Stimulation Induced Modulation of Sleep

描述（由申请人提供）：外周化学感受器（主要是颈动脉和主动脉体）检测动脉血氧和二氧化碳的变化，并启动对低氧血症期间维持体内平衡很重要的反射。对二氧化碳（CO2）水平变化的反应会导致呼吸驱动发生重大变化，这对睡眠时控制通气尤为重要。颈动脉体对高原通气适应至关重要，在一定程度上有助于运动诱导的过度通气，对睡眠期间周期性呼吸的产生至关重要。增强的外周化学反射可以促进睡眠呼吸暂停的严重程度，以及睡眠呼吸暂停综合征中高血压的发展。在充血性心力衰竭，增强颈动脉化学反射有助于增加交感驱动，所以典型的疾病。此外，这种化学反射增益的增加与死亡率的增加和睡眠、运动甚至休息清醒时的周期性呼吸有关。“化学反射调节的睡眠呼吸暂停”一词涵盖了化学反射对睡眠呼吸的全部影响。对于化疗反射依赖性或调节性睡眠呼吸暂停患者，这一问题在充血性心力衰竭（CHF）人群中尤为普遍，目前尚无临床需求，需要开发新的治疗方法。目前还没有安全调节颈动脉化学反射的方法。直流电神经刺激在实验神经学中有着悠久的历史。颈部的颈动脉体可以接受直流电刺激，这既可以抑制也可以增强神经活动。外周化学反射兴奋性（阳极）调节可以为肥胖、低通气和一些中枢神经呼吸驱动不足的神经系统疾病以及慢性高山病提供新的治疗选择，而抑制性（阴极）调节可能在中枢和化学反射调节的睡眠呼吸暂停、某些形式的高血压、周期性呼吸导致的高海拔睡眠断裂、并允许安全减少病理性增强的颈动脉化学反射和心衰中的交感驱动。经颈直流电刺激也可以调节慢性阻塞性肺疾病患者的呼吸困难感觉。本研究的长期目标是开发一种安全有效地调节颈动脉化学反射的可穿戴设备。申请人已经开发了创新的新方法来分型睡眠呼吸暂停，并使用二氧化碳作为化学反射调节睡眠呼吸暂停的辅助治疗。目前的I期SBIR提案的目标是评估健康志愿者的安全性（包括对压力反射的不良影响），经宫颈直流刺激的急性生理效应，以及对化学反射调节的睡眠呼吸暂停的探索性影响。颈动脉体在健康和几种疾病状态下对调节血液中正常的氧气和二氧化碳量至关重要。目前还没有安全调节颈动脉体活动的方法。直流电刺激可以抑制或增强神经组织的活动，使用兴奋性（阳极）直流电调节可以为肥胖、低通气和一些中枢神经呼吸驱动不足的神经系统疾病以及慢性高山病提供新的治疗选择，而抑制性（阴极）调节可以在管理中枢性睡眠呼吸暂停、某些形式的高血压、高海拔睡眠不良等方面发挥核心作用。并允许在心衰时安全地减少病理性增强的颈动脉身体活动。经颈直流电刺激也可以减轻慢性肺病患者的呼吸困难感。本研究的长期目标是开发一种安全有效地调节颈动脉化学反射的可穿戴设备。当前建议的目标是评估耐受性，安全性，对呼吸的影响，并探索对中枢形式的睡眠呼吸暂停的影响。

DESCRIPTION (provided by applicant): The peripheral chemoreceptors (carotid primarily, and the aortic bodies) detect changes in arterial blood oxygen and carbon dioxide, and initiate reflexes that are important for maintaining homeostasis during hypoxemia. The response to changing carbon dioxide (CO2) levels produces major changes in respiratory drive, of special importance to the control of ventilation during sleep. The carotid bodies are critical for ventilatory acclimatization to high altitude, and contribute in part to exercise-induced hyperventilation, and are critical for the generation of periodic breathing during sleep. Augmented peripheral chemoreflexes can contribute to the severity of sleep apnea, and the development of hypertension in sleep apnea syndromes. In congestive heart failure, augmented carotid chemoreflexes contributes to the increased sympathetic drive so typical of the disease. Moreover, this increase in chemoreflex gain is associated with increased mortality and periodic breathing during sleep, during exercise or even while resting wake. The term "chemoreflex-modulated sleep apnea" captures the whole spectrum of influence of the chemoreflexes on sleep-breathing. There is an unmet clinical need for the development of new therapeutic approaches for patients with chemoreflex-dependent or modulated sleep apnea, a problem especially prevalent in the congestive heart failure (CHF) population. There is currently no method to safely modulate the carotid chemoreflexes. Direct current (DC) electrical neural stimulation has a long history in experimental neurology. The carotid bodies in the neck are accessible to DC stimulation, which can both suppress or enhance neural activity. Peripheral chemoreflex excitatory (anodal) modulation could offer new treatment options for obesity hypoventilation and several neurological illnesses with insufficient central neural respiratory drive, and chronic mountain sickness, while inhibitory (cathodal) modulation could have a central role in management of central and chemoreflex modulated sleep apnea, certain forms of hypertension, high-altitude sleep fragmentation from periodic breathing, and allow safe reductions in the pathologically enhanced carotid chemoreflexes and sympathetic drive in heart failure. Transcervical DC stimulation may also be able to modulate the sensation of dyspnea in chronic obstructive lung disease. The long-term goal of this research is to develop a wearable device to safely and effectively modulate the carotid chemoreflexes. The applicants have already developed innovative new methods for phenotyping sleep apnea, and to use CO2 as adjunctive therapy for chemoreflex-modulated sleep apnea. The goal of the current Phase I SBIR proposal is to assess the safety (including adverse effects on the baroreflexes), acute physiological effects of cathodal and anodal transcervical DC stimulation in healthy volunteers, and exploratory effects on chemoreflex-modulated sleep apnea. PUBLIC HEALTH RELEVANCE: Narrative The carotid body in the neck is critical for regulating the normal amounts of oxygen and carbon dioxide in the blood in health and several disease states. There is currently no method to safely modulate carotid body activity. Direct Current (DC) stimulation can suppress or enhance activity of nervous tissue and using excitatory (anodal) DC current modulation could offer new treatment options for obesity hypoventilation and several neurological illnesses with insufficient central neural respiratory drive, and chronic mountain sickness, while inhibitory (cathodal) modulation could have a central role in management of central sleep apnea, certain forms of hypertension, poor sleep at high altitude, and allow safe reductions in the pathologically enhanced carotid body activity in heart failure. Transcervical DC stimulation may also be able to reduce the sensation of breathlessness in patients with chronic lung disease. The long-term goal of this research is to develop a wearable device to safely and effectively modulate the carotid chemoreflexes. The goal of the current proposal is to assess tolerance, safety, effects on breathing, and explore effects on central forms of sleep apnea.