Nerve Research Articles

AAV1.tMCK.NT-3 gene therapy improves phenotype in Sh3tc2-/- mouse model of Charcot-Marie-Tooth type 4C

Abstract Charcot-Marie-Tooth type 4C (CMT4C) is associated with mutations in the SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene, primarily expressed in Schwann cells (SCs). Neurotrophin-3 (NT-3) is an important autocrine factor for SC survival and differentiation, and it stimulates neurite outgrowth and myelination. In this study, scAAV1.tMCK.NT-3 was delivered intramuscularly to four-week-old Sh3tc2−/− mice, a model for CMT4C, and treatment efficacy was assessed at six months post-gene delivery. Efficient transgene production was verified with the detection of NT-3 in serum from the treated cohort. NT-3 gene therapy improved functional and electrophysiological outcomes including rotarod, grip strength, and nerve conduction velocity. Qualitative and quantitative histopathological studies showed that hypomyelination of peripheral nerves and denervated status of neuromuscular junctions at lumbrical muscles were also improved in the NT-3 treated mice. Morphometric analysis in mid sciatic and tibial nerves showed treatment-induced distally prominent regenerative activity in the nerve, and an increase in the estimated SCs density. This indicates that SC proliferation and differentiation, including the promyelination stage, are normal in the Sh3tc2-/- mice, consistent with the previous findings that Sh3tc2 is not involved in early stages of myelination. Moreover, in size distribution histograms the number of myelinated axons within the 3-6 µm diameter range increased, suggesting that treatment resulted in continuous radial growth of regenerating axons over time. In conclusion, this study demonstrates the efficacy of AAV1.NT-3 gene therapy in the Sh3tc2−/− mouse model of CMT4C, the most common recessively inherited demyelinating CMT subtype.

Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1).

Consensus recommendation published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation to enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a "Symposium on Atypical Neurofibroma: State of the Science". Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling, and recommend molecular profiling for clinically or radiologically worrisome non-cutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming "low-grade MPNST" to "ANNUBP with increased proliferation" to avoid the use of the "malignant" term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms.

Infantile Krabbe disease (0-12 months), progression, and recommended endpoints for clinical trials.

Krabbe disease is due to deficiency of galactocerebrosidase, resulting in progressive neurodegeneration due to demyelination. The purpose of this study is to document disease progression in the newly classified infantile-onset (0-12 months). We evaluated the outcomes of hematopoietic stem cell transplantation (HSCT) and described meaningful clinical endpoints. Patients with infantile Krabbe disease were prospectively evaluated between 2000 and 2022. All patients underwent comprehensive and standardized protocols. Descriptive statistics and Kaplan-Meier survival curves were used for analysis. One hundred and thirty-seven children with infantile Krabbe disease were included (68 males and 69 females). Of the 137, 96 were not treated and 41 underwent hematopoietic stem cell transplantation. Twenty-three were asymptomatic and 18 symptomatic. Initial symptoms included irritability, developmental delay or loss of milestones, feeding difficulties, spasticity, and reflux with an average survival of 2.2. Abnormalities in nerve conduction studies, auditory brainstem responses, and brain MRIs were evident in both groups of patients. Age at transplantation and signs and symptoms determined functional outcomes. Symptomatic and asymptomatic transplanted patients showed an increase in galactocerebrosidase and a decrease in psychosine, but did not reach the normal range. The median survival for transplanted symptomatic patients was 5 years while asymptomatic was extended to 15.5 years. Infantile Krabbe disease with onset before 12 months is rapidly progressive. Irreversible brain damage occurs unless timely HSCT is performed. HSCT does not prevent the progression of peripheral nerve disease. This study can be used to monitor patients and evaluate the effects of future therapies.

Efficacy of Integrative Korean Medicine Treatment Including Ultrasound-Guided Pharmacopuncture in Patients with Lumbar Stenosis Accompanied by Peripheral Nerve Entrapments: Considering Double Crush Syndrome in This Report of Three Cases

Efficacy of Integrative Korean Medicine Treatment Including Ultrasound-Guided Pharmacopuncture in Patients with Lumbar Stenosis Accompanied by Peripheral Nerve Entrapments: Considering Double Crush Syndrome in This Report of Three Cases

Whole-body MRI-based long-term evaluation of pediatric NF1 patients without initial tumor burden with evidence of newly developed peripheral nerve sheath tumors

BackgroundPatients with neurofibromatosis type 1 (NF1) can develop plexiform neurofibromas (PN). Large tumor burden is a predictor for the development of malignant peripheral nerve sheath tumors. Whole-body magnetic resonance imaging (WB-MRI) is the recommended imaging method for the evaluation of PN. WB-MRI is recommended for NF1 patients at transition from adolescence to adulthood. In the absence of internal PN further follow-up WB-MRI is not considered necessary. PN are often detected in early childhood, leading to the assumption that they may be congenital lesions. It remains unclear whether this invariably applies to all patients or whether patients who initially displayed no tumors can still develop PN over time. Therefore, we retrospectively reviewed WB-MRI scans of pediatric patients with NF1 without initial tumor burden and compared these with long-term follow-up scans for presence of newly developed PN.MethodsWe retrospectively reviewed WB-MRI scans of 17 NF1-children (twelve male; median age at initial scan: 9 [IQR 6.1–11.9] years) who initially displayed no PN. MRI scans with a follow-up interval of at least 6 years (median follow-up interval: 9 [IQR 5.6–12.4] years) were reviewed in consensus by two radiologists regarding the development of new PN over time.ResultsNew PN were identified in two out of 17 children without initial tumor burden in follow-up examinations. One of these two patients developed two larger distinct PN of 4.5 cm on the right upper arm and of 2.5 cm on the left thoracic wall between the age of ten and twelve. The second child developed multiple smaller PN along the major peripheral nerves between the age of eleven and 16. In addition, 15 of the children without initial tumor burden did not develop any distinct tumors for a period of at least 6 years.ConclusionOur results indicate that PN can be newly detected in pediatric patients over time, even if no PN were detected on initial MRI scans. Therefore, it seems reasonable to perform at least a second MRI in pediatric NF1 patients at transition to adulthood, even if they did not display any tumor burden on initial MRI, and when the MRI was performed significantly under the age of 18. With this approach, tumors that may have developed between scans can be detected and patients at risk for complications can be identified.

Practice and challenges related to regional anesthesia in Amhara regional hospitals, Northwest-Ethiopia: a web-based survey study

BackgroundRegional anesthesia (RA) can improve patient outcomes and reduce perioperative complications including deaths. Despite its benefits, RA is less utilised in low-resource settings. The purpose of this study was to assess practice and challenges related to RA in Amhara Regional Hospitals, Northwest-Ethiopia.MethodsA web- based survey was distributed among 360 anesthetists working in Amhara Regional Hospitals, Northwest-Ethiopia from November 15 - January 30, 2023. An English, semi-structure, self-administered questionnaire was disseminated by email and telegram following ethical clearance. The survey included questions about the use of RA, socio-demographic characteristics of anesthetist, types of practiced regional blocks, and barriers to perform RA. All volunteer respondents who filled online questionnaire during study period were included. The data were coded and analyzed using statistical package for social Sciences (SPSS) software-version 20. Both inferential and descriptive statistics were used to describe the results.ResultsThe overall response rate was 63.3% (223 out of 360 completed surveys). A total of 132 respondents (36.7%) did not provide a response, and 5 respondents (1.4%) submitted incomplete) surveys. The most frequently self-reported barriers to performing peripheral nerve blocks were a lack of equipment (regional procedure kit including block needle, ultrasound, nerve stimulator, or epidural set) 185 (82.9%), lack of knowledge 171(76.7%), lack of practical skills 112 (50.2%), and lack of drugs/medication 50 (22.4%).ConclusionsThe principal findings indicate that all respondents perform spinal anaesthesia, while the practice of peripheral RA varies. Reported barriers to performing RA are related to knowledge and training, as well as a lack of equipment (there aren’t enough regional procedure kits available that include an epidural set, block needle, nerve stimulator, and ultrasound). A more stringent approach with specific requirements, distinguishing between neuraxial and peripheral blocks, enhance training opportunities for peripheral nerve blocks are required in Ethiopia.

Evaluation of the Impact of Advanced Glycation End-Products on Peripheral Neuropathy Outcomes in Type 2 Diabetes

Background: Type 2 diabetes (T2DM) affects over 500 million people worldwide, and over 50% of this group experience the most common complication, diabetic peripheral neuropathy (DPN). The presence of advanced glycation end-products (AGEs) has been linked with the development of DPN. The present study assessed AGE levels in participants with type 2 diabetes and explored the hypothesis that there may be increased AGE levels in more severe DPN. Methods: A total of 124 participants with T2DM were consecutively recruited, and they underwent skin autofluorescence, clinical assessment for peripheral neuropathy, peripheral nerve ultrasound, nerve conduction studies, and axonal excitability assessment. Results: AGE accumulation showed weak but significant correlations with neuropathy severity and reduced nerve conduction function. However, after adjusting for confounding variables, a linear regression analysis did not reveal significant associations between the AGE levels and neuropathy outcomes. Conclusions: The present study suggests that the accumulation of AGE is not associated with the clinical, electrophysiological, and morphological measures of neuropathy in T2DM.

The Role of Pain Medications in Modulating Peripheral Nerve Injury Recovery.

Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.

Challenges and Long-Term Outcomes of Cementless Total Hip Arthroplasty in Patients Under 30: A 24-Year Follow-Up Study with a Minimum 8-Year Follow-Up, Focused on Developmental Dysplasia of the Hip

Background: Total hip arthroplasty (THA) is a well-established and effective treatment for advanced osteoarthritis (OA) of the hip joint. While commonly performed in older patients, THA is increasingly used in younger individuals, especially in cases of secondary coxarthrosis. Technological advances have led to the development of specialized implants, which allow surgeons to address severe post-inflammatory or dysplastic deformities. Younger patients undergoing THA, often in their 20s or 30s, present higher functional expectations. Despite limited long-term studies, research indicates a higher rate of revision surgeries in this age group compared to older populations, making these procedures a unique challenge. Methods: This retrospective study analyzed 5263 primary total hip arthroplasties (THAs) performed at our center between May 1985 and December 2016. After excluding cemented and hybrid implants, as well as patients lost to follow-up or with other etiologies, 101 uncemented THA procedures in 92 patients aged 30 years or younger were included. The majority (64.4%) were due to dysplastic coxarthrosis (DDH), while avascular necrosis (26.7%) and juvenile rheumatoid arthritis (8.9%) accounted for the rest. The average patient age was 25.6 years, with a mean follow-up period of over 24 years. Surgical technique involved the anterolateral approach, with implants placed in the true acetabular region. Implants included Munich/Plasmacup, Mittelmeier, and P-M designs. Implant survival was estimated using the Kaplan–Meier estimator to determine the probability of implant longevity over the follow-up period. Outcomes were assessed using Merle d’Aubigné and Postel scores, modified by Charnley, alongside radiographic evaluations based on the Crowe, De Lee, and Gruen classifications. Results: Preoperatively radiological assessment of all hips was classified as grade IV according to the Kellgren–Lawrence scale. Over an average follow-up of 24 years, final outcomes using the modified Merle d’Aubigné and Postel (MAP) classification were excellent in 24%, good in 37%, satisfactory in 8%, and poor in 32% of cases. Results compared between DDH group and control group indicate significantly more poor results for the DDH group compared to the control group (p-value < 0.05). All poor outcomes were associated with prosthesis loosening, primarily involving P-M and Mittelmeier acetabular components. Complications included intraoperative fractures in five cases, peripheral nerve dysfunction in six cases, and heterotopic ossification in eight cases. Postoperative pain scores on the VAS scale improved from 6.8 to 1.7. The Kaplan–Meier estimator indicated 10-year survival rates of 85.2% for the entire prosthesis, with 69.8% survival at 15 years and 54.5% at 20 years. For each period the bio-functionality according to Kaplan–Meier estimator was in favor of the control group. Conclusions: Cementless THA in patients aged 30 or younger has demonstrated itself to be an efficacious treatment for hip osteoarthritis, yielding favorable bio-functional outcomes in both short- and long-term follow-up. Nevertheless, THA performed in the context of developmental dysplasia of the hip (DDH) carries a significantly elevated risk of postoperative complications, most notably aseptic loosening, which critically undermines implant survival rates. Given the young demographic and the anticipated prolonged functional lifespan of the prosthesis, there is an increased propensity for loosening over time, necessitating vigilant and sustained postoperative surveillance.

TGF-β superfamily-induced transcriptional activation pathways establish the RAD52-dependent ALT machinery during malignant transformation of MPNSTs

To study telomere maintenance mechanism (TMM) activation during malignant transformation, we compared neurofibroma (NF) and malignant peripheral nerve sheath tumor (MPNST) in the same patient with type-1 neurofibromatosis (NF1), a total of 20 NF-MPNST pairs in 20 NF1 patients. These comparisons minimized genetic bias and contrasted only changes associated with malignant transformation, while subtracting changes that developed upon the transformation of normal cells to the benign tumor. TGF-β superfamily genes were found to activate the PAX and SOX transcription factors, leading to TMM activation. BMPER activates PAX6 through BMP2 and PAX7 through BMP4; BMP15 activates SOX14; and INHBC activates PAX9 and SOX14. The activated PAX and SOX genes sequentially establish the core architecture of the RAD52-dependent alternative lengthening of telomeres (ALT). Specifically, PAX7 activates the recombinase (RAD52) and a negative regulator (SLX4IP). PAX6 and SOX14 activate positive regulators (BLM and BRCA2, respectively). PAX9 and SOX14 activate RAD9B and FEN1, which are responsible for the stability of homologous recombination intermediates and increase, together with RAD52, the telomere length. Telomere elongation achieved by the activation of PAX7 and PAX9 is associated with a poor prognosis. We demonstrated that TGF-β superfamily-induced transcriptional activation pathways activated the RAD52-dependent ALT during malignant transformation of MPNSTs.

The periaxonal space as a conduit for cerebrospinal fluid flow to peripheral organs

Mechanisms controlling the movement of the cerebrospinal fluid (CSF) toward peripheral nerves are poorly characterized. We found that, in addition to the foramina Magendie and Luschka for CSF flow toward the subarachnoid space and glymphatic system, CSF outflow could also occur along periaxonal spaces (termed "PAS pathway") from the spinal cord to peripheral organs, such as the liver and pancreas. When interrogating the latter route, we found that serotonin, acting through 5-HT2B receptors expressed in ependymocytes that line the central canal, triggered Ca2+ signals to induce polymerization of F-actin, a cytoskeletal protein, to reduce the volume of ependymal cells. This paralleled an increased rate of PAS-mediated CSF redistribution toward peripheral organs. In the liver, CSF was received by hepatic stellate cells. CSF efflux toward peripheral organs through the PAS pathway represents a mechanism dynamically connecting the nervous system with the periphery. Our findings are compatible with the traditional theory of CSF efflux into the glymphatic system to clear metabolic waste from the cerebral parenchyma. Thus, we extend the knowledge of CSF flow and expand the understanding of connectivity between the CNS and peripheral organs.

Mature mediastinal teratoma with adhesions to the pericardium: A rare case report.

Mature mediastinal teratoma (MMT) is a benign tumor that is composed of well-differentiated tissues from all three germ cell layers. Malignant tumors have a distinct feature of adhering to the surrounding organs. Therefore, adhesion of MMT to the adjacent tissues, as a benign tumor, is rare and considered a surgical challenge. It leads to incomplete tumor resection to avoid damage to the surrounding tissues. MMT is a germ cell tumor that contains well-differentiated tissues from ectodermal, mesodermal, and endodermal germ cell layers. MMT comprises approximately 3%-12% of mediastinal tumors in adults and 60%-70% of mediastinal germ cell tumors. Complete surgical resection is the standard treatment. When adhesion to the surrounding tissues is present, residual tissues could be retained to reduce the injury of the peripheral blood vessels and nerves. We are reporting a rare case of MMT with adhesions to the pericardium and discussing the diagnostic and surgical challenges.

Ultrasound-guided popliteal sciatic nerve block for surgical anesthesia in wound care patients with ongoing anticoagulant/antiaggregant therapy: A single-center, prospective study.

Ultrasound-guided peripheral nerve blocks may be a good alternative in patients under antithrombotic drugs. We evaluated the efficacy of ultrasound-guided popliteal sciatic nerve block in patients undergoing lower extremity wound debridement of whom antithrombotic drugs could not be stopped. We focused on hemorrhagic complications related to sciatic nerve block. Wound care patients followed by Cardiovascular Surgery Department scheduled for lower extremity wound surgery were included in this prospective observational study. Data was collected between March 2021 and September 2022. All patient were under antithrombotic therapy and discontinuation of anticoagulant drugs were not possible. Single-insertion and multiple-injection sciatic nerve block at popliteal region was applied to all patients under ultrasound guidance. Primary outcome was the rate of hemorrhage. Secondary outcomes were block onset times, block success and postoperative analgesia times. Data of 105 patients was evaluated, 87 were male and 18 were female. Mean patient age was 61.92 ± 10.06, mean patient body mass index was 25.68 ± 6.33. All patients were under 1 or more antithrombotic drugs. Only one minor hematoma was detected by postoperative ultrasonography control in 1 patient. Hemorrhage complication rate was 1 of 105 (% 0.95, 95% CI, 0.00024-0.051). Overall block success rate was 99.05%. Mean block onset time was 16.27 ± 5.69 minutes. Mean postoperative analgesia time was 19.5 ± 11.22 hours. Sciatic nerve block under ultrasound guidance using in-plane technique was safe and provided sufficient surgical anesthesia and postoperative analgesia for lower extremity wound debridement surgery in patients on antithrombotic drugs.

Fibroblast-derived IL-33 exacerbates orofacial neuropathic pain via the activation of TRPA1 in trigeminal ganglion neurons.

Damage to the peripheral nerves of trigeminal ganglion (TG) neurons leads to intractable orofacial neuropathic pain through the induction of neuroinflammation. However, the details of this process are not yet fully understood. Here, we found that fibroblast-derived interleukin (IL)-33 was required for the development of mechanical allodynia in whisker pad skin following infraorbital nerve injury (IONI). The amount of IL-33 in the TG increased after IONI when the mice exhibited mechanical allodynia. Neutralization of IL-33 in the TG inhibited the development of IONI-induced mechanical allodynia. Conversely, intra-TG administration of recombinant human IL-33 (rhIL-33) elicited mechanical allodynia in naïve mice. IL-33 and its receptor were exclusively expressed in fibroblasts and neurons, respectively, in the TG. Fibroblast ablation caused the loss of IL-33 in the TG and delayed the development of mechanical allodynia after IONI. rhIL-33 elicited an increase in intracellular Ca2+ concentration and subsequent enhancement of Ca2+ influx via transient receptor potential ankyrin 1 (TRPA1) in primary cultured TG neurons. Additionally, rhIL-33 facilitated membrane translocation of TRPA1 in the TG. Mechanical allodynia caused by intra-TG administration of rhIL-33 was significantly inhibited by pharmacological blockade or gene silencing of TRPA1 in the TG. Inhibition of protein kinase A abrogated TRPA1 membrane translocation and delayed mechanical allodynia after IONI. Substance P stimulation caused upregulation of IL-33 expression in primary cultured fibroblasts. Preemptive administration of a neurokinin-1 receptor antagonist in the TG attenuated mechanical allodynia and IL-33 expression following IONI. Taken together, these results indicate that fibroblast-derived IL-33 exacerbates TG neuronal excitability via suppression of tumorigenicity 2 (ST2)-TRPA1 signaling, ultimately leading to orofacial neuropathic pain.

Feasibility of a simultaneous ultrasound (US) and peripheral nerve stimulation (PNS) guided interscalene brachial plexus injection in calves

Feasibility of a simultaneous ultrasound (US) and peripheral nerve stimulation (PNS) guided interscalene brachial plexus injection in calves

The Role of Peripheral Nerve Stimulation in Perioperative Analgesia

The Role of Peripheral Nerve Stimulation in Perioperative Analgesia

Neuroplasticity and neuroimmune interactions in fatal asthma.

Alteration of airway neuronal function and density and bidirectional interaction between immune cells and sensory peripheral nerves have been proposed to trigger and perpetuate inflammation that contribute to asthma severity. To date, few studies analysed neuroplasticity and neuroinflammation in tissue of asthmatic individuals. We hypothesized that the presence of these phenomena would be a pathological feature in fatal asthma. We have quantified the expression of the pan-neuronal marker PGP9.5 and the neuronal sensory-derived neuropeptide calcitonin gene-related peptide (CGRP) in the large airways of 12 individuals deceased due to an asthma attack and compared to 10 control lung samples. The proximity between nerve bundles to eosinophils, mast cells and CADM1+ cells was also quantified. We have additionally developed a hPSC-derived sensory neuron/mast cell co-culture model, from where mast cells were purified and differences in gene expression profile assessed. Fatal asthma patients presented a higher PGP9.5 and CGRP positive area in the airways, indicating sensory neuroplasticity. Eosinophils, mast cells and CADM1+ cells were observed in close contact or touching the airway nerve bundles, and this was found to be statistically higher in fatal asthma samples. Invitro co-culture model showed that human mast cells adhere to sensory neurons and develop a distinct gene expression profile characterized by upregulated expression of genes related to heterophilic adhesion, activation and differentiation markers, such as CADM4, PTGS2, C-KIT, GATA2, HDC, CPA3, ATXN1 and VCAM1. Our results support a significant role for neuroplasticity and neuroimmune interactions in fatal asthma, that could be implicated in the severity of the fatal attack. Accordingly, the presence of physical neuron and mast cell interaction leads to differential gene expression profile in the later cell type.

A neuromuscular clinician's guide to magnetic resonance neurography.

Magnetic resonance neurography (MRN) is increasingly used in clinical practice for the evaluation of patients with a wide spectrum of peripheral nerve disorders. This review article discusses the technical aspects of MRN highlighting the core sequences performed for clinical care. A robust, high-resolution, heavily T2-weighted fluid-sensitive sequence performed on a 3.0 Tesla magnet system remains the main workhorse MRN sequence. In specific clinical scenarios, adjunct techniques such as diffusion-weighted imaging can be added to a protocol for disease characterization. In addition, gadolinium-based contrast material can also be administered for the purposes of image optimization (suppress adjacent vascular signal) and disease characterization. Technical modifications to field of view and planes of imaging can be made based on the clinical question and discussion with the radiologist(s). On fluid-sensitive MRN sequences, a normal peripheral nerve exhibits iso- to minimally hyperintense signal relative to skeletal muscle with a predictable trajectory, preserved "fascicular" architecture, and tapered caliber from proximal to distal. Peripheral nerve abnormalities on MRN include alterations in signal, caliber, architecture, diffusion characteristics as well as enhancement and provide information regarding the underlying etiology. Although some MRN findings including nerve hyperintensity and long-segmental enlargement are nonspecific, there are certain diagnoses that can be made with high certainty based on imaging including benign peripheral nerve tumors, high-grade peripheral nerve injury, and intraneural ganglia. The purpose of this article is to familiarize a neuromuscular clinician with fundamentals of MRN acquisition and interpretation to facilitate communication with the neuromuscular radiologist and optimize patient care.

Determining the degree of proximal nerve fascicle rotation in healthy controls using ultrahigh-frequency neuromuscular ultrasound: A pilot study.

Ultrahigh-frequency ultrasound (UHFUS) allows improved visualization and higher resolution images of nerve fascicles than standard high-frequency ultrasound. Dynamic UHFUS may detect the presence of fascicular entwinement, the recently described sonographic phenomenon of pathologic fascicular rotation seen in neuralgic amyotrophy. This pilot study aims to establish normative reference values and degrees of fascicular rotation for the proximal portions of commonly involved upper limb nerves in healthy controls using UHFUS. Twenty healthy participants underwent sonographic examination of the median, musculocutaneous, and radial nerves on both upper limbs using UHFUS with a 48 MHz linear transducer. A single rater assessed the degree of fascicular rotation in each peripheral nerve. Fascicular rotation appears to occur in the proximal portion of each of these nerves. The mean degree of fascicular rotation for each of the measured nerves was median 94.5°, musculocutaneous 97.9°, and radial 50.9°. The maximum observed fascicular rotation in each nerve was 180°. Age, sex, height, weight, body mass index, and race did not predict degree of fascicular rotation (all p > .103). A single-factor ANOVA test showed the degree of fascicular rotation differed in median, musculocutaneous, and radial nerves (F = 4.748, p = .011). UHFUS allows quantification of fascicular rotation in healthy controls in the median, musculocutaneous, and radial nerves, and provides normative data. The data from this pilot study may serve as control data for future comparative studies in conditions where fascicular rotation occurs, such as neuralgic amyotrophy.

P66shc deficiency attenuates high glucose-induced autophagy dysfunction in Schwann cells.

Schwann cells are the most abundant cells in the peripheral nervous system, maintaining the development, function and regeneration of peripheral nerves. Defects in these Schwann cells injury response potentially contribute to the pathogenesis of diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus. The protein p66shc is essential in regulating oxidative stress responses, autophagy induction and cell survival, and is also vital in the development of DPN. In this study, we hypothesized that p66shc mediates high glucose-induced oxidative stress and autophagic dysfunction. In Schwann cells treated with high glucose; p66shc expression, levels of reactive oxygen species, autophagy impairment, and early apoptosis were elevated. Inhibition of p66shc gene expression by siRNA reversed high glucose-induced oxidative stress, autophagy impairment, and early apoptosis. We also demonstrated that the levels of p66shc was increased, while autophagy-related proteins p62 and LC3 (LC3-II/I) were suppressed in the sciatic nerve of streptozotocin-induced diabetes mice. P66shc-deficient mice exhibited the improvement in autophagy impairment after diabetes onset. Our findings suggest that the p66 plays a crucial role in Schwann cell dysfunction, identifying its potential as a therapeutic target.