Reversing Breathing Paralysis through Optimization of Intermittent Hypoxia Treatment after Cervical Spinal Cord Injury

Abstract

Spinal cord injury (SCI) most commonly occurs at the cervical level and can interrupt descending neural pathways, causing paralysis of the diaphragm, as well as profound breathing motor difficulties which threaten survival and greatly decrease quality of life. Intermittent hypoxia (IH) treatment is often utilized in preclinical models to attenuate breathing motor deficits resulting from cervical SCI by inducing a prolonged increase in respiratory motor output known as long term facilitation (LTF), a form of breathing motor plasticity. IH typically consists of the repeated, alternating exposure of a subject to consistent and equal 5‐minute periods of hypoxia and normoxia and thus can be fittingly termed fixed interval intermittent hypoxia (FIH). FIH exhibits similarity to the psychological construct of operant conditioning in which the increased incidence and persistence of a desired, spontaneous behavior is trained through reinforcement. As such, each interval of hypoxia can be construed as the period during which the subject responds with heightened respiratory drive and is subsequently reinforced by an interval of normoxia. Provided that IH is a form of operant conditioning, it can be optimized through application of seminal psychological findings which established variable interval schedules of reinforcement as more effective than fixed interval schedules for learning. Therefore, using the duration of the hypoxic interval as our independent variable, we hypothesize that varied interval intermittent hypoxia (VIH) treatment will induce a greater, more prolonged increase in respiratory motor output than FIH after injury. We utilized the C2 hemisection injury model in rats and treated with VIH or FIH for 5 days at 1‐week post‐injury. Following treatment, we conducted diaphragm electromyograph recordings to assess breathing motor recovery within each animal by comparing baseline activity to maximal output induced by nasal occlusion, occurring immediately after cessation of IH treatment. Preliminary results show that 1‐week post‐injury VIH treated animals exhibited recovery on average equaling 33.87±7.89% as compared to the 19.28±6.02% recovery in FIH treated animals (differences nonsignificant by unpaired t‐test, p>0.05 with uncertainty shown as standard error of the mean). These data suggest that VIH may induce more increased and prolonged recovery than FIH in post‐injury models. Ongoing work includes evaluation of VIH treatment in animals at 8 weeks after injury and will expand outcome measurement timepoints to include 1 week after cessation of treatment to interrogate the persistence of induced recovery. Additionally, further exploration will focus on the molecular markers present within the phrenic motor nucleus of the cervical spinal cord and on the development of IH paradigms based on breathing frequency.Support or Funding InformationNINDS R01NS101105 (Warren J. Alilain)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.