This proposal aims to determine the mechanisms of sleep-disordered breathing (SDB) in patients with chronic cervical spine injury, a devastating condition with very high frequency of sleep-disordered breathing. Our preliminary data demonstrated that two thirds of patients with cervical SCI demonstrated a central sleep- disordered breathing, manifesting as central sleep apnea (CSA) or periodic breathing pattern during sleep with high propensity to develop central sleep apnea (CSA), despite normal breathing during wakefulness. Understanding the fundamental mechanisms of central sleep apnea (CSA) is critically important to understanding upper airway obstruction in susceptible individuals. Our central hypothesis is that cervical SCI promotes central SDB via sleep-related hypoventilation, and hence increased plant gain, resulting in recurrent apnea/hypopnea, chronic intermittent hypoxia, and subsequent sensory long-term facilitation (LTF), manifesting by increased peripheral chemoresponsiveness and enhanced LTF following acute intermittent hypoxia. We will demonstrate that dampening peripheral chemoresponsiveness with hyperoxia, and plant gain with acetazolamide, will alleviate central apnea in these patients and may pave the way for effective treatment. Therefore, we will test the following Specific Aims: First, to determine the effect of cervical SCI on peripheral chemoreflex sensitivity. We propose to measure central and peripheral chemoreflex sensitivity tests during NREM sleep in cervical and thoracic SCI patients. We will also test the effect of dampening peripheral chemoreceptor activity in patients with cervical SCI and central apnea with hyperoxia on CSA propensity. Second, to determine the effect of acute episodic hypoxia (EH) on chemoreflex sensitivity and ventilatory long- term facilitation in patients with cervical SCI. We will test the development of ventilatory LTF following cute episodic hypoxia.
Specific Aim 3 is to determine the effect of decreasing plant gain with acetazolamide on central SDB in SCI patients with central apnea or narrow CO2 reserve. We propose to compare the effect of acetazolamide vs. placebo on central apnea propensity. This work is very significant, addressing critical need for patients who suffer from disparity in access to care. This work is also innovative, identifying a new mechanism of breathing instability in this vulnerable population. innovative;we anticipate that it will yield significant new knowledge that improves the health and quality of life of these patients.

Public Health Relevance

Patients with spinal cord injury suffer from a multitude of sleep disorders, including sleep- disordered breathing. Unfortunately, the underlying mechanisms of sleep-disordered breathing in patients with chronic spinal cord injury, especially cervical spine injury have not received sufficient attention and investigation. Our proposed studies will be the first comprehensive, mechanistic investigation of sleep and breathing in a large number of patients, spanning two different health systems. Our study will focus on understanding the underlying mechanisms of sleep-disordered breathing, especially central apnea. Our study will have significant impact on the identification, diagnosis and management of sleep disorders in this population. It is likely to inform future therapeutic interventions that will improve the health an quality of life of spinal cord-injured veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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John D Dingell VA Medical Center
United States
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