This proposal aims to investigate the mechanisms of sleep-disordered breathing (SDB) and to explore therapeutic approaches for SDB in patients with chronic cervical spine (C-SCI) injury. We have discovered that patients with C-SCI demonstrate a central sleep-disordered breathing (SDB), manifesting as central sleep apnea (CSA) or periodic breathing pattern, associated with narrow CO2 reserve (≤1mmHg and modestly elevated upper airway Pcrit (≤ 2cmH2O, independent of respiratory mechanics or daytime arterial blood gases. Our preliminary data in patients with C-SCI demonstrated enhanced ventilatory LTF; thus, promoting breathing stability. Therefore, we will examine v-LTF during sleep in C-SCI patients before and after treatment of SDB to determine if increased v-LTF is a reversible phenomenon, due to pre-conditioning with chronic intermittent hypoxia OR an immutable phenomenon, due to the injury per se. Our preliminary data also reveal increased peripheral chemoreflex activity in patients with C-SCI. Therefore, we will determine the effect of dampening peripheral chemoresponsiveness with supplemental oxygen and the effect of alleviating CIH with O2 on breathing instability during sleep. Finally, our preliminary data showed decreased arousal threshold in C-SCI patients. Therefore , we will test the effect of decreasing the frequency of arousals with Zolpidem on central apnea in these patients. Our proposed protocols will address the following Specific Aims. Specific Aim 1 is to test the hypothesis that treatment of SDB in patients with C-SCI will attenuate vLTF and peripheral chemoreceptor activity. This aim will be accomplished by measuring the effect of acute episodic hypoxia on post-hypoxic ventilation and upper airway mechanics before and after treatment of SDB in patients with C-SCI and SDB. Specific Aim 2 is to test the hypothesis that dampening chemoreceptor sensitivity in patients with C-SCI and central SDB with supplemental O2 will reduce central respiratory events and decrease respiratory variability during sleep. This aim will be accomplished by providing supplemental O2 to patients with C-SCI and central SDB. Specific Aim 3 is to test the hypothesis that administration of zolpidem, in patients with cervical spinal cord injury and central SDB will decrease respiratory-related arousals and the central apneas index compared to placebo. To accomplish this aim, Zolpidem, a short-acting hypnotic will be administered to C-SCI patients with central SDB. This aim may also indicate an effective therapeutic intervention that will improve the care of patients suffering with C-SCI and central SBD. The proposed experiments will identify potentially generalizable pathophysiologic pathways for the treatment of central SDB in patients with neuromuscular disease and across the continuum of SDB. We anticipate that it will yield significant new knowledge that improves the health and quality of life of these patients.