜睡，并增加心血管风险和死亡率。持续气道正压(CPAP)治疗是有效的，并降低了行为和心血管风险，但40%的中到重度疾病患者不能或不会耐受这种一线治疗，替代疗法作为长期治疗不是非常可预测的。测试阻塞性睡眠呼吸暂停综合征的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。我们的建议是在兔OSA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的总体解剖学相似，以及它的大小、成本和气质。我们将在睡眠期间通过部分鼻咽阻塞、舌根注射硅胶填充物产生的呼吸道拥堵产生反复阻塞，并验证人类OSA中存在的终点，包括交感兴奋(心率和血压增加)和睡眠不稳定。我们将描述阻塞的部位(S)和呼吸道的上游压力-流量行为。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，后者具有通过脑干机制激活和协调双侧上呼吸道肌肉激活的能力。目的1是研究、验证和检查麻醉下上呼吸道阻塞的产生，目的2是记录睡眠及其各阶段的特定后果，即人类阻塞性睡眠呼吸暂停的病理中间终点。此外，电极将检测皮质状态相关诱发电位和呼吸肌激活，血压和心率变异性将检测自主神经传出效应。我们将缓解HNS和CNS的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，并使用不同的频率和幅度走向非传统范例，以激活适当的传出纤维与传入纤维。目标1中的交付成果是演示可行性和功能，使用 在药物诱导的手术麻醉中改变上呼吸道僵硬和阻力以及检查呼吸控制的刺激方法。在目标2中，我们验证了算法的稳定性和保真度。 该模型用于人类OSA，监测睡眠(In)稳定性和自主神经结果。我们将使用HNS立即逆转OSA，并研究其对靶区腭咽和口咽部位的影响，以达到治疗目的，减轻交感兴奋，以及靶外对感觉或运动皮质和自主神经反射行为的影响。这项应用创造了一种工具，呼吸控制、上呼吸道生理学和生物医学工程方面的科学家可以在其中解决作为治疗常见睡眠障碍的模型神经治疗效果和副作用。

 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.