Cervical Spinal Stimulation and Respiratory Recovery after Upper Cervical Spinal Cord Injury

Abstract

Over half of all spinal cord injuries (SCI) occur at the cervical level leading to disruption of bulbospinal pathways to respiratory motor neurons, respiratory muscle paralysis, and diminished breathing capacity. Of the 6,000 new cervical spinal injuries per year, ~20% will require mechanical ventilatory support. Even when mechanical ventilation is not necessary, breathing impairment greatly increases susceptibility to life‐threatening lung infections. In fact, the leading cause of morbidity and mortality in cervical SCI is respiratory impairment. In this study, rats were implanted with bilateral cervical (C4) stimulating electrodes and bilateral diaphragm EMG recording electrodes. Our previous data have shown that cervical spinal stimulation elicits evoked potentials and modulates diaphragm EMG (Dale et al., 2015). In this study, after obtaining baseline data, rats were given a C2 hemisection (C2HS). After recovery, rats were placed in either control (evoked potentials only; n=6) or Quipazine + stimulation (n=8) groups and were tested at 1, 2, and 4 weeks post‐C2HS. After eliciting spinal evoked potentials (SEP) of increasing intensity, rats received Quipazine (0.3mg/kg; IP), a broad‐spectrum serotonergic agonist, and diaphragm EMG was recorded for 20 min. Next, each rat received 3 bouts (interspersed with 5 min no stim) of cervical stimulation (bipolar) at increasing frequencies but at sub‐motor threshold intensity (5 min at 40Hz, 5min at 80Hz, and 5 min at 100Hz). Another set of SEPs was elicited upon stimulation completion. Our goal is to restore respiratory function in a rat model of cervical spinal injury by utilizing cervical spinal epidural electrical stimulation in combination with serotonergic agonists (e.g. quipazine). By inducing respiratory plasticity after synergistic modulation of the phrenic motor network (e.g. cervical epidural stimulation plus quipazine), we hypothesize that enhancing the contributions from spared motor neurons could be an avenue for preserving ventilatory capacity. This project may lead to novel therapies to extend and improve life for patients with cervical spinal cord injury by preserving breathing.Support or Funding InformationChristopher and Dana Reeve Foundation and NIH U01EB007615