A Perspective on Electrical Stimulation and Sympathetic Regeneration in Peripheral Nerve Injuries

Abstract

Peripheral nerve injuries (PNIs) are common and devastating. The current standard of care relies on the slow and inefficient process of nerve regeneration after surgical intervention. Electrical stimulation (ES) has been shown to both experimentally and clinically result in improved regeneration and functional recovery after PNI for motor and sensory neurons; however, its effects on sympathetic regeneration have never been studied. Sympathetic neurons are responsible for a myriad of homeostatic processes that include, but are not limited to, blood pressure, immune response, sweating, and the structural integrity of the neuromuscular junction. Almost one quarter of the axons in the sciatic nerve are from sympathetic neurons, and their importance in bodily homeostasis and the pathogenesis of neuropathic pain should not be underestimated. Therefore, as ES continues to make its way into patient care, it is not only important to understand its impact on all neuron subtypes, but also to ensure that potential adverse effects are minimized. This piece gives an overview of the effects of ES in animals models and in humans while offering a perspective on the potential effects of ES on sympathetic axon regeneration.

Keywords: axonal injury; axonal regeneration; neuroexcitation; peripheral nerve injury; regeneration.

FIG. 1.

Cycle of how clinical scenarios inform basic science research, which then informs future standards of care for patients. The current standard of care of the treatment of peripheral nerve injuries relies on the slow and inefficient process of intrinsic axon regeneration with very few patients achieving full functional recovery. Therefore, in rats, 1 h of electrical stimulation (ES) of the proximal stump after surgical repair was found to be a viable method to promote motor axon regeneration into the distal stump. A clinical trial of ES in patients with severe carpal tunnel syndrome requiring surgical decompression resulted in improved functional recovery. On the basic science side, researchers continue to study different nerve injury scenarios and seek to understand and improve adjunctive therapeutic methods that will inform the future of patient care. Created with Biorender.com.

FIG. 2.

Anatomy schematic of the sciatic nerve. Cross-section diagram of the rat sciatic nerve. Unmyelinated sensory and post-ganglionic sympathetic neurons are clustered in Remak bundles. Figure adapted from Schmalbruch, 1986.

FIG. 3.

Post-ganglionic sympathetic neurons sprouting into the dorsal root ganglia (DRG) in response to peripheral nerve injury (PNI). The cell bodies of pre-ganglionic sympathetic neurons (green) are in the lateral horns of spinal cord levels T1–L2. Their projections travel along the ventral roots then through the white rami to innervate post-ganglionic sympathetic neurons (magenta) in the sympathetic chain. The pre-ganglionic neurons (green) can traverse several levels of the sympathetic chain before synapsing on post-ganglionic neurons. Most post-ganglionic axons exit the sympathetic ganglia (SG) through the gray rami and into the ventral and dorsal rami of the spinal nerves to innervate distal targets. Some will send projections to their adjacent DRG (sensory neurons in blue) to reach blood vessels and the surface of the DRG. These projections may sprout and contribute to neuropathic pain after PNI, such as that to the sciatic nerve, which in a mouse contains contributions mainly from the L3, L4, and L5 spinal nerve roots.^, For simplicity, only one neuron at each potential synapse is represented. Figure adapted from Xie and colleagues 2016.