Motor Unit Number Index of the Upper Trapezius: A Meta-Analysis and Cross-sectional Study of Its Reliability.

Motor unit number index of the upper trapezius (MUNIX-Trapezius) is a candidate biomarker for bulbar lower motor neuron function; however, reliability data is incomplete. To assess MUNIX-Trapezius reliability in controls, we conducted a systematic review, a cross-sectional study (n = 20), and a meta-analysis. We demonstrated a high inter- and intra-rater intraclass correlation (0.86 and 0.94, respectively), indicating that MUNIX-Trapezius is reliable with between-study variability moderated by age and MUNIX technique. With further validation, this measure can serve as a disease monitoring and response biomarker of bulbar function in the therapeutic development for amyotrophic lateral sclerosis.

Nerve excitability measured with the TROND protocol in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

This meta-analysis assessed the 30+ nerve excitability indices generated by the TROND protocol to identify potential biomarkers for amyotrophic lateral sclerosis (ALS). A comprehensive search was conducted in multiple databases to identify human studies that tested median motor axons. Forest plot analyses were performed using a random-effects model to determine the pooled effect (Z-score), heterogeneity (I2), and Cohen's d for potential biomarker identification. Out of 2,866 studies, 23 studies met the inclusion criteria, incorporating data from 719 controls and 942 patients with ALS. Seven indices emerged as potential biomarkers: depolarizing threshold electrotonus (TEd) 90-100 ms, strength-duration time constant (SDTC), superexcitability, TEd 40-60 ms, resting I/V slope, 50% depolarizing I/V, and subexcitability (ranked by the magnitude of the difference between patients and controls from largest to smallest). In a sensitivity analysis focusing on patients with larger compound muscle action potentials (CMAPs), only four indices were potential biomarkers: TEd 10-20 ms, TEd 90-100 ms, superexcitability, and SDTC. Among the extensive range of 30+ excitability indices generated by the TROND protocol, we have identified seven indices that effectively differentiate patients with ALS from healthy controls. Furthermore, a smaller subset of four indices shows promise as potential biomarkers when the CMAP remains relatively large. However, most studies were considered to be at moderate risk of bias due to case-control designs and absence of sensitivity and specificity calculations, underscoring the need for more prospective diagnostic test-accuracy studies with appropriate disease controls.NEW & NOTEWORTHY This meta-analysis uncovers seven potential axonal excitability biomarkers for lower motor neuron pathology in ALS, shedding light on ion channel dysfunction. The identified dysfunction aligns with the primary pathology-protein homeostasis disruption. These biomarkers could fill a gap to detect presymptomatic spread of the disease in the spinal cord and monitor treatments targeting protein homeostasis and limiting spread, toward enhancing patient care.

Fifty Years of Motor Unit Number Estimation.

The objective was to use bibliometric analysis to create an infographic of motor unit number estimation methods over the past 50 years. The original method was published in 1971, but secondary and tertiary waves of research using alternative methods occurred in the early 2000s and a decade later. A metric of influence was used to determine if different methods had clear peaks of use over the past 50 years. While the original method continues to register influence, the MUNIX method introduced in 2004 stands out as the most influential method to estimate the innervation status of skeletal muscles.

Coupling of single cutaneous afferents in the hand with ankle muscles, and their response to rapid light touch displacements.

Light touch reduces sway during standing. Unexpected displacement of a light touch reference at the finger can produce rapid responses in ankle muscles when standing, suggesting cutaneous receptors in the hand are functionally coupled with ankle muscles. Using microneurography in the median nerve, we tested the hypotheses: 1) that cutaneous afferent activity of mechanoreceptors of the hand would modulate electromyographic (EMG) activity of ankle muscles, and 2) that displacement of a light touch contact across a receptor's sensory territory would be encoded in the afferent activity. Spike-triggered averaging of EMG activity of tibialis anterior (TA) and soleus (SOL) demonstrated that 34 of 42 (81%) cutaneous afferents recorded modulated activity of ankle muscles with latencies between 40 and 119 ms. Cutaneous afferents of all types (slow and fast adapting, types I and II) demonstrated responses in TA and SOL, in both the ipsilateral and contralateral leg. Activity from 11 cutaneous afferents was recorded while a light touch contact was displaced across their receptive fields. Afferent activity increased with stimulus onset and remained elevated for the stimulus duration for all afferents recorded. These results suggest that cutaneous afferents from the hand consistently form connections with motor pools of the leg at latencies implicating spinal pathways. In addition, the same population of afferents is readily excited by the displacement of a light touch contact. Therefore, cutaneous receptors of the hand can be recruited and used to alter motoneuron pool excitability in muscles important to balance control, at latencies relevant for rapid balance responses.NEW & NOTEWORTHY Light touch provides cutaneous feedback argued to contribute to balance control and shown to reduce postural sway. We demonstrate that activity of cutaneous afferents in the median nerve modulates motor pool excitability of ankle muscles at short latencies and that these afferents respond when a light touch contact is displaced. These findings suggest that cutaneous receptors of the hand can contribute to rapid regulation of muscle activity important to standing balance.

Nerve excitability differences in slow and fast motor axons of the rat: more than just Ih.

The objective was to determine biophysical differences between fast and slow motor axons using threshold tracking and demonstrate confounds related to anesthetic. Nerve excitability of motor axons innervating the slow-twitch soleus (SOL) and fast-twitch tibialis anterior (TA) muscles was tested. The experiments were conducted with pentobarbital sodium (SP) anesthetic and compared with previous results that used ketamine-xylazine (KX). Nerve excitability indices measured with SP show definitive differences between TA and SOL motor axons that extend beyond previous reports. Nerve excitability indices sensitive to changes in Ih indicated an increase in SOL axons compared with TA axons [e.g., S3 t = 7.949 (df = 10), P < 0.001; hyperpolarizing threshold electrotonus (90-100 ms), t = 2.659 (df = 20); P = 0.01; hyperpolarizing I/V slope, t = 4.308 (df = 19); P < 0.001]. SOL axons also had a longer strength-duration time constant [t = 3.35 (df = 20); P = 0.003] and a longer and larger magnitude relative refractory period [RRP (ms) t = 3.53 (df = 12); P = 0.004; Refractoriness at 2 ms, t = 0.0055 (df = 9); P = 0.006]. Anesthetic choice affected many measures of peripheral nerve excitability with differences most apparent in tests of threshold electrotonus and recovery cycle. For example, recovery cycle with KX lacked a clear superexcitable and late subexcitable period. We conclude that KX had a confounding effect on nerve excitability results consistent with ischemic depolarization. Results using SP revealed the full extent of differences in nerve excitability measures between putative slow and fast motor axons of the rat. These results provide empirical evidence, beyond conduction velocity, that the biophysical properties of motor axons vary with the type of muscle fiber innervated. These differences suggest that fast axons may be predisposed to dysfunction during hyperpolarizing stresses, e.g., electrogenic sodium pumping following sustained impulse conduction.NEW & NOTEWORTHY Nerve excitability testing is a tool used to provide insight into the properties of ion channels in peripheral nerves. It is used clinically to assess pathophysiology of axons. Researchers customarily think of motor axons as homogeneous; however, we demonstrate there are clear differences between fast and slow axons in the rat. This is important for interpreting results with selective motor neuronopathy, like aging where fast axons are at high risk of degeneration.

Intentions of Canadian health professionals towards recommending exercise for people living with ALS.

BACKGROUND: To provide a nationwide overview of the attitudes, social pressure, perceived ability and intentions of health professionals toward exercise prescription for people living with ALS (pALS). METHODS: An online survey of physician and non-physician health professionals (HPs) working in academic ALS clinics across Canada. RESULTS: The response rate was 48% (84/176) with 30% of respondents identifying as physicians, 63% as other HPs and the remainder as administrative or research personnel. Respondents were sharply divided in their intentions to provide exercise counsel: 24% unlikely and 45% likely. Respondents with low intentions were HPs that considered this activity outside their scope of practice. Measures of intention and attitude were more positive for flexibility compared to strength and aerobic exercise. Perceptions of social pressure and ability to provide exercise counsel were significantly correlated with intention across the three exercise modes in all respondents. Qualitative themes identified as barriers to exercise prescription were lack of confidence or competence (31% physicians, 32% HP), patient tolerance (30% HP), lack of evidence (22% physicians) and lack of infrastructure (22% physicians). CONCLUSIONS: While "lack of evidence" for the benefit of exercise was a deterrent for physicians, the larger issue for all respondents was building competence and confidence in exercise prescription for pALS.

Resveratrol improves exercise performance and skeletal muscle oxidative capacity in heart failure.

We investigated whether treatment of mice with established pressure overload-induced heart failure (HF) with the naturally occurring polyphenol resveratrol could improve functional symptoms of clinical HF such as fatigue and exercise intolerance. C57Bl/6N mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks postsurgery, a cohort of mice with established HF (%ejection fraction <45) was administered resveratrol (~450 mg·kg-1·day-1) or vehicle for 2 wk. Although the percent ejection fraction was similar between both groups of HF mice, those mice treated with resveratrol had increased total physical activity levels and exercise capacity. Resveratrol treatment was associated with altered gut microbiota composition, increased skeletal muscle insulin sensitivity, a switch toward greater whole body glucose utilization, and increased basal metabolic rates. Although muscle mass and strength were not different between groups, mice with HF had significant declines in basal and ADP-stimulated O2 consumption in isolated skeletal muscle fibers compared with sham mice, which was completely normalized by resveratrol treatment. Overall, resveratrol treatment of mice with established HF enhances exercise performance, which is associated with alterations in whole body and skeletal muscle energy metabolism. Thus, our preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in HF patients.NEW & NOTEWORTHY Resveratrol treatment of mice with heart failure leads to enhanced exercise performance that is associated with altered gut microbiota composition, increased whole body glucose utilization, and enhanced skeletal muscle metabolism and function. Together, these preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in heart failure via these mechanisms.

Interleaved neuromuscular electrical stimulation: Motor unit recruitment overlap.

INTRODUCTION: In this study, we quantified the "overlap" between motor units recruited by single pulses of neuromuscular electrical stimulation (NMES) delivered over the tibialis anterior muscle (mNMES) and the common peroneal nerve (nNMES). We then quantified the torque produced when pulses were alternated between the mNMES and nNMES sites at 40 Hz ("interleaved" NMES; iNMES). METHODS: Overlap was assessed by comparing torque produced by twitches evoked by mNMES, nNMES, and both delivered together, over a range of stimulus intensities. Trains of iNMES were delivered at the intensity that produced the lowest overlap. RESULTS: Overlap was lowest (5%) when twitches evoked by both mNMES and nNMES produced 10% peak twitch torque. iNMES delivered at this intensity generated 25% of maximal voluntary dorsiflexion torque (11 Nm). DISCUSSION: Low intensity iNMES leads to low overlap and produces torque that is functionally relevant to evoke dorsiflexion during walking. Muscle Nerve 55: 490-499, 2017.

Influence of an Exercise-Specific Face Mask on Physiological and Perceptual Responses to Graded Exercise.

The impact of exercise-specific face masks (ESFMs) in aerobically fit individuals on physiological, perceptual, respiratory, and performance responses remains unclear. How ESFMs mitigate exercise-induced bronchoconstriction (EIB) is also unknown. Thus, this study aimed to determine how an ESFM altered within-exercise physiological, perceptual, respiratory, and performance responses to graded treadmill exercise. Twenty-four individuals (11 females) completed a discontinuous graded exercise test on a treadmill under two conditions (ESFM and unmasked). Physiological, respiratory function, and perceptual measures were assessed. Performance was determined by time to exhaustion. Statistical analyses included linear mixed-effects modeling, repeated measures analysis of variance, and pairwise comparisons using an alpha value of 0.05. ESFM use significantly impaired performance (median = -150.5 s) and decreased arterial oxygen saturation at maximal intensity (mean = -3.7%). Perceptions of air hunger and work of breathing were elevated across submaximal and maximal intensities. Perceived exertion and breathing discomfort were significantly elevated submaximally but not maximally. Spirometry measures were not significantly different at termination but were significantly improved at submaximal intensities in participants with and without EIB. ESFM use in fit individuals increased perceptual discomfort, impaired performance, and augmented arterial desaturation. Respiratory function improvements were observed but were accompanied by adverse perceptual sensations. Despite this, performance impairments may limit the real-world utility of ESFMs for athletes.

Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats.

Exercise training (ET) improves endurance capacity by increasing both skeletal muscle mitochondrial number and function, as well as contributing to favourable cardiac remodelling.Interestingly, some of the benefits of regular exercise can also be mimicked by the naturally occurring polyphenol, resveratrol (RESV). However, it is not known whether RESV enhances physiological adaptations to ET. To investigate this, male Wistar rats were randomly assigned to a control chow diet or a chow diet that contained RESV (4 g kg⁻¹ of diet) and subsequently subjected to a programme of progressive treadmill running for 12 weeks. ET-induced improvements in exercise performance were enhanced by 21% (P <0.001) by the addition of RESV to the diet. In soleus muscle, ET+RESV increased both the twitch (1.8-fold; P <0.05) and tetanic(1.2-fold; P <0.05) forces generated during isometric contraction, compared to ET alone. In vivo echocardiography demonstrated that ET+RESV also increased the resting left ventricular ejection fraction by 10% (P <0.05), and reduced left ventricular wall stress compared to ET alone.These functional changes were accompanied by increased cardiac fatty acid oxidation (1.2-fold;P <0.05) and favourable changes in cardiac gene expression and signal transduction pathways that optimized the utilization of fatty acids in ET+RESV compared to ET alone. Overall, our findings provide evidence that the capacity for fatty acid oxidation is augmented by the addition of RESV to the diet during ET, and that this may contribute to the improved physical performance of rats following ET.

GABA facilitates spike propagation through branch points of sensory axons in the spinal cord.

Movement and posture depend on sensory feedback that is regulated by specialized GABAergic neurons (GAD2+) that form axo-axonic contacts onto myelinated proprioceptive sensory axons and are thought to be inhibitory. However, we report here that activating GAD2+ neurons directly with optogenetics or indirectly by cutaneous stimulation actually facilitates sensory feedback to motor neurons in rodents and humans. GABAA receptors located at or near nodes of Ranvier of sensory axons cause this facilitation by preventing spike propagation failure at the many axon branch points, which is otherwise common without GABA. In contrast, GABAA receptors are generally lacking from axon terminals and so cannot inhibit transmitter release onto motor neurons, unlike GABAB receptors that cause presynaptic inhibition. GABAergic innervation near nodes and branch points allows individual branches to function autonomously, with GAD2+ neurons regulating which branches conduct, adding a computational layer to the neuronal networks generating movement and likely generalizing to other central nervous system axons.

Carotid chemoreceptor modulation of blood flow during exercise in healthy humans.

Carotid chemoreceptor (CC) inhibition reduces sympathetic nervous outflow in exercising dogs and humans. We sought to determine if CC suppression increases muscle blood flow in humans during exercise and hypoxia. Healthy subjects (N = 13) were evaluated at rest and during constant-work leg extension exercise while exposed to either normoxia or hypoxia (inspired O(2) tension, F(IO(2)), ≈ 0.12, target arterial O(2) saturation = 85%). Subjects breathed hyperoxic gas (F(IO(2)) ≈ 1.0) and/or received intravenous dopamine to inhibit the CC while femoral arterial blood flow data were obtained continuously with pulsed Doppler ultrasound. Exercise increased heart rate, mean arterial pressure, femoral blood flow and conductance compared to rest. Transient hyperoxia had no significant effect on blood flow at rest, but increased femoral blood flow and conductance transiently during exercise without changing blood pressure. Similarly, dopamine had no effect on steady-state blood flow at rest, but increased femoral blood flow and conductance during exercise. The transient vasodilatory response observed by CC inhibition with hyperoxia during exercise could be blocked with simultaneous CC inhibition with dopamine. Despite evidence of dopamine reducing ventilation during hypoxia, no effect on femoral blood flow, conductance or mean arterial pressure was observed either at rest or during exercise with CC inhibition with dopamine while breathing hypoxia. These findings indicate that the carotid chemoreceptor contributes to skeletal muscle blood flow regulation during normoxic exercise in healthy humans, but that the influence of the CC on blood flow regulation in hypoxia is limited.

Asymmetric electrotonic coupling between the soma and dendrites alters the bistable firing behaviour of reduced models.

The goal of the study was to investigate the influence of asymmetric coupling, between the soma and dendrites, on the nonlinear dynamic behaviour of a two-compartment model. We used a recently published method for generating reduced two-compartment models that retain the asymmetric coupling of anatomically reconstructed motor neurons. The passive input-output relationship of the asymmetrically coupled model was analytically compared to the symmetrically coupled case. Predictions based on the analytic comparison were tested using numerical simulations. The simulations evaluated the nonlinear dynamics of the models as a function of coupling parameters. Analytical results showed that the input resistance at the dendrite of the asymmetric model was directly related to the degree of coupling asymmetry. In contrast, a comparable symmetric model had identical input resistances at both the soma and dendrite regardless of coupling strength. These findings lead to predictions that variations in dendritic excitability, subsequent to changes in input resistance, might change the current threshold and onset timing of the plateau potential generated in the dendrite. Since the plateau potential underlies bistable firing, these results further predicted that asymmetric coupling might alter nonlinear (i.e. bistable) firing patterns. The numerical simulations supported analytical predictions, showing that the fully bistable firing pattern of the asymmetric model depended on the degree of coupling asymmetry and its correlated dendritic excitability. The physiological property of asymmetric coupling plays an important role in generating and stabilizing the bistability of motor neurons by interacting with the excitability of dendritic branches.

Decreased excitability of motor axons contributes substantially to contraction fatigability during neuromuscular electrical stimulation.

The present study was designed to (i) determine the time course of changes in motor axon excitability during and after neuromuscular electrical stimulation (NMES); and (ii) characterize the relationship between contraction fatigability, NMES frequency, and changes at the axon, neuromuscular junction, and muscle. Eight neurologically intact participants attended 3 sessions. NMES was delivered over the common peroneal nerve at 20, 40, or 60 Hz for 8 min (0.3 s "on", 0.7 s "off"). Threshold tracking was used to measure changes in axonal excitability. Supramaximal stimuli were used to assess neuromuscular transmission and force-generating capacity of the tibialis anterior muscle. Torque decreased by 49% and 62% during 8 min of 40 and 60 Hz NMES, respectively. Maximal twitch torque decreased only during 60 Hz NMES. Motor axon excitability decreased by 14%, 27%, and 35% during 20, 40, and 60 Hz NMES, respectively. Excitability recovered to baseline immediately (20 Hz) and at 2 min (40 Hz) and 4 min (60 Hz) following NMES. Overall, decreases in axonal excitability best predicted how torque declined over 8 min of NMES. During NMES, motor axons become less excitable and motor units "drop out" of the contraction, contributing substantially to contraction fatigability and its dependence on NMES frequency. Novelty: The excitability of motor axons decreased during NMES in a frequency-dependent manner. As excitability decreased, axons failed to reach threshold and motor units dropped out of the contraction. Overall, decreased excitability best predicted how torque declined and thus is a key contributor to fatigability during NMES.

Heart rate variability and muscle sympathetic nerve activity response to acute stress: the effect of breathing.

Previous research has suggested a relationship between low-frequency power of heart rate variability (HRV; LF in normalized units, LFnu) and muscle sympathetic nerve activity (MSNA). However, investigations have not systematically controlled for breathing, which can modulate both HRV and MSNA. Accordingly, the aims of this experiment were to investigate the possibility of parallel responses in MSNA and HRV (LFnu) to selected acute stressors and the effect of controlled breathing. After data were obtained at rest, 12 healthy males (28 +/- 5 yr) performed isometric handgrip exercise (30% maximal voluntary contraction) and the cold pressor test in random order, and were then exposed to hypoxia (inspired fraction of O(2) = 0.105) for 7 min, during randomly assigned spontaneous and controlled breathing conditions (20 breaths/min, constant tidal volume, isocapnic). MSNA was recorded from the peroneal nerve, whereas HRV was calculated from ECG. At rest, controlled breathing did not alter MSNA but decreased LFnu (P < 0.05 for all) relative to spontaneous breathing. MSNA increased in response to all stressors regardless of breathing. LFnu increased with exercise during both breathing conditions. During cold pressor, LFnu decreased when breathing was spontaneous, whereas in the controlled breathing condition, LFnu was unchanged from baseline. Hypoxia elicited increases in LFnu when breathing was controlled, but not during spontaneous breathing. The parallel changes observed during exercise and controlled breathing during hypoxia suggest that LFnu may be an indication of sympathetic outflow in select conditions. However, since MSNA and LFnu did not change in parallel with all stressors, a cautious approach to the use of LFnu as a marker of sympathetic activity is warranted.

Derivation of cable parameters for a reduced model that retains asymmetric voltage attenuation of reconstructed spinal motor neuron dendrites.

Spinal motor neurons have voltage gated ion channels localized in their dendrites that generate plateau potentials. The physical separation of ion channels for spiking from plateau generating channels can result in nonlinear bistable firing patterns. The physical separation and geometry of the dendrites results in asymmetric coupling between dendrites and soma that has not been addressed in reduced models of nonlinear phenomena in motor neurons. We measured voltage attenuation properties of six anatomically reconstructed and type-identified cat spinal motor neurons to characterize asymmetric coupling between the dendrites and soma. We showed that the voltage attenuation at any distance from the soma was direction-dependent and could be described as a function of the input resistance at the soma. An analytical solution for the lumped cable parameters in a two-compartment model was derived based on this finding. This is the first two-compartment modeling approach that directly derived lumped cable parameters from the geometrical and passive electrical properties of anatomically reconstructed neurons.

Development and use of the incremental twitch subtraction MUNE method in mice.

We have used a technique to estimate the number of functioning motor units (MUNE) innervating a muscle in mice based on twitch tension. The MUNE technique was verified by modeling twitch tensions from isolated ventral root stimulation. Analysis by twitch tensions allowed us to identify motor unit fiber types. The MUNE technique was used to compare normal mice with transgenic superoxide dismutase-1 mutation (G94A) mice to assess the time course of motor unit loss with respect to fiber type. Motor unit loss was found to occur well in advance of behavioral changes and the degree of reinnervation is dependent upon motor unit fiber types.

Change in excitability of motor axons modifies statistical MUNE results.

Motor unit number estimation (MUNE) techniques--whether they reflect a true motor unit count or some related index--should not be confounded by changes in the neuromuscular system other than a decline in the number of functional motor units. In neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), there is evidence of changes in the excitability of motor axons. If changes in axon excitability confound a particular MUNE technique, this would influence the use of that technique in ALS patients. We hypothesized on the basis of computational models that changes in axon membrane excitability would change the outcome of a statistical MUNE test, even though the true number of motor units remained unchanged. To test the validity of the model predictions we induced changes in axon excitability of healthy control subjects by applying a polarizing current while simultaneously carrying out a statistical MUNE test. In a group of 7 subjects we found a significant difference in MUNE as a result of the change in axon excitability produced by the polarizing current (paired t-test, P < 0.05). We conclude that the statistical MUNE method is confounded by changes in axon excitability. Since increasing evidence shows that axon excitability is altered as part of the pathophysiological process underlying ALS, clinical researchers should be cautious when using statistical MUNE with this patient population.

A review of acute responses, after-effects and chronic complications related to microneurography.

Microneurography, a technique used to detect postganglionic sympathetic nerve traffic in humans, is increasingly used to further the understanding of autonomic regulation in health and disease. The technique involves the transcutaneous insertion of a microelectrode into a peripheral nerve, following which, a variety of adverse acute responses; after-effect and chronic complications have been documented. Here, we comprehensively review the potential adverse outcomes of microneurography and provide updated quantifiable incidence rates of their occurrence within a general population. We also present recommendations for risk assessment and management of such outcomes, as well as recommendations to improve future reporting. This review aims to use objective evidence to improve the understanding of the rare, but present, adverse outcomes of microneurography.

Conditioning electrical stimulation promotes functional nerve regeneration.

Peripheral nerve regeneration following injury is often incomplete, resulting in significant personal and socioeconomic costs. Although a conditioning crush lesion prior to surgical nerve transection and repair greatly promotes nerve regeneration and functional recovery, feasibility and ethical considerations have hindered its clinical applicability. In a recent proof of principle study, we demonstrated that conditioning electrical stimulation (CES) had effects on early nerve regeneration, similar to that seen in conditioning crush lesions (CCL). To convincingly determine its clinical utility, establishing the effects of CES on target reinnervation and functional outcomes is of utmost importance. In this study, we found that CES improved nerve regeneration and reinnervation well beyond that of CCL. Specifically, compared to CCL, CES resulted in greater intraepidermal skin and NMJ reinnervation, and greater physiological and functional recovery including mechanosensation, compound muscle action potential on nerve conduction studies, normalization of gait pattern, and motor performance on the horizontal ladder test. These findings have direct clinical relevance as CES could be delivered at the bedside before scheduled nerve surgery.