Electroacupuncture at Neiguan (PC6) attenuates cardiac dysfunction caused by cecal ligation and puncture via the vagus nerve.

PURPOSE: Previous studies proved the benefits of electroacupuncture (EA) on heart in ischemia reperfusion injury and chronic heart failure. However, the role of EA on sepsis-induced cardiac dysfunction has rarely been elucidated before. In this study, we aimed to investigate the effects of EA on cardiac dysfunction in a rat model of sepsis and to speculate the underlying mechanisms. METHODS: Sepsis was induced by cecum ligation and puncture in anesthetized rats. EA at the acupoint "Neiguan (PC6)" was applied 0.5 h after the induction of sepsis for 20 min. Heart rate variability was obtained immediately after EA to evaluate autonomic balance. Echocardiography was performed at 6 h and 24 h after sepsis induction in vivo. Measurements of hemodynamics, blood gases, cytokines and biochemistry were collected at 24 h. Cardiac tissue underwent immunofluorescence staining to determine the expression of α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages. RESULTS: EA increased vagus nerve activity, prevented the development of hyperlactatemia, attenuated the decline of left ventricle ejection fraction, suppressed systemic and cardiac inflammation and alleviated the histopathological manifestations of heart in sepsis rats. Furthermore, the cardiac tissue from EA treated rats showed increased expressions of α7nAChR on macrophages. The cardio-protective and anti-inflammatory effects of EA were partly or completely prevented in rats with vagotomy. CONCLUSION: EA at PC6 attenuates left ventricle dysfunction and decreases inflammation in sepsis-induced cardiac dysfunction. The cardio-protective effects of EA are mediated through vagus nerve mediated cholinergic pathway.

Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus.

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

Ghrelin-insulin-like growth factor-1 axis is activated via autonomic neural circuits in the non-alcoholic fatty liver disease.

BACKGROUND: The correlation of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) with non-alcoholic fatty liver disease (NAFLD) has been reported in epidemiological studies. However, the mechanisms of molecular and inter-organ systems that render these factors to influence on NAFLD have not been elucidated. In this study, we examined the induction of ghrelin which is the GH-releasing hormone and IGF-1, and involvement of autonomic neural circuits, in the pathogenesis of NAFLD. METHODS: The expression of gastric and hypothalamic ghrelin, neural activation in the brain, and serum IGF-1 were examined in NAFLD models of choline-deficient defined l-amino-acid diet-fed, melanocortin 4 receptor knockout mice, and partial hepatectomy mice with or without the blockades of autonomic nerves to test the contribution of neural circuits connecting the brain, liver, and stomach. KEY RESULTS: The fatty changes in the liver increased the expression of gastric ghrelin through the autonomic pathways which sends the neural signals to the arcuate nucleus in the hypothalamus through the afferent vagal nerve which reached the pituitary gland to release GH and then stimulate the IGF-1 release from the liver. In addition, high levels of ghrelin expression in the arcuate nucleus were correlated with NAFLD progression regardless of the circuits. CONCLUSIONS: Our study demonstrated that the fatty liver stimulates the autonomic nervous signal circuits which suppress the progression of the disease by activating the gastric ghrelin expression, the neural signal transduction in the brain, and the release of IGF-1 from the liver.

Two-Year Outcomes of Vagal Nerve Blocking (vBloc) for the Treatment of Obesity in the ReCharge Trial.

BACKGROUND: The ReCharge Trial demonstrated that a vagal blocking device (vBloc) is a safe and effective treatment for moderate to severe obesity. This report summarizes 24-month outcomes. METHODS: Participants with body mass index (BMI) 40 to 45 kg/m2, or 35 to 40 kg/m2 with at least one comorbid condition were randomized to either vBloc therapy or sham intervention for 12 months. After 12 months, participants randomized to vBloc continued open-label vBloc therapy and are the focus of this report. Weight loss, adverse events, comorbid risk factors, and quality of life (QOL) will be assessed for 5 years. RESULTS: At 24 months, 123 (76 %) vBloc participants remained in the trial. Participants who presented at 24 months (n = 103) had a mean excess weight loss (EWL) of 21 % (8 % total weight loss [TWL]); 58 % of participants had ≥5 % TWL and 34 % had ≥10 % TWL. Among the subset of participants with abnormal preoperative values, significant improvements were observed in mean LDL (-16 mg/dL) and HDL cholesterol (+4 mg/dL), triglycerides (-46 mg/dL), HbA1c (-0.3 %), and systolic (-11 mmHg) and diastolic blood pressures (-10 mmHg). QOL measures were significantly improved. Heartburn/dyspepsia and implant site pain were the most frequently reported adverse events. The primary related serious adverse event rate was 4.3 %. CONCLUSIONS: vBloc therapy continues to result in medically meaningful weight loss with a favorable safety profile through 2 years. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01327976.

Effect of low-level laser therapy (LLLT) on peripheral nerve regeneration using fibrin glue derived from snake venom.

OBJECTIVES: The purpose of this study was to assess whether the adhesive permits the collateral repair of axons originating from a vagus nerve to the interior of a sural nerve graft, and whether low-level laser therapy (LLLT) assists in the regeneration process. MATERIALS AND METHODS: Study sample consisted of 32 rats randomly separated into three groups: Control Group (CG; n=8), from which the intact sural nerve was collected; Experimental Group (EG; n=12), in which one of the ends of the sural nerve graft was coapted to the vagus nerve using the fibrin glue; and Experimental Group Laser (EGL; n=12), in which the animals underwent the same procedures as those in EG with the addition of LLLT. Ten weeks after surgery, the animals were euthanized. Morphological analysis by means of optical and electron microscopy, and morphometry of the regenerated fibers were employed to evaluate the results. RESULTS: Collateral regeneration of axons was observed from the vagus nerve to the interior of the autologous graft in EG and EGL, and in CG all dimensions measured were greater and presented a significant difference in relation to EG and EGL, except for the area and thickness of the myelin sheath, that showed significant difference only in relation to the EG. CONCLUSIONS: The present study demonstrated that the fibrin glue makes axonal regeneration feasible and is an efficient method to recover injured peripheral nerves, and the use of low-level laser therapy enhances nerve regeneration.

An autopsy case of vagus nerve stimulation following acupuncture.

Acupuncture is one of the most popular oriental medical techniques in China, Korea and Japan. This technique is also popular as alternative therapy in the Western World. Serious adverse events are rare following acupuncture, and fatal cases have been rarely reported. A male in his late forties died right after acupuncture treatment. A medico-legal autopsy disclosed severe haemorrhaging around the right vagus nerve in the neck. Other organs and laboratory data showed no significant findings. Thus, it was determined that the man could have died from severe vagal bradycardia and/or arrhythmia resulting from vagus nerve stimulation following acupuncture. To the best of our knowledge, this is the first report of a death due to vagus nerve injury after acupuncture.

Electro-acupuncture of Tsusanli and Shangchuhsu regulates gastric activity possibly through mediation of the vagus-solotary complex.

BACKGROUND/AIMS: Acupuncture has been reportedly used to treat gastrointestinal diseases, however, its precise mechanism remains unknown. METHODOLOGY: In our study, the effects and mechanism of electro-acupuncture (EA) at Tsusanli (ST 36), Shangchuhsu (ST 37) on regulation of gastric activity were observed. RESULTS: EA at Tsusanli showed that gastric electric change was the most obvious, with significantly higher frequency and wave amplitude compared with that of the Shangchuhsu group and other groups. EA at Shangchuhsu demonstrated that the change of gastric electric level was much higher than that of the non-acupoint group and control group. After bilateral vagotomy, Tsusanlis was electro-acupunctured, the changes of electro-gastric graph (EGG) weren't significant with the control group. The frequency of electro-physiological activity in nucleus of solitary tract (NTS) and dorsal motor nucleus of the vagus nerve (DMV) in the Tsusanli group was markedly increased compared with that in the other group. Fos and GFAP expression in NTS and DMV in the Tsusanli group was significantly higher than that in other groups and control group. The results have indicated that EA at Tsusanli and Shangchuhsu cannot only regulate gastric activity, but also activate neurons and astrocytes in NTS and DMV. The effects on regulation and activation of EA at Tsusanli were very obvious. CONCLUSIONS: Our study suggests that this electroacupuncture regulation of gastric activity may partially depend upon integrated nerve pathway and related central neurons and astrocytes in the vagus-solitary complex.

Vagus nerve stimulation in intractable childhood epilepsy: a Korean multicenter experience.

We evaluated the long-term outcome of vagus nerve stimulation (VNS) in 28 children with refractory epilepsy. Of these 28 children, 15 (53.6%) showed a >50% reduction in seizure frequency and 9 (32.1%) had a >75% reduction. When we compared seizure reduction rates according to seizure types (generalized vs. partial) and etiologies (symptomatic vs. cryptogenic), we found no significant differences. In addition, there was no correlation between the length of the stimulation period and treatment effect. The seizure reduction rate, however, tended to be inversely related to the seizure duration before VNS implantation and age at the time of VNS therapy. VNS also improved quality of life in this group of patients, including improved memory in 9 (32.1%), improved mood in 12 (42.9%), improved behavior in 11 (39.3%), improved alertness in 12 (42.9%), improved achievement in 6 (21.4%), and improved verbal skills in 8 (28.6%). Adverse events included hoarseness in 7 patients, dyspnea at sleep in 2 patients, and wound infection in 1 patient, but all were transient and successfully managed by careful follow-up and adjustment of parameters. These results indicate that VNS is a safe and effective alternative therapy for pediatric refractory epilepsy, without significant adverse events.

Vagus Nerve Stimulation in Intractable Childhood Epilepsy: a Korean Multicenter Experience

We evaluated the long-term outcome of vagus nerve stimulation (VNS) in 28 children with refractory epilepsy. Of these 28 children, 15 (53.6%) showed a >50% reduction in seizure frequency and 9 (32.1%) had a >75% reduction. When we compared seizure reduction rates according to seizure types (generalized vs. partial) and etiologies (symptomatic vs. cryptogenic), we found no significant differences. In addition, there was no correlation between the length of the stimulation period and treatment effect. The seizure reduction rate, however, tended to be inversely related to the seizure duration before VNS implantation and age at the time of VNS therapy. VNS also improved quality of life in this group of patients, including improved memory in 9 (32.1%), improved mood in 12 (42.9%), improved behavior in 11 (39.3%), improved altertness in 12 (42.9%), improved achievement in 6 (21.4%), and improved verbal skills in 8 (28.6%). Adverse events included hoarseness in 7 patients, dyspnea at sleep in 2 patients, and wound infection in 1 patient, but all were transient and successfully managed by careful follow-up and adjustment of parameters. These results indicate that VNS is a safe and effective alternative therapy for pediatric refractory epilepsy, without significant adverse events.

Thoracic vagal efferent nerve stimulation evokes substance P-induced early airway bronchonstriction and late proinflammatory and oxidative injury in the rat respiratory tract.

Electrical stimulation of efferent thoracic vagus nerve (TVN) evoked neurogenic inflammation in respiratory tract of atropine-treated rats by an undefined mechanism. We explored whether efferent TVN stimulation via substance P facilitates neurogenic inflammation via action of nuclear factor-kappaB (NF-kappaB) activation and reactive oxygen species (ROS) production. Our results showed that increased frequency of TVN stimulation concomitantly increased substance P-enhanced hypotension, and bronchoconstriction (increases in smooth muscle electromyographic activity and total pulmonary resistance). The enhanced SP release evoked the appearance of endothelial gap in silver-stained leaky venules, India-ink labeled extravasation, and accumulations of inflammatory cells in the respiratory tract, contributing to trachea plasma extravasation as well as increases in blood O (2)(-) and H(2)O(2) ROS amount. L-732138 (NK(1) receptor antagonist), SR-48968 (NK(2) receptor antagonist), dimethylthiourea (H(2)O(2) scavenger) or catechins (O (2)(-) and H(2)O(2) scavenger) pretreatment reduced efferent TVN stimulation-enhanced hypotension, bronchoconstriction, and plasma extravasation. Increased frequency of TVN stimulation significantly upregulated the expression of nuclear factor-kappaB (NF-kappaB) in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue. The upregulation of NF-kappaB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In conclusion, TVN efferent stimulation increases substance P release to trigger NF-kappaB mediated ICAM-1 expression and O (2)(-) and H(2)O(2) ROS production in the respiratory tract.

Histopathologic features of the vagus nerve after electrical stimulation in swine.

This paper describes the histological features of the vagus nerve after its stimulation with an electrostimulation system that is being developed for morbid obesity treatment. An electrostimulation system was implanted laparoscopically around the ventral vagal trunk of five Large White female pigs (49.63+/-1.94 kg.). Vagal nerve stimulation was performed by continuous constant voltage current pulses. Thoracic samples of both ventral and dorsal vagal trunks were obtained thoracoscopically one month after implantation. Animals were sacrificed one month after thoracoscopic vaguectomy. Tissue samples were then harvested from the vagal nerve at the implantation site, 1cm cranial to it, thoracic portion of ventral and dorsal vagal trunks, sub-diaphragmatic dorsal vagal trunk, left and right vagus nerves. Specimens were analysed with light microscope. The severity of the lesions was graded from 0 to 4 (0: no lesion, 1: mild, 2: moderate, 3: severe and 4: extremely severe), taking into account fibrosis, vascularization, necrosis, fiber degeneration and inflammation. Electrode implantation resulted in thickened epineurium and endoneural connective tissue. The greatest lesion score was evidenced at the leads implantation site in the ventral vagal trunk, followed by, in order of decreasing lesion severity, left vagus nerve, thoracic portion of ventral vagal trunk, subdiaphragmatic dorsal vagal trunk, thoracic portion of dorsal vagal trunk and right vagus nerve. The stimulation device used in this study caused connective tissue growth, greatest in the samples located closer to the implantation site. However, there was no sign of altered vascularization in any studied specimen.

Vagus nerve stimulation therapy after failed cranial surgery for intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry.

OBJECTIVE: To determine the effectiveness of vagus nerve stimulation (VNS) therapy among patients with persistent or recurrent seizures after lobar resection, callosotomy, and other cranial operations for intractable epilepsy. METHODS: Data were obtained from the VNS therapy patient outcome registry, which was established after United States Food and Drug Administration approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. RESULTS: Two nonconsecutive cohorts were compared: patients tracked in the registry who had previously undergone cranial surgery for epilepsy (CS group, n = 921) and those who had not (non-CS group, n = 3822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months, and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0%, 52.9%, 60.0%, 62.7%, and 66.7%, respectively. In the CS group, seizures were reduced by at least 50% in 55.1% of patients, at least 75% in 31.4% of patients, at least 90% in 17.3% of patients, and 100% in 5.1% of patients after 24 months of VNS therapy. Response rates were more pronounced in the non-CS group: at least 50% in 62.2% of patients, at least 75% in 43.7% of patients, at least 90% in 26.8% of patients, and 100% in 8.3% of patients. Patients in both groups experienced marked improvements in quality of life parameters. CONCLUSION: The effectiveness of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time. Patients in whom prior cranial surgery had failed did not respond as favorably as all other patients receiving VNS therapy. Nonetheless, many of the former group improved substantially. Thus, on the basis of these open-label data, VNS therapy represents a potentially palliative treatment option for patients with refractory seizures after failed cranial surgery.

Controlled intermittent asystole cardiac therapy induced by pharmacologically potentiated vagus nerve stimulation in normal and hibernating myocardium.

BACKGROUND: Pharmacologically potentiated electrical stimulation of the right vagus nerve achieves controlled intermittent asystole cardiac therapy. The present study examined pathophysiologic consequences of repetitive intermittent asystoles on contractile function, myocardial blood flow, and vagus nerve function and morphology. METHODS: Open-chest anesthetized canines, with either normal left anterior descending (LAD) coronary arteries (n = 8) or severely stenotic LADs (n = 8), received pharmacologic pretreatment with pyridostigmine (0.5 mg/kg), propranolol (80 microg/kg), and verapamil (50 microg/kg) before vagus nerve stimulation. Time-matched control animals with normal (n = 4) or severely stenotic LADs (n = 6) received drugs but no vagus nerve stimulation. The vagus nerve was stimulated for 12 seconds ("on") and rested for 15 seconds ("off"). This algorithm was repeated for 15 on-off cycles, simulating using controlled intermittent asystole during the placement of 15 sutures in a distal coronary anastomosis. This 15-cycle sequence was repeated twice more, simulating a three-vessel bypass. RESULTS: Normal coronary arteries: Ninety minutes after three sets of controlled intermittent asystole, LAD blood flow was unchanged from base line (36.6 +/- 4.5 versus 33.0 +/- 4.2 mL/min, p = 0.4), and global left ventricular performance (impedance catheter, end-systolic pressure-volume relations) was similar to baseline (7.4 +/- 1.2 versus 7.2 +/- 1.0 mm Hg/mL, p = 0.1). Left anterior descending coronary artery stenosis model: Ninety minutes after CIA, there were no significant differences versus control animals in regional LAD blood flow (27 +/- 4 versus 29 +/- 5 mL/min, p = 0.4) or fractional shortening of LAD myocardium (sonomicrometry; 6.2% +/- 1.8% versus 5.4% +/- 1.2%, p = 0.1). Vagus nerve conduction and morphology were unchanged from baseline. CONCLUSIONS: Repetitive controlled intermittent asystole does not impair poststimulation coronary blood flow, cardiac contractile function, or vagus nerve function. Controlled intermittent asystole may be useful to facilitate off-pump or endoscopic coronary artery bypass grafting.

Enhancing the effectiveness of drug-based cancer therapy by electroporation (electropermeabilization).

Many conventional chemotherapeutic drugs, as well as DNA for cancer gene therapy, require efficient access to the cell interior to be effective. The cell membrane is a formidable barrier to many of these drugs, including therapeutic DNA constructs. Electropermeabilization (EP, often used synonymously with "electroporation") has become a useful method to temporarily increase the permeability of the cell membrane, allowing a broad variety of molecules efficient access to the cell interior. EP is achieved by the application of short electrical pulses of relatively high local field strength to the target tissue of choice. In cancer therapy, EP can be applied in vivo directly to the tumor to be treated, in order to enhance intracellular uptake of drugs or DNA. Alternatively, EP can be used to deliver DNA into cells of healthy tissue to achieve longer-lasting expression of cancer-suppressing genes. In addition, EP has been used in ex vivo therapeutic approaches for the transfection of a variety of cells in suspension. In this paper, we communicate results related to the development of a treatment for squamous cell carcinomas of the head and neck, using electropermeabilization to deliver the drug bleomycin in vivo directly into the tumor cells. This drug, which is not particularly effective as a conventional therapeutic, becomes highly potent when the intracellular concentration is enhanced by EP treatment. In animal model experiments we found a drug dose of 1 U/cm(3) tumor tissue (delivered in 0.25 mL of an aqueous solution/cm3 tumor tissue) and an electrical field strength of 750 V/cm or higher to be optimal for the treatment of human squamous cell tumors grown subcutaneously in mice. Within 24-48 hours, the majority of tumor cells are rapidly destroyed by this bleomycin-electroporation therapy (B-EPT). This raises the concern that healthy tissue may be similarly affected. In studies with large animals we showed that normal muscle and skin tissue, normal tissue surrounding major blood vessels and nerves, as well as healthy blood vessels and nerves themselves, are much less affected than tumor tissue. Normal tissues did show acute, focal, and transitory effects after treatment, but these effects are relatively minor under standard treatment conditions. The severity of these effects increases with the number of electric pulse cycles and applied voltage. The observed histological changes resolved 20 to 40 days after treatment or sooner, even after excessive EP treatment. Thus, B-EPT is distinct from other ablative therapies, such as thermal, cryo, or photodynamic ablation, which equally affect healthy and tumor tissue. In comparison to surgical or radiation therapy, B-EPT also has potential as a tissue-sparing and function-preserving therapy. In clinical studies with over 50 late stage head and neck cancer patients, objective tumor response rates of 55-58%, and complete tumor response rates of 19-30% have been achieved.

Histological appearance of a chronically stimulated vagus nerve in a pediatric patient.

Histological analysis of chronically stimulated human vagus nerves is lacking in the literature. In this study, we describe the first microscopic findings in a chronically stimulated left vagus nerve from a pediatric patient. Our results show many histological changes in and around the stimulated nerve with severe demyelination. Further long-term clinical and postmortem examinations of chronically stimulated vagus nerves in both children and adults are needed to ascertain whether prolonged exposure to electrical current can cause clinical dysfunction of this nerve.

Dysautonomia in Parkinsonism: a clinicopathological study.

Necropsy studies were done on six patients with idiopathic paralysis agitans, one with multiple system atrophy including features of Parkinsonism, and one control. Autonomic functions had been evaluated during life to a varying degree. Intra-arterial blood pressure studies were carried out on two patients with paralysis agitans (cases 4 and 6) and the one with multiple system atrophy (case 7). Lewy bodies with or without cell loss were seen in the sympathetic ganglia of five cases of paralysis agitans. Three of these had orthostatic hypotension and the severity of the lesion approximately correlated with the degree of hypotension. It is concluded that the lesions of the sympathetic ganglia may play a major role in the production of orthostatic hypotension in idiopathic paralysis agitans.