James C. Leiter - US grants

Occlusion of the upper airway during sleep is the essential event of obstructive sleep apnea (OSA). Diminished activity of upper airway muscles during sleep as well as relatively smaller and more compliant airways during wakefulness have been found in patients with OSA. Of the many muscles of the upper airway, the tongue (genioglossus) plays an especially important role in the pathogenesis of OSA because it forms the anterior border of the narrowest part of the upper airway, the oropharynx. Hence, activation of the genioglossus that is insufficient to resist the negative pharyngeal pressure generated by inspiratory muscles may allow the tongue to lapse backward and occlude the airway. To date, electrical activity of the genioglossus and upper airway mechanics have been studied in separate experiments, but the relationships between genioglossal activity and a physiologically relevant mechanical effect of genioglossal activity, pharyngeal resistance, has not been studied. The study of this relationship in normal subjects and patients with OSA is the aim of the first studies I have proposed. Subsequent studies are designed to investigate in awake humans the role of reflex mechanisms controlling upper airway muscle activity that have been described only in anesthetized animals. The relevance of these reflexes in normal upper airway control is tested in the next study, which looks at the effect of changing nasal resistance on pharyngeal resistance and genioglossal electromyographic (EMG) activity: I suspect that changing nasal resistance will stimulate reflex mechanisms enhancing upper airway muscle activity. Using quantitative data on the neuromechanical coupling between genioglossal EMG activity and upper airway mechanics derived from the experiments above, I plan to develop a computer model of the upper airway to test the effect of alterations in airway function that are allegedly important in the pathogenesis of OSA. Finally, if diminished genioglossal activity is important in the pathogenesis of OSA, then external stimulation of the tongue might prevent airway occlusion. We have already developed a noninvasive surface EMG electrode for the tongue that I hope to develop as a genioglossal stimulating electrode for therapeutic use.

DESCRIPTION (provided by applicant): Evidence of CO2 chemosensitivity has been found in at least five brainstem sites: the rostroventral medulla (RVM, which contains the retrotrapezoid nucleus), the caudal raphe, the locus coeruleus, the nucleus tractus solitarius (NTS) and the preBotzinger complex of the nucleus ambiguus. When studies have been done in anesthetized or decerebrate animals, unilateral lesions of any one of these sites profoundly reduced ventilatory output, but lesions in awake animals have remarkably modest, even transient effects. The presence of widespread sites of CO2 chemosensitivity in bilaterally symmetrical nuclei (except the raphe) immediately raises two questions: How is chemosensory activity coordinated among these sites, and what is the role of this redundancy of CO2 chemosensory function? Studies in anesthetized animals make it look as if every site is essential (unilateral inhibition of even one site dramatically reduces ventilatory output), but studies of intact awake or sleeping animals suggest that the predominant site(s) is dynamic and depends on arousal state - suggesting a relationship among chemosensory sites that is more democratic and robust. Our own studies point to an important, possibly dominant role for the NTS in CO2 chemosensitivity in intact animals, and an important role for gap junctions in the NTS in central chemosensory function in younger animals. Using the isolated perfused juvenile rat brainstem and intact, chronically instrumented rats, we will examine coordination of CO2 chemosensitivity within the NTS and coordination between the NTS and disparate CO2 chemosensory nuclei in the brainstem. In Specific Aim I, we will test the hypothesis that gap junctions provide an important amplification of signal intensity within the NTS. In Specific Aim II, we will examine the effect of acute unilateral inhibition within the locus coeruleus and rostroventral medulla on chemosensitivity within the NTS to test the hypothesis that coordination among chemosensitive sites is hierarchical. We believe that the dominant control site lies within the NTS. In Specific Aim III, we will examine the effect of chronic unilateral lesions within the NTS on CO2 chemosensitivity to test the hypothesis that relationships between chemoreceptor sites are plastic over time.