Electrical Stimulation As a Conditioning Lesion for Promoting Peripheral Nerve Regeneration

Background: Peripheral nerve regeneration following injury is often incomplete with significant personal and socioeconomic costs. Although it has been well demonstrated that conditioning lesion (a nerve crush delivered prior to injury and repair) markedly accelerates nerve regrowth, it cannot be applied clinically because it is unethical to intentionally injure a healthy nerve. Recently, in a proof of principle study, we showed that conditioning electrical stimulation (CES) of the fibular nerve enhances upregulation of regeneration-associated-genes (RAGs) and axonal growth. However, whether similar beneficial effects can be generalized to other nerves and whether CES can improve functional recovery remain unknown. This knowledge is critical before applying CES for clinical use.

 

Objectives: To determine if CES upregulates RAGs, enhances nerve regeneration and improve sensory and motor function in a rat tibial nerve injury model.

Methods:  Sprague Dawley rats were divided based on the type of conditioning to the tibial nerve: i) CES, ii) conditioning crush lesion (CCL), iii) sham-CES controls, and iv) unconditioned controls. Expression of RAGs (GAP43, BDNF, pCREB, GFAP) were analyzed at 3-days post-conditioning (n=3). The length of regeneration was assessed at 7-days (n=6), and physiological and behavioral testing was performed at 7-weeks post-coaptation (n=10).

 

Results: Similar patterns of RAG upregulation and axonal growth were found in animals conditioned with electrical stimulation and crush compared to controls. Sensory testing (von Frey filaments, intraepidermal nerve fiber density counts), gait analysis (toe spread evaluation, horizontal ladder testing) and gastrocnemius muscle reinnervation (muscle weight, neuromuscular junction analysis) were significantly improved in the CES animals compared to not only the controls, but also the crush-conditioned cohort. Nerve conduction studies shows significantly larger compound muscle action potential amplitude in CES compared to controls.

Conclusions: Our data supports that preoperative electrical stimulation delivers a conditioning-like effect in the tibial nerve, with upregulation of RAGs and enhanced axonal outgrowth.  Interestingly, CES induced improvements in sensorimotor outcomes beyond those obtained with traditional methods of conditioning. As electrical stimulation has been shown to be safe and well-tolerated by patients, CES is likely a clinically feasible intervention that can potentially improve the sensorimotor recovery of patients with peripheral nerve injury.