Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral and anal sphincter function. Part 4: Effectiveness of the motor reinnervation.

In pilot work, we showed that somatic nerve transfers can restore motor function in long-term decentralized dogs. We continue to explore the effectiveness of motor reinnervation in 30 female dogs. After anesthesia, 12 underwent bilateral transection of coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. Twelve months postdecentralization, eight underwent transfer of obturator nerve branches to pelvic nerve vesical branches, and sciatic nerve branches to pudendal nerves, followed by 10 mo recovery (ObNT-ScNT Reinn). The remaining four were euthanized 18 mo postdecentralization (Decentralized). Results were compared with 18 Controls. Squat-and-void postures were tracked during awake cystometry. None showed squat-and-void postures during the decentralization phase. Seven of eight ObNT-ScNT Reinn began showing such postures by 6 mo postreinnervation; one showed a return of defecation postures. Retrograde dyes were injected into the bladder and urethra 3 wk before euthanasia, at which point, roots and transferred nerves were electrically stimulated to evaluate motor function. Upon L2-L6 root stimulation, five of eight ObNT-ScNT Reinn showed elevated detrusor pressure and four showed elevated urethral pressure, compared with L7-S3 root stimulation. After stimulation of sciatic-to-pudendal transferred nerves, three of eight ObNT-ScNT Reinn showed elevated urethral pressure; all showed elevated anal sphincter pressure. Retrogradely labeled neurons were observed in L2-L6 ventral horns (in laminae VI, VIII, and IX) of ObNT-ScNT Reinn versus Controls in which labeled neurons were observed in L7-S3 ventral horns (in lamina VII). This data supports the use of nerve transfer techniques for the restoration of bladder function.NEW & NOTEWORTHY This data supports the use of nerve transfer techniques for the restoration of bladder function.

Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ \pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ \pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral, and anal sphincter function in a dog model. Part 3. nicotinic receptor characterization.

Very little is known about the physiological role of nicotinic receptors in canine bladders, although functional nicotinic receptors have been reported in bladders of many species. Utilizing in vitro methods, we evaluated nicotinic receptors mediating bladder function in dogs: control (9 female and 11 male normal controls, 5 sham operated), Decentralized (9 females, decentralized 6-21 mo), and obturator-to-pelvic nerve transfer reinnervated (ObNT-Reinn; 9 females; decentralized 9-13 mo, then reinnervated with 8-12 mo recovery). Muscle strips were collected, mucosa-denuded, and mounted in muscle baths before incubation with neurotransmitter antagonists, and contractions to the nicotinic receptor agonist epibatidine were determined. Strip response to epibatidine, expressed as percent potassium chloride, was similar (∼35% in controls, 30% in Decentralized, and 24% in ObNT-Reinn). Differentially, epibatidine responses in Decentralized and ObNT-Reinn bladder strips were lower than controls after tetrodotoxin (TTX, a sodium channel blocker that inhibits axonal action potentials). Yet, in all groups, epibatidine-induced strip contractions were similarly inhibited by mecamylamine and hexamethonium (ganglionic nicotinic receptor antagonists), SR 16584 (α3ß4 neuronal nicotinic receptor antagonist), atracurium and tubocurarine (neuromuscular nicotinic receptor antagonists), and atropine (muscarinic receptor antagonist), indicating that nicotinic receptors (particularly α3ß4 subtypes), neuromuscular and muscarinic receptors play roles in bladder contractility. In control bladder strips, since tetrodotoxin did not inhibit epibatidine contractions, nicotinic receptors are likely located on nerve terminals. The tetrodotoxin inhibition of epibatidine-induced contractions in Decentralized and ObNT-Reinn suggests a relocation of nicotinic receptors from nerve terminals to more distant axonal sites, perhaps as a compensatory mechanism to recover bladder function.

Targeted muscle reinnervation at the time of amputation to prevent the development of neuropathic pain.

INTRODUCTION: Targeted muscle reinnervation (TMR) is an established modality for the surgical management of neuropathic pain. Although the preventive effect of primary (acute) TMR at the time of amputation has been demonstrated previously, it remains unclear how many and which patients benefit most. Therefore, this study investigated the proportion of patients achieving sustained pain prophylaxis following amputation, as well as factors associated with its efficacy. METHODS: Primary patients who underwent TMR with a minimum follow-up of 6 months between 2018 and 2023 were enrolled. Pain outcomes (numeric rating scale [NRS], 0-10), comorbidities, and surgical factors were collected from chart review. Patients achieving sustained pain prophylaxis (NRS of ≤3 for ≥3 months until final follow-up) were identified. Multilevel mixed-effect models and multivariable regression were used to visualize pain courses and identify associated factors. RESULTS: Seventy-five patients who underwent primary TMR were included (median follow-up: 2.0 years), of whom 57.3% achieved sustained pain prophylaxis whereas 26.7% reported pain disappearance. Distal amputation levels (p = 0.036), a lower Elixhauser Comorbidity Index (p = 0.001), and the absence of psychiatric comorbidities (p = 0.039) were associated with pain prophylaxis. CONCLUSION: This study demonstrates that more than half of all patients undergoing primary TMR achieved sustained pain prophylaxis, and approximately a quarter of patients achieved sustained pain disappearance. Several factors associated with these favorable outcomes are described. These results will aid in preoperative counseling, managing patient expectations, and selecting patients who may benefit most from primary TMR surgery. LEVEL OF EVIDENCE: IV - Therapeutic.

Biology and pathophysiology of symptomatic neuromas.

ABSTRACT: Neuromas are a substantial cause of morbidity and reduction in quality of life. This is not only caused by a disruption in motor and sensory function from the underlying nerve injury but also by the debilitating effects of neuropathic pain resulting from symptomatic neuromas. A wide range of surgical and therapeutic modalities have been introduced to mitigate this pain. Nevertheless, no single treatment option has been successful in completely resolving the associated constellation of symptoms. While certain novel surgical techniques have shown promising results in reducing neuroma-derived and phantom limb pain, their effectiveness and the exact mechanism behind their pain-relieving capacities have not yet been defined. Furthermore, surgery has inherent risks, may not be suitable for many patients, and may yet still fail to relieve pain. Therefore, there remains a great clinical need for additional therapeutic modalities to further improve treatment for patients with devastating injuries that lead to symptomatic neuromas. However, the molecular mechanisms and genetic contributions behind the regulatory programs that drive neuroma formation-as well as the resulting neuropathic pain-remain incompletely understood. Here, we review the histopathological features of symptomatic neuromas, our current understanding of the mechanisms that favor neuroma formation, and the putative contributory signals and regulatory programs that facilitate somatic pain, including neurotrophic factors, neuroinflammatory peptides, cytokines, along with transient receptor potential, and ionotropic channels that suggest possible approaches and innovations to identify novel clinical therapeutics.

Demographic Representation in 3 Leading Artificial Intelligence Text-to-Image Generators.

Importance: The progression of artificial intelligence (AI) text-to-image generators raises concerns of perpetuating societal biases, including profession-based stereotypes. Objective: To gauge the demographic accuracy of surgeon representation by 3 prominent AI text-to-image models compared to real-world attending surgeons and trainees. Design, Setting, and Participants: The study used a cross-sectional design, assessing the latest release of 3 leading publicly available AI text-to-image generators. Seven independent reviewers categorized AI-produced images. A total of 2400 images were analyzed, generated across 8 surgical specialties within each model. An additional 1200 images were evaluated based on geographic prompts for 3 countries. The study was conducted in May 2023. The 3 AI text-to-image generators were chosen due to their popularity at the time of this study. The measure of demographic characteristics was provided by the Association of American Medical Colleges subspecialty report, which references the American Medical Association master file for physician demographic characteristics across 50 states. Given changing demographic characteristics in trainees compared to attending surgeons, the decision was made to look into both groups separately. Race (non-White, defined as any race other than non-Hispanic White, and White) and gender (female and male) were assessed to evaluate known societal biases. Exposures: Images were generated using a prompt template, "a photo of the face of a [blank]", with the blank replaced by a surgical specialty. Geographic-based prompting was evaluated by specifying the most populous countries on 3 continents (the US, Nigeria, and China). Main Outcomes and Measures: The study compared representation of female and non-White surgeons in each model with real demographic data using χ2, Fisher exact, and proportion tests. Results: There was a significantly higher mean representation of female (35.8% vs 14.7%; P < .001) and non-White (37.4% vs 22.8%; P < .001) surgeons among trainees than attending surgeons. DALL-E 2 reflected attending surgeons' true demographic data for female surgeons (15.9% vs 14.7%; P = .39) and non-White surgeons (22.6% vs 22.8%; P = .92) but underestimated trainees' representation for both female (15.9% vs 35.8%; P < .001) and non-White (22.6% vs 37.4%; P < .001) surgeons. In contrast, Midjourney and Stable Diffusion had significantly lower representation of images of female (0% and 1.8%, respectively; P < .001) and non-White (0.5% and 0.6%, respectively; P < .001) surgeons than DALL-E 2 or true demographic data. Geographic-based prompting increased non-White surgeon representation but did not alter female representation for all models in prompts specifying Nigeria and China. Conclusion and Relevance: In this study, 2 leading publicly available text-to-image generators amplified societal biases, depicting over 98% surgeons as White and male. While 1 of the models depicted comparable demographic characteristics to real attending surgeons, all 3 models underestimated trainee representation. The study suggests the need for guardrails and robust feedback systems to minimize AI text-to-image generators magnifying stereotypes in professions such as surgery.

The Case for Neurosurgical Intervention in Cancer Neuroscience.

The emerging field of cancer neuroscience reshapes our understanding of the intricate relationship between the nervous system and cancer biology; this new paradigm is likely to fundamentally change and advance neuro-oncological care. The profound interplay between cancers and the nervous system is reciprocal: Cancer growth can be induced and regulated by the nervous system; conversely, tumors can themselves alter the nervous system. Such crosstalk between cancer cells and the nervous system is evident in both the peripheral and central nervous systems. Recent advances have uncovered numerous direct neuron-cancer interactions at glioma-neuronal synapses, paracrine mechanisms within the tumor microenvironment, and indirect neuroimmune interactions. Neurosurgeons have historically played a central role in neuro-oncological care, and as the field of cancer neuroscience is becoming increasingly established, the role of neurosurgical intervention is becoming clearer. Examples include peripheral denervation procedures, delineation of neuron-glioma networks, development of neuroprostheses, neuromodulatory procedures, and advanced local delivery systems. The present review seeks to highlight key cancer neuroscience mechanisms with neurosurgical implications and outline the future role of neurosurgical intervention in cancer neuroscience.

Anatomical Location of the Vesical Branches of the Inferior Hypogastric Plexus in Human Cadavers.

We have demonstrated in canines that somatic nerve transfer to vesical branches of the inferior hypogastric plexus (IHP) can be used for bladder reinnervation after spinal root injury. Yet, the complex anatomy of the IHP hinders the clinical application of this repair strategy. Here, using human cadavers, we clarify the spatial relationships of the vesical branches of the IHP and nearby pelvic ganglia, with the ureteral orifice of the bladder. Forty-four pelvic regions were examined in 30 human cadavers. Gross post-mortem and intra-operative approaches (open anterior abdominal, manual laparoscopic, and robot-assisted) were used. Nerve branch distances and diameters were measured after thorough visual inspection and gentle dissection, so as to not distort tissue. The IHP had between 1 to 4 vesical branches (2.33 ± 0.72, mean ± SD) with average diameters of 0.51 ± 0.06 mm. Vesical branches from the IHP arose from a grossly visible pelvic ganglion in 93% of cases (confirmed histologically). The pelvic ganglion was typically located 7.11 ± 6.11 mm posterolateral to the ureteral orifice in 69% of specimens. With this in-depth characterization, vesical branches from the IHP can be safely located both posterolateral to the ureteral orifice and emanating from a more proximal ganglionic enlargement during surgical procedures.

Proximal forearm nerve branching patterns: an anatomical study and its clinical significance.

OBJECTIVE: The aim of this study was to add to the understanding of nerve branching patterns in the proximal forearm and consider optimal nerve transfer options to address the various injuries that affect the function of the upper extremity. METHODS: Eleven upper-extremity cadaveric specimens were dissected to expose the radial, median, and ulnar nerves in the proximal forearm. The site of origin of nerve branches from the major nerves was assessed, with measurements made in reference to the lateral epicondyle for the radial nerve branches and the medial epicondyle for the median and ulnar nerve branches. The distances to where these branches entered their respective muscles (muscle entry point) were assessed using the same landmarks. To plan a transfer, the length of the nerve branches was then calculated as the difference from the apparent origin from the main nerve trunk to the location where the nerve entered the muscle. Importantly, the nerve branch origin was established as the location of obvious separation from the main nerve trunk without additional fascicular dissection from the major nerve trunk. The number of branches was determined, and the diameter for each branch was measured using a Vernier caliper. RESULTS: The radial nerve branch to the extensor carpi radialis brevis (ECRB) muscle had an average length of 50.7 mm and average diameter of 1.6 mm. The mean medial and lateral lengths of the radial branches to the supinator muscle were found to be 22.2 mm (diameter 1.4 mm) and 15.3 mm (diameter 1.3 mm), respectively. The anterior interosseous nerve (AIN) branch of the median nerve was found 67.8 mm distal to the medial epicondyle with a diameter of 2.3 mm. The flexor carpi ulnaris (FCU) muscle innervation from the ulnar nerve was provided by 3 or 4 branches in most specimens. The second and third of these branches were the longest, with means of 30.5 mm (diameter 1.4 mm) and 30.7 mm (diameter 1.3 mm), respectively. CONCLUSIONS: While there is variability of the nerve branching pattern in the proximal forearm between specimens, the authors provide evidence of commonalities (branching patterns and distances) that can facilitate planning for upper-extremity nerve reconstructions. Importantly, all measurements are provided with reference to easily identified bony landmarks and to their muscle entry points to aid operative decision-making. These data complement the growing practice of nerve transfers in the upper extremity for a variety of pathologies.

Restoring bladder function using motor and sensory nerve transfers: a cadaveric feasibility study.

OBJECTIVE: Bladder dysfunction after nerve injury has a variable presentation, and extent of injury determines whether the bladder is spastic or atonic. The authors have proposed a series of 3 nerve transfers for functional innervation of the detrusor muscle and external urethral sphincter, along with sensory innervation to the genital dermatome. These transfers are applicable to only cases with low spinal segment injuries (sacral nerve root function is lost) and largely preserved lumbar function. Transfer of the posterior branch of the obturator nerve to the vesical branch of the pelvic nerve provides a feasible mechanism for patients to initiate detrusor contraction by thigh adduction. External urethra innervation (motor and sensory) may be accomplished by transfer of the vastus medialis nerve to the pudendal nerve. The sensory component of the pudendal nerve to the genitalia may be further enhanced by transfer of the saphenous nerve (sensory) to the pudendal nerve. The main limitations of coapting the nerve donors to their intrapelvic targets are the bifurcation or arborization points of the parent nerve. To ensure that the donor nerves had sufficient length and diameter, the authors sought to measure these parameters. METHODS: Twenty-six pelvic and anterior thigh regions were dissected in 13 female cadavers. After the graft and donor sites were clearly exposed and the branches identified, the donor nerves were cut at suitable distal sites and then moved into the pelvis for tensionless anastomosis. Diameters were measured with calipers. RESULTS: The obturator nerve was bifurcated a mean ± SD (range) of 5.5 ± 1.7 (2.0-9.0) cm proximal to the entrance of the obturator foramen. In every cadaver, the authors were able to bring the posterior division of the obturator nerve to the vesical branch of the pelvic nerve (located internal to the ischial spine) in a tensionless manner with an excess obturator nerve length of 2.0 ± 1.2 (0.0-5.0) cm. The distance between the femoral nerve arborization and the anterior superior iliac spine was 9.3 ± 1.8 (6.5-15.0) cm, and the distance from the femoral arborization to the ischial spine was 12.9 ± 1.4 (10.0-16.0) cm. Diameters were similar between donor and recipient nerves. CONCLUSIONS: The chosen donor nerves were long enough and of sufficient caliber for the proposed nerve transfers and tensionless anastomosis.

Spinal motor neuron transplantation to enhance nerve reconstruction strategies: Towards a cell therapy.

Nerve transfers have become a powerful intervention to restore function following devastating paralyzing injuries. A major limitation to peripheral nerve repair and reconstructive strategies is the progressive, fibrotic degeneration of the distal nerve and denervated muscle, eventually precluding recovery of these targets and thus defining a time window within which reinnervation must occur. One proven strategy in the clinic has been the sacrifice and transfer of an adjacent distal motor nerve to provide axons to occupy, and thus preserve (or "babysit"), the target muscle. However, available nearby nerves are limited in severe brachial plexus or spinal cord injury. An alternative and novel proposition is the transplantation of spinal motor neurons (SMNs) derived from human induced pluripotent stem cells (iPSCs) into the target nerve to extend their axons to occupy and preserve the targets. These cells could potentially be delivered through minimally invasive or percutaneous techniques. Several reports have demonstrated survival, functional innervation, and muscular preservation following transplantation of SMNs into rodent nerves. Advances in the generation, culture, and differentiation of human iPSCs now offer the possibility for an unlimited supply of clinical grade SMNs. This review will discuss the previous reports of peripheral SMN transplantation, outline key considerations, and propose next steps towards advancing this approach to clinic. Stem cells have garnered great enthusiasm for their potential to revolutionize medicine. However, this excitement has often led to premature clinical studies with ill-defined cell products and mechanisms of action, particularly in spinal cord injury. We believe the peripheral transplantation of a defined SMN population to address neuromuscular degeneration will be transformative in augmenting current reconstructive strategies. By thus removing the current barriers of time and distance, this strategy would dramatically enhance the potential for reconstruction and functional recovery in otherwise hopeless paralyzing injuries. Furthermore, this strategy may be used as a permanent axon replacement following destruction of lower motor neurons and would enable exogenous stimulation options, such as pacing of transplanted SMN axons in the phrenic nerve to avoid mechanical ventilation in high cervical cord injury or amyotrophic lateral sclerosis.

Common Topics of Publication and Levels of Evidence in the Current Hand Surgery Literature.

Background Scientific publications are the primary vehicle for the distribution of scientific findings, but there has been limited research on literature topic surveillance. We sought to identify and characterize the most commonly published topic domains in the hand surgery literature. Methods We performed a 6-month hypothesis testing phase to identify the most frequently published topics in three hand surgery journals: Hand, The Journal of Hand Surgery (American), and The Journal of Hand Surgery (European). We reviewed all of the published articles in these journals from June 2010 to May 2015 to identify and characterize publications related to the three most common topic domains. Results A total of 2,146 articles were published during the 5-year study period. The three most frequent topics domains included distal radius (DR) (11% of all articles), flexor tendon (FT) (9%), and carpal tunnel (CT) (7.5%). These subjects accounted for a total of 584 articles (27% of all publications) and 3,014 published pages during the study period. FT, CT, and DR publications were cited on average 2.3 times per year (2.5, 2.4, and 2.0, respectively). Conclusion A small subset of topic domains makes up a significant proportion of scientific publications in hand surgery.

Surgical Management of Chronic Wounds.

In this article, we outline the important role the surgeon plays in the management of chronic wounds. Debridement and washout are required for grossly infected wounds and necrotizing soft tissue infections. Cutaneous cancers such as squamous cell carcinomas may contribute to chronic wounds and vice versa; if diagnosed, these should be treated with wide local excision. Arterial, venous, and even lymphatic flows can be restored in select cases to enhance delivery of nutrients and removal of metabolic waste and promote wound healing. In cases where vital structures, such as bones, joints, tendons, and nerves, are exposed, vascularized tissue transfers are often required. These tissue transfers can be local or remote, the latter of which necessitates anastomoses of arteries and veins. Pressure sores are managed by relieving pressure, treating acute trauma or infection, and using rotation fasciocutaneous flaps. Lastly, the surgeon must always consider the possibility of osteomyelitis and retained foreign body as etiology for chronic wounds.

The Mechanism of Hyperbaric Oxygen Therapy in the Treatment of Chronic Wounds and Diabetic Foot Ulcers.

Non-healing wounds are a growing public health concern, and more than $25 billion per year in the US are spent caring for patients with chronic wounds. Many of these patients are referred to specialized wound centers, where hyperbaric oxygen therapy (HBO2T) has become a mainstay in healing wounds, especially diabetic foot ulcers (DFU). However, it is costly, with a typical course of therapy running into the tens of thousands of dollars. Presently, as many as 30-40% of DFU patients with Wagner's Grade 3 and 4 ulcers treated with HBO2T fail to heal by 24 weeks. Unfortunately, the patient will have already received lengthy therapy (30-60 daily treatments over 6-10 week time period) before having the wound deemed non-responsive. Currently, practitioners employ a combination of clinical markers, diagnostic testing and a four-week preliminary healing response, but this approach is inaccurate and delays definitive identification of HBO2T responder and non-responder phenotypes.

Anthropogenic Radio-Frequency Electromagnetic Fields Elicit Neuropathic Pain in an Amputation Model.

Anecdotal and clinical reports have suggested that radio-frequency electromagnetic fields (RF EMFs) may serve as a trigger for neuropathic pain. However, these reports have been widely disregarded, as the epidemiological effects of electromagnetic fields have not been systematically proven, and are highly controversial. Here, we demonstrate that anthropogenic RF EMFs elicit post-neurotomy pain in a tibial neuroma transposition model. Behavioral assays indicate a persistent and significant pain response to RF EMFs when compared to SHAM surgery groups. Laser thermometry revealed a transient skin temperature increase during stimulation. Furthermore, immunofluorescence revealed an increased expression of temperature sensitive cation channels (TRPV4) in the neuroma bulb, suggesting that RF EMF-induced pain may be due to cytokine-mediated channel dysregulation and hypersensitization, leading to thermal allodynia. Additional behavioral assays were performed using an infrared heating lamp in place of the RF stimulus. While thermally-induced pain responses were observed, the response frequency and progression did not recapitulate the RF EMF effects. In vitro calcium imaging experiments demonstrated that our RF EMF stimulus is sufficient to directly contribute to the depolarization of dissociated sensory neurons. Furthermore, the perfusion of inflammatory cytokine TNF-α resulted in a significantly higher percentage of active sensory neurons during RF EMF stimulation. These results substantiate patient reports of RF EMF-pain, in the case of peripheral nerve injury, while confirming the public and scientific consensus that anthropogenic RF EMFs engender no adverse sensory effects in the general population.