Electrical epidural stimulation of the cervical spinal cord: implications for spinal respiratory neuroplasticity after spinal cord injury

Abstract

Traumatic cervical spinal cord injury (cSCI) can lead to damage of bulbospinal pathways to the respiratory motor nuclei and consequent life-threatening respiratory insufficiency due to respiratory muscle paralysis/paresis. Reports of electrical epidural stimulation (EES) of the lumbosacral spinal cord to enable locomotor function after SCI are encouraging, with some evidence of facilitating neural plasticity. Here, we detail the development and success of EES in recovering locomotor function with consideration of stimulation parameters and safety measures to develop effective EES protocols. EES is just beginning to be applied in other motor, sensory, and autonomic systems; however, there has only been moderate success in preclinical studies aimed at improving breathing function after cSCI. Thus, we explore rationale for applying EES to the cervical spinal cord, targeting the phrenic motor nucleus for the restoration of breathing. We also suggest cellular/molecular mechanisms by which EES may induce respiratory plasticity including a brief examination of sex-related differences in these mechanisms. Finally, we suggest more attention be paid to the effects of specific electrical parameters that have been used in the development of EES protocols and how that can impact the safety and efficacy for those receiving this therapy. Ultimately, we aim to inform readers about the potential benefits of EES in the phrenic motor system and encourage future studies in this area.

Closed-Loop, Cervical, Epidural Stimulation Elicits Respiratory Neuroplasticity after Spinal Cord Injury in Freely Behaving Rats

“…This proof-of-principle study marks the first exploration of epidural stimulation to restore respiratory function after an upper cSCI in freely behaving rats. Because these were the first studies of their kind, our rationale to implant the two stimulating electrodes bilaterally over the C4 spinal segment was based largely on anatomy and published reports of phrenic motor circuitry and plasticity (for review, see Malone et al, 2021 ). Modeling ( Struijk et al, 1993 ; Murg et al, 2000 ; Capogrosso et al, 2013 ; Minassian et al, 2016 ) and cadaver ( Swiontek et al, 1976 ) studies suggest that current is unlikely to spread throughout many segments of the cord.…”

“…The rhythm generators for breathing, however, lie within the ventral respiratory column of the brainstem ( Smith et al, 1991 ), several segments rostral to the motor pools that they innervate and thereby are preserved after injury. Endogenous signals from intact rhythm generators provide the unique opportunity to harness activity-dependent mechanisms of neuroplasticity by stimulating respiratory motor pools in phase with a recorded rhythm (for review, see Malone et al, 2021 ). We predict using the breathing signal from intact components to time epidural stimulation in a closed-loop manner could be advantageous over open-loop paradigms (i.e., unpaired from respiratory rhythm), since (1) spinal respiratory circuits may be stimulated in a fatigue-resistant fashion; (2) stimulation will be endogenously adjusted to native respiratory load; and (3) the respiratory circuitry is highly plastic and could be “trained” via closed-loop reinforcement (e.g., Hebbian, activity-dependent plasticity).…”

Tissue Engineering in Neuroscience: Applications and Perspectives

“…In the last 2 decades, electrospinning has been available in the production of nanofiber-based scaffolds for SCI treatment [ 80 , 81 ]. Although numerous fabrication techniques, such as self-assembly, super drawing, and phase separation, have been reported for nanofiber fabrication, electrospinning is still assumed to be one of the most versatile techniques for producing nanofibers with diameters ranging from a few to several hundred nanometers due to its simple processing, broad applicability, and enormous industrialization potential [ 82 – 85 ].…”

“…Despite the fact that electrospun nanofibrous scaffolds alone can provide chemical cues and maintain structural stability due to their appropriate mechanical properties, their efficiency in promoting SCI regeneration and functional recovery is unsatisfactory. To further improve the SCI repair outcomes, other biochemical or biophysical factors, including bioactive component delivery, cell therapy, and external electrical or magnetic stimulation, have been introduced to generate a synergistic effect with the physical cues provided by electrospun scaffolds [ 80 , 81 , 90 , 91 ]. For instance, Zhang et al [ 92 ] created a 3D scaffold with an aligned electrospun fiber bundle as the core part to physically direct the alignment of regenerating axons and collagen matrix as the sheath part to sustainably release glial cell-derived NF (GDNF) and several microRNAs (miRs), such as miR-132, miR-222, and miR-431 for biologically enhancing and regulating axon regeneration (Fig.…”

Electrical stimulation for the treatment of spinal cord injuries: A review of the cellular and molecular mechanisms that drive functional improvements

“…Epidural electrical stimulation involves the application of electrical stimulation over the spinal cord via an implanted paddle electrode array. Stimulation is generally applied over the lumbosacral spinal cord to promote locomotion; however, cervical EES may also be used depending on the desired outcome (Malone et al, 2021). To deliver EES, a paddle electrode array is surgically implanted over the spinal cord via a laminectomy, with electrode positioning confirmed via x-ray, fluoroscopy and electrophysiology (Calvert et al, 2019a).…”