Intermittent Hypoxia Induces Greater Functional Breathing Motor Recovery as a Fixed Rather Than Varied Duration Treatment after Cervical Spinal Cord Injury in Rats

Intermittent hypoxia treatment (IH) has been shown to improve respiratory function in both pre-clinical animal models and human subjects following spinal cord injury (SCI), historically consisting of alternating and equal intervals of hypoxic and normoxic exposure. We describe such a procedure as fixed duration IH (FD-IH) and modulation of its severity, intermittency, and post-injury time-point of application differentially affects expression of breathing motor plasticity. As such, the established IH protocol exhibits similarity to instrumental conditioning and can be described as behavioral training through reinforcement. Findings from the field of operant conditioning, a form of more advanced learning, inspire the consideration that FD-IH protocols may be improved through exchanging fixed for varied durations of hypoxia between reinforcement. Thus, we hypothesized that varied duration intermittent hypoxia treatment (VD-IH) would induce greater breathing motor recovery ipsilateral to injury than FD-IH after cervical SCI in rats. To test this hypothesis, we treated animals with VD-IH or FD-IH for 5 days at 1 week and at 8 weeks following cervical SCI, then assessed breathing motor output by diaphragm electromyography (EMG) recording, and compared between groups. At 1 week post-injury, VD-IH-exposed animals trended slightly toward exhibiting greater levels of respiratory recovery in the hemidiaphragm ipsilateral to lesion than did FD-IH-Treated animals, but at 8 weeks FD-IH produced significantly greater respiratory motor output than did VD-IH. Thus, these results identify a novel sensitivity of respiratory motor function to variations in the IH protocol that may lead to development of more effective treatments following SCI.