AFFERENT AND CNS MECHANISMS UNDERLYING DYSPNEA

呼吸困难（感觉呼吸困难）是主要的 心血管和呼吸系统疾病的症状。了解 呼吸困难的潜在机制将有助于诊断和症状缓解。我们 在过去的赠款期间，努力是为了了解 “空气饥饿”的感觉（不舒服的呼吸冲动）。我们认为这 感觉是患者呼吸困难的重要组成部分， 健康人在剧烈运动或长时间运动时感觉到的呼吸困难 屏住呼吸。 在过去的几年里，我们在定义传入神经方面取得了进展。 空气饥饿的来源。特别是，我们已经表明：空气饥饿产生 来自不涉及呼吸肌传入的输入; 肺和胸壁中的机械感受器提供了强有力的缓解， 空气饥饿;空气饥饿在两天内适应慢性升高 PCO 2水平。我们已经定义了正常的刺激反应 二氧化碳引起的空气饥饿的特征。这些发现直接导致 我们建议研究的问题：是否有一种不适感， 通货膨胀本身不充分？缺氧是否比高碳酸血症在 引起空气饥饿感为了检验这些问题，我们将测量感觉 在固定机械通气的等二氧化碳缺氧期间， 缺乏化疗敏感性的患者自主抑制呼吸， 在呼吸机依赖性四肢瘫痪患者中（将抑制胸乳肌， alae nasi EMG），并在脑干活动的变化引起的 机械感受器反射而不是血气变化。 一个重要的，但被广泛忽视的，考虑在理解 伴随放电的作用是呼吸驱动的来源--皮层 （意志性）vs脑干（自动性）。我们将采取一些策略， 调用这些来源中的每一个，我们将探索运动前脑电图的使用， 电位和功能磁共振成像来测量皮质 对这些呼吸动作的贡献。 扩大我们的调查范围，超越对空气饥饿本身的研究，我们 将研究空气饥饿与其他潜在来源的关系， 呼吸困难：伴随呼吸增加的工作和努力的感觉 或呼吸能力下降。尽管我们的研究表明， 努力并不是呼吸困难的主要来源，仍然有可能 努力和工作是呼吸困难的重要组成部分。的确， 患者可能被迫在空气饥饿（如果他们减少 呼吸，以避免不舒服的努力）或不舒服的努力（如果他们 用力呼吸以缓解空气饥饿）。检查的作用 中枢呼吸驱动投射（必然放电）vs 呼吸肌传入神经在产生工作、努力和疲劳中的作用 我们将在部分时间内测量正常受试者的感觉， 麻痹，呼吸肌疲劳，以及 影响呼吸肌的神经肌肉疾病。

Dyspnea (perception of difficulty in breathing) is one of the leading symptoms of cardiovascular and respiratory disease. Understanding the mechanisms underlying dyspnea will aid diagnosis and symptom relief. Our efforts over the past grant period were directed towards understanding the sensation of 'air hunger' (uncomfortable urge to breathe). We view this sensation as an important component of dyspnea in patients, and of the dyspneic sensations healthy people feel during heavy exercise or long breath hold. Over the past several years we have made progress in defining the afferent sources of air hunger. In particular we have shown that: air hunger arises from inputs that do not involve respiratory muscle afferents; mechanoreceptors in the lung and chest wall provide a powerful relief of air hunger; and air hunger adapts within two days to chronically elevated levels of PCO2. We have defined the normal stimulus-response characteristic of CO2-induced air hunger. These findings lead directly to questions we propose to study: Is there a sense of discomfort from inadequate inflation per se? Is hypoxia less potent than hypercapnia in evoking air hunger? To examine these questions we will measure sensations during isocapnic hypoxia at fixed mechanical ventilation, during voluntarily suppressed breathing in patients lacking chemosensitivity and in ventilator-dependent quadriplegics (who will suppress sternomastoid and alae nasi EMG), and during changes in brainstem activity evoked by a mechanoreceptor reflex rather than blood gas changes. An important, yet widely neglected, consideration in understanding the role of corollary discharge is the source of respiratory drive -- cortex (volitional) vs brainstem (automatic). We will use maneuvers thought to invoke each of these sources, and we will explore the use of premotor EEG potentials and functional magnetic resonance imaging to measure cortical contribution to these respiratory maneuvers. Broadening our investigations beyond the study of air hunger per se, we will examine the relationship of air hunger to other potential sources of dyspnea: the sense of work and effort that comes with increased breathing or decreased ability to breathe. Although our studies have shown that effort is not the primary source of dyspnea, there remains the likelihood that effort and work are an important component of dyspnea. Indeed, patients may be forced to choose between air hunger (if they reduce breathing to avoid uncomfortable effort) or uncomfortable effort (if they breathe hard to get relief from air hunger). To examine the roles of projection of central respiratory drives (corollary discharge) vs respiratory muscle afferents in generation of work, effort, and fatigue sensations we will measure sensations in normal subjects during partial paralysis, induced fatigue of respiratory muscles, and in patients with neuromuscular disease affecting respiratory muscles.