Effects Of Vagus Nerve Stimulation Research Articles

Atrial GIRK Channels Mediate the Effects of Vagus Nerve Stimulation on Heart Rate Dynamics and Arrhythmogenesis.

Diminished parasympathetic influence is central to the pathogenesis of cardiovascular diseases, including heart failure and hypertension. Stimulation of the vagus nerve has shown promise in treating cardiovascular disease, prompting renewed interest in understanding the signaling pathway(s) that mediate the vagal influence on cardiac physiology. Here, we evaluated the contribution of G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels to the effect of vagus nerve stimulation (VNS) on heart rate (HR), HR variability (HRV), and arrhythmogenesis in anesthetized mice. As parasympathetic fibers innervate both atria and ventricle, and GIRK channels contribute to the cholinergic impact on atrial and ventricular myocytes, we collected in vivo electrocardiogram recordings from mice lacking either atrial or ventricular GIRK channels, during VNS. VNS decreased HR and increased HRV in control mice, in a muscarinic receptor-dependent manner. This effect was preserved in mice lacking ventricular GIRK channels, but was nearly completely absent in mice lacking GIRK channels in the atria. In addition, atrial-specific ablation of GIRK channels conferred resistance to arrhythmic episodes induced by VNS. These data indicate that atrial GIRK channels are the primary mediators of the impact of VNS on HR, HRV, and arrhythmogenesis in the anesthetized mouse.

Acute cardiovascular and hemodynamic effects of vagus nerve stimulation in conscious hypertensive rats.

Hypertension (HTN) affects over 1 billion people worldwide, with a significant number who are unable to control their blood pressure (BP) with conventional therapies. Recently, novel device-based therapies targeting the autonomic nervous system have been evaluated for treating HTN, including vagus nerve stimulation (VNS). Numerous studies have indicated the beneficial effects of chronic VNS in various models of HTN, however the acute effects of VNS on physiological responses have not been widely investigated. To better understand the acute effects of VNS, this study evaluates cardiovascular and hemodynamic responses from conscious hypertensive rats implanted with VNS stimulators and physiological telemeters for simultaneous monitoring of BP and heart rate (HR) as therapy is applied. We demonstrated that there are no acute changes in mean BP, HR and contractility measures as a result of VNS stimulation. However, there were significant increases in both HR variability and BP variability during VNS, which returned to baseline levels immediately at the cessation of therapy. The small acute changes observed during intermittent VNS could be additive, leading to beneficial chronic changes in BP and HR control, and may help in furthering the understanding of beneficial effects demonstrated in chronic use of VNS therapy.

Effects of Vagal Nerve Stimulation on Ganglionated Plexi Nerve Activity and Ventricular Rate in Ambulatory Dogs With Persistent Atrial Fibrillation.

This study was designed to test the hypothesis that low-level vagal nerve stimulation (VNS) reduces the ventricular rate (VR) during atrial fibrillation (AF) through the activation of the inferior vena cava (IVC)-inferior atrial ganglionated plexus nerve activity (IAGPNA). Increased IVC-IAGPNA can suppress atrioventricular node conduction and slow VR in canine models of AF. Persistent AF was induced in 6 dogs and the IVC-IAGPNA, right vagal nerve activity, left vagal nerve activity, and an electrocardiogram were recorded. After persistent AF was documented, VNS was programed to 14 s "on" and 1.1 min "off." After 1 week, the VNS was reprogramed to 3 min off and stimulation continued for another week. Neural remodeling of the stellate ganglion (SG) was assessed with tyrosine hydroxylase staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining. Average IVC-IAGPNA was increased during both VNS 1.1 min off (8.20 ± 2.25 μV [95% confidence interval (CI): 6.33 to 9.53 μV]; p= 0.002) and 3 min off (7.96 ± 2.03 μV [95% CI: 6.30 to 9.27 μV]; p= 0.001) versus baseline (7.14 ± 2.20 μV [95% CI: 5.35 to 8.52 μV]). VR was reduced during both VNS 1.1 min off (123.29 ± 6.29 beats/min [95% CI: 116.69 to 129.89 beats/min]; p= 0.001) and 3 min off (120.01 ± 4.93 beats/min [95% CI: 114.84 to 125.18 beats/min]; p= 0.001) compared to baseline (142.04 ± 7.93 bpm [95% CI: 133.72 to 150.37]). Abnormal regions were observed in the left SG, but not in the right SG. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive neurons were found in 22.2 ± 17.2% [95% CI: 0.9% to 43.5%] of left SG cells and 12.8 ± 8.4% [95% CI: 2.4% to 23.2%] of right SG cells. Chronic low-level VNS increases IVC-IAGPNA and damages bilateral stellate ganglia. Both mechanisms could contribute to the underlying mechanism of VR control during AF.

Improved Outcomes of Cardiopulmonary Resuscitation in Rats Treated With Vagus Nerve Stimulation and Its Potential Mechanism.

Studies have demonstrated that vagus nerve stimulation (VNS) reduces ischemia/reperfusion injury. In this study, we investigated the protective effects of VNS in a rat model of cardiopulmonary resuscitation (CPR). We further investigated whether the beneficial effects of VNS were dependent on the alpha 7 nicotinic acetylcholine receptor (α7nAChR). Forty animals were randomized into four groups and all underwent CPR (n = 10 each): CPR alone (control); VNS during CPR; α7nAChR antagonist methyllycaconitine citrate (MLA) with VNS; α7nAChR agonist 3-(2, 4-dimethoxybenzylidene) anabaseine (GTS-21 dihydrochloride) without VNS. The right vagus nerve was exteriorized in all animals. Ventricular fibrillation was induced and untreated for 8 min. Defibrillation was attempted after 8 min of CPR. VNS was initiated at the beginning of precordial chest compressions and continued for 4 h after return of spontaneous circulation (ROSC) in both the VNS and MLA groups. Hemodynamic measurements and myocardial function, including ejection fraction and myocardial performance index, were assessed at baseline, 1 and 4 h after ROSC. The neurological deficit score was measured at 24-h intervals for a total of 72 h. The heart rate was reduced in the VNS and MLA groups, while no difference was found in mean arterial pressure between the four groups. Better post-resuscitation myocardial and cerebral function and longer duration of survival were observed in the VNS-treated animals. The protective effects of VNS could be abolished by MLA and imitated by GTS-21. In addition, VNS decreased the number of electrical shocks and the duration of CPR required. VNS improves multiple outcomes after CPR.

Vagal Nerve Stimulation: A Potentially Useful Adjuvant to Treatment of Sepsis

Aim of review: The hyper-inflammatory response is the classical pathogenesis of course. It has been shown that efferent nerve stimulation can regulate inflammatory response through a combination of acetylcholine and special α7 nicotinic acetylcholine receptor expressed on macrophages, which is defined as the cholinergic anti-inflammatory pathway (CAP). Furthermore, therapeutic methods related to CAP have been studied on lots of pathologic conditions, such as sepsis, ischemia/reperfusion injury, pancreatitis and hemorrhagic shock, etc. The aim of this review is to provide the evidence that VNS may be an effective adjuvant treatment bringing benefits for prognosis of by controlling excessive inflammatory response.Methods: We searched literatures published in the Pubmed with keywords inflammation, sepsis and vagal nerve stimulation (VNS) from January, 1986 to November, 2016, analyzed them and then assessed the evidence as to whether VNS may be an effective adjuvant for treatment of sepsis. In this review, the evidence regarding the role of hyper-inflammatory response in the pathogenesis of and inflammatory regulation of CAP will first be described. Then, the possible beneficial effects of VNS on inflammatory response of by modulating CAP will be provided.Recent findings: Sepsis is complex interactions between infecting microorganism and host's immune, inflammatory, and coagulation systems. The beneficial effects provided by CAP activation have been demonstrated on lots of pathologic conditions related to inflammation. Furthermore, VNS has been shown to promote the gastrointestinal motility and provide protection of intestinal barrier, reducing organ injury. In addition, VNS has been effectively used for treatment of some diseases in clinical practice.Summary: There is limited number of effective therapies available for septic patients. Because the CAP plays an important role in the regulation of inflammatory response, we consider that with the standard intensive care therapy, VNS may be an effective adjuvant treatment bringing benefits for prognosis of by controlling excessive inflammatory response. If efficiency of this new intervention is proved by clinical experiments, it may represent an exciting opportunity to develop novel therapeutics recovering unregulated inflammatory response in septic patients. Citation: Gui-Zhen Yang, Fu-Shan Xue, Chao Sun, Xu Liao, Jian-Hua Liu. Vagal nerve stimulation: a potential useful adjuvant to treatment of sepsis. J Anesth Perioper Med 2017; x: x-x. doi: 10.24015/JAPM.2017.0012This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Functional characterization of oxazolone-induced colitis and survival improvement by vagus nerve stimulation.

BackgroundOxazolone-induced colitis has been frequently used in literature as a model of IBD, but insights into the underlying immune response and pathological features are surprisingly still very limited. Vagus nerve stimulation (VNS) has proven to be effective in innate and Th1/Th17 predominant inflammatory models, including pre-clinical models of colitis, however to what extent VNS is also effective in ameliorating Th2-driven colitis remains to be studied. In the present study, we therefore further characterized the immune response in oxazolone-induced colitis and investigated the potential therapeutic effect of VNS.MethodsColitis was induced in Balb/c mice by cutaneous sensitization with 3% oxazolone followed by intracolonic administration of 1% oxazolone 7 days later. To evaluate the effect of VNS on the development of Th2-driven colitis, VNS and sham-treated mice were challenged with 1% oxazolone.ResultsIntracolonic oxazolone administration resulted in a severe destruction of the colonic mucosa and a rapid drop in body temperature leading to a 65% mortality rate at day 5. Severe infiltration of neutrophils and monocytes was detected 6h after oxazolone administration which was associated with a Th2-type inflammatory response. VNS significantly improved survival rate which correlated with decreased levels of HMGB1 and reduced colonic (il6 and cxcl1 mRNA) and serum cytokine levels (IL-6, TNFα and CXCL1) compared to sham treated mice.ConclusionsOxazolone-induced colitis rather represents a model of sepsis and, at best, may resemble a severe type of ulcerative colitis, associated with early and severe mucosal damage and a high mortality rate. VNS reduces colonic inflammation and improves survival in this model, supporting the anti-inflammatory properties of VNS, even in an aggressive model as oxazolone-induced colitis.

Some technical issues of vagal nerve stimulation. An approach using a hippocampal formation theta rhythm

Previously, we have demonstrated that hippocampal (HPC) theta rhythm can be produced, depending on current intensity, directly during vagal nerve stimulation (VNS) or with a time delay following stimulation. This suggests that theta EEG pattern can also be used as a bio-indicator of the efficiency of VNS. In the present study, we focused on three specific, technical issues related to the stimulation procedure of the vagal nerve: i/does the type of the electrode used for VNS and the technique of its implantation affect the parameters of the HPC theta rhythm? ii/does the type of electrode used determine the current intensity threshold of VNS-induced HPC theta? iii/is the repeatability of the VNS effect determined by the type of electrode used?We demonstrated that a platinum-iridium cuff electrode offers some important advantages over a tungsten electrode. Firstly, despite some possible mechanical and compression nerve damage related to permanent contact with the vagal nerve, it offers a lower current intensity threshold for inducing theta oscillations. Secondly, and most importantly, the cuff electrode offers repeatability of the VNS effect on the HPC theta rhythm. However, one disadvantage of using this type of an electrode is that the permanent pressure on the vagal nerve by the cuff itself may decrease the amplitude of the investigated field potential.

Mo1906 - The Effects of Vagus Nerve Stimulation in Biologicrefractory Crohn's Disease: A Prospective Clinical Trial

Mo1906 - The Effects of Vagus Nerve Stimulation in Biologicrefractory Crohn's Disease: A Prospective Clinical Trial

Long Term Effects of Vagal Nerve Stimulation on Seizure Control and Quality of Life (P2.341)

Long Term Effects of Vagal Nerve Stimulation on Seizure Control and Quality of Life (P2.341)

Effect of Chronic Vagal Nerve Stimulation on Glucose Tolerance in Conscious Rats

Previously, we demonstrated that cervical vagal nerve stimulation (VNS) inhibits insulin secretion and markedly increases resting blood glucose levels in anesthetized rats. Based on these findings, we hypothesized that chronic cervical VNS induces impaired glucose tolerance in conscious rats.All animal experiments were approved by the Institutional Animal Care and Use Committee of The University of Iowa. Rats were chronically instrumented with telemetric blood pressure sensors inserted into the aorta through the femoral artery and right‐sided cervical vagal nerve stimulators. Three and six days following surgery, repeated glucose tolerance tests (1.5 g dextrose/kg BW, i.p.) were performed after overnight fasting with the vagal nerve stimulators on or off (sham stimulation) in randomized order. VNS (3V, 5Hz, 1ms pulse duration, 1h on 1h off) or sham stimulation was started on the day before the glucose tolerance test. The stimulators were switched to a continuous stimulation mode (instead of 1 h on, 1 h off) for the entire duration of the glucose tolerance tests (2–3 hours) and switched off thereafter. Effectiveness of VNS was confirmed in all animals by the heart rate response to VNS (assessed through the telemetric blood pressure sensors).The study is still ongoing at the time of this writing. Preliminary results from three animals that completed the study so far indicate that baseline blood glucose levels were elevated in animals that received overnight VNS (168±16 mg/dL, n=3) compared to sham stimulated animals (123±15 mg/dL, n=3, P=0.11). The maximal increase in blood glucose levels during the oral glucose tolerance tests (time point 30 min) was greater in rats with VNS (+412±23 mg/dL, n=3) compared to sham stimulated animals (+233±41 mg/dL, n=3, P=0.11). Furthermore, two‐way Analysis of Variance revealed that glucose levels were significantly elevated throughout the 120 min of the glucose tolerance tests in rats with VNS compared to sham‐stimulated animals (P<0.01).These preliminary results suggest that cervical VNS impairs glucose tolerance in conscious rats. It remains to be determined if human patients treated with VNS are at greater risk to develop type 2 diabetes.Support or Funding InformationSupported by a pilot grant from the University of Iowa Hospitals and Clinics Center for Hypertension Research and the German Research Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Vagus Nerve Stimulation in a Murine Model of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease that predominantly affects women at a ratio of 9:1 over males. Renal inflammation is prevalent in SLE and this contributes to the pathogenesis of renal injury and hypertension in the disease. In addition, there is autonomic dysfunction in SLE: increased sympathetic and decreased parasympathetic nervous system activation. The parasympathetic vagus nerve is implicated in an endogenous neuroimmune mechanism, the cholinergic anti‐inflammatory pathway, which regulates inflammation. Upon detection of increased inflammation, the efferent vagus nerve stimulates the splenic nerve to release norepinephrine. Norepinephrine then acts on the β2‐receptor‐expressing T cells in the spleen, which express choline acetyltransferase. These T cells are able to release acetylcholine, which then binds to α7‐nicotinic acetylcholine receptor‐expressing macrophages and other cytokine secreting immune cells to inhibit release of pro‐inflammatory cytokines. Given that chronic inflammation and decreased parasympathetics accompany SLE, we hypothesized that vagus nerve stimulation (VNS) using electrical implants will decrease inflammatory cytokines via accentuation of the cholinergic anti‐inflammatory pathway and protect against renal injury and development of hypertension. At 25 weeks of age, vagus nerve stimulators were chronically implanted on the right vagus nerve in 17 female NZBWF1 mice, a well‐established murine model of SLE, which were divided into VNS (n=10) and sham (n=7) groups. Only female mice were used due to the prevalence of the SLE in women. Stimulators were set to target the efferent vagus nerve (3V, 5 Hz, 800 μs, at 1 hour on/off cycles) continuously for 2 weeks. At the end of the study, tissues were collected and analyzed for inflammatory markers. Spleen weight was slightly increased in SLE/VNS mice compared to SLE/sham mice (0.11 ± 0.01 vs 0.14 ± 0.03g, respectively; P=0.210). The incidence of albuminuria, an index of renal injury measured by Albustix, was also decreased in SLE/VNS mice compared to shams (29% vs 10%). Moreover, flow cytometry indicated that SLE/VNS mice had slightly less CD3+/CD4+ bone marrow T‐cells when compared with SLE/sham mice (27.30 ± 9.41% vs 40.17 ± 7.01%; P=0.334). These results hint at possible protection following vagus nerve stimulation in SLE; however future studies are needed to determine the impact of this therapy on blood pressure. Furthermore, clinical trials (NCT02822989) are being conducted to assess the effects of VNS and cholinergic anti‐inflammatory pathway activation on musculoskeletal pain that SLE patients experience. The results from our lab will provide evidence of potential use of VNS in SLE patients to not only manage pain, but also to quell chronic renal inflammation and delay or prevent renal injury and hypertension.Support or Funding InformationFunded by an AHA Scientist Development Grant (14SDG18320033) to KWM and UNTHSC Intramural FundingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Stochastic vagus nerve stimulation affects acute heart rate dynamics in rats.

Vagus nerve stimulation (VNS) is an approved therapy for treatment of epilepsy and depression. While also shown to be promising in several preclinical and clinical studies to treat cardiovascular diseases, optimal therapeutic stimulation paradigms are still under investigation. Traditionally, parameters such as frequency, current, and duty cycle are used to adjust the efficacy of VNS therapy. This study explored the effect of novel stochastic VNS (S-VNS) on acute heart rate (HR) dynamics. The effect of S-VNS was evaluated in Sprague Dawley rats by comparing the acute HR and HR variability (HRV) responses to standard, periodic VNS (P-VNS) across different frequencies (FREQs, 10–30 Hz). Our results demonstrate that both S-VNS and P-VNS produced negative chronotropic effects in a FREQ-dependent manner with S-VNS inducing a significantly smaller drop in HR at 10 Hz and 20 Hz compared to P-VNS (p<0.05). S-VNS demonstrated a FREQ-dependent drop in the SD1/SD2 ratio, a measure of HRV, which was absent in P-VNS, suggesting that S-VNS may acutely modulate the nonlinear relationship between short- and long-term HRV. In conclusion, S-VNS is a novel stimulation procedure that may provide different physiological outcomes from standard P-VNS, as indicated by our analysis of HR dynamics. Our study provides a rationale for further detailed investigations into the therapeutic potential of S-VNS as a novel neuromodulation technique.

Electroencephalographic correlates of low-frequency vagus nerve stimulation therapy for Crohn’s disease

ObjectivesIn the context of the first clinical trial of vagus nerve stimulation (VNS) in Crohn’s disease (CD), our main objective was to quantify the acute and chronic effects of VNS on brain activity in CD patients. MethodsWe measured the electroencephalogram (EEG) in 9CD patients under VNS at 10 Hz just before VNS initiation, after 6 weeks and after 12 months of chronic VNS. ResultsAcute VNS induced increased spectral power in delta and theta bands on frontal, temporal and occipital electrodes. The main significant modulation was the 12 months’ chronic effect of VNS which consisted mainly in a decreased power in the alpha frequency band which was correlated with the normalization of bowel mucosal inflammation, anxiety state and vagal tone. ConclusionsIn addition to the activation of vagal efferent fibers that regulate the autonomic nervous system, our data suggest that chronic VNS has a regulatory action via afferent vagal fibers on anxio-depressive symptomatology associated to CD, which could be directly highlighted by the modulation of EEG alpha power known to be associated to depressed states. SignificanceThis is the first report of the central effects of VNS in CD patients.

Antiarrhythmic effects of vagal nerve stimulation after cardiac sympathetic denervation in the setting of chronic myocardial infarction

Neuraxial modulation with cardiac sympathetic denervation (CSD) can potentially reduce burden of ventricular tachyarrhythmia (VT). However, despite catheter ablation and CSD, VT can recur in patients with cardiomyopathy and the role of vagal nerve stimulation (VNS) in this setting is unclear. The purpose of this study was to evaluate the electrophysiological effects of VNS after CSD in normal and infarcted hearts. In 10 normal and 6 infarcted pigs, electrophysiological and hemodynamic parameters were evaluated before and during intermittent VNS pre-CSD (bilateral stellectomy and T2-T4 thoracic ganglia removal) as well as post-CSD. The effect of VNS during isoproterenol was also assessed pre- and post-CSD. Multielectrode ventricular activation recovery interval (ARI) recordings, a surrogate of action potential duration, were obtained. VT inducibility was tested during isoproterenol infusion after CSD with and without VNS. VNS increased the global ARI by 4% ± 4% pre-CSD and by5% ± 6% post-CSD, with enhanced effects observed during isoproterenol infusion (10% ± 8% pre-CSD and 12% ± 9% post-CSD) in normal animals. In infarcted animals pre-CSD, VNS increased ARI by 6% ± 7% before and by 13% ± 8% during isoproterenol infusion. Post-CSD, VNS increased ARI by 6% ± 5% before and by 11% ± 7% during isoproterenol infusion. VT was inducible in all infarcted animals post-CSD during isoproterenol infusion; this inducibility was reduced by 67% with VNS (P = .01). In all animals, the hemodynamic effects of VNS remained after CSD. After CSD, the beneficial electrophysiological effects of VNS remain. Furthermore, VNS can reduce VT inducibility beyond CSD in the setting of circulating catecholamines, suggesting a role for additional parasympathetic modulation in the treatment of ventricular arrhythmias.

Regaining Consciousness: The Effect of Vagal Nerve Stimulation on a Patient in a Permanent Vegetative State.

Regaining Consciousness: The Effect of Vagal Nerve Stimulation on a Patient in a Permanent Vegetative State.

Cognition-enhancing effect of vagus nerve stimulation on refractory epilepsy secondary to lissencephaly: A case report.

Cognition-enhancing effect of vagus nerve stimulation on refractory epilepsy secondary to lissencephaly: A case report.

The cholinergic anti-inflammatory pathway revisited.

Inflammatory bowel disease negatively affects the quality of life of millions of patients around the world. Although the precise etiology of the disease remains elusive, aberrant immune system activation is an underlying cause. As such, therapies that selectively inhibit immune cell activation without broad immunosuppression are desired. Inhibition of immune cell activation preventing pro-inflammatory cytokine production through neural stimulation has emerged as one such treatment. These therapeutics are based on the discovery of the cholinergic anti-inflammatory pathway, a reflex arc that induces efferent vagal nerve signaling to reduce immune cell activation and consequently mortality during septic shock. Despite the success of preclinical and clinical trials, the neural circuitry and mechanisms of action of these immune-regulatory circuits are controversial. At the heart of this controversy is the protective effect of vagal nerve stimulation despite an apparent lack of neuroanatomical connections between the vagus and target organs. Additional studies have further emphasized the importance of sympathetic innervation of these organs, and that alternative neural circuits could be involved in neural regulation of the immune system. Such controversies also extend to the regulation of intestinal inflammation, with the importance of efferent vagus nerve signals in question. Experiments that better characterize these pathways have now been performed by Willemze etal. in this issue of Neurogastroenterology & Motility. These continued efforts will be critical to the development of better neurostimulator based therapeutics for inflammatory bowel disease.

Effects of vagus nerve stimulation on heart rate variability in children with epilepsy

PurposeThe aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) on heart rate variability (HRV) in children with epilepsy. MethodsThe subgroups of HRV, namely time domain (Standard deviation of NN interval (SDNN), SDNN index, Standard deviation of the averages of NN intervals (SDANN), Root mean square of successive differences (RMMSD), Adjacent NN intervals differing by more than 50 ms in the entire recording divided by the total number of all NN intervals (PNN50), triangular index) and frequency domain (Low-frequency (LF), High-frequency (HF), LF/HF), were investigated in 20 pediatric patients before and after 6 and 12months of VNS treatment during day and night by comparing their data with those of 20 control subjects. In addition, subgroups of age, epilepsy duration and localization, and antiepileptic drugs (AEDs) were also evaluated if they had further effects on basal HRV levels. ResultsIncreased heart rates (HRs); decreased SDNN, SDANN, RMMSD, and PNN50; and increased LF/HF ratios were identified before VNS therapy (p<0.05). Even though remarkable improvement was seen after 6months of VNS treatment (p<0.05), no further changes were observed in 12-month compared with 6-month levels (p>0.05) in all parameters, still even significantly lower than those of controls (p<0.05). Longer duration of epilepsy and localization of epileptic focus, such as in the temporal lobe, were also found to further contribute to diminished basal HRV levels (p<0.05). ConclusionThe cardiovascular system is under deep sympathetic influence in children with epilepsy. Although VNS seems to provide a substantial improvement by achieving increased parasympathetic effects in short-term therapy, the levels were still lower than those of healthy children after either short- or long-term therapy. Therefore, impaired cardiovascular autonomic regulation may be associated with the epileptic process itself as well as with the contribution of some additional factors. Overall, different aspects such as age, epilepsy duration, epileptic focus, seizure frequency, and AEDs should also be considered for their further possible effects on HRV during VNS therapy.

P574 The effects of vagus nerve stimulation in biologic-refractory Crohn’s disease: A prospective clinical trial

P574 The effects of vagus nerve stimulation in biologic-refractory Crohn’s disease: A prospective clinical trial

Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex.

Orexins, produced in the lateral hypothalamus, are important neuropeptides that participate in the sleep/wake cycle, and their expression coincides with the projection area of the vagus nerve in the brain. Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury. In the present study, we investigated whether vagus nerve stimulation promotes wakefulness and affects orexin expression. A rat model of traumatic brain injury was established using the free fall drop method. In the stimulated group, rats with traumatic brain injury received vagus nerve stimulation (frequency, 30 Hz; current, 1.0 mA; pulse width, 0.5 ms; total stimulation time, 15 minutes). In the antagonist group, rats with traumatic brain injury were intracerebroventricularly injected with the orexin receptor type 1 (OX1R) antagonist SB334867 and received vagus nerve stimulation. Changes in consciousness were observed after stimulation in each group. Enzyme-linked immunosorbent assay, western blot assay and immunohistochemistry were used to assess the levels of orexin-A and OX1R expression in the prefrontal cortex. In the stimulated group, consciousness was substantially improved, orexin-A protein expression gradually increased within 24 hours after injury and OX1R expression reached a peak at 12 hours, compared with rats subjected to traumatic brain injury only. In the antagonist group, the wake-promoting effect of vagus nerve stimulation was diminished, and orexin-A and OX1R expression were decreased, compared with that of the stimulated group. Taken together, our findings suggest that vagus nerve stimulation promotes the recovery of consciousness in comatose rats after traumatic brain injury. The upregulation of orexin-A and OX1R expression in the prefrontal cortex might be involved in the wake-promoting effects of vagus nerve stimulation.