Electrical Stimulation Of Vagus Nerve Research Articles

Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis.

To investigate the potential benefits of vagus nerve stimulation in a clinically-relevant large animal model of progressive sepsis. Prospective, controlled, randomized trial. University animal research laboratory. Twenty-five domestic pigs were divided into three groups: 1) sepsis group (eight pigs), 2) sepsis + vagus nerve stimulation group (nine pigs), and 3) control sham group (eight pigs). Sepsis was induced by cultivated autologous feces inoculation in anesthetized, mechanically ventilated, and surgically instrumented pigs and followed for 24 hours. Electrical stimulation of the cervical vagus nerve was initiated 6 hours after the induction of peritonitis and maintained throughout the experiment. Measurements of hemodynamics, electrocardiography, biochemistry, blood gases, cytokines, and blood cells were collected at baseline (just before peritonitis induction) and at the end of the in vivo experiment (24 hr after peritonitis induction). Subsequent in vitro analyses addressed cardiac contractility and calcium handling in isolated tissues and myocytes and analyzed mitochondrial function by ultrasensitive oxygraphy. Vagus nerve stimulation partially or completely prevented the development of hyperlactatemia, hyperdynamic circulation, cellular myocardial depression, shift in sympathovagal balance toward sympathetic dominance, and cardiac mitochondrial dysfunction, and reduced the number of activated monocytes. Sequential Organ Failure Assessment scores and vasopressor requirements significantly decreased after vagus nerve stimulation. In a clinically-relevant large animal model of progressive sepsis, vagus nerve stimulation was associated with a number of beneficial effects that resulted in significantly attenuated multiple organ dysfunction and reduced vasopressor and fluid resuscitation requirements. This suggests that vagus nerve stimulation might provide a significant therapeutic potential that warrants further thorough investigation.

Anti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation.

Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, side effects from cervical vagal nerve stimulation (VNS) are often reported by patients. Here we hypothesized that stimulating the vagus nerve closer to the end organ will have fewer off-target effects and will effectively reduce intestinal inflammation. Specifically, we aimed to: (i) compare off-target effects during abdominal and cervical VNS; (ii) verify that VNS levels were suprathreshold; and (iii) determine whether abdominal VNS reduces chemically-induced intestinal inflammation in rats. An electrode array was developed in-house to stimulate and record vagal neural responses. In a non-recovery experiment, stimulation-induced off-target effects were measured by implanting the cervical and abdominal vagus nerves of anaesthetized rats (n = 5) and recording changes to heart rate, respiration and blood pressure during stimulation (10 Hz; symmetric biphasic current pulse; 320 nC per phase). In a chronic experiment, the efficacy of VNS treatment was assessed by implanting an electrode array onto the abdominal vagus nerve and recording in vivo electrically-evoked neural responses during the implantation period. After 14 days, the intestine was inflamed with TNBS (2.5% 2,4,6-trinitrobenzene sulphonic acid) and rats received therapeutic VNS (n = 7; 10 Hz; 320 nC per phase; 3 h/day) or no stimulation (n = 8) for 4.5 days. Stool quality, plasma C-reactive protein and histology of the inflamed intestine were assessed. Data show that abdominal VNS had no effect (two-way RM-ANOVA: P ≥ 0.05) on cardiac, respiratory and blood pressure parameters. However, during cervical VNS heart rate decreased by 31 ± 9 beats/minute (P ≥ 0.05), respiration was inhibited and blood pressure decreased. Data addressing efficacy of VNS treatment show that electrically-evoked neural response thresholds remained stable (one-way RM ANOVA: P ≥ 0.05) and therapeutic stimulation remained above threshold. Chronically stimulated rats, compared to unstimulated rats, had improved stool quality (two-way RM ANOVA: P < 0.0001), no blood in feces (P < 0.0001), reduced plasma C-reactive protein (two-way RM ANOVA: P < 0.05) and a reduction in resident inflammatory cell populations within the intestine (Kruskal–Wallis: P < 0.05). In conclusion, abdominal VNS did not evoke off-target effects, is an effective treatment of TNBS-induced inflammation, and may be an effective treatment of IBD in humans.

Electrical Vagal Nerve Stimulation in Ulcerative Colitis

Electrical Vagal Nerve Stimulation in Ulcerative Colitis

Developmental Exposure to Chlorpyrifos Modulates Pulmonary Function in Adult Rats

Acute OP intoxication is well known to cause bronchoconstriction and increase airway secretions via inhibition of acetylcholinesterase (AChE). However, occupational and environmental exposures to organophosphorus pesticides (OP) at levels not expected to significantly inhibit AChE are associated with increased incidence of asthma and other pulmonary diseases. In support of the epidemiological data, acute exposure of adult guinea pigs and rats to OPs at levels that do not inhibit AChE in the lung, blood or brain have been shown to cause airway hyperreactivity (AHR). More recently, epidemiologic studies have suggested that exposure to OPs during development is also associated with increased risk of asthma. To address whether developmental OP exposures are also causally linked to AHR, we measured respiratory physiology in young adult rats exposed to the OP chlorpyrifos (CPF) at 0, 0.1, 0.3 and 1 mg/kg/d (sc) from postnatal days 1–4. Using a Flexivent mechanical ventilator, airway responsiveness to electrical stimulation of the vagus nerves was quantified. Preliminary findings suggest that adult female rats exposed developmentally to CPF exhibit significantly decreased airway resistance and elastance in response to electrical vagal stimulation relative to vehicle controls. In contrast, male rats exposed developmentally to CPF did not exhibit any changes in airway resistance and elastance in response to electrical vagal stimulation relative to vehicle controls. These results suggest that early life exposure to CPF triggers atypical expansion of the large and small conducting airways in the lungs of female, but not male rats. These findings will significantly advance our understanding of the role of OPs in respiratory diseases, and ultimately, inform risk assessments used to protect human health and safety. The United States Environmental Protection Agency currently uses acetylcholinesterase inhibition as a biomarker of OP toxicity; however, OPs modulate lung function at levels significantly lower than those that inhibit AChE. The findings of this research could potentially provide a scientifically rational basis for reassessment of exposure limits for OPs as well as help direct future research on therapeutic agents for treating/respiratory disorders in OP‐exposed children and adolescents.Support or Funding InformationWork was supported by the NIH (R01 ES017592 to PL and pilot project funding to ACG from P30 ES023513).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Microscopic magnetic stimulation of the cervical vagus nerve

Introduction: Electrical vagus nerve stimulation (VNS) is an FDA-approved treatment for drug-resistant epilepsy, depression, and headache. However, oxidation/reduction reactions at the electrode tissue interface can result in damage and reduce the efficacy of stimulation. Micro-magnetic stimulation (μMS) of the vagus nerve has the potential to be an alternative to electrical VNS. μMS is accomplished by running alternating current through a sub-millimeter coil to produce time-varying magnetic fields which can in turn induce electrical fields, leading to neuronal activation. The small size of the coils involved leads to high spatial resolution of μMS. μMS is distinct from electrical stimulation in that it can activate axons based on the particular coil orientation, and in that it does not require charge-balanced stimulation waveform shapes, which are needed in electrical stimulation to avoid electrophoresis. The coils used in μMS do not undergo oxidation/reduction reactions and are compatible with imaging devices such as MRI. Thus, μMS represents a groundbreaking step forward from the traditional electrical stimulation of neurons. Here, we describe the effect of micro-magnetic VNS (μM-VNS) on physiological parameters in rats.

Abstract #17: Microscopic Magnetic Stimulation of the Vagus Nerve: Initial Recordings

Introduction: In this recent study we have employed a novel type of stimulation, micro-magnetic stimulation (μMS), for vagus nerve stimulation (VNS). Electrical VNS is commonly used to treat drug-resistant epilepsy, depression, and headache. However, oxidation/reduction reactions at the electrode-tissue interface can result in damage and reduce the efficacy of stimulation, while concerns regarding device and tissue damage prevent patients with VNS implants from receiving the diagnostic benefits of imaging devices such as magnetic resonance imaging (MRI).

Precious cargo: Modulation of the mesenteric lymph exosome payload after hemorrhagic shock.

Trauma/hemorrhagic shock (T/HS) causes a release of proinflammatory mediators into the mesenteric lymph (ML) that may trigger a systemic inflammatory response and subsequent organ failure. Recently, we showed that exosomes in postshock ML are biologically active mediators of this inflammation. Because the specific inflammatory mediators in postshock ML exosomes have yet to be characterized, we hypothesized that T/HS would lead to a distinct ML proinflammatory exosome phenotype that could be identified by proteomic analysis. We further hypothesized that their regulation by the neuroenteric axis via the vagus nerve would modify this proinflammatory profile. Male rats underwent an established T/HS model including 60 minutes of HS followed by resuscitation. Mesenteric lymph was collected before HS (preshock) and after resuscitation (postshock). A subset of animals underwent cervical vagus nerve electrical stimulation (VNS) after the HS phase. Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) followed by protein identification, label free quantification, and bioinformatic analysis was performed on exosomes from the pre-shock and post-shock phases in the T/HS and T/HS + vagus nerve electrical stimulation groups. Biological activity of exosomes was evaluated using a monocyte nuclear factor kappa B (NF-κB) activity assay. ML exosomes express a distinct protein profile after T/HS with enrichment in pathways associated with cell signaling, cell death and survival, and the inflammatory response. Stimulation of the vagus nerve following injury attenuated the transition of ML exosomes to this T/HS-induced inflammatory phenotype with protein expression remaining similar to pre-shock. Monocyte NF-κB activity was increased after exposure to ML exosomes harvested after T/HS, while ML exosomes from preshock had no effect on monocyte NF-κB expression. Postshock ML exosomes carry a distinct, proinflammatory protein cargo. Stimulating the vagus nerve prevents the T/HS-induced changes in ML exosome protein payload and suggests a novel mechanism by which the neuroenteric axis may limit the systemic inflammatory response after injury.

Stimulation Pattern Efficiency in Percutaneous Auricular Vagus Nerve Stimulation: Experimental Versus Numerical Data.

Percutaneous electrical stimulation of the auricular vagus nerve (pVNS) is an electroceutical technology. The selection of stimulation patterns is empirical, which may lead to under-stimulation or over-stimulation. The objective is to assess the efficiency of different stimulation patterns with respect to individual perception and to compare it with numerical data based on in-silico ear models. Monophasic (MS), biphasic (BS) and triphasic stimulation (TS) patterns were tested in volunteers. Different clinically-relevant perception levels were assessed. In-silico models of the human ear were created with embedded fibers and vessels to assess different excitation levels. TS indicates experimental superiority over BS which is superior to MS while reaching different perception levels. TS requires about 57% and 35% of BS and MS magnitude, respectively, to reach the comfortable perception. Experimental thresholds decrease from non-bursted to bursted stimulation. Numerical results indicate a slight superiority of BS and TS over MS while reaching different excitation levels, whereas the burst length has no influence. TS yields the highest number of asynchronous action impulses per stimulation symbol for the used tripolar electrode set-up. The comparison of experimental and numerical data favors the novel TS pattern. The analysis separates excitatory pVNS effects in the auricular periphery, as accounted by in-silico data, from the combination of peripheral and central pVNS effects in the brain, as accounted by experimental data. The proposed approach moves from an empirical selection of stimulation patterns towards efficient and optimized pVNS settings.

Vagus Nerve Stimulation to Treat Inflammatory Bowel Disease: A Chronic, Preclinical Safety Study in Sheep

Aim: Electrical stimulation of the left cervical vagus nerve is a feasible therapy for inflammatory bowel disease (IBD). However, due to the location of the electrode placement, stimulation is often associated with side effects. Methods: We developed a cuff electrode array, designed to be implanted onto the vagus nerve of the lower thorax or abdomen, below branches to vital organs, to minimize off-target effects to stimulation. Results: Following chronic implantation and electrical stimulation, electrodes remained functional and neural thresholds stable, while there were minimal off-target affects to stimulation. No nerve damage or corrosion of stimulated electrodes was observed. Conclusion: This novel electrode array, located on the vagus nerve below branches to vital organs, is a safe approach for the treatment of inflammatory bowel disease.

Cutting Edge: Human Vagus Produces Specialized Proresolving Mediators of Inflammation with Electrical Stimulation Reducing Proinflammatory Eicosanoids.

Inflammatory resolution is a process that, when uncontrolled, impacts many organs and diseases. As an active, self-limited inflammatory process, resolution involves biosynthesis of specialized proresolving mediators (SPM) (e.g., lipoxins, resolvins [Rv], protectins, and maresins). Because vagal stimulation impacts inflammation, we examined human and mouse vagus ex vivo to determine if they produce lipid mediators. Using targeted lipid mediator metabololipidomics, we identified lipoxins, Rv, and protectins produced by both human and mouse vagus as well as PGs and leukotrienes. Human vagus produced SPM (e.g., RvE1, NPD1/PD1, MaR1, RvD5, and LXA4) on stimulation that differed from mouse (RvD3, RvD6, and RvE3), demonstrating species-selective SPM. Electrical vagus stimulation increased SPM in both human and mouse vagus as did incubations with Escherichia coli. Electrical vagus stimulation increased SPM and decreased PGs and leukotrienes. These results provide direct evidence for vagus SPM and eicosanoids. Moreover, they suggest that this vagus SPM circuit contributes to a new proresolving vagal reflex.

Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex.

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1–60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.

Influence of vagus nerve on multiple organ function and immune reaction of T lymphocytes in septic rats

Objective: To explore influence of vagus nerve on multiple organ function and immune reaction of T lymphocytes in septic rats. Methods: Forty Sprague-Dawley rats were divided into sham injury group, sepsis group, vagus nerve stimulation (VNS) group, and vagotomy (VGX) group, according to the random number table, with 10 rats in each group. Rats in sepsis group, VNS group, and VGX group were inflicted with sepsis by cecal ligation and puncture (CLP). Rats in VNS group were given electrical stimulation on left cervical vagus nerve for 15 min right after CLP. Rats in VGX group underwent vagotomy of left cervical vagus nerve at 30 min before CLP. At 24 h after CLP, serum of rats was collected to detect levels of alanine transaminase (ALT), aspartate aminotransferase (AST), glycocholic acid (CG), creatine kinase (CK), myocardial creatine kinase (CK-MB), blood urea nitrogen (BUN), and serum creatinine by fully automatic biochemistry analyzer. The left lung of rats was collected to determine wet or dry mass, and wet to dry (W/D) ratio was calculated. The right lung of rats was collected to measure the activity of pulmonary myeloperoxidase (MPO) by enzyme linked immunosorbent assay (ELISA). Spleen of rats was collected to determine the proliferative activity of CD4(+) T lymphocytes by cell counting kit 8, and real-time fluorescence quantitative polymerase chain reaction and ELISA were used to quantify mRNA expressions and levels of interleukin 2 (IL-2), interferon-γ, and IL-4, respectively. Data were processed with one-way analysis of variance and Tukey's honest significant difference test. Results: (1) The levels of serum ALT, AST, CG, CK, CK-MB, BUN, and creatinine, pulmonary W/D ratio, as well as MPO activity of rats in sepsis group were significantly higher than those in sham injury group and VNS group (P<0.01) and were significantly lower than those in VGX group (P<0.01). (2) The proliferative activity of CD4(+) T lymphocytes of rats in sepsis group was 0.93±0.03, which was significantly lower than 1.54±0.07 of rats in sham injury group (P<0.01). The proliferative activity of CD4(+) T lymphocytes of rats in VNS group was 1.15±0.15, which was significantly higher than that of rats in sepsis group (P<0.01). The proliferative activity of CD4(+) T lymphocytes of rats in VGX group was 0.75±0.06, which was obviously lower than that of rats in sepsis group (P<0.01). (3) In comparison with those of rats in sham injury group, the levels of IL-2 and interferon-γ in CD4(+) T lymphocytes of rats in sepsis group were markedly decreased (P<0.01), while the level of IL-4 was significantly increased (P<0.01). In comparison with those of rats in sepsis group, the levels of IL-2 and interferon-γ in CD4(+) T lymphocytes of rats in VNS group were obviously increased (P<0.01), while the level of IL-4 was markedly decreased (P<0.01). As compared with those of rats in sepsis group, the levels of IL-2 and interferon-γ in CD4(+) T lymphocytes of rats in VGX group were markedly decreased (P<0.01), while the level of IL-4 was significantly increased (P<0.01). (4) As compared with those of rats in sham injury group, expressions of IL-2 and interferon-γ mRNA in CD4(+) T lymphocytes of rats in sepsis group were markedly decreased (P<0.01), while expression of IL-4 mRNA was significantly increased (P<0.01). Expressions of IL-2 and interferon-γ mRNA in CD4(+) T lymphocytes of rats in VNS group were obviously increased when compared with those of rats in sepsis group (P<0.01), while expression of IL-4 mRNA was markedly decreased (P<0.01). In comparison with those of rats in sepsis group, expressions of IL-2 and interferon-γ mRNA in CD4(+) T lymphocytes of rats in VGX group were markedly decreased (P<0.01), while expression of IL-4 mRNA was significantly increased (P<0.01). Conclusions: Electrical stimulation of vagus nerve can significantly improve multiple organ dysfunction and reverse immunosuppression of T lymphocytes in septic rats, while vagotomy of vagus nerve may enhance the susceptibility of rats to sepsis.

Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice.

The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non-invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos+ cells. Gene and protein expression of IL-6, MCP-1, IL-1β as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNFα, and IL-1β serum levels were analyzed 3hours after lipopolysaccharide administration. tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI.

Modulating the Inflammatory Reflex in Rats Using Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve

Tumor necrosis factor α (TNF-α) is linked to several chronic inflammatory diseases. Electrical vagus nerve stimulation reduces serum TNF-α levels but may cause chronic nerve damage and requires surgery. Alternatively, we proposed focused ultrasound stimulation of the vagus nerve (uVNS), which can be applied non-invasively. In this study, we induced an inflammatory response in rats using lipopolysaccharides (LPS) and collected blood to analyze the effects of uVNS on cytokine concentrations. We applied one or three 5-min pulsed focused ultrasound stimulation treatments to the vagus nerve (250 kHz, ISPPA = 3 W/cm2). Animals receiving a single ultrasound application had an average reduction in TNF-α levels of 19%, similar to the 16% reduction observed in electrically stimulated animals. With multiple applications, uVNS therapy statistically reduced serum TNF-α levels by 73% compared with control animals without any observed damage to the nerve. These findings suggest that uVNS is a suitable way to attenuate TNF-α levels.

Effect of Electrical Vagus Nerve Stimulation on Cerebral Blood Flow and Neurological Outcome in Asphyxial Cardiac Arrest Model of Rats.

Vagus nerve stimulation (VNS) during post-resuscitation may increase recovery of cerebral blood flow (CBF) and reduce neurological injury. This study was designed to investigate the effect of electrical VNS on neurological outcomes following cardiac arrest (CA). Male Sprague-Dawley rats (n = 48) were subjected to the asphyxial CA model and blindly allocated to the VN isolation (CA + VN isolation) or VNS group (CA + VNS group). Cardiopulmonary resuscitation was initiated 450s after pulseless electrical arrest, and the left cervical vagus nerve was electrically stimulated (0.05mA, 1Hz) for 3h in the CA + VNS group. The neurological deficit score (NDS) and overall performance category (OPC) were assessed at 24h after resuscitation, and histological injury of the hippocampus was evaluated. Independent experiments were performed to evaluate the effect of VNS on global cortical CBF after resuscitation using laser speckle Doppler imaging through a thinned skull window from pre-arrest to 6h after resuscitation. The baseline characteristics were not significantly different between the two groups. The NDS was significantly higher, and the OPC was substantially lower in the CA + VNS group (p = 0.022 and p = 0.049, respectively) supported by decrease in histological injury of the hippocampal CA1 region. CBF in the early period of post-return of spontaneous circulation (ROSC) was significantly higher in the CA + VNS group (p < 0.05 at post-ROSC 2h and 4h), and 4-hydroxynonenal was significantly lower in the CA + VNS group (p = 0.026). VNS improved cerebral perfusion and neurological outcomes at 24h after ROSC in an asphyxial CA model of rats.

Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension

This study aimed to elucidate the therapeutic effects of electrical vagal nerve stimulation (VNS) onsevere pulmonary arterial hypertension in a rat model. In a pathophysiological study, VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In a survival study, VNSsignificantly improved the survival rate in both the prevention (VNS from 0 to 5 weeks afteraSU5416 injection) and treatment (VNS from 5to 10 weeks) protocols. Thus, VNS may serveasanovel therapeutic strategy for pulmonary arterial hypertension.

Central activation of cardiac vagal nerve by α2-adrenergic stimulation is impaired in streptozotocin-induced type 1 diabetic rats

To elucidate the abnormality of cardiac vagal control in streptozotocin-induced type 1 diabetic rats, we measured left ventricular myocardial interstitial acetylcholine (ACh) release in response to α2-adrenergic stimulation as an index of in vivo cardiac vagal nerve activity. A cardiac microdialysis technique was applied to the rat left ventricle, and the effect of α2-adrenergic stimulation by intravenous medetomidine (100 μg/kg) on myocardial interstitial ACh levels was examined in anesthetized diabetic rats (4-6 weeks after intraperitoneal streptozotocin) and age-matched control rats (protocol 1). The effect of electrical vagal nerve stimulation on ACh levels was also examined in separate rats (protocol 2). In protocol 1, medetomidine increased the ACh levels in control (from 1.76 ± 0.65 to 3.13 ± 1.41 nM, P < 0.05, n = 7) but not in diabetic rats (from 2.01 ± 0.47 to 1.62 ± 0.34 nM, not significant, n = 7). In protocol 2, electrical vagal nerve stimulation at 20 Hz significantly increased the ACh levels in both control (from 1.49 ± 0.26 to 6.39 ± 1.81 nM, P < 0.001, n = 6) and diabetic rats (from 1.77 ± 0.54 to 6.98 ± 1.38 nM, P < 0.001, n = 6). In conclusion, medetomidine-induced central vagal activation was impaired in diabetic rats, whereas peripheral cardiac vagal control of ACh release was preserved. The impairment of central vagal activation may lead to relative sympathetic predominance and promote cardiovascular complications in diabetes.

Abstract P387: Sub-Perception Transdermal Vagal Stimulation in Postural Tachycardia Syndrome

Postural Tachycardia Syndrome (POTS) is a clinical syndrome characterized by an excessive increase in heart rate (&gt;= 30 bpm) on standing in the absence of orthostatic hypotension, and frequent orthostatic symptoms for more than 6 months. While most researchers focus on the hyperadrenergic features of POTS, these patients also have significant cardio-vagal (parasympathetic) impairment. We tested the hypothesis that transdermal electrical stimulation of the auricular branch of the vagus nerve will enhance cardio-vagal modulation, reduce heart rate, upright symptoms, and improve orthostatic tolerance. We studied 14 patients with POTS (31.5+/-11.7 years, BMI 22.6+/-3.9 kg/m 2 ). Sham or sub-perception threshold transdermal electrical vagal stimulation was applied in random order to the auricular branch in the right ear in supine and during graded tilt maneuver. Patients with low vagal modulation (low high frequency HF &lt; 200 ms 2 ) responded to vagal stimulation (Kruskal Wallis p=0.01, n=7, Fig left) with significant increase in HF power (eg @50Hz: +51+/-10 ms 2 , p=0.0032). Vagal stimulation during upright tilt tended to reduce orthostatic tachycardia and overall orthostatic symptom score. It improved significantly tilt time (+5.3+/-2.6 min, p=0.0156, Fig right). Patients with higher baseline vagal modulation (HF &gt;= 200 ms 2 ) did not respond to vagal stimulation (interaction p=0.41). This proof of concept study indicates that auricular transdermal vagal stimulation improves supine cardio-vagal function in POTS patients with low vagal modulation. Further research will determine if this approach can be used therapeutically, alone or in combination with other therapies.

Bioelectronic Approaches to Control Neuroimmune Interactions in Acute Kidney Injury.

Recent studies have shown renal protective effects of bioelectric approaches, including ultrasound treatment, electrical vagus nerve stimulation, and optogenetic brainstem C1 neuron stimulation. The renal protection acquired by all three modalities was lost in splenectomized mice and/or α7 subunit of the nicotinic acetylcholine receptor-deficient mice. C1 neuron-mediated renal protection was blocked by β2-adrenergic receptor antagonist. These findings indicate that all three methods commonly, at least partially, activate the cholinergic anti-inflammatory pathway, a well-studied neuroimmune pathway. In this article, we summarize the current understanding of neuroimmune axis-mediated kidney protection in preclinical models of acute kidney injury by these three modalities. Examination of the differences among these three modalities might lead to a further elucidation of the neuroimmune axis involved in renal protection and is of interest for developing new therapeutic approaches.

Effects of Electrical Transcutaneous Vagus Nerve Stimulation on the Perceived Intensity of Repetitive Painful Heat Stimuli: A Blinded Placebo- and Sham-Controlled Randomized Crossover Investigation.

Transcutaneous vagus nerve stimulation (TVNS) is a promising treatment for acute and chronic pain. However, experimental studies yielded controversial results. We examined if TVNS reduces the perceived intensity of repetitive painful heat stimulation and temporal summation of pain (TSP) in healthy volunteers in comparison with placebo and sham stimulation, as well as no intervention. In 4 sessions, 90 heat pulse stimuli at individual pain tolerance temperature were applied to the ventral forearm of 49 healthy volunteers (25 women) using a Contact Heat Evoked Potential Stimulator thermode (Medoc, Ramat Yishai, Israel). Pain intensity was assessed with verbal ratings on a numeric pain scale (0-100) at every tenth heat pulse. After the first session in which pain intensities without intervention were evaluated, participants completed 3 sessions in a single-blinded randomized crossover manner: (1) sham stimulation applied at the earlobes, (2) placebo stimulation (inactive device), or (3) TVNS applied at the cymbas conchae. Primary data were analyzed using analysis of variance for repeated measures and t test for paired samples. Pain intensity decreased during all interventions as compared to no intervention (ηp = 0.22, P < .001; mean difference TVNS versus no intervention 9.5; 95% confidence interval [CI], 3.6-15.4; P < .001). Hypoalgesic effect of TVNS was better than that of placebo and sham in men before the onset of TSP (mean differences for TVNS versus placebo 6.2; 95% CI, 0.2-12.1; TVNS versus sham 6.2; 95% CI, 0.2-12.1; P < .05). In women, TSP response under TVNS was decreased if compared to no intervention (median difference, 7.5; 95% CI, 3.5-15.0; P = .003). TVNS, placebo, and sham stimulation exerted comparable effects under experimental heat pain stimulation. Only in male participants, TVNS was superior to sham and placebo conditions in the reduction of heat pain before the onset of TSP.