OBJECTIVE:Early repair of transected peripheral nerves is advocated to maximize recovery; however, clinical delays are common. Conditioning, a well-known method accelerating nerve regeneration, has never been used in a postinjury setting. The authors tested whether postinjury, prerepair conditioning electrical stimulation (CES) can biologically bridge the interval to surgery so that a delayed repair (DR) yields outcomes comparable to, or greater than, an immediate repair (IR). METHODS:Adult male Sprague Dawley rats were randomized to 4 cohorts: 1) CES-cut-IR (CES 1 week before nerve cut + IR), 2) cut-IR (cut and IR, no CES), 3) cut-DR (cut, DR 10 days later, no CES), and 4) cut-CES-DR (nerve cut, CES on postinjury day 3, DR 7 days later). Outcomes evaluated included axon extension 14 days postrepair, sensory recovery (von Frey thresholds, intraepidermal nerve fiber density), and motor recovery (toe-spread and ladder-rung performance, compound muscle action potential [CMAP] amplitudes, gastrocnemius mass, and innervated neuromuscular junctions [NMJs]). RESULTS:For all outcomes evaluated, postinjury CES significantly improved regeneration and reinnervation when compared with no-CES controls. Furthermore, this cohort also had outcomes comparable to the IR cohort that had been treated with CES. Axon extension was comparable between the cut-CES-DR (12.5 ± 0.9 mm) and the CES-cut-IR positive-control cohort (12.1 ± 0.7 mm), and significantly longer than cut-IR (6.9 ± 0.6 mm, p < 0.001) and cut-DR (7.2 ± 0.5 mm, p < 0.001) controls. Between 7 and 8 weeks postrepair, sensory recovery assessed with von Frey filaments identified sensory recovery in the cut-CES-DR cohort comparable to the CES-cut-IR positive control, and significantly greater than the cut-IR and cut-DR controls (both p < 0.001); these results were confirmed on intraepidermal nerve fiber density counts. At 8 weeks, motor function was improved in the cut-CES-DR cohort (toe spread 73.2% contralateral; ladder score 5.0 ± 0.1) versus cut-IR and cut-DR cohorts (approximately 43%; scores 3.6 and 3.3, respectively; p < 0.001), approximating CES-cut-IR cohort. This was confirmed by CMAP amplitudes, gastrocnemius muscle mass, and quantification of innervation NMJs, which demonstrated similar trends. CONCLUSIONS:A single, brief CES session delivered after injury and before repair enables delayed neurorrhaphy to recapitulate IR biology, significantly improving regeneration and reinnervation over delayed or IR without CES. This is the first demonstration of a conditioning-like effect in the clinically relevant situation of an already transected nerve. These results position postinjury CES as a practical bridge to surgery for timing-constrained nerve repairs.

INTRODUCTION/AIMS:Digital nerve lacerations are common. Current methods employed to differentiate intact and transected digital nerves lack diagnostic accuracy. This may result in patients with intact nerves undergoing unnecessary surgery. The objective of the study was to determine the best diagnostic method for detecting true sensory nerve transections and to delineate the sensitivities and specificities of common sensory tests. METHODS:Patients aged 18-65 years with suspected complete digital nerve lacerations were recruited. Sensory testing including static two-point discrimination (s2PD), Semmes-Weinstein Monofilaments, and Quantitative Sensory Testing were used prior to surgical exposure to evaluate different categories of sensory nerve fibers. Likelihood ratios, sensitivity, and specificity of each test were compared to direct visualization intraoperatively. Receiver operating characteristic (ROC) curves were used to determine the area under the curve (AUC) for each test. RESULTS:Of the 60 patients recruited, 41 (68%) had complete digital nerve transections while 19 (32%) had intact nerves. Heat pain threshold testing showed the greatest AUC at 0.812 ± 0.067 with a sensitivity of 90% and specificity of 65% at a cutoff of 22.1 just noticeable difference (JND). However, combining s2PD (7 mm, 100% sensitivity, 32% specificity) and warm detection threshold (WDT) (25 JND, 100% sensitivity, 37% specificity) in a two-step algorithm achieved 100% sensitivity and increased the specificity to 58%. DISCUSSION:Implementing a two-step diagnostic algorithm combining s2PD and WDT can effectively diagnose complete digital nerve laceration with high sensitivity and improved specificity. These findings underscore the utility of both tests in accurately identifying complete digital nerve lacerations.

OBJECTIVE:Carpal tunnel syndrome (CTS) can drastically impair one's ability to work and interferes with activities of daily living. We recently demonstrated that, in rodents, conditioning electrical stimulation (CES) delivered to the nerve 7 days prior to surgery imparts a conditioning lesion-like effect by accelerating the rate of regeneration along the entire length of the nerve. The goal of this study is to test the hypothesis that CES could accelerate nerve regeneration and improve function in patients with moderate or severe CTS. METHODS:Using a double-blind randomized controlled study design, patients received surgery + CES or surgery + sham stimulation. They were evaluated at regular intervals for 12 months following intervention. Primary outcome was motor unit number estimation (MUNE), supplemented with secondary outcomes including motor and sensory nerve conduction studies, Semmes Weinstein Monofilaments, and Moberg Pick-Up Test. RESULTS:Sixty-four participants were randomized to either the treatment or control groups. There was no significant demographic or physiological difference at baseline between the groups. No major adverse event was found with treatment. Following intervention, there was significantly greater increase in MUNE of 62 ± 71 in the treatment group compared to 25 ± 66 in the controls after 12 months. In the treatment group, there was correspondingly better physiological and functional recovery and hand dexterity compared with the controls. INTERPRETATION:CES is a safe, feasible, and efficacious treatment to improve nerve reinnervation and functional outcomes in patients with moderate or severe CTS. This may open future possibilities for more effective treatment for other peripheral nerve injuries. ANN NEUROL 2026;99:1251-1262.

Regeneration after peripheral nerve injury is often insufficient for functional recovery. Postoperative electrical stimulation (PES) following injury and repair significantly improves clinical outcomes; recently, conditioning electrical stimulation (CES), delivered before nerve injury, has been introduced as a candidate for clinical translation. PES accelerates the crossing of regenerating axons across the injury site, whereas CES accelerates the intrinsic rate of axonal regeneration; thus, it is likely that their mechanisms are distinct. The large body of literature investigating the mechanisms of electrical stimulation has not differentiated between CES and PES. In this review, we investigate the CES and PES paradigms within the existing literature, distinguish their mechanistic insights, and identify gaps in the literature. A systematic literature review was conducted, selecting articles identifying the pro-regenerative effects of electrical stimulation in the setting of peripheral nerve injury. As a mechanistic template, both paradigms implicate cation channels for the initiation of numerous signaling pathways that together upregulate regeneration-associated genes. CES and PES feature some overlap; activation of PI3K and MAPK signaling pathways, and upregulation of BDNF, GAP43, and GFAP are similar. Currently, the inflammatory environment in which PES is administered predominantly differentiates these mechanisms. However, gaps within the literature complicate the comparison between paradigms. Systematic review revealed the mechanisms for both CES and PES paradigms remain fragmented; though much of the literature assumes the involvement of particular signaling pathways, the evidence remains limited. Though it is likely there is overlap between mechanisms, further investigation is needed.

Background: Established barriers to general exercise and physical activity among individuals with head and neck cancer include dry mouth, difficulty eating, weight loss, fear of injury, comorbidities, and treatment-related symptoms of pain and fatigue. Methods/Design: A 12-week pragmatic randomized controlled trial was conducted followed by an optional supported exercise transition phase. Eligible participants were individuals with head and neck cancers who had undergone surgery and/or radiation therapy to lymph node regions in the neck. Participants were randomized to a comparison group involving a shoulder and neck physiotherapeutic exercise protocol, or to a combined experimental group comprising the shoulder and neck physiotherapeutic exercise protocol and lower-body resistance exercise training. The primary outcome of this study was fatigue-related quality of life. Results: Sixty-one participants enrolled, 59 (97%) completed the randomized trial phase, 55 (90%) completed the 24-week follow-up, and 52 (85%) completed the one-year follow-up. Statistically significant between-group differences were found in favor of the combined experimental group for the fatigue-related quality of life, fitness outcomes, and overall physical activity. Paired comparisons confirmed significant within-group improvements for both groups from baseline to one-year follow-up across most outcomes. Discussion: A group-based combined physiotherapeutic and lower-body resistance exercise program was feasible and effective. Findings are limited to individuals who had undergone a surgical neck dissection procedure. Given the complexity of head and neck cancer, further pragmatic interdisciplinary research is warranted.

Peripheral nerve injury is common and can have devastating consequences. In severe cases, functional recovery is often poor despite surgery. This is primarily due to the exceedingly slow rate of nerve regeneration at only 1-3 mm/day. The local environment in the distal nerve stump supportive of nerve regrowth deteriorates over time and the target end organs become atrophic. To overcome these challenges, investigations into treatments capable of accelerating nerve regrowth are of great clinical relevance and are an active area of research. One intervention that has shown great promise is perioperative electrical stimulation. Postoperative stimulation helps to expedite the Wallerian degeneration process and reduces delays caused by staggered regeneration at the site of nerve injury. By contrast, preoperative "conditioning" stimulation increases the rate of nerve regrowth along the nerve trunk. Over the past two decades, a rich body of literature has emerged that provides molecular insights into the mechanism by which electrical stimulation impacts nerve regeneration. The end result is upregulation of regeneration-associated genes in the neuronal body and accelerated transport to the axon front for regrowth. The efficacy of brief electrical stimulation on patients with peripheral nerve injuries was demonstrated in a number of randomized controlled trials on compressive, transection and traction injuries. As approved equipment to deliver this treatment is becoming available, it may be feasible to deploy this novel treatment in a wide range of clinical settings.

SUMMARY:Treatment of painful neuromas has long posed a significant challenge for peripheral nerve patients. The regenerative peripheral nerve interface (RPNI) provides the transected nerve with a muscle graft target to prevent neuroma formation. Discrepancies in RPNI surgical techniques between animal models ("inlay" RPNI) and clinical studies ("burrito" RPNI) preclude direct translation of results from bench to bedside and may account for variabilities in patient outcomes. The authors compared outcomes of these 2 surgical techniques in a rodent model. Animals treated with burrito RPNI after tibial nerve neuroma formation demonstrated no improvement in pain assessment, and tissue analysis revealed complete atrophy of the muscle graft with neuroma recurrence. By contrast, animals treated with inlay RPNI had significant improvement in pain with viable muscle grafts. The results suggest superiority of the inlay RPNI surgical technique for the management of painful neuroma in rodents. CLINICAL RELEVANCE STATEMENT:RPNIs are currently being used to prevent and treat neuroma and phantom limb pain. This preclinical study suggests the superiority of one surgical technique over the other.

INTRODUCTION: Nerve transfers (NTs) have been recognized as a promising strategy to improve traumatic spine cord injury (tSCI) patient function. Although different tSCI NT options have been detailed, little is known about the epidemiological and injury-related aspects of this patient population. METHODS: TSCI patients presenting to our institution were identified through a prospectively collected tSCI data registry. Inclusion criteria consisted of: i) admission with cervical tSCI (C1-T1) between 2005-2019, ii);18-years-old, iii) documented tSCI severity using the ASIA Impairment Scale (AIS). Two peripheral nerve (PN) experts independently evaluated each patient’s suitability for NT. Demographic, and traumatic and neurological injury-related variables were collected and analyzed. RESULTS: A total of 224 (32%) patients were selected for based on tSCI level (C1-T1). After initial review, there was 94% agreement between PN experts with discordant cases being discussed before reaching a final consensus. A total of 108 patients (15% of tSCIs and 48% of cervical tSCIs) were deemed appropriate NT candidates. Average age was 43-years-old and the majority were male (82/108, 76%). TSCI severity range included: 54 (50%) patients being AIS A, 17 (16%) AIS B, 34 (31%) AIS C, and 3 (3%) AIS D. AIS motor level range included: 7 (6%) C4, 40 (37%) C5, 22 (20%) C6, 38 (35%) C7, and 1 (1%) C8 patient. CONCLUSIONS: To our knowledge, this is the first study to detail the number of tSCI patients that may qualify for NT from a large prospective database. A large proportion of cervical tSCI patients were found to be candidates. Better characterizing the epidemiological and injury patterns of this patient population will form an important first step to increase awareness and inform tSCI NT candidate identification.

ABSTRACT: Introduction: Despite the importance of timing of nerve surgery after peripheral nerve injury, optimal timing of intervention has not been clearly delineated. The goal of this study is to explore factors that may have a significant impact on clinical outcomes of severe peripheral nerve injury that requires reconstruction with nerve transfer or graft. Materials and Methods: Adult patients who underwent peripheral nerve transfer or grafting in Alberta were reviewed. Clustered multivariable logistic regression analysis was used to examine the association of time to surgery, type of nerve repair, and patient characteristics on strength outcomes. Cox proportional hazard regression analysis model was used to examine factors correlated with increased time to surgery. Results: Of the 163 patients identified, the median time to surgery was 212 days. For every week of delay, the adjusted odds of achieving Medical Research Council strength grade ≥ 3 decreases by 3%. An increase in preinjury comorbidities was associated with longer overall time to surgery (aHR 0.84, 95% CI 0.74–0.95). Referrals made by surgeons were associated with a shorter time to surgery compared to general practitioners (aHR 1.87, 95% CI 1.14–3.06). In patients treated with nerve transfer, the adjusted odds of achieving antigravity strength was 388% compared to nerve grafting; while the adjusted odds decreased by 65% if the injury sustained had a pre-ganglionic injury component. Conclusion: Mitigating delays in surgical intervention is crucial to optimizing outcomes. The nature of initial nerve injury and surgical reconstructive techniques are additional important factors that impact postoperative outcomes.

: Introduction: Traumatic spinal cord injuries (tSCI) are common, often leaving patients irreparably debilitated. Therefore, novel strategies such as nerve transfers (NT) are needed for mitigating secondary SCI damage and improving function. Although different tSCI NT options exist,littleisknown abouttheepidemiologicalandinjury-relatedaspectsofthispatientpopulation.Here,wereportsuchcharacteristicsto better identify and understand the number and types of tSCI individuals who may benefit from NTs. Materials and Methods: Two peripheral nerve experts independently evaluated all adult tSCI individuals < 80 years old admitted with cervical tSCI (C1 – T1) between 2005 and 2019 with documented tSCI severity using the ASIA Impairment Scale for suitability for NT (nerve donor with MRC strength ≥ 4/5 and recipient ≤ 2/5). Demographic, traumatic injury, and neurological injury variables were collected and analyzed. Results: A total of 709 tSCI individuals were identified with 224 (32%) who met the selection criteria for participation based on their tSCI level (C1 – T1). Of these, 108 (15% of all tSCIs and 48% of all cervical tSCIs) were deemed to be appropriate NT candidates. Due to recovery, 6 NT candidates initially deem appropriate no longer qualified by their last follow-up. Conversely, 19 individuals not initially considered appropriate then become eligible by their last follow-up. Conclusion: We found that a large proportion

BACKGROUND AND OBJECTIVES:Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) surgeries manage neuroma pain; however, there remains considerable discord regarding the best treatment strategy. We provide a direct comparison of TMR and RPNI surgery using a rodent model for the treatment of neuroma pain. METHODS:The tibial nerve of 36 Fischer rats was transected and secured to the dermis to promote neuroma formation. Pain was assessed using mechanical stimulation at the neuroma site (direct pain) and von Frey analysis at the footpad (to assess tactile allodynia from collateral innervation). Once painful neuromas were detected 6 weeks later, animals were randomized to experimental groups: (a) TMR to the motor branch to biceps femoris, (b) RPNI with an extensor digitorum longus graft, (c) neuroma excision, and (d) neuroma in situ. The TMR/RPNIs were harvested to confirm muscle reinnervation, and the sensory ganglia and nerves were harvested to assess markers of regeneration, pain, and inflammation. RESULTS:Ten weeks post-TMR/RPNI surgery, animals had decreased pain scores compared with controls ( P < .001) and they both demonstrated neuromuscular junction reinnervation. Compared with neuroma controls, immunohistochemistry showed that sensory neuronal cell bodies of TMR and RPNI showed a decrease in regeneration markers phosphorylated cyclic AMP receptor binding protein and activation transcription factor 3 and pain markers transient receptor potential vanilloid 1 and neuropeptide Y ( P < .05). The nerve and dorsal root ganglion maintained elevated Iba-1 expression in all cohorts. CONCLUSION:RPNI and TMR improved pain scores after neuroma resection suggesting both may be clinically feasible techniques for improving outcomes for patients with nerve injuries or those undergoing amputation.

BACKGROUND:Reverse end-to-side (RETS) nerve transfer has become increasingly popular in patients with severe high ulnar nerve injury, but the reported outcomes have been inconsistent.OBJECTIVE:To evaluate the "babysitting effect," we compared outcomes after anterior interosseous nerve RETS transfer with nerve decompression alone. To evaluate the source of regenerating axons, a group with end-to-end (ETE) transfer was used for comparisons.METHODS:Electrophysiology measures were used to quantify the regeneration of anterior interosseous nerve (AIN) and ulnar nerve fibers while functional recovery was evaluated using key pinch and Semmes-Weinstein monofilaments. The subjects were followed postsurgically for 3 years.RESULTS:Sixty-two subjects (RETS = 25, ETE = 16, and decompression = 21) from 4 centers in Western Canada were enrolled. All subjects with severe ulnar nerve injury had nerve compression at the elbow except 10 in the ETE group had nerve laceration or traction injury. Postsurgically, no reinnervation from the AIN to the abductor digiti minimi muscles was seen in any of the RETS subjects. Although there was no significant improvement in compound muscle action potentials amplitudes and pressure detection thresholds in the decompression and RETS group, key pinch strength significantly improved in the RETS group (P < .05).CONCLUSION:The results from published clinical trials are conflicting in part because crossover regeneration from the donor nerve has never been measured. Unlike those with ETE nerve transfers, we found that there was no crossover regeneration in the RETS group. The extent of reinnervation was also no different from decompression surgery alone. Based on these findings, the justifications for this surgical technique need to be carefully re-evaluated.

The role of afferent feedback and central motor drive in muscle activation has a profound impact on our understanding of movement control in health and disease. Dr. Richard B. Stein was a pioneer who made major contributions to the field. In addition to fundamental discoveries using animal models, he translated this to the clinic to benefit patients with spinal cord and other neurological injuries. Along the way, he inspired a generation of scientists around the world.

It is important to quantify the amount of crossover innervation from the anterior interosseous nerve (AIN) through Martin‐Gruber anastomosis (MGA) particularly in patients with high ulnar nerve injury who undergo nerve transfer surgery. The objective of this study is to describe a novel electrophysiological method for quantifying innervation from the AIN that can be done using conventional nerve conduction study setup and commonly available software for analysis.

Kristine M. Chapman, Michael J. Berger , Christopher Doherty, Dimitri J. Anastakis, Heather L. Baltzer, Kirsty Usher Boyd, Sean G. Bristol, Brett Byers, K. Ming Chan , Cameron J.B. Cunningham, Kristen M. Davidge, Jana Dengler, Kate Elzinga, Jennifer L. Giuffre, Lisa Hadley, A Robertson Harrop, Mahdis Hashemi, J. Michael Hendry, Kristin L. Jack, Emily M. Krauss, Timothy J. Lapp, Juliana Larocerie, Jenny C. Lin, Thomas A. Miller, Michael Morhart, Christine B. Novak, Russell O’Connor, Jaret L. Olsen, Benjamin R. Ritsma, Lawrence R. Robinson , Douglas C. Ross, Christiaan Schrag, Alexander Seal, David T. Tang, Jessica Trier, Gerald Wolff, Justin Yeung

OBJECTIVE Chronically injured nerves pose a significant clinical challenge despite surgical management. There is no clinically feasible perioperative technique to upregulate a proregenerative environment in a chronic nerve injury. Conditioning electrical stimulation (CES) significantly improves sensorimotor recovery following acute nerve injury to the tibial and common fibular nerves. The authors' objective was to determine if CES could foster a proregenerative environment following chronically injured nerve reconstruction. METHODS The tibial nerve of 60 Sprague Dawley rats was cut, and the proximal ends were inserted into the hamstring muscles to prevent spontaneous reinnervation. Eleven weeks postinjury, these chronically injured animals were randomized, and half were treated with CES proximal to the tibial nerve cut site. Three days later, 24 animals were killed to evaluate the effects of CES on the expression of regeneration-associated genes at the cell body (n = 18) and Schwann cell proliferation (n = 6). In the remaining animals, the tibial nerve defect was reconstructed using a 10-mm isograft. Length of nerve regeneration was assessed 3 weeks postgrafting (n = 16), and functional recovery was evaluated weekly between 7 and 19 weeks of regeneration (n = 20). RESULTS Three weeks after nerve isograft surgery, tibial nerves treated with CES prior to grafting had a significantly longer length of nerve regeneration (p < 0.01). Von Frey analysis identified improved sensory recovery among animals treated with CES (p < 0.01). Motor reinnervation, assessed by kinetics, kinematics, and skilled motor tasks, showed significant recovery (p < 0.05 to p < 0.001). These findings were supported by immunohistochemical quantification of motor endplate reinnervation (p < 0.05). Mechanisms to support the role of CES in reinvigorating the regenerative response were assessed, and it was demonstrated that CES increased the proliferation of Schwann cells in chronically injured nerves (p < 0.05). Furthermore, CES upregulated regeneration-associated gene expression to increase growth-associated protein-43 (GAP-43), phosphorylated cAMP response element binding protein (pCREB) at the neuronal cell bodies, and upregulated glial fibrillary acidic protein expression in the surrounding satellite glial cells (p < 0.05 to p < 0.001). CONCLUSIONS Regeneration following chronic axotomy is impaired due to downregulation of the proregenerative environment generated following nerve injury. CES delivered to a chronically injured nerve influences the cell body and the nerve to re-upregulate an environment that accelerates axon regeneration, resulting in significant improvements in sensory and motor functional recovery. Percutaneous CES may be a preoperative strategy to significantly improve outcomes for patients undergoing delayed nerve reconstruction.

See article on pages 40–45 in this issue.