Exploration of rich-club reorganization in facial synkinesis: insights from structural and functional brain network analysis.

Facial palsy therapies based on cortical plasticity are in development, but facial synkinesis progress is limited. Studying neural plasticity characteristics, especially network organization and its constitutive elements (nodes/edges), is the key to overcome the bottleneck. We studied 55 participants (33 facial synkinesis patients, 22 healthy controls) with clinical assessments, functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI). We analyzed rich-club organization and metrics of structural brain networks (rich-club coefficients, strength, degree, density, and efficiency). Functional brain network metrics, including functional connectivity and its coupling with the structural network, were also computed. Patients displayed reduced strength and density of rich-club nodes and edges, as well as decreased global efficiency. All nodes exhibited decreased nodal efficiency in patients. Patients had significantly increased functional connectivity and decreased structural-functional coupling strength in rich-club nodes, rich-club edges, and feeder edges. Our study indicates that facial synkinesis patients have weakened structural connections but enhanced functional transmission from rich-club nodes. The loss of connections and efficiency in structural network may trigger compensatory increases in functional connectivity of rich-club nodes. Two potential biomarkers, rich-club edge density and structural-functional coupling strength, may serve as indicators of disease outcome. These findings provide valuable insights into synkinesis mechanisms and offer potential targets for cortical intervention.

Prevalence and prognosis of hard-to-heal wounds with comorbidities in China.

OBJECTIVE: Regular retrospective analysis is necessary for potential improvement in clinical practice for the treatment of hard-to-heal wounds. Comorbidities and outcomes have demonstrated spatial and temporal diversity, emphasising the importance of updates in epidemiology. The complexity of healing hard-to-heal wounds has long been known, and so we sought evidence-based improvement on the current principles of treatment. METHOD: Demographic and clinical information of patients from the WoundCareLog database was collected. Patients who met the inclusion criteria and completed follow-up after treatment were included. Comorbidities were diagnosed and classified into eight categories based on ICD-10. We compared the demographic and aetiological characteristics between patients with and without comorbidities by t-test and Chi-squared test. The impact of comorbidities on wound healing were evaluated with a multivariate Cox model. RESULTS: A total of 2163 patients met the inclusion criteria and were enrolled, of whom 37.0% were aged 61-80 years, 36.0% were aged 41-60 years and 60.8% were male. The lower extremities and buttocks were the most commonly affected areas with hard-to-heal wounds. Non-traumatic wounds accounted for 66.6% of cases, and infection, pressure and diabetes were the most common causes. Paralysis and diabetes were the most important factors which led to a prolonged healing process and inferior clinical outcomes. CONCLUSION: Comorbidities of hard-to-heal wounds were treated as separate contributors and their weighted effect on outcome was calculated through correlation analysis. Paralysis and diabetes were the most unfavourable comorbidities affecting the treatment of non-traumatic hard-to-heal wounds. Our study highlighted the priority of comorbidity treatment through data-driven approaches. It provides potential value in developing better public health strategies and preventive medicine.

Identifying Modulated Functional Connectivity in Corresponding Cerebral Networks in Facial Nerve Lesions Patients With Facial Asymmetry.

Facial asymmetry is the major complaint of patients with unilateral facial nerve lesions. Frustratingly, although patients experience the same etiology, the extent of oral commissure asymmetry is highly heterogeneous. Emerging evidence indicates that cerebral plasticity has a large impact on clinical severity by promoting or impeding the progressive adaption of brain function. However, the precise link between cerebral plasticity and oral asymmetry has not yet been identified. In the present study, we performed functional magnetic resonance imaging on patients with unilateral facial nerve transections to acquire in vivo neural activity. We then identified the regions of interest corresponding to oral movement control using a smiling motor paradigm. Next, we established three local networks: the ipsilesional (left) intrahemispheric, contralesional (right) intrahemispheric, and interhemispheric networks. The functional connectivity of each pair of nodes within each network was then calculated. After thresholding for sparsity, we analyzed the mean intensity of each network connection between patients and controls by averaging the functional connectivity. For the objective assessment of facial deflection, oral asymmetry was calculated using FACEgram software. There was decreased connectivity in the contralesional network but increased connectivity in the ipsilesional and interhemispheric networks in patients with facial nerve lesions. In addition, connectivity in the ipsilesional network was significantly correlated with the extent of oral asymmetry. Our results suggest that motor deafferentation of unilateral facial nerve leads to the upregulated ipsilesional hemispheric connections, and results in positive interhemispheric inhibition effects to the contralesional hemisphere. Our findings provide preliminary information about the possible cortical etiology of facial asymmetry, and deliver valuable clues regarding spatial information, which will likely be useful for the development of therapeutic interventions.

Effective connectivity decreases in specific brain networks with postparalysis facial synkinesis: a dynamic causal modeling study.

Currently, the treatments for postparalysis facial synkinesis are still inadequate. However, neuroimaging mechanistic studies are very limited and blurred. Instead of mapping activation regions, we were devoted to characterizing the organizational features of brain regions to develop new targets for therapeutic intervention. Eighteen patients with unilateral facial synkinesis and 19 healthy controls were enrolled. They were instructed to perform task functional magnetic resonance imaging (eye blinking and lip pursing) examinations and resting-state scans. Then, we characterized group differences in task-state fMRI to identify three foci, including the contralateral precentral gyrus (PreCG), supramarginal gyrus (SMG), and superior parietal gyrus (SPG). Next, we employed a novel approach (using dynamic causal modeling) to identify directed connectivity differences between groups in different modes. Significant patterns in multiple regions in terms of regionally specific actions following synkinetic movements were demonstrated, although the resting state was not significant. The couplings from the SMG to the PreCG (p = 0.03) was significant in the task of left blinking, whereas the coupling from the SMG to the SPG (p = 0.04) was significant in the task of left smiling. We speculated that facial synkinesis affects disruption among the brain networks, and specific couplings that are modulated simultaneously can compensate for motor deficits. Therefore, behavioral or brain stimulation technique treatment could be applied to alter reorganization within specific couplings in the rehabilitation of facial function.

Efficacy and safety of CO2 laser in the treatment of chronic wounds: A Retrospective Matched Cohort Trial.

OBJECTIVES: Treating chronic cutaneous wounds is challenging, and debridement is a central concept in treating them. Studies have shown that CO2 laser debridement can control local infection and promote the wound healing process. The present study aimed to investigate the efficacy and safety of fully ablative CO2 laser debridement compared to routine surgical debridement in the treatment of chronic wounds. METHODS: The retrospective cohort study was conducted on patients with chronic (>1 month) cutaneous wounds (≥1 cm2 ) between December 1, 2017, and December 1, 2020, in the Wound Healing Center at Shanghai Ruijin Hospital, China. Patients treated with CO2 laser debridement with a DEKA SmartXide2 C80 (DEKA) (the CO2 laser group) were compared with matched control patients with similar baseline characteristics who had undergone routine surgical debridement (the routine group). The primary outcome was time-to-heal (days) for chronic wounds in two groups, and secondary outcomes included the wound area and BWAT (Bates-Jensen wound assessment tool) score before treatment, and at 1, 2, 3, and 4 weeks after treatment. RESULTS: The study included 164 patients (82 in the CO2 laser group and 82 matched in the routine group). The time-to-heal for patients in the CO2 laser group (41.30 ± 17.11) was significantly shorter than that of the patients in the routine group (48.51 ± 24.32) (p = 0.015). At 3 and 4 weeks after treatment, the absolute wound area of the CO2 laser group was significantly smaller than that of the routine group. Also, the CO2 laser group exhibited a significantly lower relative area at 2, 3, and 4 weeks after treatment. The CO2 laser group yielded significantly lower BWAT scores at 2, 3, and 4 weeks after treatment. Additionally, the relative BWAT score was significantly lower in the CO2 laser group than the relative scores in the routine group at 2, 3, and 4 weeks after treatment. No adverse events related to the treatments were observed in either group during the study period. CONCLUSIONS: The present study has shown that fully ablative CO2 laser debridement has several advantages over routine sharp surgical debridement. It is superior at ameliorating wound status and reducing wound area, and it also significantly reduces the time-to-heal for chronic wounds, without causing any adverse events.

Successful Postoperative Nephrocutaneous Fistula Treatment With Omental Flap Grafting: A Case Report.

Nephrocutaneous fistula (NCF) is a rare and severe complication of renal disease and surgical procedures. Treatments for NCF are based on the renal function, and can include nephrectomy, heminephrectomy, nephroureterectomy, endourological maneuvers or antibiotic therapy alone. Here we report a case of a chronic NCF which occurred 5 years after partial nephrectomy. In this report, we describe a new surgical approach for the management of a patient with postoperative NCF. In the present case, in addition to removing the fistulous tract, we also performed an omental flap grafting to tightly cover the kidney. In addition to limiting and controlling the local inflammation, the omental flap prevents contact between the kidney and the flank muscle on its posterior rim. No recurrence or complications occurred throughout 10 months of follow-up. The NCF was successfully treated with completely removal of the sinus tract and omental flap grafting, without nephrectomy. This case adds new aspects to the treatment of NCF.

Distribution and Antibiotic Resistance Patterns of Pathogenic Bacteria in Patients With Chronic Cutaneous Wounds in China.

Background: To determine the distribution and antimicrobial susceptibility pattern of pathogenic bacteria in patients with chronic cutaneous wounds on a national scale. Methods: A retrospective study was conducted using the data recorded between January 1, 2018 and January1, 2020 in 195 hospitals across China. After screening the data, 815 patients with chronic wounds were finally analyzed. The data collected included information about the patients' general condition and local cutaneous wound assessments, especially microbial culture and antibiotic susceptibility tests. The analyses were performed using SPSS Version 26. Results: The study included 815 patients (290 [35.6%] females; 63 [50-74] years). The most common causes of chronic cutaneous wounds were diabetes (183, 22.5%), infection (178, 21.8%), and pressure (140, 17.2%). Among these, 521(63.9%) samples tested yielded microbial growth, including 70 (13.4%) polymicrobial infection and 451 (86.6%) monomicrobial infection. The positive rate of microbial culture was highest in wound tissue of ulcers caused by infection (87.6%), followed by pressure (77.1%), diabetes (68.3%), and venous diseases (67.7%). Bates-Jensen wound assessment tool (BWAT) scores >25 and wounds that lasted for more than 3 months had a higher positive rate of microbial culture. BWAT scores >25 and wounds in the rump, perineum, and feet were more likely to exhibit polymicrobial infection. A total of 600 strains were isolated, of which 46.2% (277 strains) were Gram-positive bacteria, 51.3% (308 strains) were Gram-negative bacteria, and 2.5% (15 strains) were fungi. The most common bacterial isolates were Staphylococcus aureus (29.2%), Escherichia coli (11.5%), Pseudomonas aeruginosa (11.0%), Proteus mirabilis (8.0%), and Klebsiella pneumoniae (5.8%). The susceptibility tests showed that 116 cultured bacteria were Multidrug resistant (MDR) strains. The resistance rates of S. aureus were 92.0% (161/175) to penicillin, 58.3% (102/175) to erythromycin, and 50.9% (89/175) to clindamycin. Vancomycin was the most effective antibiotic (0% resistance rate) against all Gram-positive bacteria. Besides, the resistance rates of E. coli were 68.1% (47/69) to ampicillin, 68.1% (47/69) to ciprofloxacin, 60.9% (42/69) to levofloxacin. However, all the isolated Gram-negative bacteria showed low resistance rates to tigecycline (3.9%) and amikacin (3.6%). Conclusions: The distribution of bacteria isolated from chronic cutaneous wounds varies with the BWAT scores, causes, duration, and the location of wounds. Multidrug resistance is a serious health issue, and therefore antibiotics used in chronic wounds must be under strict regulation. Our findings may help clinicians in making informed decisions regarding antibiotic therapy.

Structural remodeling in related brain regions in patients with facial synkinesis.

Facial synkinesis is a troublesome sequelae of facial nerve malfunction. It is difficult to recover from synkinesis, despite improved surgical techniques for isolating the peripheral facial nerve branches. Furthermore, it remains unclear whether long-term dysfunction of motor control can lead to irreversible plasticity-induced structural brain changes. This case-control study thus investigated the structural brain alterations associated with facial synkinesis. The study was conducted at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China. Twenty patients with facial synkinesis (2 male and 18 female, aged 33.35 ± 6.97 years) and 19 healthy volunteers (2 male and 17 female, aged 33.21 ± 6.75 years) underwent magnetic resonance imaging, and voxel-based and surface-based morphometry techniques were used to analyze data. There was no significant difference in brain volume between patients with facial synkinesis and healthy volunteers. Patients with facial synkinesis exhibited a significantly reduced cortical thickness in the contralateral superior and inferior temporal gyri and a reduced sulcal depth of the ipsilateral precuneus compared with healthy volunteers. In addition, sulcal depth of the ipsilateral precuneus was negatively correlated with the severity of depression. These findings suggest that there is a structural remodeling of gray matter in patients with facial synkinesis after facial nerve malfunction. This study was approved by the Ethics Review Committee of the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China (approval No. 2017-365-T267) on September 13, 2017, and was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800014630) on January 25, 2018.

Overexpression of NPTX2 Promotes Malignant Phenotype of Epithelial Ovarian Carcinoma via IL6-JAK2/STAT3 Signaling Pathway Under Hypoxia.

BACKGROUND: Epithelial ovarian cancer (EOC) is the main subtype of ovarian cancer and shows an aggressive phenotype and poor prognosis. Neuronal pentraxin II (NPTX2) is a member of the neuronal pentraxin family and plays a contradictory role in different tumors. However, there has been no report about the possible role and effect of NPTX2 in EOC. METHODS: Bioinformatics analysis, qPCR, western blotting and immunohistochemistry were used to detect the expression of NPTX2 in EOC. Lentivirus-based transfection for NPTX2 overexpression or knockdown was performed on the EOC cell lines A2780, HEY, SKOV3 and OVCAR-3. The effect of NPTX2 on the malignant phenotype of EOC was examined through methods of MTS assay, Edu assay, transwell assay, western blotting analysis, qPCR analysis, luciferase reporter assay and xenograft experiment. RESULTS: EOC tissues showed higher NPTX2 expression than the normal tissues with poor prognosis. NPTX2 overexpression can promote the proliferation, invasion, migration and tumorigenesis of EOC via IL6-JAK2/STAT3 signaling pathway. Moreover, hypoxia-inducible factor-1(HIF-1) can promote the transcription and expression of NPTX2 under the hypoxic environment. NPTX2 knockdown abolished the hypoxia-induced malignant phenotypes in ECO. CONCLUSIONS: The above results suggest that NPTX2 may play a novel role in ovarian cancer's malignant phenotype and act as a promising treatment target for EOC molecular therapy.

Alteration of spatial patterns at the network-level in facial synkinesis: an independent component and connectome analysis.

BACKGROUND: The treatment of post-facial palsy synkinesis (PFPS) remains inadequate. Previous studies have confirmed that brain plasticity is involved in the process of functional restoration. Isolated activation has been well studied, however, the brain works as an integrity of several isolated regions. This study aimed to assess the alteration of the brain network topology with overall and local characteristics of information dissemination. Understanding the neural mechanisms of PFPS could help to improve therapy options and prognosis. METHODS: Patients with facial synkinesis and healthy controls (HCs) were estimated using functional magnetic resonance imaging (fMRI) of resting-state. Subsequently, an independent component analysis (ICA) was used to extract four subnets from the whole brain. Then we used the measurements of graph theory and calculated in the whole-brain network and each sub-network. RESULTS: We found no significant difference between the patient group and the HCs on the whole-brain scale. Then we identified four subnetworks from the resting-state data. In the sub-network property analysis, patients' locally distributed properties in the sensorimotor network (SMN) and ventral default mode network (vDMN) were reduced. It revealed that γ (10,000 permutations, P=0.048) and S (10,000 permutations, P=0.022) within the SMN progressively decreased in patients with PFPS. For the analysis of vDMN, significant differences were found in γ (10,000 permutations, P=0.019), Elocal (10,000 permutations, P=0.008), and ß (10,000 permutations, P=0.011) between the groups. CONCLUSIONS: Our results demonstrated a reduction in local network processing efficiency in patients with PFPS. Therefore, we speculate that decreased characteristics in the intra-vDMN and intra-SMN, rather than the whole-brain network, may serve distinct symptoms such as facial nerve damage or more synkinetic movements. This finding of the alteration of network properties is a small step forward to help uncover the underlying mechanism.

MEK1/2 Inhibitor (GDC0623) Promotes Osteogenic Differentiation of Primary Osteoblasts Inhibited by IL-1ß through the MEK-Erk1/2 and Jak/Stat3 Pathways.

OBJECTIVE: We evaluated the effects and mechanisms of GDC0623 on osteogenic differentiation of osteoblasts induced by IL-1ß. Methodology. Osteoblasts were treated with 20 ng/ml IL-1ß and 0.1 µM GDC0623. Cell proliferation levels were evaluated by the cell counting kit 8 (CCK8), EdU assay, and western blotting [proliferating cell nuclear antigen (PCNA) and Cyclin D1]. Osteoblasts were cultured in an osteogenic induction medium for 1-3 weeks after which their differentiations were assessed by alkaline phosphatase (ALP) staining, Alizarin Red staining, calcium concentration, immunocytochemistry staining, real-time quantitative PCR (RT-qPCR), and immunofluorescence staining. The osteogenesis-associated mechanisms were further evaluated by western blotting using appropriate antibodies. RESULTS: Relative to the control group, IL-1ß induced the rapid proliferation of osteoblasts and suppressed their osteogenic differentiations by upregulating the activities of MEK-Erk1/2 as well as Jak-Stat3 pathways and by elevating MMP13 and MMP9 levels. However, blocking of the MEK-Erk1/2 signaling pathway by GDC0623 treatment reversed these effects. CONCLUSION: Inhibition of Jak-Stat3 pathway by C188-9 downregulated the expression levels of MMP9 and MMP13, activated MEK-Erk1/2 pathway, and inhibited osteogenic differentiation.

Functional Organization of Brain Network in Peripheral Neural Anastomosis Rats after Electroacupuncture: An ICA and Connectome Analysis.

Acupuncture is a mild therapy in rehabilitation practice of peripheral nerve injury. Previous studies confirmed the deep participation of brain plasticity in the process of functional restoration. The therapeutic effect of acupuncture is also believed to be closely associated with brain plasticity, especially in the hypothalamus and limbic system. But the fuzzy neural mechanism somehow limits the application or improvement of this therapy. There is little information about the effect of acupuncture on topological properties of brain networks. Instead of functional segregation approach, we utilized graph theory method to analyze the large-scale and distributed properties of information processing. We first established rat model of sciatic nerve injury and performed rehabilitation therapy of electroacupuncture for 120 days. Meanwhile, we used independent component analysis to extract seven sub-networks from the whole brain. Then measurements of graph theory were calculated in each sub-network as well as the whole brain network. We found no significant difference of any measurement in whole brain network among intervention group, model group and normal group. But the assortativity, hierarchy, small-world properties of sub-network displayed significant differences among three groups. It induces changes of neural plasticity in several sub-networks instead of whole brain network. We attributed the changes to the enhancement of the short-term compensatory adaptation and the reduction of the long-term overacting regional information transmission. The present study may shed light on the vague distinction of large-scale property of brain networks after electroacupuncture, which leads to a better understanding of this ancient traditional Chinese therapy.

Fibroblast growth factor 2 contributes to the effect of salidroside on dendritic and synaptic plasticity after cerebral ischemia/reperfusion injury.

Ischemic stroke, a serious neurological disease, is associated with cell death, axonal and dendritic plasticity, and other activities. Anti-inflammatory, anti-apoptotic, promote dendritic and synaptic plasticity are critical therapeutic targets after ischemic stroke. Fibroblast growth factor-2 (FGF2), which is involved in the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/CAMP response element (CRE)-binding protein (CREB) pathway, has been shown to facilitate dendritic and synaptic plasticity. Salidroside (Sal) has been reported to have anti-inflammatory, anti-oxidative, and anti-apoptotic effects; however, the underlying mechanisms of Sal in promoting dendritic and synaptic plasticity remain unclear. Here, the anti-inflammatory, anti-apoptotic, dendritic and synaptic plasticity effects of Sal were investigated in vitro in PC12 cells under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions and in vivo in rats with middle cerebral artery occlusion/reperfusion (MCAO/R). We investigated the role of Sal in promoting dendritic and synaptic plasticity in the ischemic penumbra and whether the FGF2-mediated cAMP/PKA/CREB pathway was involved in this process. The present study demonstrated that Sal could significantly inhibit inflammation and apoptosis, and promote dendritic and synaptic plasticity. Overall, our study suggests that Sal is an effective treatment for ischemic stroke that functions via the FGF2-mediated cAMP/PKA/CREB pathway to promote dendritic and synaptic plasticity.

Shifted hub regions in the brain network of rat neuropathic pain model after electroacupuncture therapy.

Electroacupuncture has been considered an effective neurorehabilitative approach to relieve neuropathic pain originating in the central nervous system. However, the neural mechanism underlying the effect of electroacupuncture on pain-relief remains largely unknown. The objective of this study was to investigate the alteration of hub configurations of brain networks caused by the sustained impact of electroacupuncture on a clinically relevant animal model of neuropathic pain. Rats were divided into four groups: normal, model, electroacupuncture, and sham-electroacupuncture. Rats of the last three groups received complete brachial plexus avulsion to evoke neuropathic pain. Electroacupuncture was conducted continuously for three months on the electroacupuncture group, while the sham intervention was performed on the sham-electroacupuncture group. Mechanical withdrawal thresholds were evaluated at the end of the first and third month of intervention. Graph theoretical network analysis compared the regional topological parameters and explored hub configurations of brain networks by longitudinal resting-state fMRI. Three-months electroacupuncture showed a significant pain-relief effect. Not the spatial distribution of hubs, but the hubness distribution showed a significant difference among groups after a three-month intervention. The proportion of more highly connected hub regions was significantly higher in the model rats than the normal rats, while that of the electroacupuncture group was considerably lower than the model group. Additionally, regional parameter changes showed a very similar distribution of hub proportions. It was concluded that long-term electroacupuncture might restore an adaptive equilibrium to a disrupted network and suppress maladaptive plastic changes that follow neuropathic pain. This may provide an important avenue for future strategies appropriate for therapeutic interventions.

Acupuncture Induces Reduction in Limbic-Cortical Feedback of a Neuralgia Rat Model: A Dynamic Causal Modeling Study.

Background: Neuropathic pain after brachial plexus avulsion remained prevalent and intractable currently. However, the neuroimaging study about neural mechanisms or etiology was limited and blurred. Objective: This study is aimed at investigating the effect of electroacupuncture on effective connectivity and neural response in corticolimbic circuitries during implicit processing of nociceptive stimulus in rats with brachial plexus pain. Methods: An fMRI scan was performed in a total of 16 rats with brachial plexus pain, which was equally distributed into the model group and the electroacupuncture group. The analysis of task-dependent data determined pain-related activation in each group. Based on those results, several regions including AMY, S1, and h were recruited as ROI in dynamic causal modeling (DCM) analysis comparing evidence for different neuronal hypotheses describing the propagation of noxious stimuli in regions of interest and horizontal comparison of effective connections between the model and electroacupuncture groups. Results: In both groups, DCM revealed that noxious stimuli were most likely driven by the somatosensory cortex, with bidirectional propagation with the hypothalamus and amygdala and the interactions in them. Also, the 3-month intervention of acupuncture reduced effective connections of h-S1 and AMY-S1. Conclusions: We showed an evidence that a full connection model within the brain network of brachial plexus pain and electroacupuncture intervention reduces effective connectivity from h and AMY to S1. Our study for the first time explored the relationship of involved brain regions with dynamic causal modeling. It provided novel evidence for the feature of the organization of the cortical-limbic network and the alteration caused by acupuncture.

Pain Relief Dependent on IL-17-CD4+ T Cell-ß-Endorphin Axis in Rat Model of Brachial Plexus Root Avulsion After Electroacupuncture Therapy.

BACKGROUND AND PURPOSE: Neuropathic pain is the typical symptom of brachial plexus root avulsion (BPRA), and no effective therapy is currently available. Electroacupuncture (EA), as a complementary and alternative therapy, plays a critical role in the management of pain-associated diseases. In the present study, we aimed to reveal the peripheral immunological mechanism of EA in relieving the pain of BPRA through the IL-17-CD4+ T lymphocyte-ß-endorphin axis. METHODS: After receiving repeated EA treatment, the pain of BPRA in rats along with the expressions of a range of neurotransmitters, the contents of inflammatory cytokines, and the population of lymphocytes associated were investigated. CD4+ T lymphocytes were either isolated or depleted with anti-CD4 monoclonal antibody. The titers of IL-17A, interferon-γ (IFN-γ), and ß-endorphin were examined. The markers of T lymphocytes, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), macrophages, and natural killer (NK) cells were assessed. The activation of the nuclear transcription factor κB (NF-κB) signaling pathway was tested. RESULTS: The pain of BPRA was significantly relieved, and the amount of CD4+ T lymphocytes was increased after EA treatment. The release of ß-endorphin was up-regulated with the up-regulation of IL-17A in CD4+ T lymphocytes. The titer of IL-17A was enhanced, leading to an activated NF-κB signaling pathway. The release of ß-endorphin and the analgesic effect were almost completely abolished when CD4+ T lymphocytes were depleted. CONCLUSION: We, for the first time, showed that the neuropathic pain caused by BPRA was effectively relieved by EA treatment via IL-17-CD4+ T lymphocyte-ß-endorphin mediated peripheral analgesic effect, providing scientific support for EA clinical application.

Diffusional plasticity induced by electroacupuncture intervention in rat model of peripheral nerve injury.

Electroacupuncture (EA) is an adjuvant therapy for peripheral nerve injury (PNI). Both peripheral and central alterations contribute to the rehabilitation process. We employed diffusion tensor imaging (DTI) to investigate the diffusion plasticity of afferent and efferent pathways caused by EA in model of peripheral nerve injury and reparation. Twenty-four rats were divided into three groups: normal group, model group and intervention group. Rats of the model group and the intervention group underwent sciatic nerve transection and anastomosis. EA intervention was performed on the intervention group at ST-36 and GB-30 for three months. Gait assessment and DTI were conducted at days post-operative (DPO) 30, 60 and 90. We selected corticospinal tract, spinothalamic tract and internal capsule as regions of interest and analyzed diffusion metrics including fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). FA values and RD values displayed significant differences or obvious tendency while AD values maintained a stable level. RD values displayed better indicative performance than FA in internal capsule. The intervention group presented significant correlation between RD values and Regularity Index (RI) during the intervention period. The effect of EA on peripheral nerve injury repairing rats appeared to be accelerated recovery process of sensory and motor neural pathway. We proposed that RD was a potential in vivo indicator for structural plasticity caused by EA and PNI.

Evaluation of Neuropathic Pain in a Rat Model of Total Brachial Plexus Avulsion from Behavior to Brain Metabolism.

BACKGROUND: Approximately 30% to 80% of patients with brachial plexus avulsion (BPA) developed neuropathic pain. It is an intolerable neuropathic pain, which brings heavy burden to family and society. In addition to motor and sensory deficits, neuropathic pain can be another serious sequela that equally influences the patient. The development of a microsurgical technique has promoted the treatment and rehabilitation of brachial plexus injury, but pain relief after BPA is still a difficult problem. OBJECTIVES: The present study aimed to semi-quantify changes in the behavior, spinal cord and cerebral metabolism in a neuropathic pain model following BPA injury in rats. STUDY DESIGN: Controlled animal study. SETTING: Institute of Rehabilitation Medicine, Shanghai, China. METHODS: A total of 15 Sprague-Dawley rats, weighing 200 to 220 g, were randomly divided into 2 groups: experimental group (n = 10) and control group (n = 5). In the experimental group, neuropathic pain induced by BPA was established by directly avulsing the C5, C6, C7, C8, and T1 roots on the right side from the spinal cord. Rats in the control group only received open-close surgery. The autotomic behavior of biting their own digits was recorded and scored at 2 months after the surgery. Small animal positron emission tomography/computed tomography (PET/CT) images after injection of a 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) tracer were acquired to evaluate glucose metabolism in pain-related brain regions before and after the surgery, respectively. Semi-quantitative values of cortical to cerebellum standardized uptake value (SUV) ratios were calculated. Then, the animals were euthanized and the cervical segments of the spinal cord were removed for detection of glial fibrillary acidic protein (GFAP) expression in the astrocytes by immunohistochemical assay. RESULTS: Nine of the 10 rats (90%) in the experimental group showed autotomic behavior at 2 months after the surgery. Slight autotomic behavior was noted only in one of 5 rats (20%) from the control group. The autotomic score in the experimental group was significantly higher than that in the control group (5.4 ± 1.0 vs. 0.2 ± 0.4, P < 0.05). The experimental group showed significantly higher SUV ratio in both the right and left thalamus, compared to the control group (P < 0.05). Immunohistochemical assay demonstrated that GFAP positive astrocytes in the dorsal horn at the injured side significantly increased compared to the control group (P < 0.05). LIMITATIONS: There are differences between small animals and human beings, and the structure and function of the human brain is more complex than in rodents. Therefore, extrapolation of the present conclusion should be cautious. CONCLUSIONS: The present study reported a unique model of neuropathic pain following total BPA in rodents, which was demonstrated by a higher rate and score of autotomic behavior. More astrocytes were found activated in the spinal cord at the corresponding level of C5 and C6 spinal cord. In the small animal PET/CT imaging, significantly higher standardized glucose metabolic activity was found in both the right and left thalamus in the experimental group. The present study semi-quantified the neuropathic pain behavior in rats and explored the plastic changes in the spinal and brain metabolism. KEY WORDS: Brachial plexus avulsion, small animal PET/CT, glucose metabolism, neuropathic pain, astrocyte, 18F-FDG.

Motor Control Deficits in Facial Synkinesis Patients: Neuroimaging Evidences of Cerebral Cortex Involvement.

Objective: Facial synkinesis is a severe sequelae of facial nerve malfunction. Once the synkinesis is established, it is extremely difficult for patients to recover. Given that the restoration of motor or sensory function after peripheral nerve injury was closely related with cortical plasticity, we investigated cortical plasticity in facial synkinesis patients by the frequency-specific data which remains largely uncharacterized. Materials and Methods: Resting-state fMRI was conducted in 20 facial synkinesis patients and 19 healthy controls, and the amplitude of low-frequency fluctuation (ALFF) in five different frequency bands (slow-6: 0-0.01 Hz; slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; slow-3: 0.073-0.167 Hz; and slow-2: 0.167-0.25 Hz) was calculated, respectively. And the relationship between ALFF and clinical outcomes was also analyzed. Results: Comparing with the healthy controls, facial synkinesis patients showed significantly different ALFF values, mainly in the sensorimotor areas. Furthermore, increased ALFF of the ipsilateral insula in the slow-6 band was significantly related with better facial nerve function. Conclusion: Increased ALFF values in the ipsilateral insula might reflect an abnormal state of hypercompensation in motor control of facial synkinesis patients. It provided valuable spatial information about the functionally aberrant regions, which implied the possible involvement of motor control system in facial synkinesis.

Alteration of metabolic connectivity in a rat model of deafferentation pain: a 18F-FDG PET/CT study.

OBJECTIVE: Refractory deafferentation pain has been evidenced to be related to central nervous system neuroplasticity. In this study, the authors sought to explore the underlying glucose metabolic changes in the brain after brachial plexus avulsion, particularly metabolic connectivity. METHODS: Rats with unilateral deafferentation following brachial plexus avulsion, a pain model of deafferentation pain, were scanned by small-animal 2-deoxy-[18F]fluoro-d-glucose (18F-FDG) PET/CT to explore the changes of metabolic connectivity among different brain regions. Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) of the intact forepaw were also measured for evaluating pain sensitization. Brain metabolic connectivity and TWL were compared from baseline to 1 week after brachial plexus avulsion. RESULTS: Alterations of metabolic connectivity occurred not only within the unilateral hemisphere contralateral to the injured forelimb, but also in the other hemisphere and even in the connections between bilateral hemispheres. Metabolic connectivity significantly decreased between sensorimotor-related areas within the left hemisphere (contralateral to the injured forelimb) (p < 0.05), as well as between areas across bilateral hemispheres (p < 0.05). Connectivity between areas within the right hemisphere (ipsilateral to the injured forelimb) significantly increased (p = 0.034). TWL and MWT of the left (intact) forepaw after surgery were significantly lower than those at baseline (p < 0.001). CONCLUSIONS: This study revealed that unilateral brachial plexus avulsion facilitates pain sensitization in the opposite limb. A specific pattern of brain metabolic changes occurred in this procedure. Metabolic connectivity reorganized not only in the sensorimotor area corresponding to the affected forelimb, but also in extensive areas involving the bilateral hemispheres. These findings may broaden our understanding of central nervous system changes, as well as provide new information and a potential intervention target for nosogenesis of deafferentation pain.