DESCRIPTION (provided by applicant): Pathogenesis of Sleep Disordered Breathing in Spinal Cord Injury Patients PI: AG Sankri-Tarbichi, MD, PhD ABSTRACT A. Objective: Spinal cord injury (SCI) is associated with significant increase in the sleep- disordered breathing (SDB) prevalence. More than 60% of cervical SCI patients suffer from SDB at six months post-injury. However the underlying mechanisms responsible for the development of SDB in SCI patients are not known. Recent data showed that cervical SCI predispose to alterations in ventilatory motor output suggesting important role for breathing instability in the development of SDB in SCI patients. The central hypothesis is that the high prevalence of sleep apnea in cervical SCI patients is due to central breathing instability that is serotonin dependent and a target for new treatments. B. Research Plan: To this end the research proposal is aimed as the followings: Specific Aim (1): To determine the mechanism of SDB in cervical vs. thoracic SCI. Hypothesis (1a): Cervical SCI patients are more susceptible to hypocapnic central apnea than thoracic SCI patients. Hypothesis (1b): Increased susceptibility to hypocapnic central apnea in cervical SCI is due to increased peripheral chemoreflex sensitivity. Specific Aim (2): To test the hypothesis that SCI will have enhanced long-term facilitation (LTF) compared to able-bodied individuals. Hypothesis: LTF is higher in SCI patients compared to matched able individuals. We will measure the LTF in response to intermittent hypoxia during sleep. Specific Aim (3): To determine the stimulatory effect of systemic serotonin receptors agonists on ventilatory motor activity in SCI patients during sleep. Hypothesis (3a): Buspirone (5-HT1A agonist) widens the CO2 reserve in SCI patients. Hypothesis (3b): Trazodone (5-HT2C agonist) widens the CO2 reserve in SCI patients. Specific Aim (4): To determine in an animal model the extent and level of SCI responsible for breathing instability. Hypothesis (4a): central breathing instability post SCI is due to cervical injury in a rat model. Hypothesis (4b): bilateral carotid body excision aftr cervical SCI improves central breathing instability during sleep in rats. C. Methods: We will study subjects with SCI at T6 or above who are not on artificial ventilation. To characterize the sleep and breathing state of each subject, polysomnography and upper airway collapsibility will be measured at baseline. Then the following experiments will be conducted: First, the susceptibility to develop central apnea will be determined by inducing hypocapnic central apnea to measure the apneic threshold. Second, an episodic hypoxia protocol vs. normoxia (sham) will be used to determine the presence of ventilatory plasticity (long-term facilitation, a serotoin dependent process). Third, to determine the effect of serotonin A1 receptor agonists on the susceptibility to develop central apnea in SCI, randomized placebo controlled cross-over study will be conducted using two FDA approved drugs (1) Buspiron vs. placebo for 2 weeks and (2) Trazodone vs. placebo for 2 weeks, followed by 2 weeks wash out period and crossed-over. Fourth, to assess the effect of cervical SCI on breathing and sleep, SCI will be induced in adults' rats by cervical (C2) hemisection and compared to sham procedure. Then bilateral carotids excisions will be performed to assess the relative contribution of peripheral chemosensitivity on the development of unstable breathing. D. Clinical Relevance to the Veterans: It is estimated that 1,275,000 people in the United States alone are living with SCI with an estimated at least 100,000 veterans with SCI making VA the largest integrated health care system in the world for SCI. SDB is strongly linked to SCI and affects the quality of life an may increase incidence of respiratory and cardiovascular disorders. The identification of the mechanism of SDB in SCI patients will establish a strong scientific frame work for further investigations using novel therapies for SDB in SCI patients in particular and potentially in the general population.

PUBLIC HEALTH RELEVANCE: It is estimated that spinal cord injury affects approximately 12,000 new individuals every year in the United States, with the majority are cervical and/or upper thoracic injuries. The majorities of these patients are young and most likely will suffer from significant respiratory and non- respiratory impairments leading to serious complications. Recent reports found that more than half of the cervical SCI will develop sleep apnea in their first year post injury, which is strongl linked to adverse consequences such as heart disease and stroke. This proposal addresses the mechanisms of sleep apnea in spinal cord injury patients, a large disabled group in our society and among veterans. It investigates systematically why spinal cord injury is associated with a higher propensity to develop sleep apnea. The results of this investigation may provide new treatments of sleep apnea in patients with SCI.