Modulation of respiratory output by cervical epidural stimulation in the anesthetized mouse

Abstract

Respiration is produced and controlled by well-characterized brain stem nuclei, but the contributions of spinal circuits to respiratory control and modulation remain under investigation. Many respiratory studies are conducted in in vitro preparations (e.g., brain stem slice) obtained from neonatal rodents. While informative, these studies do not fully recapitulate the complex afferent and efferent neural circuits that are likely to be involved in eupnea (i.e., quiet breathing). To begin to investigate spinal contributions to respiration, we electrically stimulated the cervical spinal cord during unassisted respiration in anesthetized, intact mice. Specifically, we used epidermal electrical stimulation at 20 Hz and varied current intensity to map changes in respiration. Stimulating at 1.5 mA at cervical level 3 (C3) consistently caused a significant increase in respiratory frequency compared with prestimulation baseline and when compared with sham stimulations. The increase in respiratory frequency persisted for several minutes after epidural stimulation ceased. There was no change in tidal volume, and the estimated minute ventilation was increased as a consequence of the increase in respiratory frequency. Sigh frequency also increased during epidural stimulation at C3. Neither the increase in respiratory frequency nor the increase in sighing were observed after stimulation at other dorsal cervical levels. These findings suggest that the spinal circuits involved in the modulation of eupnea and sighing may be preferentially activated by specific endogenous inputs. Moreover, the cervical spinal cord may play a role in respiratory modulation that affects both eupneic respiration and sigh production in intact, adult mice.

High-density spinal cord stimulation selectively activates lower urinary tract afferents

“…We have further demonstrated in this study that high-density spinal cord arrays are able to produce completely different recruitment patterns within the same spinal level simply by changing the active electrode within the array. This result suggests that high-density electrode arrays could be particularly beneficial to optimize SCS for improving bladder function-or any other function of interest at other spinal levels [40][41][42][43][44][45] -and that existing commercial stimulation leads may be inadequate.…”

Epidural electrical stimulation of the cervical spinal cord opposes opioid‐induced respiratory depression

“…The surgically accessible locations targeted for epidural stimulation comprised eight dorsal locations of the cervical spinal cord corresponding to each spinal level in addition to the site between C3 and C4 (C3/4). We identified C3/4 as a potential target for modulating respiration in our previous study of mice (Huang et al, 2016) (Fig. 1A).…”

A Latent Propriospinal Network Can Restore Diaphragm Function after High Cervical Spinal Cord Injury

“…Finally, future experiments aiming to identify spinal PMN excitatory burst populations in more anatomical detail could lead to a diaphragm “pacing” device (Huang et al, 2016; Kowalski et al, 2013). We demonstrate pacing of spinal cord derived PMN bursting at a rate similar to fictive inspiration, and given considerable technical advancements, this proof-of-concept could be therapeutically relevant in vivo after cervical spinal cord injury.…”

“…Nonetheless, there is also data indicating that in the absence of supraspinal (rVRG) input, PMN activity can be initiated centrally by various pharmacological manipulations (Coglianese et al, 1977; Ghali and Marchenko, 2016; Reinoso et al, 1996; Viala et al, 1979; Zimmer and Goshgarian, 2007), or by electrical stimulation (Huang et al, 2016; Kowalski et al, 2013). Although it has been suggested that this activity might be generated by a spinal analogue of the preBötC (Ghali and Marchenko, 2016), the origin of this activity has always been elusive.…”