Augmenting nerve regeneration with electrical stimulation

Objective: Poor functional recovery after peripheral nerve injury is generally attributed to irreversible target atrophy. In rats, we addressed the functional outcomes of prolonged neuronal separation from targets (chronic axotomy for up to 1 year) and atrophy of Schwann cells (SCs) in distal nerve stumps, and whether electrical stimulation (ES) accelerates axon regeneration. In carpal tunnel syndrome (CTS) patients with severe axon degeneration and release surgery, we asked whether ES accelerates muscle reinnervation. Methods: Reinnervated motor unit (MUs) and regenerating neuron numbers were counted electrophysiologically and with dye-labeling after chronic axotomy, chronic SC denervation and after immediate nerve repair with and without trains of 20 Hz ES for 1 hour to 2 weeks in rats and in CTS patients. Results: Chronic axotomy reduced regenerative capacity to 67% and was alleviated by exogenous growth factors. Reduced regeneration to ∼10% by SC denervation atrophy was ameliorated by forskolin and transforming growth factor-β SC reactivation. ES (1 h) accelerated axon outgrowth across the suture site in association with elevated neuronal neurotrophic factor and receptors and in patients, promoted the full reinnervation of thenar muscles in contrast to a non-significant increase in MU numbers in the control group. Discussion: The rate limiting process of axon outgrowth, progressive deterioration of both neuronal growth capacity and SC support, but not irreversible target atrophy, account for observed poor functional recovery after nerve injury. Brief ES accelerates axon outgrowth and target muscle reinnervation in animals and humans, opening the way to future clinical application to promote functional recovery.