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Background: Brachial plexus avulsion (BPA) injuries can cause severe deafferentation pain. This has been successfully treated with dorsal root entry zone (DREZ) lesioning. Distortions in anatomy following a BPA injury can make identifying neural structures challenging. We describe a modification to the operative technique that improves the surgical view and the advanced intraoperative neuromonitoring (IONM) employed to identify DREZ. We have analysed the long-term outcomes for pain, quality of life, and complications in patients undergoing DREZ lesioning. Methods: This is a single-centre retrospective case series including patients who underwent DREZ lesioning with IONM for brachial plexus avulsion between 2012 and 2022. Analysed data included pre- and postoperative pain (VAS), quality of life score for chronic pain, and complications. The evolution of the surgical approach is discussed. Results: 44 consecutive patients underwent a DREZ lesioning procedure with intraoperative monitoring and mapping. In these patients the mean VAS score improved from 8.9 (7–10) to 1.87 (0–6) (p < 0.0001) at the time of discharge. 31 patients were followed-up for more than 12 months with a mean duration of follow-up of 41 months and their results were as follows: the mean VAS improved from 9.0 (7–10) to 4.1 (0–9) (p < 0.0001) at the last follow-up and the mean QOL values improved from 3.7 (2–6) to 7.4 (4–10) (p < 0.0001). The long-term outcomes were 'good' in 39%, 'fair' in 29% and 'poor' in 32% of patients. 55% of the patients were able to stop or reduce pain medications. Conclusions: Modifications of surgical technique provide better exposure of DREZ, and IONM aids in identifying DREZ in the presence of severe intra-dural changes. Long-term outcomes of DREZ lesioning indicate not only a reduction in pain but also a significant improvement in quality of life. [ABSTRACT FROM AUTHOR]

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate brain activity changes in patients suffering from neuropathic pain (NP) following brachial plexus avulsion (BPA). Methods: Fifteen patients with NP following BPA and eight healthy participants (HP) were recruited for this study. All participants underwent examination using resting-state functional MRI. The amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were calculated and compared between the BPA group, left-BPA subgroup, right-BPA subgroup, and the HP group using independent samples t-tests. Results: In the BPA group, there were notable increases in ALFF/ReHo observed in the left rolandic operculum, insula, and supramarginal gyrus, while decreases were observed in the left paracentral lobule, fusiform gyrus, calcarine fissure and surrounding cortex, lingual gyrus, precuneus, as well as the bilateral anterior/median cingulate and paracingulate gyri, supplementary motor area, and cerebellum. In the left-BPA subgroup, elevated ALFF/ReHo levels were identified in the left middle/inferior frontal gyri, rolandic operculum, and supramarginal gyrus, with corresponding decreases in the left calcarine fissure and surrounding cortex, inferior occipital gyrus, fusiform gyrus, lingual gyrus, as well as the bilateral anterior/median cingulate and paracingulate gyri, postcentral gyri, supplementary motor area, paracentral lobules, and cerebellum. The right-BPA subgroup displayed increased ALFF/ReHo in the left frontal lobe, rolandic operculum, insula, fusiform gyrus, and lingual gyrus, as well as the right cerebellum. Conversely, decreases in ALFF/ReHo were observed in the bilateral anterior/median cingulate and paracingulate gyri, calcarine fissure and surrounding cortex, cuneus, and occipital lobes. Conclusions: The NP after BPA caused spontaneous activity changes in brain regions associated with linguistic, visual, somatosensory, and motor coordination and processing function. The majority of these abnormal areas were situated in the left cerebral hemisphere, while the effect of cingulate gyri and cerebellum seemed to be bilateral.

Dorsal root entry zone (DREZ) lesioning may be used to treat neuropathic pain in patients with traumatic brachial plexus injuries. The clinical outcome after surgery is variable in the medical literature. We aimed to report the surgical outcome after DREZ lesioning by radiofrequency and to analyze prognostic factors such as the presence of a spinal cord injury identified before surgery. We conducted a retrospective study that included 57 patients who had experienced traumatic brachial plexus injuries and exhibited neuropathic pain that did not respond to conservative treatment methods. They were submitted to DREZ lesioning. We defined the inclusion and exclusion criteria, collected sociodemographic and clinical characteristics, and identified and classified spinal cord lesions based on magnetic resonance imaging. We applied statistical tests to evaluate the association between pain intensity after surgery and the radiological profile and sociodemographic characteristics. Immediately after surgery, the pain outcome was considered good or excellent in 50 patients (89.28%). At the last follow-up, it was good or excellent in 39 patients (68.43%). There was no association (P > 0.05) between the pain outcome and the variables analyzed (time interval between trauma and DREZ lesioning, presence of spinal cord injury, age, the number of avulsed roots, and the type of pain). DREZ lesioning using radiofrequency represents a significant therapeutic approach for managing neuropathic pain after a traumatic brachial plexus injury. Importantly, we found that the presence of a spinal cord injury is not associated with the surgical outcome. [ABSTRACT FROM AUTHOR]

Abstract: Dorsal root entry zone (DREZ) lesioning is a classical and effective treatment for brachial plexus avulsion (BPA). However, because of a limited number of cases reported in the literature, the factors affecting surgical outcomes are not known. Furthermore, whether this ablative procedure in the spinal level can change the status of phantom limb pain (PLP) and phantom limb sensation (PLS) is unknown. We retrospectively reviewed the patients with preganglionic BPA who underwent DREZ lesioning at a single center. Patients' baseline characteristics and long-term pain and complications were collected. Postoperative changes in PLP and PLS were recorded. Kaplan-Meier analysis was used to evaluate pain-free survival. Multivariate Cox regression analysis was performed to identify factors affecting pain outcomes. A total of 112 patients met the study inclusion criteria. With an average (range) follow-up of 47.4 (10-134) months, the long-term effectiveness and complication rate were 82.1% and 25.9%, respectively. Of 37 patients (33.0%) who developed PLS, 67.6% (25/37) experienced pain relief, whereas in 45.9% (17/37), PLS disappeared or changed after DREZ lesioning. Multivariate analysis showed that patients with shorter pain duration (≤5 years) and PLS had worse pain outcomes. This study revealed factors that predict the pain outcome of DREZ lesioning based on a large series of cases. The diverse postoperative changes in phantom limb indicate that the mechanisms underlying PLS and PLP at the spinal or supraspinal level may vary among patients with BPA. Future studies should investigate the contribution of maladaptive brain plasticity to the outcomes of patients undergoing DREZ lesioning. [ABSTRACT FROM AUTHOR]

Highlights • Quercetin (QCN) promotes motoneuron survival and accelerates axonal regeneration after brachial plexus root avulsion/re-implantation in rats. • QCN improves motor function recovery of the forelimb. • QCN exhibits neuroprotective effects via inhibiting neuroinflammation and upregulating the neurotrophins. • QCN alleviates the avulsion-induced oxidative damage in rats. • QCN inhibits the avulsion-induced neuronal apoptosis in rats. • QCN modulates Nrf2/HO-1 and neurotrophin/Akt/MAPK signaling pathways.

Abstract Background Intractable chronic pain, as well as motor, sensory, and autonomic neuropathy, significantly reduces the quality of life of brachial plexus avulsion (BPA) patients. We report the successful application of cervical selective nerve root injection (CSNRI) in a patient with BPA. Case presentation A 40-year-old man had been diagnosed with complete left BPA due to a motorcycle accident and underwent intercostal nerve transplantation at the age of 18 years and had been experiencing pain ever since. His pain increased after fracture of the left humerus, and he was referred to our pain management clinic. As his exacerbated pain was suspected to be due to peripheral nerve hypersensitivity, we performed repetitive ultrasound-guided CSNRI (3 mL of 1% mepivacaine of each) targeted C5 and 6 intervertebral foramina, and his symptoms gradually improved. Conclusions Repetitive CSNRI may help diagnose and treat BPA-associated peripheral neuropathic pain, even in patients diagnosed with BPA.

Axotomy-induced synaptic stripping modulates survival and axon regeneration of injured motoneurons. Celsr2 is supposed to mediate homophilic interactions of neighboring cells during development, and its role in synaptic stripping remains unknow. In a model of brachial plexus avulsion, Celsr2 knockout improved functional recovery, motoneuron survival, and axon regeneration. Celsr2 was indicated to express in spinal motoneurons, excitatory and inhibitory interneurons, astrocytes, and a subset of oligodendrocytes using Celsr2LacZ mice. Double immunostaining showed that the coverage of inhibitory and excitatory vesicles on injured motoneurons were remarkably reduced after injury, whereas more inhibitory vesicles were maintained in Celsr2−/− mutants than control mice. In the ultrastructure, the density of inhibitory F-boutons on injured motoneurons was higher in Celsr2−/− mutants than controls. Conditional knockout of Celsr2 in astrocytes or oligodendrocytes showed the similar axotomy-induced synaptic withdrawal to the control. RNAseq of injured spinal samples identified 12 MHC I molecules with significant changes between Celsr2−/− and control mice. After injury, expression of MHC I surrounding injured motoneurons was increased, particularly high in Celsr2−/− mutants. In conclusion, Celsr2 knockout enhances MHC I signaling, alleviates inhibitory synaptic stripping cell-autonomously, and contributes to motoneuron survival and regeneration, and Celsr2 is a potential target for neural repair. [ABSTRACT FROM AUTHOR]

Introduction: Brachial plexus avulsion (BPA) injury develops frequent and intense neuropathic pain, involving in both peripheral and central nervous systems. The incidence of anxiety or depression caused by BPA-induced neuropathic pain is high, but the underlying mechanism remains unclear. Methods: We established a BPA mice model and assessed its negative emotions through behavioral tests. To further explore the role of the microbiota-gut-brain axis in the unique emotional behavior after BPA, we performed intestinal fecal 16s and metabolomics assays. Psychobiotics (PB) supplementation was administered to BPA mice to check the probiotics effects on BPA-induced anxiety behaviors. Results: Pain related anxiety-like behavior was observed at the early stage after BPA (7 days), while no depression-like behavior was detected. Intriguingly, gut microbiota diversity was increased in BPA mice, and the most abundant probiotics, Lactobacillus, showed obvious changes. Lactobacillus_reuteri was significantly decreased in BPA mice. Metabolomics analysis showed that Lactobacillus_reuteri-related bile acid pathway and some neurotransmitter amino acids were significantly altered. Further PB (dominated by Lactobacillus_reuteri) supplementation could significantly relieve BPA-induced anxiety-like behaviors in mice. Conclusion: Our study suggests that pathological neuralgia after BPA could alter intestinal microbiota diversity, especially Lactobacillus, and the changes in neurotransmitter amino acid metabolites may be the key reason for the onset of anxiety-like behaviors in BPA mice. [ABSTRACT FROM AUTHOR]

Neuroinflammation results in neuropathic pain (NP) following brachial plexus avulsion (BPA). This research was designed for investigating the function of miR-506-3p in BPA-induced NP. A total brachial plexus root avulsion model was produced in adult rats as well as IL-1β-treated motoneuron-like NSC-34 cells and the LPS-treated microglia cell line BV2 for in vivo and in vitro experiments, respectively. RT-PCR and Western blot were performed to detect the profiles of miR-506-3p, CCL2 and CCR2, NF-κB, FOXO3a, TNF-α, IL-1β, and IL-6 in cells or the spinal cord close to the tBPI lesion. Neuronal apoptosis was evaluated by immunohistochemistry in vivo. CCK8, TUNEL staining, and the lactic dehydrogenase kit were adopted for the evaluation of neuronal viability or damage in vitro. RNA immunoprecipitation and dual luciferase reporter gene assays analyzed the targeted association between miR-506-3p and CCL2. As shown by the data, miR-506-3p was vigorously less expressed, while CCL2-CCR2, NF-κB TNF-α, IL-1β, and IL-6 were upregulated in the spinal cord with tBPI. Overexpression of miR-506-3p attenuated neuronal apoptosis and microglial inflammation. Mechanistically, CCL2 was a downstream target of miR-506-3p. Upregulating miR-506-3p dampened CCL2-CCR2 and NF-κB activation in the spinal cord and microglia. miR-506-3p had neuroprotective and inflammation-fighting functions in the tBPI rat model via CCL2/CCR2/NF-κB axis. [ABSTRACT FROM AUTHOR]

Background: Intractable chronic pain, as well as motor, sensory, and autonomic neuropathy, significantly reduces the quality of life of brachial plexus avulsion (BPA) patients. We report the successful application of cervical selective nerve root injection (CSNRI) in a patient with BPA. Case presentation: A 40-year-old man had been diagnosed with complete left BPA due to a motorcycle accident and underwent intercostal nerve transplantation at the age of 18 years and had been experiencing pain ever since. His pain increased after fracture of the left humerus, and he was referred to our pain management clinic. As his exacerbated pain was suspected to be due to peripheral nerve hypersensitivity, we performed repetitive ultrasound-guided CSNRI (3 mL of 1% mepivacaine of each) targeted C5 and 6 intervertebral foramina, and his symptoms gradually improved. Conclusions: Repetitive CSNRI may help diagnose and treat BPA-associated peripheral neuropathic pain, even in patients diagnosed with BPA. [ABSTRACT FROM AUTHOR]

Brachial plexus avulsion (BPA), which commonly occurs in neonatal birth injuries and car accidents, severely disrupts spinal cord segments and nerve roots. Avulsion is usually located in the transitional zone at the junction of spinal nerve roots and starting point of the spinal cord, which places heavy disability burdens on patients due to sensory and motor function loss in the innervated areas. Primary mechanical injuries and secondary pathogenesis, such as inflammatory infiltration and oxidative stress, lead to inefficient management and poor prognosis. Astaxanthin (AST) has a strong ability to bleach singlet oxygen and capture free radicals, quench singlet oxygen and trap free radicals, and folic acid (FC) can effectively inhibit the inflammatory response. This study aimed to investigate the therapeutic effects of AST and FC on BPA. The 24 h after BPA was considered the acute phase of the injury, and the combination of AST and FC had the best therapeutic effect due to the synergistic effect of AST's antioxidant and FC's anti-inflammatory properties. At 6 weeks after BPA, AST-FC promoted the recovery of biceps motor functions, increased myofiber diameter, enlarged the amplitude of musculocutaneous nerve-biceps compound action potential, and improved Terzis grooming test (TGT) scores. Meanwhile, more functional ventral horn motor neurons in the spinal cord were maintained. In conclusion, AST-FC combined therapy has a potential role in the clinical management of BPA since it can effectively alleviate oxidative stress and the inflammatory response in the acute phase of BPA, increase the survival rate of neurons, and promote neuronal regeneration and recovery of motor functions in the late stage of BPA. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the literature on the effectiveness of virtual reality (VR)- and augmented reality (AR)-based treatments for phantom limb pain (PLP) in postamputation or brachial plexus avulsion (BPA) populations. Methods: Multiple databases were queried in July 2021 with the keywords "virtual reality," "augmented reality," and "phantom limb pain." Included studies utilized VR or AR to treat PLP with outcome measurement. Two independent reviewers assessed methodological quality using the Physiotherapy Evidence Databsae (PEDro) Scale and the Methodological Index for Nonrandomized Studies (MINORS) scoring. Studies were separated into immersive and nonimmersive AR/VR systems, with further categorization according to the specific methodologies used. Results: Of 110 results from the database queries, 20 publications met the inclusion criteria. There was one unblinded, randomized, control trial (RCT), one single-blinded, randomized, crossover trial (RCxT), three comparative case series, 13 noncomparative case series, and two case reports. Seven of the 20 studies were classified as nonimmersive. Six studies reported decreased PLP after AR/VR treatments, of which four reported significant reductions. One study reported a reduction in PLP with no significant difference from control conditions. Thirteen of the 20 studies were classified as immersive AR/VR. Twelve studies reported decreased PLP after AR/VR treatments, of which eight reported significant reductions. One study found no change in PLP, compared to baseline. Conclusions: The number of studies using AR/VR in PLP treatment has expanded since a 2017 review on the topic. The majority of these studies offer support for the efficacy of treating PLP with AR/VR-based treatments. Research has expanded on the customization, outcome measurements, and statistical analysis of AR/VR treatments. While results are promising, most publications remain at the case series level, and clinical indications should be cautioned. With improvements in the quality of evidence, there remain avenues for further investigations, including increased sampling, randomization, optimization of treatment duration, and comparisons to alternative therapies. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a prevalent complication following brachial plexus avulsion (BPA). Ferroptosis has been implicated in various nervous system disorders. However, the association between ferroptosis and neuropathic pain induced by BPA remains unclear. This study aimed to investigate the role of ferroptosis in BPA-induced neuropathic pain. A rat model of neuropathic pain was established via BPA induction. Pain thresholds of rats were measured after BPA surgery and intraperitoneal injection of Fer-1. On day 14 postsurgery, spinal dorsal horn (SDH) samples were collected for Western blotting, biochemical analysis, and immunohistochemistry to analyze the expression and distribution of ferroptosis-related markers. The relationships among 5-HT3a receptor, calcium/calmodulin (CaM) pathway, and ferroptosis were assessed via Western blotting, biochemical analysis, and lipid peroxidation assays, including iron and calcium content, reactive oxygen species, glutathione peroxidase 4 (GPX4), ACSL, and CaM expression. BPA-induced neuropathic pain was associated with iron accumulation, increased lipid peroxidation, dysregulated expression of Acyl-CoA synthetase long-chain family member 4, and GPX4, and changes in transferrin receptor, divalent metal transporter 1, and ferroportin-1 (FPN1). Intraperitoneal administration of Fer-1 reversed all of these alterations and mitigated mechanical and cold hypersensitivity. Inhibition of the 5-HT3a receptor reduced the extent of ferroptosis. Furthermore, the 5-HT3a receptor can regulate the calcium/CaM pathway via L-type calcium channels (LTCCs), and blocking LTCCs with nifedipine also alleviated ferroptosis in the SDH of BPA rats. Taken together, in rats with BPA, the development of neuropathic pain involves ferroptosis, which is regulated by the 5-HT3a receptor through the LTCCs and the calcium/CaM signaling pathway in the SDH.

Introduction: Brachial plexus avulsion significantly increased brain‐derived neurotrophic factor (BDNF) release in the spinal cord. Here we investigated the involvement of the BDNF–TrkB–KCC2 pathway in neuropathic pain caused by BPA injury. We hypothesized that activation of BDNF–TrkB may inhibit neuronal excitability by downregulating KCC2 to maintain a high intracellular Cl‐concentration. We established a neuropathic pain rat model by avulsion of the lower trunk brachial plexus, and investigated the effects of the TrkB‐specific antibody K‐252a on the expression of BDNF, TrkB, and KCC2. Methods: We randomly divided 40 male SD rats into four groups. In the brachial plexus avulsion group, C8‐T1 roots were avulsed from the spinal cord at the lower trunk level. In the K252a group, 5uL K252a was applied intrathecally daily for three days after avulsion. In the sham surgery group, expose only and without damage. The control group did not undergo any treatment. Mechanical hyperalgesia and cold allodynia were analyzed by electronic pain measuring instrument and acetone spray method at different time points on days 1, 3, 7, 10, 14, and 21 after surgery. At 21 days after surgery, the expression of BDNF and TrkB in dorsal horn neurons and GFAP in astrocytes were detected by immunohistochemistry at the C5‐T1 segment of the spinal cord. The expression levels of BDNF, TrkB, and KCC2 in the C5‐T1 spinal cord were measured by Western Blot at 7 and 21 days. Results: Mechanical hyperalgesia and cold allodynia were significantly reduced in the K252a group compared with the brachial plexus avulsion group. Compared with the BPA group, BDNF, TrkB and GFAP were significantly decreased in the K252a group at 21 days after treatment by immunohistochemical test. In the WB test, the expressions of BDNF and TrkB in the K252a group were quantitatively detected to be decreased, while the expression of KCC2 was increased, which was obvious at 7 and 21 days. Conclusion: BDNF‐TrkB‐KCC2 pathway can significantly relieve neuropathic pain after BPA, and is a potential target for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Adult brachial plexus root avulsion can cause serious damage to nerve tissue and impair axonal regeneration, making the recovery of nerve function difficult. Nogo-A extracellular peptide residues 1-40 (NEP1-40) promote axonal regeneration by inhibiting the Nogo-66 receptor (NgR1), and poly (D, L-lactide-co-glycolide)-poly (ethylene glycol)-poly (D, L-lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel can be used to fill in tissue defects and concurrently function to sustain the release of NEP1-40. In this study, we established an adult rat model of brachial plexus nerve root avulsion injury and conducted nerve root replantation. PLGA-PEG-PLGA hydrogel combined with NEP1-40 was used to promote nerve regeneration and functional recovery in this rat model. Our results demonstrated that functional recovery was enhanced, and the survival rate of spinal anterior horn motoneurons was higher in rats that received a combination of PLGA-PEG-PLGA hydrogel and NEP1-40 than in those receiving other treatments. The combined therapy also significantly increased the number of fluorescent retrogradely labeled neurons, muscle fiber diameter, and motor endplate area of the biceps brachii. In conclusion, this study demonstrates that the effects of PLGA-PEG-PLGA hydrogel combined with NEP1-40 are superior to those of other therapies used to treat brachial plexus nerve root avulsion injury. Therefore, future studies should investigate the potential of PLGA-PEG-PLGA hydrogel as a primary treatment for brachial plexus root avulsion. [ABSTRACT FROM AUTHOR]

Abstract Background Contralateral cervical 7 nerve (cC7) was used to repair two recipient nerves simultaneously for patients with total brachial plexus avulsion (TBPA). Objective To evaluate the effect of cC7 transfer to axillary and median nerves in rats with TBPA. Methods Eighty S-D rats were divided into 4 groups randomly on average. Group A: cC7-median nerve, Group B: cC7-axillary nerve, Group C: cC7-median and axillary nerves, Group D: TBPA without repair. The evaluation tools included behavioral tests, electromyogram (EMG), measurement of cross-sectional area of muscle fiber, nerve fiber count and gene expression assay. Results The effective rates of EMG were 90 and 70% in Flexor Carpi Radialis (FCR) in Group A and C, while 70 and 60% in deltoid (DEL) in Group B and C, respectively. In behavioral test, the differences of effective rates between groups were not significant. The mean cross-sectional area of FCR in Group A or C was significantly larger than that in Group D. Either the number of median or axillary nerve fibers in Group A, B or C was statistically more than that in Group D. No matter for FCR or DEL, there were no significant differences in the ratios of relative expression of Muscle Atrophy F-box(MAFBOX)and Muscle RING Finger 1(MURF1)among these groups. Conclusion Compared with cC7 transfer to median nerve, cC7 transfer to both median and axillary nerves did not affect median nerve recovery. The deltoid muscle also could be restored. The recovery proportion of axillary nerve was less than that of median nerve.

Accumulating evidence indicates that oxidative stress and inflammation are implicated in brachial plexus avulsion (BPA). Quercetin has anti-inflammatory, anti-oxidant, anti-apoptotic, and neuroprotective properties. This study investigated the therapeutic efficacy of a temperature-sensitive poly(D,L-lactide-co-glycolide)-poly(ethylene-glycol)-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel sustained-release system of quercetin in BPA. In situ injections of the hydrogel loaded with different concentrations of quercetin were conducted in a rat model of BPA. Significantly reduced reactive oxygen species and interleukin-6 levels in the injured spinal cord 24 h post-surgery, increased number of anterior horn motor and functional neurons in the spinal cord 6 weeks post-surgery, thickened biceps muscle fibres and enlarged endplate area with clear structure, reduced demyelinated peripheral nerves, and significantly increased Terzis grooming test scores were found in the groups with 50 or 100 mg/mL quercetin-loaded hydrogels compared with the control and blank hydrogel groups. In conclusion, the temperature-sensitive quercetin loaded PLGA-PEG-PLGA hydrogel sustained-release system can alleviate oxidative damage and inflammation in the spinal cord, increase neuron survival rate, and promote nerve regeneration and motor function recovery in rats with early BPA. The findings suggest that this drug-loaded hydrogel has potential applications in the clinical treatment of BPA.

Introduction: Brachial plexus avulsion (BPA) injuries commonly occur secondary to motor vehicle collisions, usually in the young adult population. These injuries are associated with significant morbidity, and up to 90% of patients suffer from deafferentation pain. Neuromodulation procedures can be efficacious in the treatment of refractory neuropathic pain, although the treatment of pain due to BPA can be challenging. Dorsal root entry zone (DREZ) lesioning is a classical and effective neurosurgical technique which has become underutilized in treating refractory root avulsion pain.Methods: A systematic review of the different technical nuances, procedural efficacy, and complication profiles regarding DREZ lesioning for BPA injuries in the literature is included. We also present an institutional case series of 7 patients with BPA injuries who underwent DREZ lesioning.Results: In the literature, 692 patients were identified to have undergone DREZ lesioning for pain related to BPA. In 567 patients, the surgery was successful in reducing pain intensity by over 50% in comparison to baseline (81.9%). Complications included transient motor deficits (11%) and transient sensory deficits (11%). Other complications including permanent disability, cardiovascular complications, infections, or death were rare (50% reduction in pain intensity, with the mean pre-operative pain of 7.9 ± 0.63 (visual analog scale) reduced to 2.1 ± 0.99 at last follow-up (p < 0.01).Conclusion: Both the literature and the current case series demonstrate excellent pain severity reduction following DREZ ablation for deafferentation pain secondary to BPA.

• Mechanical and cold hypersensitivity occurred in the brachial plexus avulsion (BPA) rats. • Immunohistochemistry and western blot revealed the increased expression level of 5-HT3a receptor in spinal dorsal horn neurons and microglia. • Central sensitization and neuroinflammation occurred in spinal dorsal horn in rats with BPA-induced neuropathic pain. • Blockade of 5-HT3a receptor attenuated mechanical and cold allodynia and central sensitization and neuroinflammation associated with BPA. As a frequently occurring complication resulting from brachial plexus avulsion (BPA), neuropathic pain significantly impacts the quality of life of patients and places a substantial burden on their families. Recent reports have suggested that the 5-HT3a receptor may play a role in the development and regulation of neuropathic pain. The current study aimed to explore the involvement of the 5-HT3a receptor in neuropathic pain resulting from BPA in rats. A rat model of neuropathic pain was induced through brachial plexus avulsion (BPA). The pain thresholds of the rats were measured after BPA. The spinal dorsal horn (SDH) of rats was collected at day 14 after surgery, and the expression and distribution of the 5-HT3a receptor were analyzed using immunohistochemistry and western blotting. The expression levels of various factors related to central sensitization were measured by western blot, including c-Fos, GFAP, IBA-1, IL-1β and TNF-α. The effects of 5-HT3a receptor antagonists on hyperalgesia were assessed through behavioral tests after intrathecal administration of ondansetron. Additionally, at 120 min postinjection, the SDH of rats was acquired, and the change of expression levels of protiens related to central sensitization were measured by western blot. BPA induced mechanical and cold hypersensitivity in rats. The 5-HT3a receptor was increased and mainly distributed on neurons and microglia in the SDH after BPA, and the level of central sensitization and expression of inflammatory factors, such as c-Fos, GFAP, IBA-1, IL-1β and TNF-α, were also increased markedly. Ondansetron, which is a selective 5-HT3a receptor antagonist, reversed the behavioral changes caused by BPA. The antagonist also decreased the expression of central sensitization markers and inflammatory factors. The results suggested that the 5-HT3a receptor is involved in neuropathic pain by regulating central nervous system sensitization in a rat brachial plexus avulsion model. Targeting the 5-HT3a receptor may be a promising approach for treating neuropathic pain after brachial plexus avulsion. [ABSTRACT FROM AUTHOR]

Chong Meng,1–3 Xun Yang,1–3 Yuzhou Liu,1–3 Yingjie Zhou,1–3 Jing Rui,1–3 Shenqian Li,1–3 Ce Xu,1–3 Yongqing Zhuang,4 Jie Lao,1–3 Xin Zhao1–31Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of China; 2Key Laboratory of Hand Reconstruction, Ministry of Health, Shanghai 200032, People’s Republic of China; 3Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai 200032, People’s Republic of China; 4Hand Surgery Department, Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of ChinaPurpose: Neuropathic pain (NP) is a challenging clinical problem due to its complex pathogenesis. In our previous study using microarray, we found that the levels of lncRNA Malat1 were decreased in the spinal cord of NP rat after brachial plexus avulsion, but its contribution to NP remain unclear. The purpose of this study was to investigate its role in the pathogenesis of NP.Methods: In the NP model of complete brachial plexus avulsion rat, spinal cords were harvested, and fluorescence in situ hybridization (FISH) was used to test the spatial expression of Malat1 and qRT-PCR was used to confirm the quantitative expression of Malat1. In primary cultured neurons, Malat1 expression interfered with adenovirus. Spontaneous electric activities of neurons were tested using multi-electrode arrays and apoptosis of neurons was tested using TUNEL method. The change of intracellular calcium concentration was analyzed using calcium imaging method.Results: Decreased Malat1 expression was confirmed using qRT-PCR, and Malat1 was identified in the cytoplasm of neurons in spinal cord, but not in glia. In vitro, the decrease of Malat1 resulted in an increase in the frequency of spontaneous electric activity in neurons but had no effect on neuronal apoptosis. Further analysis indicated during glutamate stimulation, the change of intracellular calcium concentration in neurons with downregulated Malat1 expression was significantly greater than that in normal neurons.Conclusion: Reduced Malat1 expression may induce NP by increasing neuronal excitability in the spinal cord via regulation of calcium flux.Keywords: neuropathic pain, lncRNA, Malat1, spinal cord, neuron, multielectrode array, brachial plexus avulsion

Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a critical molecule targeting several genes associated with ischemia-hypoxia damage and angiogenesis. In this study, a rat model of brachial plexus avulsion-reimplantation was established, in which C5–7 ventral nerve roots were avulsed and only the C6 root reimplanted. Different implants were immediately injected using a microsyringe into the avulsion-reimplantation site of the C6 root post-brachial plexus avulsion. Rats were randomly divided into five groups: phosphate-buffered saline, negative control of lentivirus, hypoxia-inducible factor 1α (hypoxia-inducible factor 1α overexpression lentivirus), gel (pluronic F-127 hydrogel), and gel + hypoxia-inducible factor 1α (pluronic F-127 hydrogel + hypoxia-inducible factor 1α overexpression lentivirus). The Terzis grooming test was performed to assess recovery of motor function. Scores were higher in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups (in particular the gel + hypoxia-inducible factor 1α group) compared with the phosphate-buffered saline group. Electrophysiology, fluorogold retrograde tracing, and immunofluorescent staining were further performed to investigate neural pathway reconstruction and changes of neurons, motor endplates, and angiogenesis. Compared with the phosphate-buffered saline group, action potential latency of musculocutaneous nerves was markedly shortened in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Meanwhile, the number of fluorogold-positive cells and ChAT-positive neurons, neovascular area (labeled by CD31 around avulsed sites in ipsilateral spinal cord segments), and the number of motor endplates in biceps brachii (identified by α-bungarotoxin) were all visibly increased, as well as the morphology of motor endplate in biceps brachil was clear in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Taken together, delivery of hypoxia-inducible factor 1α overexpression lentiviral vectors mediated by pluronic F-127 effectively promotes spinal root regeneration and functional recovery post-brachial plexus avulsion. All animal procedures were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.

Background: Patients with brachial plexus avulsion (BPA) usually experience phantom sensations and phantom limb pain (PLP) in the deafferented limb. It has been suggested that evoking the sensation of touch in the deafferented limb by stimulating referred sensation areas (RSAs) on the cheek or shoulder might alleviate PLP. However, feasible rehabilitation techniques using this approach have not been reported. Objective: The present study sought to examine the analgesic effects of simple electrical stimulation of RSAs in BPA patients with PLP. Methods: Study 1: Electrical stimulation of RSAs for 60 minutes was conducted for six BPA patients suffering from PLP to examine short-term analgesic effects. Study 2: A single case design experiment was conducted with two BPA patients to investigate whether electrical stimulation of RSAs was more effective for alleviating PLP than control electrical stimulation (electrical stimulation of sites on side opposite to the RSAs), and to elucidate the long-term effects of electrical stimulation of RSAs. Results: Study 1: Electrical stimulation of RSAs evoked phantom touch sensations in the deafferented limb, and significantly alleviated PLP (p < 0.05). Study 2: PLP was alleviated more after electrical stimulation on RSAs compared with control electrical stimulation (p < 0.05). However, the analgesic effects of electrical stimulation on RSAs were observed only in the short term, not in the long term (p > 0.05). Conclusions: Electrical stimulation of RSAs not only evoked phantom touch sensation but also alleviated PLP in the short term. The results indicate that electrical stimulation of RSAs may provide a useful practical rehabilitation technique for PLP. Future studies will be required to clarify the mechanisms underlying immediate PLP alleviation via electrical stimulation of RSAs. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that oxidative stress and inflammation are implicated in brachial plexus avulsion (BPA). Quercetin has anti-inflammatory, anti-oxidant, anti-apoptotic, and neuroprotective properties. This study investigated the therapeutic efficacy of a temperature-sensitive poly(D,L-lactide-co-glycolide)-poly(ethylene-glycol)-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel sustained-release system of quercetin in BPA. In situ injections of the hydrogel loaded with different concentrations of quercetin were conducted in a rat model of BPA. Significantly reduced reactive oxygen species and interleukin-6 levels in the injured spinal cord 24 h post-surgery, increased number of anterior horn motor and functional neurons in the spinal cord 6 weeks post-surgery, thickened biceps muscle fibres and enlarged endplate area with clear structure, reduced demyelinated peripheral nerves, and significantly increased Terzis grooming test scores were found in the groups with 50 or 100 mg/mL quercetin-loaded hydrogels compared with the control and blank hydrogel groups. In conclusion, the temperature-sensitive quercetin loaded PLGA-PEG-PLGA hydrogel sustained-release system can alleviate oxidative damage and inflammation in the spinal cord, increase neuron survival rate, and promote nerve regeneration and motor function recovery in rats with early BPA. The findings suggest that this drug-loaded hydrogel has potential applications in the clinical treatment of BPA. [ABSTRACT FROM AUTHOR]

The DREZotomy (Dorsal Root Entry Zone tomy) is an analgesic procedure. The analgesic effect is evaluated on 30 patients with chronic pain resulting from respectively: brachial plexus avulsion (66.6%), postherpetic pain (10%), hyperspastic states (6.6%), phantom pain (6.6%), the pain in the stump (6.6%), and spinal cord injuries (3.3%). Pain intensity was evaluated using a visual analogue scale (VAS). At last evaluation, between 12 and 60 months, after DREZotomy, 93% had a good or excellent global pain relief after surgery. According to the component types of pain, 9.6% of patients had good or excellent control of the paroxysmal pain, and 84% of the continuous pain. Kaplan–Meier prediction of lasting global pain control at 60 months of follow-up was calculated at 75.5%. Comparison of the 2 corresponding Kaplan–Meier curves at long term, namely, pain control in 82.8% for the paroxysmal component and in 51.7% for the continuous component, showed a statistically significant difference (P < 0.0001). Functional effects are improved by more than 70% according to patients.

Brachial plexus avulsion (BPA) causes peripheral nerve injury complications with motor and sensory dysfunction of the upper limb. Growing evidence has shown an active role played by cold-water swimming (CWS) in alleviating peripheral neuropathic pain and functional recovery. This study examined whether CWS could promote functional recovery and pain modulation through the reduction of neuroinflammation and microglial overactivation in dorsal horn neurons at the early-stage of BPA. After BPA surgery was performed on rats, they were assigned to CWS or sham training for 5 min twice a day for two weeks. Functional behavioral responses were tested before and after BPA surgery, and each week during training. Results after the two-week training program showed significant improvements in BPA-induced motor and sensory loss (p < 0.05), lower inflammatory cell infiltration, and vacuole formation in injured nerves among the BPA–CWS group. Moreover, BPA significantly increased the expression of SP and IBA1 in dorsal horn neurons (p < 0.05), whereas CWS prevented their overexpression in the BPA–CWS group. The present findings evidenced beneficial rehabilitative effects of CWS on functional recovery and pain modulation at early-stage BPA. The beneficial effects are partially related to inflammatory suppression and spinal modulation. The synergistic role of CWS combined with other management approaches merits further investigation.

Background and Introduction: Patients with brachial plexus avulsion (BPA) injuries often suffer from chronic disabling drug refractory neuropathic pain. Dorsal root entry zone (DREZ) lesioning is currently the most effective surgical procedure for this intractable brachial neuralgia following BPA.Objective: To demonstrate a novel technique of "Micro-scissor DREZotomy" developed at our institution.Procedure: A 55-year-old gentleman underwent right cervical microscissor DREZotomy for post BPA neuralgia. Exclusive use of microscissors along the posterolateral sulcus, causing mechanical disruption of the nociceptive pathways through sharp dissection, results in precise lesioning with excellent pain free outcomes.Results: The patient had complete relief of the pain and uneventful recovery following the surgery and remains to be pain free at 1 year follow up.Conclusion: Microscissor DREZotomy is a simple cost-effective technique. It can easily be performed in the peripheral centers with limited resources and is a safe and effective technique in experienced hands. [ABSTRACT FROM AUTHOR]

After brachial plexus avulsion (BPA), microglia induce inflammation, initiating and maintaining neuropathic pain. EZH2 (enhancer of zeste homolog 2) has been implicated in inflammation and neuropathic pain, but the mechanisms by which it regulates neuropathic pain remain unclear. Here, we found that EZH2 levels were markedly upregulated during BPA-induced neuropathic pain in vivo and in vitro, stimulating pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) secretion in vivo. In rats with BPA-induced neuropathic pain, mechanical and cold hypersensitivities were induced by EZH2 upregulation and inhibited by EZH2 downregulation in the anterior cingulate cortex. Microglial autophagy was also significantly inhibited, with EZH2 inhibition activating autophagy and reducing neuroinflammation in vivo. However, this effect was impaired by inhibiting autophagy with 3-methyladenine, suggesting that the MTOR signaling pathway is a functional target of EZH2. These data suggest that EZH2 regulates neuroinflammation and neuropathic pain via a novel MTOR-mediated autophagy signaling pathway, providing a promising approach for managing neuropathic pain. [ABSTRACT FROM AUTHOR]

The DREZotomy (Dorsal Root Entry Zone tomy) is an analgesic procedure. The analgesic effect is evaluated on 30 patients with chronic pain resulting from respectively: brachial plexus avulsion (66.6%), postherpetic pain (10%), hyperspastic states (6.6%), phantom pain (6.6%), the pain in the stump (6.6%), and spinal cord injuries (3.3%). Pain intensity was evaluated using a visual analogue scale (VAS). At last evaluation, between 12 and 60 months, after DREZotomy, 93% had a good or excellent global pain relief after surgery. According to the component types of pain, 9.6% of patients had good or excellent control of the paroxysmal pain, and 84% of the continuous pain. Kaplan--Meier prediction of lasting global pain control at 60 months of follow-up was calculated at 75.5%. Comparison of the 2 corresponding Kaplan--Meier curves at long term, namely, pain control in 82.8% for the paroxysmal component and in 51.7% for the continuous component, showed a statistically significant difference (P < 0.0001). Functional effects are improved by more than 70% according to patients. [ABSTRACT FROM AUTHOR]

Background: Contralateral cervical 7 nerve (cC7) was used to repair two recipient nerves simultaneously for patients with total brachial plexus avulsion (TBPA).Objective: To evaluate the effect of cC7 transfer to axillary and median nerves in rats with TBPA.Methods: Eighty S-D rats were divided into 4 groups randomly on average. Group A: cC7-median nerve, Group B: cC7-axillary nerve, Group C: cC7-median and axillary nerves, Group D: TBPA without repair. The evaluation tools included behavioral tests, electromyogram (EMG), measurement of cross-sectional area of muscle fiber, nerve fiber count and gene expression assay.Results: The effective rates of EMG were 90 and 70% in Flexor Carpi Radialis (FCR) in Group A and C, while 70 and 60% in deltoid (DEL) in Group B and C, respectively. In behavioral test, the differences of effective rates between groups were not significant. The mean cross-sectional area of FCR in Group A or C was significantly larger than that in Group D. Either the number of median or axillary nerve fibers in Group A, B or C was statistically more than that in Group D. No matter for FCR or DEL, there were no significant differences in the ratios of relative expression of Muscle Atrophy F-box(MAFBOX)and Muscle RING Finger 1(MURF1)among these groups.Conclusion: Compared with cC7 transfer to median nerve, cC7 transfer to both median and axillary nerves did not affect median nerve recovery. The deltoid muscle also could be restored. The recovery proportion of axillary nerve was less than that of median nerve. [ABSTRACT FROM AUTHOR]

• CCL2-CCR2 is highly expressed in brachial plexus avulsion (BPA) induced neuropathic pain model. • CCR2 was mainly expressed on astrocytes and neurons in the spinal cord after BPA injury. • Spinal astrocytes-derived CCL2 interacted with CCR2 receptor in neurons to activate NMDA receptor in rats exposed BPA injury. • CCR2 could be a potential therapeutic target for BPA induced neuropathic pain. Brachial plexus avulsion (BPA) represents the most devastating nerve injury in the upper extremity and is always considered as a sophisticated problem due to its resistance to most standard pain relief medications or neurosurgical interventions. There is also a lack of understanding on the underlying mechanisms. Our study aimed to investigate whether spinal CCL2-CCR2 signaling contributed to the development of neuropathic pain following BPA via modulating glutamate N-methyl- d -aspartate receptor (NMDAR). A rat model of BPA on lower trunk (C8-T1) was established, and the sham- and BPA-operated animals were intrathecally injected with saline, C-C chemokine receptor type 2 (CCR2) inhibitor INCB3344 and NMDAR antagonist DL-AP5 one week postoperatively, the behavioral performance of the treated animals and expressions of C-C motif ligand 2 (CCL2), CCR2, and N-methyl-D-aspartic acid receptor 2B (NR2B) in spinal cord sections of each group were examined. It was shown that BPA injury significantly reduced mechanic withdrawal thresholds the next day after surgery until the end of the observation. Both CCL2 and CCR2 expressions increased in BPA rats compared to those in sham rats. CCL2 was mainly localized in astrocytes, and CCR2 was preferably expressed on astrocytes and neurons. Besides, NMDAR subunit NR2B increased in BPA-operated rats, which was reversed in response to CCR2 and NR2B inhibition. However, these inhibitors didn't change the spinal NMDAR level in sham rats. CCR2 and NMDAR inhibition efficiently alleviated mechanical allodynia caused by BPA either at early or late phase of neuropathic pain. Collectively, CCL2-CCR2 axis is associated with mechanical pain after BPA by elevating NMDAR signaling. [ABSTRACT FROM AUTHOR]

Brachial plexus avulsion (BPA) occurs when the spinal nerve roots are pulled away from the surface of the spinal cord and disconnects neuronal cell body from its distal downstream axon, which induces massive motoneuron death, motor axon degeneration and de-innervation of targeted muscles, thereby resulting in permanent paralysis of motor functions in the upper limb. Avulsion injury triggers oxidative stress and intense local neuroinflammation at the lesioned site, leading to the death of most motoneurons. Berberine (BBR), a natural isoquinoline alkaloid derived from medicinal herbs of Berberis and Coptis species, has been reported to possess neuro-protective, anti-inflammatory and anti-oxidative effects in various animal models of central nervous system (CNS)-related disorders. In this study, we aimed to investigate the effect of BBR on motoneuron survival and axonal regeneration following spinal root avulsion plus re-implantation in rats. Our results indicated BBR significantly accelerated motor function recovery in the forelimb as revealed by the increased Terzis grooming test score, facilitated motor axon regeneration as evidenced by the elevated number of Fluoro-Gold-labeled and P75-positive regenerative motoneurons. The survival of motoneurons was notably promoted by BBR administration presented with boosted ChAT-immunopositive and neutral red-stained neurons. BBR treatment efficiently alleviated muscle atrophy, attenuated functional motor endplates loss in biceps and prevented the reduction of motor axons in the musculocutaneous nerve. Additionally, BBR treatment markedly mitigated the avulsion-induced neuroinflammation via inhibiting microglial and astroglial reactivity, up-regulated the expression of antioxidative indicator Cu/Zn SOD, and down-regulated the levels of nNOS, 3-NT, lipid peroxidation and NF-κB, as well as promoted SIRT1, PI3K and Akt activation. Collectively, BBR might be a promising therapy to assist re-implantation surgery for the treatment of BPA. Image 1 • Berberine (BBR) accelerates motoneuron survival and axonal regeneration after spinal root avulsion/re-implantation in rats. • BBR improves motor functional recovery of elbow flexion. • BBR alleviates avulsion-induced oxidative damage in rats. • BBR possesses neuroprotective activity via inhibiting spinal neuroinflammation. • BBR activates SIRT1 and PI3K/Akt signaling pathway and prevents NF-κB activation. [ABSTRACT FROM AUTHOR]

This study aimed to investigate brain activity changes in patients suffering from neuropathic pain (NP) following brachial plexus avulsion (BPA). Fifteen patients with NP following BPA and eight healthy participants (HP) were recruited for this study. All participants underwent examination using resting-state functional MRI. The amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were calculated and compared between the BPA group, left-BPA subgroup, right-BPA subgroup, and the HP group using independent samples t-tests. In the BPA group, there were notable increases in ALFF/ReHo observed in the left rolandic operculum, insula, and supramarginal gyrus, while decreases were observed in the left paracentral lobule, fusiform gyrus, calcarine fissure and surrounding cortex, lingual gyrus, precuneus, as well as the bilateral anterior/median cingulate and paracingulate gyri, supplementary motor area, and cerebellum. In the left-BPA subgroup, elevated ALFF/ReHo levels were identified in the left middle/inferior frontal gyri, rolandic operculum, and supramarginal gyrus, with corresponding decreases in the left calcarine fissure and surrounding cortex, inferior occipital gyrus, fusiform gyrus, lingual gyrus, as well as the bilateral anterior/median cingulate and paracingulate gyri, postcentral gyri, supplementary motor area, paracentral lobules, and cerebellum. The right-BPA subgroup displayed increased ALFF/ReHo in the left frontal lobe, rolandic operculum, insula, fusiform gyrus, and lingual gyrus, as well as the right cerebellum. Conversely, decreases in ALFF/ReHo were observed in the bilateral anterior/median cingulate and paracingulate gyri, calcarine fissure and surrounding cortex, cuneus, and occipital lobes. The NP after BPA caused spontaneous activity changes in brain regions associated with linguistic, visual, somatosensory, and motor coordination and processing function. The majority of these abnormal areas were situated in the left cerebral hemisphere, while the effect of cingulate gyri and cerebellum seemed to be bilateral. • Extensive brain activity changes exist in NP patients after BPA. • The majority of abnormal areas located in the left cerebral hemisphere. • The changes of cingulate gyri and cerebellum seemed to be bilateral. [ABSTRACT FROM AUTHOR]

Background: The neuropathic pain (NPP) after brachial plexus avulsion (BPA) is common and difficult to cure, and thalamus and postcentral gyrus have been accepted to be the key nodes of mechanisms and pathways for pain. However, little attention has been paid on the thalamus-postcentral gyrus functional connectivity changes in NP patients after BPA., Methods: Eighteen patients with NPP after BPA and twenty age and gender matched healthy controls were enrolled and underwent resting-state functional MRI (rs-fMRI) scans in this study. The Pearson's r-value of functional connection (bilateral thalamus and postcentral gyrus as regions of interest) was generated and examined using two sample t-test. The linear regression analysis was used to select possible related factors, and multiple linear regression of the possible predictors was used to identify the variables that significantly predicted Visual Analogue Score (VAS)., Results: The standardized Pearson r-values of the left thalamus-right thalamus, left thalamus-left postcentral gyrus, left thalamus-right postcentral gyrus, right thalamus-left postcentral gyrus and right thalamus-right postcentral gyrus in the control group were 0.759 ± 0.242, 0.358 ± 0.297, 0.383 ± 0.270, 0.317 ± 0.295 and 0.333 ± 0.304, respectively. And the corresponding standardized Pearson r-values in patients group were 0.510 ± 0.224,0.305 ± 0.212,0.281 ± 0.225,0.333 ± 0.193 and 0.333 ± 0.210, respectively. The functional connectivity strength of the left thalamus-right thalamus in control group was significantly higher than that in the patients group (P < 0.05). Linear regression analysis showed that the functional connectivity strength of the left thalamus-right thalamus was negatively correlated with the patients' VAS score (P < 0.05)., Conclusions: NPP patients after BPA had a significant pain-related bilateral thalamus functional connection reorganization, with the purpose to limit the pain signal inputs within the unilateral cerebral hemisphere., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cortical reorganization in response to peripheral nervous system damage is only poorly understood. In patients with complete brachial plexus avulsion and subsequent reconnection of the end of the musculocutaneous nerve to the side of a phrenic nerve, reorganization leads to a doubled arm representation in the primary motor cortex. Despite, homuncular organization being one of the most fundamental principles of the human brain, movements of the affected arm now activate 2 loci: the completely denervated arm representation and the diaphragm representation. Here, we investigate the details behind this peripherally triggered reorganization, which happens in healthy brains. fMRI effective connectivity changes within the motor network were compared between a group of patients and age matched healthy controls at 7 Tesla (6 patients and 12 healthy controls). Results show the establishment of a driving input of the denervated arm area to the diaphragm area which is now responsible for arm movements. The findings extend current knowledge about neuroplasticity in primary motor cortex: a denervated motor area may drive an auxilliary area to reroute its motor output.

>bold<>italic/italic<>/bold< Brachial plexus avulsion (BPA) generally causes a chronic persistent pain that lacks efficacious treatment. Curcumin has been found to possess anti-inflammatory abilities. However, little is known about the mechanisms and effects of curcumin in an animal model of BPA. >bold<>italic/italic<>/bold< Mechanical withdrawal thresholds (MWT) were examined by von Frey filaments. Cold allodynia was tested by the acetone spray test. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in rat spinal cords were analyzed by the enzyme-linked immunosorbent assay, and the expression levels of c-Fos and nerve growth factor (NGF) were measured by Western blot. The expression level of glial fibrillary acidic protein (GFAP) was observed by immunofluorescence and Western blot. >bold<>italic/italic<>/bold< After curcumin treatment, the MWT showed a significant increase when compared to the BPA group on both hind paws. A remarkable decrease of paw-withdrawal response frequency was observed compared with the BPA group. In addition, curcumin treatment significantly decreased the levels of TNF-α and IL-6 in rat spinal cords that were exceedingly upregulated in the BPA group. The protein levels of c-Fos and NGF were decreased by treatment with curcumin compared with the corresponding protein levels in the BPA group. Besides, curcumin reduced the number of GFAP positive cells and GFAP expression. >bold<>italic/italic<>/bold< Our findings suggest that curcumin significantly extenuates the BPA-induced pain and inflammation by reducing the expression level of proinflammatory cytokines and pain-associated proteins and inhibiting the activity of astrocytes. [ABSTRACT FROM AUTHOR]

Highlights • Neuropathic pain induced by brachial plexus avulsion was investigated in rats. • Small animal PET was applied to investigate metabolic changes before and after deafferentation. • The correlation analysis was calculated between the average SUVs in ROIs and thermal withdrawal latency. Abstract The present study aimed to investigate cerebral metabolic changes in a neuropathic pain model following deafferentation. A total of 24 Sprague-Dawley rats were included for modeling of right brachial plexus avulsion (BPA) through the posterior approach. As nerve injury would cause central sensitization and facilitate pain sensitivity in other parts of the body, thermal withdrawal latency (TWL) of the intact forepaw was assessed to investigate the level of pain perception following BPA-induced neuropathic pain. [Fluorine-18]-fluoro-2-deoxy- d -glucose (18F-FDG) positron emission tomography (PET) was applied to the brain before and after brachial plexus avulsion to explore metabolic changes in neuropathic pain following deafferentation. The TWL of the left (intact) forepaw was significantly lower after BPA than that of baseline (p < 0.001). Using TWL as a covariate, standardized uptake values (SUVs) of 18F-FDG significantly increased in the ipsilateral dorsolateral thalamus and contralateral anterodorsal hippocampus after BPA. Conversely, SUVs in multiple brain regions decreased, including the contralateral somatosensory cortex, ipsilateral cingulate cortex, and ipsilateral temporal association cortex. The Pearson correlation analysis showed that the SUVs of the contralateral anterodorsal hippocampus and ipsilateral dorsolateral thalamus were negatively related to the TWL of the intact forepaw, whereas the SUVs in the contralateral somatosensory cortex and ipsilateral cingulate cortex were positively related to it (p < 0.05). These findings indicate that upregulation of metabolism in the anterodorsal hippocampus and dorsolateral thalamus and downregulation metabolism in the contralateral somatosensory cortex and ipsilateral cingulate cortex could be a unique pattern of metabolic changes for neuropathic pain following brachial plexus avulsion. [ABSTRACT FROM AUTHOR]

Purpose: Neuropathic pain (NP) is a challenging clinical problem due to its complex pathogenesis. In our previous study using microarray, we found that the levels of lncRNA Malat1 were decreased in the spinal cord of NP rat after brachial plexus avulsion, but its contribution to NP remain unclear. The purpose of this study was to investigate its role in the pathogenesis of NP. Methods: In the NP model of complete brachial plexus avulsion rat, spinal cords were harvested, and fluorescence in situ hybridization (FISH) was used to test the spatial expression of Malat1 and qRT-PCR was used to confirm the quantitative expression of Malat1. In primary cultured neurons, Malat1 expression interfered with adenovirus. Spontaneous electric activities of neurons were tested using multi-electrode arrays and apoptosis of neurons was tested using TUNEL method. The change of intracellular calcium concentration was analyzed using calcium imaging method. Results: Decreased Malat1 expression was confirmed using qRT-PCR, and Malat1 was identified in the cytoplasm of neurons in spinal cord, but not in glia. In vitro, the decrease of Malat1 resulted in an increase in the frequency of spontaneous electric activity in neurons but had no effect on neuronal apoptosis. Further analysis indicated during glutamate stimulation, the change of intracellular calcium concentration in neurons with downregulated Malat1 expression was significantly greater than that in normal neurons. Conclusion: Reduced Malat1 expression may induce NP by increasing neuronal excitability in the spinal cord via regulation of calcium flux. [ABSTRACT FROM AUTHOR]

In this study, we investigated the electrophysiologic recovery of the abductor pollicis brevis (APB) muscle after contralateral seventh cervical (cC7) nerve transfer for the treatment of global brachial plexus avulsion (GBPA). We retrospectively analyzed the electromyography records of 95 patients with GBPA, comprising 81 men and 14 women, focusing on the motor unit potential (MUP) recovery of the APB. All patients underwent cC7-median nerve (MN) transfer. The cC7 nerve was transferred to the MN alone in 58 patients (One-Nerve Group), whereas 37 patients underwent cC7 transfer to the MN and another nerve (Two-Nerve Group). Fifty-three patients (MUP Group) exhibited MUP recovery of the APB, whereas 42 patients did not (No-MUP Group). The MUP Group comprised 32 patients from the One-Nerve Group and 21 patients from the Two-Nerve Group. The mean age of the MUP Group was significantly lower than that of the No-MUP Group. In summary, electrophysiologic recovery of the APB was common in patients with GBPA after cC7-MN transfer, indicating that it may be possible to restore the function of the intrinsic muscles of the hand after GBPA. The rehabilitation strategy for patients with GBPA, which overlooks the restoration of intrinsic hand muscle function, may require amendment. [ABSTRACT FROM AUTHOR]

Introduction: Neuropathic pain induced by brachial plexus avulsion (BPA) is a pathological condition. We hypothesized that inhibition of histone deacetylase (HDAC) could suppress BPA-induced neuropathic pain through inhibition of transient reception potential (TRP) overexpression and protein kinase B (Akt)-mediated mammalian target of rapamycin (mTOR) activation.Methods: We generated a rat BPA model; administered HDAC inhibitor tricostatin A (TSA) for 7 days postsurgery; and assessed the effects on HDAC expression, Akt phosphorylation, neuroinflammation, and mTOR activation.Results: TSA treatment alleviated BPA-induced mechanical hyperalgesia, suppressed Akt phosphorylation, and increased HDAC. We found suppressed proinflammatory cytokine levels, TRPV1 and TRPM8 expression, and mTOR activity in TSA-treated BPA rats.Discussion: Our results suggest that altered HDAC and Akt signaling are involved in BPA-induced neuropathic pain and that inhibition of HDAC could be an effective therapeutic approach in reducing neuropathic pain. Muscle Nerve 58: 434-440, 2018. [ABSTRACT FROM AUTHOR]

The phrenic nerve being transferred to the posterior division of the lower trunk with end-to-end neurorrhaphy is reported to be effective in restoring the function of digit extension in literature. However, the phrenic nerve is extremely important in respiration. We designed an animal experiment to discover whether the phrenic nerve being transferred to the posterior division of the lower trunk with end-to-side neurotization was feasible and provided the theoretical basis. A sum of 36 Sprague-Dawley rats was randomly assigned to one of two groups. In Group A, the phrenic nerve was transferred to the posterior division of the lower trunk with end-to-side neurotization. In Group B, the posterior division of the lower trunk was directly sutured. The results of behavioral assessment, electrophysiology, histology and nerve fiber count and muscle weight at 12 weeks postoperatively were recorded. In Group A, none of the rats experienced tachypnea. The motion of slight toe extension was observed. The results of electrophysiology, histology and nerve fiber count and muscle weight in Group A were not as well as those of Group B, but gradually improved with time. The phrenic nerve being transferred to the posterior division of lower trunk with end-to-side neurotization can partially restore the function of toe extension in a rat model. Whether the function of digit extension can be restored by the phrenic nerve with end-to-side neurotization in humans still needs more practice in clinic. [ABSTRACT FROM AUTHOR]

We have applied bipolar dual-lead spinal cord stimulation (SCS) between two cylinder-type electrodes placed on the ventral and dorsal sides of the spinal cord (dual-VD-SCS). A 36-year-old man suffered from burning pain from his right elbow down to his hand after brachial plexus avulsion. The areas with paresthesia induced by conventional SCS did not include the painful hand area. However, dual-VD-SCS completely induced paresthesia in the painful hand area. We speculate that dual-VD-SCS can be applied to stimulate deeper sites of the dorsal column and dorsal horn than conventional SCS and is useful for pain reduction. [ABSTRACT FROM AUTHOR]

Aims: To address the feasibility and importance of intraoperative neurophysiological monitoring (IONM) in dorsal root entry zone (DREZ) lesioning for brachial plexus avulsion pain. Methods: Muscle motor evoked potential (mMEP) and somatosensory evoked potential (SSEP) were applied during DREZ lesioning for brachial plexus avulsion pain. Results: IONM of mMEPs and SSEPs was feasible for monitoring of the spinal cord during DREZ lesioning. With the exception of 3 unrecordable mMEPs in ipsilateral arms, mMEPs were preserved and referenced to look for changes according to lesioning in 6 upper extremities (66.6%) and 8 lower extremities. All 3 patients with >50% reduction in baseline mMEP amplitude after lesioning in either the ipsilateral upper or lower extremities showed postoperative ataxia and weakness of the lower extremities (100%). Only 2 out of 9 patients (22.2%) with brachial plexus avulsion pain had discernible baseline SSEPs in the ipsilateral upper extremities. One of 2 patients with discernible SSEPs in the upper extremities showed significant SSEP events during the DREZ lesioning and experienced postoperative ataxia and weakness in the legs despite the absence of a SSEP event in the lower extremities. Conclusion: Significant events on IONM were common during DREZ lesioning for brachial plexus avulsion pain and were closely related to the occurrence of postoperative neurological deficits. [ABSTRACT FROM AUTHOR]

Background Complete brachial plexus avulsion injury is a severe disabling injury due to traction to the brachial plexus. Brachial plexus reimplantation is an emerging surgical technique for the management of complete brachial plexus avulsion injury. Objective We assessed the functional recovery in 15 patients who underwent brachial plexus reimplantation surgery after complete brachial plexus avulsion injury with clinical examination and electrophysiological testing. Methods We included all patients who underwent brachial plexus reimplantation in our institution between 1997 and 2010. Patients were assessed with detailed motor and sensory clinical examination and motor and sensory electrophysiological tests. Results We found that patients who had reimplantation surgery demonstrated an improvement in Medical Research Council power in the deltoid, pectoralis, and infraspinatous muscles and global Medical Research Council score. Eight patients achieved at least grade 3 MRC power in at least one muscle group of the arm. Improved reinnervation by electromyelography criteria was found in infraspinatous, biceps, and triceps muscles. There was evidence of ongoing innervation in 3 patients. Sensory testing in affected dermatomes also showed better recovery at C5, C6, and T1 dermatomes. The best recovery was seen in the C5 dermatome. Conclusions Our results demonstrate a definite but limited improvement in motor and sensory recovery after reimplantation surgery in patients with complete brachial plexus injury. We hypothesize that further improvement may be achieved by using regenerative cell technologies at the time of repair. [ABSTRACT FROM AUTHOR]