Vagus Nerve Stimulation Group Research Articles

The dual effect of vagus nerve stimulation in pediatric patients with drug-resistant epilepsy: Is there more than seizure control?

This is a retrospective-comparative-pilot study to investigate the role of vagal nerve stimulation (VNS) in improving cognitive functions in the pediatric age group with Drug resistant epilepsy (DRE). It was conducted from January 2018 to February 2023. Children between the age of 4-18 years were divided into two groups, the “VNS group” and the “best medical treatment (BMT) group”. Follow up period was 12 months. Demographic, clinical, etiological and investigational data were noted. Cognitive assessment using the Modified Mini-Mental State Examination for children (MMSE) was recorded at baseline and 12 months later for each group. 76.4% of patients were classified as epilepsy secondary to cerebral palsy. 75% of patients showed ≥50% seizure frequency reduction among the VNS group as compared to 12.5% in the BMT group. None of both groups achieved seizure freedom. At 12 months, both BMT and VNS groups showed statistically significant improved overall cognitive score from baseline records (p=0.027) and (p=0.012), respectively, with a significantly higher improvement in VNS group. Also, statistical sub-analysis of cognitive subscales in cerebral palsy patients in both groups was conducted and revealed a significant improvement (p=0.02) in VNS group. We concluded that there is a potential role of VNS in improving cognitive functions which was proved by using a cost-effective screening tool. A significant effect was observed specially in cerebral palsy patients. This is very beneficial in limited-resources countries where VNS has high safety profile, seizure control and added values on cognitive functions.

Efficacy of vagus nerve stimulation for children with drug-resistant epilepsy: Retrospective study

IntroductionAccording to current investigations, there are controversy in our knowledge regarding the safety and efficacy of Vagus Nerve Stimulation (VNS) in children younger than 12 years old. Therefore, we performed this study and aimed to better evaluate the safety and efficacy of VNS in children younger than 12 years. MethodThe retrospective study comprised two groups. In the first group, patients (N = 19) underwent VNS implantation procedure and second group, (N = 21) received no VNS implantation. The main study parameters are as follows: (1) Primary outcome evaluated the proportion of cases with >50 % reduction of seizures at the last follow-up. (2) Changes in patients’ status in VNS group after procedure compared to before procedure. (3) Patient's complaints in VNS group compared to control group. ResultsOur results demonstrated that there was a significant reduction in the frequency of seizures (per month) in patients 6 months after VNS surgery compared to before VNS surgery (1044.3 ± 1526.7 VS 220.7 ± 421.6; P value = 0.028). 57.9 % of patients underwent VNS showed the response rate of 50 % reduction in seizure frequency. There was significant improvement in memory problem, work/ school limitation, social limitation, and tachycardia 6 months after VNS procedure compared to before VNS procedure in patients. The most common reported side effects were difficulty swallowing (31.5 %) and coughing (31.5 %) followed by stomach discomfort (15.8 %). ConclusionConsidering the significant reduction in the frequency of seizures and improvement of life aspects including in memory problem, work/ school limitation, social limitation, we recommend VNS as an effective treatment modality for drug-resistant epilepsy in children. However, the combination of VNS with other treatment modalities that could improve other aspects of quality such as energy levels, sleep pattern, and feeling management of life is recommended.

The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum.

Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3-54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.

Efficacy and safety of vagus nerve stimulation on upper extremity motor function in patients with stroke: A meta-analysis of randomized controlled trials.

In 2021, the U.S. Food and Drug Administration (FDA) approved paired vagus nerve stimulation (VNS) for patients with moderate-to-severe upper extremity motor impairments following chronic ischemic stroke. Previous meta-analyses have shown that VNS may impact stroke rehabilitation, but each has some limitations. PubMed, Ovid, Cochrane Library, ScienceDirect, Web of Science and WHO ICTRP databases were searched until July 14, 2022 for randomized controlled trials (RCTs). We defined primary outcomes as Fugl-Meyer Assessment for Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT). Subgroup analyses included types of VNS, time since onset and long-term effects. Secondary outcomes included adverse events of VNS. Eight RCTs involving 266 patients were analyzed, of which five used direct VNS and three transcutaneous auricular VNS. The results revealed that VNS enhanced upper extremity function via FMA-UE (SMD = 0.73; 95% CI: 0.48 to 0.99; P < 0.00001) and WMFT (SMD = 0.82; 95% CI:0.52 to 1.13; P < 0.00001) in comparison to the control group, but showed no significant change on long-term effects of FMA-UE (SMD = 0.69; 95% CI: - 0.06 to 1.44; P = 0.07). There was no difference in adverse events between the VNS and control groups (RR = 1.16; 95% CI: 0.46 to 2.92; P = 0.74). For stroke victims with upper limb disabilities, VNS paired with rehabilitation was significantly safe and effective. More high-quality multicentric RCTs are needed to validate this conclusion.

Meniere Disease treated with transcutaneous auricular vagus nerve stimulation combined with betahistine Mesylate: A randomized controlled trial

BackgroundMeniere Disease is a clinical condition defined by hearing loss, tinnitus, and aural fullness symptoms, there are currently no any medications approved for its treatment. ObjectiveTo determine whether taVNS as an adjunctive therapy could relieve symptoms and improve the quality of life in patients with Meniere disease. MethodsIn this Single-center, single blind, randomized trial, participants were assigned to transcutaneous auricular vagus nerve stimulation (taVNS) group and sham taVNS group. The primary outcome measures comprised Tinnitus Handicap Inventory, Dizziness Handicap Inventory, Pure Tone Auditory, Visual analogue scale of aural fullness. Secondary outcome measures comprised the 36-Item Short Form Health Survey, video head impulse test, and the caloric test. ResultsAfter 12 weeks, the THI (−11.00, 95%CI, −14.87 to −7.13; P < 0.001), DHI (−47.26, 95%CI, −50.23 to −44.29; P < 0.001), VAS of aural fullness (−2.22, 95%CI, −2.95 to −1.49; P<0.01), and Pure Tone Thresholds (−7.07, 95%CI, −9.07 to −5.06; P<0.001) were significantly differed between the two groups. In addition, SF36(14.72, 95%CI, 11.06 to 18.39; P < 0.001), vHIT (RD, 0.26, 95 % CI, −0.44 to −0.08, RR, 0.43, 95 % CI, 0.22 to 0.83, P < 0.01), and the caloric test (RD, −0.24, 95 % CI, −0.43 to −0.04, RR, 0.66, 95 % CI, 0.44 to 0.95, P = 0.02) have significant difference between two group, respectively. ConclusionsThese findings suggest that taVNS combined with Betahistine Mesylate relieve symptoms and improve the quality of life for patients with Meniere Disease. taVNS can be considered an adjunctive therapy in treatment of Meniere Disease. Trial registrationClinicalTrials.gov Identifier: NCT05328895.

An economic evaluation of vagus nerve stimulation as an adjunctive treatment to anti-seizure medications for the treatment of drug resistant epilepsy in the United States

IntroductionPeople with recurrent epileptic seizures are typically treated with anti-seizure medications (ASMs). Around a third of epilepsy patients fail to achieve an adequate response to ASMs and may be eligible to receive vagus nerve stimulation (VNS) therapy for their drug-resistant epilepsy (DRE) if they are unsuited to surgery. VNS received approval from the United States (US) Food and Drug Administration agency. However, there has to date been no comprehensive cost effectiveness evaluation of VNS within the US setting. This study was designed, using a US Medicare perspective, to estimate costs and quality-adjusted life years (QALYs) associated with VNS as an adjunct to ongoing ASM therapy, compared to ASMs alone.MethodsWe developed a cohort state transition model in Microsoft Excel, with four health states defined by different percentage reductions in seizure frequency, with a 3-month cycle and transition probabilities derived from published clinical trials and registry data. Sensitivity analyses were conducted to understand the impact of parameter uncertainty. Costs included the VNS device, placement, programming, battery changes, and removal; ASM therapy; adverse events associated with VNS (dyspnea, hoarseness, and cough); and costs associated with seizure burden (i.e. hospitalizations, emergency department visits, neurologist visits).ResultsUnder base case assumptions, treatment with VNS was associated with a 0.385 QALY gain and a $109,678 saving per patient, when compared with ASM therapy alone. The incremental net monetary benefit (iNMB) was $128,903 at a threshold of $50,000 per QALY, with the positive iNMB indicating that VNS is a highly cost effective treatment. This result is explained by the modeled reduction in relative seizure frequency and associated reduction in healthcare resource use that the VNS group experienced. Sensitivity analyses supported this conclusion.ConclusionsVNS was evaluated as a cost effective addition to the current standard of care in the treatment of DRE in the US Medicare context.

Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways.

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.

Vagus nerve stimulation attenuates acute kidney injury induced by hepatic ischemia/reperfusion injury in rats

Hepatic ischemia/reperfusion (I/R) injury, caused by limited blood supply and subsequent blood supply, is a causative factor resulting in morbidity and mortality during liver transplantation and liver resection. Hepatic I/R injury frequently contributes to remote organ injury, such as kidney, lung, and heart. It has been demonstrated that vagus nerve stimulation (VNS) is effective in remote organ injury after I/R injury. Here, our aim is to investigate the potential action of VNS on hepatic I/R injury-induced acute kidney injury (AKI) and explore its underlying mechanisms. To test this hypothesis, male Sprague–Dawley rats were randomly assigned into three experimental groups: Sham group (sham operation, n = 6); I/R group (hepatic I/R with sham VNS, n = 6); and VNS group (hepatic I/R with VNS, n = 6). VNS was performed during the entire hepatic I/R process. Our results showed that throughout the hepatic I/R process, VNS significantly regulated the expression levels of various iconic factors and greatly enhanced the protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) in the kidneys. These findings suggested that VNS may ameliorate hepatic I/R injury-induced AKI by suppressing inflammation, oxidative stress, and apoptosis probably through activating the Nrf2/HO-1 signaling pathway.

Vagus Nerve Stimulation Paired With Rehabilitation for Upper Limb Motor Impairment and Function After Chronic Ischemic Stroke: Subgroup Analysis of the Randomized, Blinded, Pivotal, VNS-REHAB Device Trial

Background Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke. Objective We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury. Methods Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in impairment measured by the Fugl–Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of 6-weeks in-clinic therapy. We explored the effect of VNS treatment by sex, age (≥62 years), time from stroke (>2 years), severity (baseline FMA-UE score >34), paretic side of body, country of enrollment (USA vs UK) and presence of cortical involvement of the index infarction. We assessed whether there was any interaction with treatment. Findings The primary outcome increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (P = .001, between group difference 2.6, 95% CI 1.03-4.2). The between group difference was similar across all subgroups and there were no significant treatment interactions. There was no important difference in rates of adverse events across subgroups. Conclusion The response was similar across subgroups examined. The findings suggest that the effects of paired VNS observed in the VNS-REHAB trial are likely to be consistent in wide range of stroke survivors with moderate to severe upper extremity impairment.

Timing of vagus nerve stimulation during fear extinction determines efficacy in a rat model of PTSD

Studies have indicated that vagus nerve stimulation (VNS) enhances extinction learning in rodent models. Here, we investigated if pairing VNS with the conditioned stimulus is required for the enhancing effects of VNS. Adult Sprague–Dawley rats were exposed to intense stress followed by fear conditioning training to produce resistant fear. Rats were then implanted with a cuff electrode around the left vagus. After recovery, rats underwent extinction training paired with VNS (0.5 s, 0.8 mA, 100 µs, and 30 Hz) or with Sham VNS (0 mA). VNS rats were randomized into the following subgroups: During VNS (delivered during presentations of the conditioned stimulus, CS), Between VNS (delivered between CS presentations), Continuous VNS (delivered during the entire extinction session), and Dispersed VNS (delivered at longer inter-stimulation intervals across the extinction session). Sham VNS rats failed to extinguish the conditioned fear response over 5 days of repeated exposure to the CS. Rats that received Between or Dispersed VNS showed modest improvement in conditioned fear at the retention test. During and Continuous VNS groups displayed the greatest reduction in conditioned fear. These findings indicate that delivering VNS paired precisely with CS presentations or continuously throughout extinction promotes the maximum enhancement in extinction learning.

Effect of Adropin on Pancreas Exocrine Function in a Rat Model: A Preliminary Study.

Simple SummaryAdropin plays an important role in the regulation of energy homeostasis and metabolism. It enhances glucose tolerance, improves insulin resistance, ameliorates lipid metabolism, and has antihyperlipidemic activity. It has previously been detected in various organs, including the pancreas. Our aim was to investigate whether adropin affects pancreas exocrine secretion. The influence of different doses of adropin was tested in basal and stimulated conditions (CCK-8 and vagal stimulation). In addition, the effect of adropin has been studied under vagotomy and capsaicin deafferentation conditions. Our results indicate that adropin inhibits pancreas exocrine secretion both in the basal and stimulated conditions, whereas vagotomy and deafferentation abolish the pancreas responses to adropin. Based on the obtained results, it can be assumed that the effect of adropin on the pancreas is related to an indirect vagal mechanism. Nevertheless, this hypothesis requires further verification.The aim was to investigate the potential effect of adropin (ADR) on pancreatic–biliary juice (PBJ) secretion (volume, protein content, trypsin activity) in a rat model. The animals were divided into control and five experimental groups: adropin, CCK-8 (CCK-8 stimulation), capsaicin (capsaicin deactivation of afferents), vagotomy (vagotomy procedure), and vagal stimulation (vagal nerve stimulation). The experiment consisted of four phases, during which vehicle (0.9% NaCl) and three ADR boluses (5, 10, and 20 µg/kg BW) were administered i.v. every 30 min. PBJ samples were collected from each rat at 15 min intervals after boluses. Exogenous ADR failed to affect the pancreatic responses after vagotomy and the capsaicin pretreatment and reduced the PBJ volume, protein outputs, and trypsin activity in the adropin, CCK-8, and vagal stimulation groups in a dose-dependent manner. In all these groups, volume of PBJ was reduced only by the highest dose of ADR (p < 0.001 for adropin group and p < 0.01 for CCK-8 and vagal stimulation groups), and the protein outputs were reduced by the administration of ADR 10 µg/kg BW (adropin and CCK-8 groups, p < 0.01 in both cases) and 20 µg/kg BW (p < 0.001 for adropin and CCK-8 groups, p < 0.01 for vagal stimulation group). The 10 µg/kg BW dose of ADR reduced the trypsin output in the CCK-8 group (p < 0.01), and the highest ADR dose reduced the trypsin output in the CCK-8 (p < 0.001) and vagal stimulation (p < 0.01) groups. In conclusion, adropin in the analyzed doses exhibits the negative feedback pathway. This mechanism seems to participate in the regulation of pancreatic juice secretion via an indirect vagal mechanism.

The efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with mild cognitive impairment: A double blinded randomized clinical trial

BackgroundThere are 9.9 million new cases of dementia in the world every year. Short-term conversion rate from mild cognitive impairment (MCI) to dementia is between 20% and 40%, but long-term in 5–10 years ranges from 60% to 100%. It is particularly important to prevent or prolong the development of MCI into dementia. Both auriculotherapy and vagus nerve stimulation are effective on improving cognitive functions. However, there is no double blinded randomized clinical trial to support the effectiveness of transcutaneous electrical stimulation of auricular acupoints in patients with MCI. MethodsThis randomized controlled trial involved patients with MCI, aged from 55 to 75 years old. Patients were randomly allocated to transcutaneous auricular vagus nerve stimulation (taVNS) group or sham taVNS group. In the taVNS group, two auricular acupoints were stimulated, including heart (concha, CO15) and kidney (CO10), which are in the distribution of vagus nerve. While in the sham taVNS group, two other auricular acupoints were stimulated, including elbow (scaphoid fossa, SF3) and shoulder (SF4,5), which are out of the distribution of vagus nerve. The primary outcome was the Montreal cognitive assessment-basic, MOCA-B. The secondary outcomes included auditory verbal learning test-HuaShan version (AVLT-H), shape trails test A&B (STT-A&B), animal fluence test (AFT), Boston naming test (BNT), Pittsburgh sleep quality index (PSQI), rapid eye movement sleep behavior disorder screening questionnaire (RBDSQ), Epworth sleepiness scale (ESS) and functional activities questionnaire (FAQ). These outcome measures were taken at baseline, 24 weeks later. ResultsAfter 24 weeks of intervention, the data of 52 patients were intended for analysis. After intervention, there was significant difference in the overall scores of MoCA-B between taVNS group and sham taVNS group (p = 0.033 < 0.05). In taVNS group, compared with before intervention, the overall scores of MOCA-B increased significantly after intervention (p < 0.001). As for N5 and N7, the two sub-indicators of AVLT-H, in taVNS group, compared with before intervention, both N5 and N7 increased significantly after intervention (both ps < 0.001). As for STTB, in taVNS group, compared with before intervention, STTB was significantly reduced after intervention (p = 0.016). For BNT, in taVNS group, compared with before intervention, BNT increased significantly after intervention (p < 0.001). In taVNS group, compared with before intervention, PSQI, RBDSQ, ESS and FAQ decreased significantly after intervention (p = 0.002, 0.025, <0.001, 0.006 respectively). 1 patient with a history of tympanic membrane perforation in taVNS group was reported with mild adverse reactions which disappeared a week after termination of taVNS. The intervention of taVNS is effective on increasing the overall scores of MoCA-B, N5 and N7. ConclusionThe clinical trial demonstrated that taVNS can improve cognitive performance in patients with MCI. This inexpensive, effective and innovative method can be recommended as a therapy for more patients with MCI in the prevention or prolonging of its development into dementia, but it is still required to be further investigated. Trial registrationhttp://www.chictr.org.cn. (ID: ChiCTR2000038868)

Short-term effectiveness of auricular vagus nerve stimulation in patients with myofascial pain syndrome

Objectives: To evaluate the effect of auricular vagus nerve stimulation (VNS) applied in addition to ischemic compression and stretching exercises on pain, trigger point (TP) sensitivity, grip strength, quality of life and autonomic functions in patients with myofascial pain syndrome (MPS). Methods: Sixty patients, who had neck pain, met the diagnostic MPS criteria of Travell and Simons were included in the study. The subjects were randomly divided into VNS group (n = 30) or control group (n = 30). Each group performed 10 sessions of TP ischemic compression and stretching exercises (5 days/week). Ten sessions of 30-minute long auricular VNS were added to the treatment in VNS group. Pain severity [Visual Analogue Scale (VAS)], TP sensitivity (algometer), grip strength (Jamar dynamometer), quality of life [Short Form-36 (SF-36)] and autonomic function [Composite Autonomic Symptom Scale-31 (Compass-31)] were evaluated before and after 10 sessions of treatment. Results: The VAS, algometer and Jamar measurements showed significant improvement in both groups. A statistically significant improvement was found in orthostatic intolerance, secretomotor and pupillomotor subscales of Compass-31 scale in the VNS group following the treatment (p &amp;lt; 0.05) while no significant difference was observed in the control group (p &amp;gt; 0.05). The control group showed significant improvement in all parameters of SF-36 scale, while the VNS group showed significant improvement in physical function, social functionality and pain parameters (p &amp;lt; 0.05). The changes in the VAS, algometer, Jamar scores and secretomotor subscale of the Compass-31 scale were statistically higher in the VNS group than in the control group (p &amp;lt; 0.001, p &amp;lt; 0.001, p = 0.001 and p = 0.011, respectively). Conclusions: It can be argued that auricular VNS increases the effectiveness of ischemic compression and stretching exercises in patients with MPS. Further and detailed studies are needed in which the effect of VNS alone or in combination with other treatments in patients with MPS is examined and the physiological mechanisms are investigated.

The effects of vagus nerve stimulation on hippocampal neuro-inflammatory and α7nAChR expression in rats with intractable epilepsy

Objective: To investigate the effects of vagus nerve stimulation(VNS) on hippocampal neuro-inflammatory and α7 nicotinic acetylcholine receptor (α7nAChR) expression in rats with intractable epilepsy (IE). Methods: Eighty adult male SD rats (SPF) were randomly divided into control group, model group, VNS group and MLA+VNS group. There were respectively 20 rats in the control group and MLA+VNS group, and because of model failure and animal death, 15 rats and 14 rats in the model group and VNS group were left respectively . Except the control group, the IE model was established in other groups. Only the vagus nerve was isolated in the control group without electrical stimulation; the model group did not take any intervention measures; the VNS group was treated for 4 weeks with VNS after the model was successful; the MLA(3.4 μg/μl, 5 μl) was given to the lateral ventricle in the MLA+VNS group, and then VNS for 4 weeks. Seizure frequency and duration in each group were observed and recorded. And then the rats were decapitated, the hippocampus were quickly separated and 10% tissue homogenate was prepared. The homogenate was centrifuged and the supernatant was extracted. The activities of AChE and ChAT in the supernatant were measured by spectrophotometry, and the levels of TNF-ɑ, IL-6 and IL-1β were detected by ELISA. The expression of α7nAChR in rat hippocampals was detected by Western blot. The expression of α7nAChR on microglias in rat hippocampals was assesed by double-labeled immunofluorescence. Results: ①After VNS for 4 weeks, the frequency and duration of seizures in rats were decreased significantly, which were lower than those of the model group (P<0.01); After treated with MLA +VNS, the frequency and duration of seizures in rats were also reduced significantly, which were lower than those of the model group, but higher than those of the VNS group (P<0.01).②Compared with the control group, the expression of ChAT in the hippocampus of rats in the model group was decreased significantly and the expression of AChE was increased significantly (P<0.01); Compared with the model group, the expressions of ChAT in the hippocampus of rats in the VNS group and MLA+VNS group were increased significantly and the expressions of AChE were decreased significantly (P<0.01); Compared with the VNS group, in the hippocampus of rats in the MLA+VNS group, the expressions of ChAT and AChE had no significant changes (P>0.05). ③Compared with the control group, the expressions of TNF-ɑ, IL-6 and IL-1β in the hippocampus of rats in the model group were increased significantly (P<0.01). Compared with the model group, the expressions of TNF-ɑ, IL-6 and IL-1β in the hippocampus of rats in the VNS group were decreased significantly (P<0.01). Compared with the VNS group, the expressions of TNF-ɑ, IL-6 and IL-1β in the hippocampus of rats in the MLA+VNS group were increased significantly(P<0.01). ④Compared with the control group, the expression of α7nAChR in hippocampus and microglia of rats in the model group was decreased significantly(P<0.01); Compared with the model group, the expression of α7nAChR in hippocampus and microglia of rats in the VNS group was up-regulated significantly (P<0.01); Compared with the VNS group, coexpression of α7nAChR on microglia wasreduced significantly in the MLA+VNS group (P<0.01). Conclusion: VNS has obvious therapeutic effect on IE rats, and its mechanism may be related to activating hippocampal microglia cholinergic anti-inflammatory pathway directly and inhibiting hippocampal neuro-inflammatory response.

Transcutaneous auricular vagus nerve stimulation promotes gastric motility by up-rgulating α7nAChR and suppressing NF-κB p65 expression in duodenum in rats with functional dyspepsia

To study the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on gastric sensitivity and motility in rats with functional dyspepsia (FD), so as to explore its underlying mechanism in improving FD. A total of 48 young SD rats were randomly divided into control (n=10), model (n=9), taVNS (n=9), subdiaphragmatic vagus nerve stimulation (SDVNS, n=9) and sham SDVNS (n=7) groups. The FD model was established by gavage of 0.1% iodoa-cetamide+2% glucose, once daily for 6 days. Rats in the taVNS group received taVNS (0.5 mA) of optopoint "Heart" and "Stomach" for 30 min, once daily for 14 days, while rats in the SDVNS group received subdiaphragmatic vagus nerve stimulation through the implanted electrode, and those of the sham SDVNS group received only application of the same electrodes without electrical stimulation. Electromyogram (EMG) of the cervical trapezius muscle (reflecting gastric sensitivity) was recorded before and after intragastric expansion via an air ballon and the gastric emptying rate was calculated for assessing the gastric motility. The contents of acetylcholine (ACh), nicotinic acetylcholine receptor α7 subunit (α7nAChR), interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the duodenum tissue were detected by enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) p65 in the duodenum tissue was determined by Western blot. In comparison with the control group, the EMG change rate at intragastric pressure levels of 40, 60 and 80 mm Hg, expression of NF-κB p65 protein, and contents of IL-6, IL-1β and TNF-α were significantly increased (P<0.05,P<0.01, P<0.001), while the gastric emptying rate, ACh and α7nAChR contents considerably decreased (P<0.05, P<0.001) in the model group. After interventions, the EMG change rate, contents of IL-6, IL-1β and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.05, P<0.01, P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.05, P<0.001) in both taVNS and SDVNS groups relevant to the model group. In comparison with the sham SDVNS group, the EMG change rate, contents of IL-6, IL-1β and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.01, P<0.05,P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.01, P<0.001) in the both SDVNS and taVNS groups. taVNS can reduce gastric sensitivity and promote gastric emptying in FD model rats, which may be closely related to its functions in up-regulating ACh and α7nAChR contents and inhibiting the activation of NF-κB p65 signaling in the duodenum.

Vagus Nerve Stimulation Improves Mitochondrial Dysfunction in Post–cardiac Arrest Syndrome in the Asphyxial Cardiac Arrest Model in Rats

Cerebral mitochondrial dysfunction during post–cardiac arrest syndrome (PCAS) remains unclear, resulting in a lack of therapeutic options that protect against cerebral ischemia–reperfusion injury. We aimed to assess mitochondrial dysfunction in the hippocampus after cardiac arrest and whether vagus nerve stimulation (VNS) can improve mitochondrial dysfunction and neurological outcomes. In an asphyxial cardiac arrest model, male Sprague–Dawley rats were assigned to the vagus nerve isolation (CA) or VNS (CA + VNS) group. Cardiopulmonary resuscitation was performed 450 s after pulseless electrical activity. After the return of spontaneous circulation (ROSC), left cervical VNS was performed for 3 h in the CA + VNS group. Mitochondrial respiratory function was evaluated using high-resolution respirometry of the hippocampal tissue. The neurologic deficit score (NDS) and overall performance category (OPC) were assessed at 24, 48, and 72 h after resuscitation. The leak respiration and oxidative phosphorylation capacity of complex I (OXPHOS CI) at 6 h after ROSC were significantly higher in the CA + VNS group than in the CA group (p = 0.0308 and 0.0401, respectively). Compared with the trends of NDS and OPC in the CA group, the trends of those in the CA + VNS group were significantly different, thus suggesting a favorable neurological outcome in the CA + VNS group (p = 0.0087 and 0.0064 between times × groups interaction, respectively). VNS ameliorated mitochondrial dysfunction after ROSC and improved neurological outcomes in an asphyxial cardiac arrest rat model.

Vagus Nerve Stimulation Reduces Neuroinflammation Through Microglia Polarization Regulation to Improve Functional Recovery After Spinal Cord Injury.

BackgroundSpinal cord injury (SCI) is a devastating disease that lacks effective treatment. Interestingly, recent studies indicated that vagus nerve stimulation (VNS), neuromodulation that is widely used in a variety of central nervous system (CNS) diseases, improved motor function recovery after SCI. But the exact underlying mechanism of how VNS ameliorates SCI is unclear. This study aimed to confirm the efficacy and further explore the potential therapeutic mechanism of VNS in SCI.MethodA T10 spinal cord compression model was established in adult female Sprague-Dawley rats. Then the stimulation electrode was placed in the left cervical vagus nerve (forming Sham-VNS, VNS, and VNS-MLA groups). Basso-Beattie-Bresnahan (BBB) behavioral scores and Motor evoked potentials (MEPs) analysis were used to detect motor function. A combination of histological and molecular methods was used to clarify the relevant mechanism.ResultsCompared with the Sham-VNS group, the VNS group exhibited better functional recovery, reduced scar formation (both glial and fibrotic scars), tissue damage, and dark neurons, but these beneficial effects of VNS were diminished after alpha 7 nicotinic acetylcholine receptor (α7nAchR) blockade. Specifically, VNS inhibited the pro-inflammatory factors TNF-α, IL-1β, and IL-6 and increased the expression of the anti-inflammatory factors IL-10. Furthermore, we found that VNS promotes the shift of M1-polarized Iba-1+/CD86+ microglia to M2-polarized Iba-1+/CD206+ microglia via upregulating α7nAchR to alleviate neuroinflammation after SCI.ConclusionOur results demonstrated that VNS promotes microglial M2 polarization through upregulating α7nAChR to reduce neuroinflammation, thus improving motor function recovery after SCI. These findings indicate VNS might be a promising neuromodulation strategy for SCI.

Transcutaneous Auricular Vagus Nerve Stimulation Promotes White Matter Repair and Improves Dysphagia Symptoms in Cerebral Ischemia Model Rats.

BackgroundClinical and animal studies have shown that transcutaneous auricular vagus nerve stimulation (ta-VNS) exerts neuroprotection following cerebral ischemia. Studies have revealed that white matter damage after ischemia is related to swallowing defects, and the degree of white matter damage is related to the severity of dysphagia. However, the effect of ta-VNS on dysphagia symptoms and white matter damage in dysphagic animals after an ischemic stroke has not been investigated.MethodsMiddle cerebral artery occlusion (MCAO) rats were randomly divided into the sham, control and vagus nerve stimulation (VNS) group, which subsequently received ta-VNS for 3 weeks. The swallowing reflex was measured once weekly by electromyography (EMG). White matter remyelination, volume, angiogenesis and the inflammatory response in the white matter were assessed by electron microscopy, immunohistochemistry, stereology, enzyme-linked immunosorbent assay (ELISA) and Western blotting.Resultsta-VNS significantly increased the number of swallows within 20 s and reduced the onset latency to the first swallow. ta-VNS significantly improved remyelination but did not alleviate white matter shrinkage after MCAO. Stereology revealed that ta-VNS significantly increased the density of capillaries and increased vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2) expression in the white matter. ta-VNS significantly alleviated the increase inTLR4, MyD88, phosphorylated MAPK and NF-κB protein levels and suppressed the expression of the proinflammatory factors IL-1β and TNF-α.ConclusionThese results indicated ta-VNS slightly improved dysphagia symptoms after ischemic stroke, possibly by increasing remyelination, inducing angiogenesis, and inhibiting the inflammatory response in the white matter of cerebral ischaemia model rats, implying that ta-VNS may be an effective therapeutic strategy for the treatment of dysphagia after ischemic stroke.

Effects of Long-Term Vagus Nerve Electrical Stimulation Therapy on Acute Cerebral Infarction and Neurological Function Recovery in Post MCAO Mice.

Background Vagus nerve stimulation therapy is proven to produce neuroprotective effects against central nervous system diseases and reduce neurological injury, having a positive effect on the recovery of neurological functions in mouse model of stroke. Objective This study was aimed at exploring a wider time window for VNS treatment, investigating the long-term behavioral improvement of long-term VNS in mice after pMCAO, and exploring the antiapoptotic properties of VNS and its role in autophagy, all of which may be a permanent deficiency potential mechanism of neuroprotection in hemorrhagic stroke. Methods Permanent focal cerebral ischemia and implantation of vagus nerve stimulator were performed through intracavitary occlusion of the right middle cerebral artery (MCA). The vagus nerve stimulation group received five times vagus nerve stimulation from 6 h after surgery for 5 days. Adhesive removal test and NSS neurological score were used to evaluate the neurological deficit of mice. TTC staining of mouse brain tissue was performed one week after surgery in order to assess the area of cerebral infarction. Additionally, frozen sections were stained with Fluoro-Jade B to observe the apoptotic cells in the ischemic penumbra of brain tissue. Finally, Western blot was used to detect the changes in the levels of apoptosis-related proteins such as cleaved-caspase3 and Bcl-2 and autophagy-related proteins such as mTOR, Beclin-1, and LC3-II in brain tissue. Results VNS can effectively reduce the behavioral score of pMCAO mice; TTC results showed that VNS could effectively reduce the infarct area after pMCAO (P < 0.05). After VNS intervention of the pMCAO group compared with the pMCAO+VNI group, the FJB-positive cells in the VNS group were significantly decreased (P < 0.05); Western Blot analysis showed that the expression of cleaved-caspase3 in the brain tissue of mice increased after pMCAO (P < 0.05), and the expression of Bcl-2 decreased (P < 0.05). This change could be effectively reversed after VNS intervention (P < 0.05). Conclusion VNS could effectively improve the behavioral performance of mice after permanent stroke in addition to significantly reducing the infarct size of the brain tissue. The mechanism may be related to the effective reduction of cell apoptosis and excessive autophagy after pMCAO by VNS.

Cervical Vagus Nerve Stimulation Improves Neurologic Outcome After Cardiac Arrest in Mice by Attenuating Oxidative Stress and Excessive Autophagy

BackgroundCerebral ischemia and reperfusion (I/R) induces oxidative stress and activates autophagy, leading to brain injury and neurologic deficits. Cervical vagus nerve stimulation (VNS) increases cerebral blood flow (CBF). In this study, we investigate the effect of VNS-induced CBF increase on neurologic outcomes after cardiac arrest (CA). Materials and MethodsA total of 40 male C57Bl/6 mice were subjected to ten minutes of asphyxia CA and randomized to vagus nerve isolation (VNI) or VNS treatment group. Eight mice received sham surgery and VNI. Immediately after resuscitation, 20 minutes of electrical stimulation (1 mA, 1 ms, and 10 Hz) was started in the VNS group. Electrocardiogram, blood pressure, and CBF were monitored. Neurologic and histologic outcomes were evaluated at 72 hours. Oxidative stress and autophagy were assessed at 3 hours and 24 hours after CA. ResultsBaseline characteristics were not different among groups. VNS mice had better behavioral performance (ie, open field, rotarod, and neurologic score) and less neuronal death (p < 0.05, vs VNI) in the hippocampus. CBF was significantly increased in VNS-treated mice at 20 minutes after return of spontaneous circulation (ROSC) (p < 0.05). Furthermore, levels of 8-hydroxy-2ʹ-deoxyguanosine in the blood and autophagy-related proteins (ie, LC-3Ⅱ/Ⅰ, Beclin-1, and p62) in the brain were significantly decreased in VNS mice. Aconitase activity was also reduced, and the p-mTOR/mTOR ratio was increased in VNS mice. ConclusionsOxidative stress induced by global brain I/R following CA/ROSC leads to early excessive autophagy and impaired autophagic flux. VNS promoted CBF recovery, ameliorating these changes. Neurologic and histologic outcomes were also improved.