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Review
. 2023 Feb 3:17:1095259.
doi: 10.3389/fncel.2023.1095259. eCollection 2023.

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

Ryan M Dorrian  1 , Carolyn F Berryman  2 , Antonio Lauto  3 , Anna V Leonard  1
Affiliations
Review

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

Ryan M Dorrian et al. Front Cell Neurosci. .

Abstract

Spinal cord injury (SCI) is a devastating condition that causes severe loss of motor, sensory and autonomic functions. Additionally, many individuals experience chronic neuropathic pain that is often refractory to interventions. While treatment options to improve outcomes for individuals with SCI remain limited, significant research efforts in the field of electrical stimulation have made promising advancements. Epidural electrical stimulation, peripheral nerve stimulation, and functional electrical stimulation have shown promising improvements for individuals with SCI, ranging from complete weight-bearing locomotion to the recovery of sexual function. Despite this, there is a paucity of mechanistic understanding, limiting our ability to optimize stimulation devices and parameters, or utilize combinatorial treatments to maximize efficacy. This review provides a background into SCI pathophysiology and electrical stimulation methods, before exploring cellular and molecular mechanisms suggested in the literature. We highlight several key mechanisms that contribute to functional improvements from electrical stimulation, identify gaps in current knowledge and highlight potential research avenues for future studies.

Keywords: epidural electrical stimulation (EES); functional electrical simulation (FES); neuroinflammation; neuroplasticity; peripheral nerve stimulation (PNS); spinal cord injury.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of secondary injury events following traumatic SCI, highlighting key pathophysiological events that occur throughout the acute, subacute, and chronic stages of injury.
FIGURE 2
FIGURE 2
Electrical stimulation devices commonly used post-SCI. EES delivers stimulation over the spinal cord via a paddle electrode array that receives power from an implanted pulse generator (IPG). PNS and FES deliver stimulation to the target nerve via implanted electrodes connected to an IPG, or via percutaneous or transcutaneous electrodes.
FIGURE 3
FIGURE 3
Various types of peripheral nerve stimulation devices. Transcutaneous and percutaneous stimulation (Left) offer temporary and minimally invasive stimulation but are less specific. Implanted electrodes (Right; extraneural or intraneural) offer more specific nerve stimulation but require invasive implantation.
FIGURE 4
FIGURE 4
Gate control theory of pain following electrical stimulation. Stimulating large-diameter afferents (blue) via electrical stimulation excites inhibitory interneurons (black) in the substantial gelatinosa. This suppresses the stimulation of projection neurons (brown) via C-Fibers, reducing pain perception.
FIGURE 5
FIGURE 5
Overview of neuroplastic mechanisms that may promote functional improvements. (1) Electrical stimulation may promote local neuroplasticity, strengthening motoneuron activation from afferent or descending inputs. (2) Stimulation may also promote the reorganization of descending pathways, or (3) promote axonal regeneration, which together could facilitate greater supraspinal control. (4) Stimulation may raise net spinal cord excitability, allowing the sub-lesioned circuitry to respond to weak residual supraspinal inputs and immediately restore function.
FIGURE 6
FIGURE 6
Brain-derived neurotrophic factor and cAMP signaling pathways. (1) Electrical stimulation may upregulate BDNF, promoting (2) synaptic plasticity through the PLC pathway, (3) neuronal survival through the PIK-Akt pathway, and (4) axonal outgrowth through EKR and pCREB. (5) BDNF can upregulate cAMP by inhibiting PDE. cAMP may promote neuroplasticity by upregulating pCREB. (6) cAMP can also reduce myelin inhibition of axonal outgrowth by inhibiting the RHO-ROCK pathway.
FIGURE 7
FIGURE 7
Summary of the potential mechanisms that electrical stimulation may improve outcomes post-SCI. (1) Electrical stimulation can immediately restore function by activating local neural circuitry and facilitating spared, residual supraspinal inputs to regain functional control below the lesion. (2) Stimulation may also modulate glial cells and neuroinflammation, and (3) upregulate neurotrophic factors. (4) When combined with long-term stimulation and rehabilitation, this may promote neuroplastic remodeling of the spinal cord and possibly axonal regeneration, facilitating supraspinal control below the injury. (5) These mechanisms may account for the restored function and neuropathic pain relief observed in electrical stimulation studies.
FIGURE 8
FIGURE 8
Alternative mechanisms that may contribute to functional recovery post SCI. (1) Providing acute electrical stimulation may reduce secondary damage through neuroinflammatory and vascular events. (2) Electrical stimulation may remove inhibitory molecules around the lesion site to facilitate regeneration.
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