Chapter 24 Electrical Stimulation for Improving Nerve Regeneration: Where do we Stand?

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While injured neurons regenerate their axons in the peripheral nervous system, it is well recognized that functional recovery is frequently poor. Animal experiments in which injured motoneurons remain without peripheral targets (chronic axotomy) and Schwann cells in distal nerve stumps remain without innervation (chronic denervation) revealed that it is the duration of chronic axotomy and Schwann cell denervation that accounts for this poor functional recovery and not irreversible muscle atrophy that has been so commonly thought to be the reason. More recently, we demonstrated that axon outgrowth across lesion sites is a major contributing factor to the long delays incurred between the injury and the reinnervation of denervated targets. In the rat, a period of 1 month transpires before all motoneurons regenerate their axons across a lesion site. We have developed a technique of 1 h low‐frequency electrical stimulation (ES) of the proximal nerve stump just after surgical repair of a transected peripheral nerve that greatly accelerates axon outgrowth. This technique has been applied in patients after carpal tunnel release surgery where the ES promoted the regeneration of all median nerves to reinnervate thenar muscles within 6–8 months, which contrasted with failure of any injured nerves to reinnervate muscles in the same time frame without ES. These findings are very promising such that the ES method could become a clinically viable tool for accelerating axon regeneration and muscle reinnervation.

Introduction

Recovery following peripheral nerve injury, particularly proximal nerve injury, remains a significant clinical problem despite the known capacity for axon regeneration in the peripheral nervous system. Poor functional outcomes following repair of peripheral nerve lesions have been attributed to two main factors impeding axonal regeneration: (1) slow growth across coaptation sites and/or nerve gaps and (2) a relatively short time frame when the injured neurons and the denervated Schwann cells can support regenerating axons following injury. Expedition of regenerating axons across repair sites in order to optimize functional regeneration is a major focus of current research. This review will consider why functional recovery in humans remains an extensive clinical problem and will discuss the developing role of electrical stimulation (ES) as a method of accelerating the outgrowth of axons across a site of nerve repair, both in animals and humans.

Section snippets

Basis for Poor Functional Recovery After Nerve Injury and Repair

Despite the permissive growth environment of the peripheral nervous system, functional recovery after surgical repair of injured peripheral nerves is often suboptimal (Kim et al., 2003, Sunderland, 1978, Terzis and Smith, 1990). This is true particularly when nerves regenerate over long distances and/or long delays occur between injury and target reinnervation. Experimentally, when axon regeneration from the proximal nerve stump and through the distal the nerve stump is delayed in rat

Wallerian Degeneration and Staggered Axon Regeneration into the Distal Nerve Stump

Axons do not regenerate across surgical sites within the time frames predicted by well‐established rates of regeneration of 1–3 mm/day. Using retrograde dyes that are taken up by regenerated axon tips and transported to the cell bodies of motoneurons and sensory neurons, we observed that the regeneration of axons across a site of nerve repair is very slow when compared with the 1–3 mm/day rate of axon regeneration (Fig. 1) (Al‐Majed et al., 2000b, Brushart et al., 2002, Gordon et al., 2008).

Conclusions

Despite continuous advancements in knowledge and technique, regeneration in the peripheral nervous system remains a significant source of morbidity. The recent application of ES to promote axonal sprouting in nerve injury has resulted in promising functional recovery in animal models. With the limitation of ES to 1 h, the translational potential of this modality is significant. To date, one study has made the translation to human trial where post-surgical ES of the median nerve following carpal

Acknowledgments

We appreciate the financial support by the Canadian Institutes for Health Research (CIHR) for operating grants to TG from CIHR and a CIHR group grant that includes Dr. Zochodne, Dr. Sayed, and Dr. Midha from University of Calgary, VMKV from University of Saskatchewan, and Dr. Chan and T.G. from University of Alberta. T.G. is an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Investigator.

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