Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from chronic pain, and sensory and motor dysfunction. One promising surgical adjunct is the application of intraoperative electrical stimulation (ES) to peripheral nerves. ES acts through second messenger cyclic AMP to augment the intrinsic molecular pathways of regeneration. Decades of animal studies have demonstrated that 20 Hz ES delivered post-surgically accelerates axonal outgrowth and end organ reinnervation. This work has been translated clinically in a series of randomized clinical trials, which suggest that ES can be used as an efficacious therapy to improve patient outcomes following PNIs. The aim of this review is to discuss the cellular physiology and the limitations of regeneration after peripheral nerve injuries. The proposed mechanisms of ES protocols and how they facilitate nerve regeneration depending on timing of administration are outlined. Finally, future directions of research that may provide new perspectives on the optimal delivery of ES following PNI are discussed.

Peripheral sensory neurons located in dorsal root ganglia relay sensory information from the peripheral tissue to the brain. Satellite glial cells (SGCs) are unique glial cells that form an envelope completely surrounding each sensory neuron soma. This organization allows for close bidirectional communication between the neuron and its surrounding glial coat. Morphological and molecular changes in SGC have been observed in multiple pathological conditions such as inflammation, chemotherapy-induced neuropathy, viral infection, and nerve injuries. There is evidence that changes in SGC contribute to chronic pain by augmenting the neuronal activity in various rodent pain models. Satellite glial cells also play a critical role in axon regeneration. Whether findings made in rodent model systems are relevant to human physiology have not been investigated. Here, we present a detailed characterization of the transcriptional profile of SGC in mice, rats, and humans at the single cell level. Our findings suggest that key features of SGC in rodent models are conserved in humans. Our study provides the potential to leverage rodent SGC properties and identify potential targets in humans for the treatment of nerve injuries and alleviation of painful conditions.

The life altering nature of major limb amputations may be further complicated by neuroma formation in up to 60% of the estimated 2 million major limb amputees in the United States. This can be a source of pain and functional limitation of the residual limb. Pain associated with neuromas may limit prosthetic limb use, require reoperation, lead to opioid dependence, and dramatically reduce quality of life. A number of management options have been described including excision alone, excision with repair, excision with transposition, and targeted muscle reinnervation. Targeted muscle reinnervation has been shown to reduce phantom limb and neuroma pain for patients with upper and lower extremity amputations. It may be performed at the time of initial amputation to prevent pain development or secondarily for the treatment of established pain. Encouraging outcomes have been reported, and targeted muscle reinnervation is emerging as a leading surgical technique for pain prevention in patients undergoing major limb amputations and pain management in patients with pre-existing amputations.

Peripheral nerve injuries often result in life-altering functional deficits even with optimal management. Unlike the central nervous system, peripheral nerves have the ability to regenerate lost axons after injury; however, axonal regeneration does not equate to full restoration of function. To overcome this physiological shortcoming, advances in nerve regeneration and repair are paramount, including electrical stimulation, gene therapy, and surgical technique advancements.

Background: Cubital tunnel syndrome has a spectrum of presentations ranging from mild paresthesias to debilitating numbness and intrinsic atrophy. Commonly, the classification of severity relies on clinical symptoms and slowing of conduction velocity across the elbow. However, changes in compound muscle action potential (CMAP) amplitude more accurately reflect axonal loss. We hypothesized that CMAP amplitude would better predict functional impairment than conduction velocity alone. Methods: A retrospective cohort of patients who underwent a surgical procedure for cubital tunnel syndrome over a 5-year period were included in the study. All patients had electrodiagnostic testing performed at our institution. Clinical and electrodiagnostic variables were recorded. The primary outcome was preoperative functional impairment, defined by grip and key pinch strength ratios. Multivariable regression identified which clinical and electrodiagnostic variables predicted preoperative functional impairment. Results: Eighty-three patients with a mean age of 57 years (75% male) were included in the study. The majority of patients (88%) had abnormal electrodiagnostic studies. Fifty-four percent had reduced CMAP amplitude, and 79% had slowing of conduction velocity across the elbow (recorded from the first dorsal interosseous). On bivariate analysis, older age and longer symptom duration were significantly associated (p < 0.05) with reduced CMAP amplitude and slowing of conduction velocity across the elbow, whereas body mass index (BMI), laterality, a primary surgical procedure compared with revision surgical procedure, Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores, and visual analog scale (VAS) scores for pain were not. Multivariable regression analysis demonstrated that reduced first dorsal interosseous CMAP amplitude independently predicted the loss of preoperative grip and key pinch strength and that slowed conduction velocity across the elbow did not. Conclusions: Reduced first dorsal interosseous amplitude predicted preoperative weakness in grip and key pinch strength, and isolated slowing of conduction velocity across the elbow did not. CMAP amplitude is a sensitive indicator of axonal loss and an important marker of the severity of cubital tunnel syndrome. It should be considered when counseling patients with regard to their prognosis and determining the necessity and timing of operative intervention. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.