Hypoxia Pathways for Early Recovery After Spinal Cord Injury

Spinal cord injury (SCI) disrupts neural pathways to respiratory motor neurons, diminishing breathing capacity and airway defense (e.g., cough). Indeed, respiratory impairment is a leading cause of infection, re-hospitalization and death after SCI. There is a critical need for new strategies to restore breathing ability and airway defense in people with SCI. Acute intermittent hypoxia (AIH) - repetitive exposure to brief episodes of low inspired oxygen - is a promising strategy to restore breathing capacity by promoting spinal neuroplasticity. Exciting outcomes in \>12 SCI trials completed to date demonstrate that AIH improves human respiratory and limb function. Unfortunately, \~40% of individuals exhibit minimal response to AIH, making it essential to 1) optimize AIH protocols to maximize functional benefits; and 2) identify genetic biomarkers distinguishing those most/least likely to benefit from AIH-based treatments. The purpose of the pilot study, to be conducted in a small sample of participants with sub-acute SCI (2 weeks to 6 months post injury), is to preliminarily compare the effects of two intermittent hypoxia protocols. Since AIH-induced plasticity may be induced via serotonin or adenosine-driven mechanisms and these pathways compete and inhibit each other, each protocol favors a distinct mechanistic pathway. Our long-term objective is to test the hypothesis that a longer duration (i.e., augmented) hypoxia protocol, favoring adenosine mechanisms, enhances respiratory motor plasticity more than an AIH protocol targeting serotonin mechanisms (low O2 + CO2) in people with sub-acute SCI. Since an individual's genetics can influence the response to rehabilitation, we are also investigating how certain genes are related to breathing changes after these treatments. Data acquired through this pilot study will be used to inform a larger, more definitive clinical trial and will contribute to estimations of the magnitude and direction of effects.