Closed-loop Epidural Stimulation Elicits Respiratory Plasticity in a Rat Model of Acute Spinal Cord Injury

Abstract

Epidural stimulation restores motor control in animal models and humans after spinal cord injury (SCI) with the most notable example being locomotion; however, it has not yet been clinically translated to breathing. Further, neuroplasticity elicited by epidural stimulation is largely unexplored. We showed in a rat C2 hemisection (C2HS) model of SCI that one bout of closed-loop epidural stimulation (CLES) restores some ipsilesional (ipsi) diaphragm EMG acutely post paralysis, and that in some rats, activity briefly lasts post CLES (<15 seconds) (Mickle et al., 2023). Here we explore if this brief plasticity increases in magnitude and duration via multiple bouts of CLES, respiratory challenge, or altered sensory input. Adult Sprague Dawley (n=5) rats were urethane anesthetized, implanted with diaphragm EMG recording electrodes and dorsal C4 stimulating electrodes and given a C2HS plus >15 minute recovery period to stabilize and confirm hemidiaphragm paralysis. Rats were delivered two <5 minute periods of CLES during which current amplitude increased by 25 uA steps every 30 breaths until breathing instability. Afferent input was removed via bilateral cervical dorsal rhizotomy (CDR) prior to CLES (n = 2) or between the first two bouts (n = 3). During the first two bouts of CLES, rats were administered 50% O2 via a cycle triggered ventilator which delivers breaths in-phase with contralesional (contra) EMG. For the 3rd bout, rats were challenged with room air and removal of ventilatory support. CLES increased contra EMG output in 5/5 and restored ipsi EMG in 4/5 rats during all bouts. There were no differences in PCO2 prior to each bout (mmHg +/- SEM: 44 +/- 6, 43 +/- 4, 41 +/- 4) though PO2 was much lower under room air (mmHg +/- SEM 172 +/- 24. 165 +/- 31, 73 +/- 5). Contra peak amplitude was elevated in the 30 seconds post-CLES vs baseline for the 1st bout of CLES (77 vs 93 mV, SE of diff. 3, p = 0.009) with no difference in rats with or without CDR (20 vs 23% increase from baseline, SE of diff. 10), and no difference in the 1st and 2nd bouts (93 vs 90 mV, SE of diff. 5). While contra peak EMG did not change between bouts, there was a trend towards an increase in length of residual ipsi activity post bout 2 vs 1 (223 vs 54 sec, SE of diff. 170). Removing the ventilator increased contra peak (77 vs 132 mV, SE of diff. 16, p = 0.025) and unveiled ipsi activity in 3/5 rats. CLES during challenge trended towards increased ipsi response during CLES (15 vs 61 V cumulative sum, SE of diff. 8) and length of residual ispi activity (223 vs 1819 sec, SE of diff. 1031). In 3/5 rats, the residual ipsi activity post challenge CLES bout continued until the end of the experimental period, in one case lasting >20 min. Finally, across all CLES bouts, the magnitude of ipsi activity in the 30 seconds post CLES was correlated with the magnitude of response during CLES (r2 0.34, p = 0.05) indicating conditions that increase response may be best for neuroplasticity. Work is ongoing to clarify the roles of multiple bouts, cervical afferents, challenge, and time post injury in eliciting the enduring activity seen in some rats, but this work represents the first evidence that CLES can elicit respiratory neuroplasticity on a timescale and magnitude which may be relevant for functional benefit. T32HL134621 (AM), R01HL153102 (ED), SPARC OT2OD023854 (ED), Craig H. Neilsen Pilot Grant (ED). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.