Enhancing the regeneration of axons is often considered to be a therapeutic target for improving functional recovery after peripheral nerve injury. In this review, the evidence for the efficacy of electrical stimulation (ES), daily exercise and their combination in promoting nerve regeneration after peripheral nerve injuries in both animal models and in human patients is explored. The rationale, effectiveness and molecular basis of ES and exercise in accelerating axon outgrowth are reviewed. In comparing the effects of ES and exercise in enhancing axon regeneration, increased neural activity, neurotrophins and androgens are considered to be common requirements. Similarly, there are sex-specific requirements for exercise to enhance axon regeneration in the periphery and for sustaining synaptic inputs onto injured motoneurons. ES promotes nerve regeneration after delayed nerve repair in humans and rats. The effectiveness of exercise is less clear. Although ES, but not exercise, results in a significant misdirection of regenerating motor axons to reinnervate different muscle targets, the loss of neuromuscular specificity encountered has only a very small impact on resulting functional recovery. Both ES and exercise are promising experimental treatments for peripheral nerve injury that seem to be ready to be translated to clinical use.

Strategies to promote peripheral nerve regeneration: electrical stimulation and/or exercise.

https://link.springer.com/content/pdf/10.1007%2Fs13311-015-0415-1.pdf

Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans

Peripheral nerve injury afflicts individuals from all walks of life. Despite the peripheral nervous system's intrinsic ability to regenerate, many patients experience incomplete functional recovery. Surgical repair aims to expedite this recovery process in the most thorough manner possible. However, full recovery is still rarely seen especially when nerve injury is compounded with polytrauma where surgical repair is delayed. Pharmaceutical strategies supplementary to nerve microsurgery have been investigated but surgery remains the only viable option. Brief low-frequency electrical stimulation of the proximal nerve stump after primary repair has been widely investigated. This article aims to review the currently known biological basis for the regenerative effects of acute brief low-frequency electrical stimulation on axonal regeneration and outline the recent clinical applications of the electrical stimulation protocol to demonstrate the significant translational potential of this modality for repairing peripheral nerve injuries. The review concludes with a discussion of emerging new advancements in this exciting area of research. The current literature indicates the imminent clinical applicability of acute brief low-frequency electrical stimulation after surgical repair to effectively promote axonal regeneration as the stimulation has yielded promising evidence to maximize functional recovery in diverse types of peripheral nerve injuries.

https://journals.sagepub.com/doi/pdf/10.1177/1545968315604399

Electrical Stimulation to Promote Peripheral Nerve Regeneration.

DARPA-funded efforts in the development of novel brain-computer interface technologies.

Dexterous hand movement is possible due to closed loop control dependent on efferent motor output and afferent sensory feedback. This control strategy is significantly altered in those with upper limb amputation as sensations of touch and movement are inherently lost. For upper limb prosthetic users, the absence of sensory feedback impedes efficient use of the prosthesis and is highlighted as a major factor contributing to user rejection of myoelectric prostheses. Numerous sensory feedback systems have been proposed in literature to address this gap in prosthetic control; however, these systems have yet to be implemented for long term use. Methodologies for communicating prosthetic grasp and touch information are reviewed, including discussion of selected designs and test results. With a focus on clinical and translational challenges, this review highlights and compares techniques employed to provide amputees with sensory feedback. Additionally, promising future directions are discussed and highlighted.

Applications of sensory feedback in motorized upper extremity prosthesis: a review.

We present a case study of a novel variation of the targeted sensory reinnervation technique that provides additional control over sensory restoration after transhumeral amputation. The use of intraoperative somatosensory evoked potentials on individual fascicles of the median and ulnar nerves allowed us to specifically target sensory fascicles to reroute to target cutaneous nerves at a distance away from anticipated motor sites in a transhumeral amputee. This resulted in restored hand maps of the median and ulnar nerve in discrete spatially separated areas. In addition, the subject was able to use native and reinnervated muscle sites to control a robotic arm while simultaneously sensing touch and force feedback from the robotic gripper in a physiologically correct manner. This proof of principle study is the first to demonstrate the ability to have simultaneous dual flow of information (motor and sensory) within the residual limb. In working towards clinical deployment of a sensory integrated prosthetic device, this surgical method addresses the important issue of restoring a usable access point to provide natural hand sensation after upper limb amputation.

Novel Targeted Sensory Reinnervation Technique to Restore Functional Hand Sensation After Transhumeral Amputation

Objective

Brief postsurgical electrical stimulation (ES) has been shown to enhance peripheral nerve regeneration in animal models following axotomy and crush injury. However, whether this treatment is beneficial in humans with sensory nerve injury has not been tested. The goal of this study was to test the hypothesis that ES would enhance sensory nerve regeneration following digital nerve transection compared to surgery alone.



Methods

Patients with complete digital nerve transection underwent epineurial nerve repair. After coaptation of the severed nerve ends, fine wire electrodes were implanted before skin closure. Postoperatively, patients were randomized to receiving either 1 hour of 20Hz continuous ES or sham stimulation in a double-blinded manner. Patients were followed monthly for 6 months by a blinded evaluator to monitor physiological recovery of spatial discrimination, pressure threshold, and quantitative small fiber sensory testing. Functional disability was measured using the Disability of Arm, Shoulder, and Hand questionnaire.



Results

A total of 36 patients were recruited, with 18 in each group. Those in the ES group showed consistently greater improvements in all sensory modalities by 5 to 6 months postoperatively compared to the controls. Although there was a trend of greater functional improvements in the ES group, it was not statistically significant (p > 0.01).



Interpretation

Postsurgical ES enhanced sensory reinnervation in patients who sustained complete digital nerve transection. The conferred benefits apply to a wide range of sensory functions. Ann Neurol 2015;77:996–1006

Electrical stimulation enhances sensory recovery: A randomized controlled trial

There is a paucity of validated tests to quantify hand function impairment due to carpal tunnel syndrome (CTS). The aim of this study was to test the validity and reliability of the Purdue Pegboard Test (PPT) in CTS patients. We compared 190 CTS patients with 122 healthy, age-matched controls. CTS severity was determined based on electrophysiologic parameters and the Levine Self-Assessment Questionnaire. The time to complete the PPT and the test-retest reliability were tested. The test-retest reliability was high with an intraclass correlation coefficient of 0.91. Compared to healthy controls, the CTS patients were significantly slower. Although the functional performance generally declined with increasing severity of electrophysiologic abnormalities, the correlation between hand function decline and symptom severity in the young and middle-aged groups was low. We conclude that the PPT is a valid and reliable tool to quantify functional impairment caused by CTS. It can be a useful outcome measure in young and middle-aged patients.

Validity and reliability of the purdue pegboard test in carpal tunnel syndrome

BACKGROUND Patients with severe cubital tunnel syndrome often have poor functional recovery with conventional surgical treatment. Postsurgical electrical stimulation (PES) has been shown to enhance axonal regeneration in animal and human studies. OBJECTIVE To determine if PES following surgery for severe cubital tunnel syndrome would result in better outcomes compared to surgery alone. METHODS Patients with severe cubital tunnel syndrome in this randomized, double-blind, placebo-controlled trial were randomized in a 1:2 ratio to the control or stimulation groups. Control patients received cubital tunnel surgery and sham stimulation, whereas patients in the stimulation group received 1-h of 20 Hz PES following surgery. Patients were assessed by a blinded evaluator annually for 3 yr. The primary outcome was motor unit number estimation (MUNE) and secondary outcomes were grip and key pinch strength and McGowan grade and compound muscle action potential. RESULTS A total of 31 patients were enrolled: 11 received surgery alone and 20 received surgery and PES. Three years following surgery, MUNE was significantly higher in the PES group (176 ± 23, mean + SE) compared to controls (88 ± 11, P < .05). The mean gain in key pinch strength in the PES group was almost 3 times greater than in the controls (P < .05). Similarly, other functional and physiological outcomes showed significantly greater improvements in the PES group. CONCLUSION PES enhanced muscle reinnervation and functional recovery following surgery for severe cubital tunnel syndrome. It may be a clinically useful adjunct to surgery for severe ulnar neuropathy, in which functional recovery with conventional treatment is often suboptimal.

Postsurgical Electrical Stimulation Enhances Recovery Following Surgery for Severe Cubital Tunnel Syndrome: A Double-Blind Randomized Controlled Trial.

Background:Current surgical management of obstetrical brachial plexus injury is primary reconstruction with sural nerve grafts. Recently, the nerve-to-nerve transfer technique has been used to treat brachial plexus injury in adults, affording the benefit of distal coaptations that minimize regenerat

Michael Morhart

Papers

Novel Targeted Sensory Reinnervation Technique to Restore Functional Hand Sensation After Transhumeral Amputation

Electrical stimulation enhances sensory recovery: A randomized controlled trial

Validity and reliability of the purdue pegboard test in carpal tunnel syndrome

Postsurgical Electrical Stimulation Enhances Recovery Following Surgery for Severe Cubital Tunnel Syndrome: A Double-Blind Randomized Controlled Trial.

Distal nerve transfers are effective in treating patients with upper trunk obstetrical brachial plexus injuries: an early experience.