Electrical Stimulation Of Vagus Nerve Research Articles

Electrical vagus nerve stimulation is a promising approach to reducing pulmonary complications after an esophagectomy: an experimental rodent model.

After esophagectomy, an imbalanced inflammatory response increases the risk of postoperative morbidity. The vagus nerve modulates local and systemic inflammatory responses, but its pulmonary branches are transected during esophagectomy as part of the oncological resection, which may account for the high incidence of postoperative (pulmonary) complications. This study investigated the effect of electrical vagus nerve stimulation (VNS) on lipopolysaccharide (LPS)-induced lung injury in rats. Rats (n = 60) were randomly assigned to a non-vagotomy or cervical vagotomy group, with VNS or without (NOSTIM). There were four non-vagotomy groups: NOSTIM and bilateral VNS with 100, 50, or 10 µA. The four vagotomy groups were NOSTIM and VNS with fixed amplitude (50 µA) bilaterally before (VNS-50-before) or after bilateral vagotomy (VNS-50-after), or unilaterally (left) before ipsilateral vagotomy (VNS-50-unilaterally). LPS was administered intratracheally after surgery. Pulmonary function, pro-inflammatory cytokines in serum, broncho-alveolar lavage fluid (BALF), and histopathological lung injury (LIS) were assessed 180min post-procedure. In non-vagotomized rats, neutrophil influx in BALF following intra-tracheal LPS (mean 30 [± 23]; P = 0.075) and LIS (mean 0.342 [± 0.067]; P = 0.142) were similar after VNS-100, compared with NOSTIM. VNS-50 reduced neutrophil influx (23 [± 19]; P = 0.024) and LIS (0.316 [± 0.093]; P = 0.043). VNS-10 reduced neutrophil influx (15 [± 6]; P = 0.009), while LIS (0.331 [± 0.053]; P = 0.088) was similar. In vagotomized rats, neutrophil influx (52 [± 37]; P = 0.818) and LIS (0.407 [SD ± 0.037]; P = 0.895) in VNS-50-before were similar compared with NOSTIM, as well as in VNS-50-after (neutrophils 30 [± 26]; P = 0.090 and LIS 0.344 [± 0.053]; P = 0.073). In contrast, VNS-50-unilaterally reduced neutrophil influx (26 [± 10]; P = 0.050) and LIS (0.296 [± 0.065]; P = 0.005). Systemic levels of cytokines TNF-α and IL-6 were undetectable in all groups. Pulmonary function was not statistically significantly affected. In conclusion,VNS limited influx of neutrophils in lungs in non-vagotomized rats and may attenuate LIS. Unilateral VNS attenuated lung injury even after ipsilateral vagotomy. This effect was absent for bilateral VNS before and after bilateral vagotomy. It is suggested that the effect of VNS is dependent on (partially) intact vagus nerves and that the level of the vagotomy during esophagectomy may influence postoperative pulmonary outcomes.

Vagus nerve electrical stimulation in the recovery of upper limb motor functional impairment after ischemic stroke

Vagus nerve electrical stimulation in the recovery of upper limb motor functional impairment after ischemic stroke

Vagus nerve stimulation in pediatric patients with drug-resistant epilepsy: a step-by-step video.

Vagus nerve stimulation (VNS) is a neuromodulatory treatment involving chronic intermittent electrical stimulation of the left vagus nerve, administered through a programmable pulse generator implanted subcutaneously in the chest. This generator connects to a bipolar lead, with electrodes wrapped around the vagus nerve in the neck. Primarily used as an adjunct therapy for patients with refractory epilepsy who cannot undergo or have not benefitted from resective surgery, VNS is generally well tolerated with few severe side effects. Herein is presented an educational surgical video providing a detailed, step-by-step technical description of VNS implantation. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID244.

Repeated Vagus nerve electrical stimulation alleviates constipation in a porcine model of opioid-induced constipation

Background: Chronic constipation (CC) is highly prevalent and affects approximately 15% of persons in the United States. Opioid-induced constipation (OIC) in particular, is a significant complication affecting up to 80% of non-cancer patients receiving opioids. Current treatments for CC suffer from adverse effects, poor compliance, and low effcacy. Progress in treatment of CC is hampered in part by the lack of studies in models of higher translational value and due to limited means to assess gut motility non-invasively. To palliate this lack of, we recently developed and validated a model of opioid-induced constipation in pigs using chronic administration of the mu-opioid agonist, loperamide[1]. Neuromodulation, of the autonomic nervous system, is now regarded as the future therapy for refractory diseases such as refractory OIC. Our previous work in naïve-anesthetized pigs indicate that acute electrical stimulation of the celiac branch of the Vagus nerve (CBVN) can increase colonic motility. It is, however, unknown whether repeated CBVN stimulation (R-CBVNS) in conscious pigs can relieve chronic constipation induced by repeated opioid exposure. Aims: To evaluate the effect of R-CBVNS in a porcine model of opioid-induced constipation induced by chronic administration of loperamide. Methods: Female minipig Yucatan (35-50 kg, 5-7 months) were surgically equipped with a cuff electrode around the CBVN and a cecal cannula. Fourteen days later, pigs received daily oral administration of loperamide at 0.2, 0.4 or 3 mg/kg/day in regular diet mixed with palatant (bananas, marshmallows or yogurt mixed with honey) for 14-30 days. After 2 days of loperamide, the effect of concurrent R-CBVNS (30 min/day, 2 Hz, 1 mA, 300 us, 30s on/90s off) was tested on chronic OIC. The intracolonic pressure signals were collected on day 2, 7 and 14, by manometric probes placed in the proximal (pc) and distal colon (dc) with a sampling frequency of 100Hz in awake pigs fitted with chronic cecal cannulas. The long-term effects of R-CBVNS was also tested on the highest dose of loperamide by monitoring motility on day 21 and day 28, 1 and 2 weeks respectively after discontinuing R-CBVNS. In the distal colon, four probes were inserted through the anus and aligned at 10, 13, 16, and 19 cm proximal to the anal verge, denoted as D10, D13, D16, D19. In the proximal colon, four probes were inserted about 10, 13, 16, and 19 cm below the ceco-colic junction, denoted as P10, P13, P16, and P19. Analysis of the intracolonic pressure signals was performed by custom scripts developed in the MATLAB version 2020b. The colon luminal pressure spectral analysis, signal power spectrum density as well as peak frequency and contraction bursts were characterized. Defecation response and stool water content changes (SWC, Bristol scale) were monitored. Results: Loperamide altered the power of dominant manometric contraction frequency band (2-7cpm) increasing it in the pc but reducing it in the dc suggesting colon-region specific responses (0.4 and 3mg/kg/day). R-CBVNS in pigs treated with 0.2, 0.4 or 3 mg/kg/day (for 14 days) increased primarily the proximal colon contraction frequency power during and post stimulation period. The increase in the proximal colon contraction power was mainly seen in the pig colon dominant frequency band (2-6 cpm). The effect of R-CBVNS was less apparent on distal colon motility. R-CBVNS improved stool shape and tended to increase stool water content, when compared to loperamide without concurrent stimulation. Moreover, after 2 weeks of R-CBVNS, the effect lasted one week after the stimulation protocol ended. Conclusions: OIC in pigs is characterized by delayed GI transit and decreased stool water content, alterations of colonic motility patterns including selective suppression of 5-6 cpm peak frequency while inducing 3 cpm peak akin to that reported in some CC patients. R-CBVNS demonstrates its effectiveness in alleviating chronic constipation in a swine model of OIC via restoring primary colonic functions, with a quasi-return of basal motility, but also probably through a pro-secretory effect as evidenced by an increase in stool water content. Reference: 1. Atmani, K., et al., A porcine model of opioid-induced constipation: colon motility characterization and evidence for intestinal opioid receptor modulation. Physiology, 2023. 38(S1): p. 5734528. Supported by NIH SPARC OT2-OD024899. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

First outcomes of a therapeutic platform for drug resistant epilepsy based on transcutaneous electrical vagus nerve stimulation

Aim: The aim of this paper is to discuss the main features and first outcomes of a therapeutic platform proposed to implement a public health therapeutic service for patients suffering refractory epilepsy. Methods: The proposal is a three-layer system composed by a new portable therapy device and two software applications. The therapy is transcutaneous electrical vagus nerve stimulation, known as tVNS. The primary layer is composed of tVNS devices, configured for each patient according to the instructions provided by the specialists. The middle layer is named “hospital data collector” (HDC), its main tasks are the patient enrollment, the device setup, and the database maintenance to store therapeutic parameters and session events together with the information cited previously. Each hospital center runs a HDC that is connected to a cloud application named “system cloud application (SCA)” which concentrates all the data supplied by the HDCs. Artificial intelligence methods are integrated in the SCA to predict the treatment effectiveness for every new patient based on the accumulated knowledge from the enrolled previously. Results: A version of the proposed system is running at the Institute of Neurology and Neurosurgery. The sensitivity of the therapeutic device with the proposed treatment protocol reaches 83.33% in the 18-patient pilot trial carried out. Conclusions: The proposed approach seems a useful therapeutic tool based on the pilot trial outcomes. The developed device is comfortable and suitable for the intended use. The proposed system has created the essential conditions to feed and grow a knowledge, a basic element to predict the treatment effectiveness for each new patient. It is a promising option for a refractory epilepsy therapy service.

Quantifying the effects of vagus nerve stimulation on gastric myoelectric activity in ferrets using an interpretable machine learning approach.

Vagus nerve stimulation (VNS) is a potential treatment option for gastrointestinal (GI) diseases. The present study aimed to understand the physiological effects of VNS on gastrointestinal (GI) function, which is crucial for developing more effective adaptive closed-loop VNS therapies for GI diseases. Electrogastrography (EGG), which measures gastric electrical activities (GEAs) as a proxy to quantify GI functions, was employed in our investigation. We introduced a recording schema that allowed us to simultaneously induce electrical VNS and record EGG. While this setup created a unique model for studying the effects of VNS on the GI function and provided an excellent testbed for designing advanced neuromodulation therapies, the resulting data was noisy, heterogeneous, and required specialized analysis tools. The current study aimed at formulating a systematic and interpretable approach to quantify the physiological effects of electrical VNS on GEAs in ferrets by using signal processing and machine learning techniques. Our analysis pipeline included pre-processing steps, feature extraction from both time and frequency domains, a voting algorithm for selecting features, and model training and validation. Our results indicated that the electrophysiological changes induced by VNS were optimally characterized by a distinct set of features for each classification scenario. Additionally, our findings demonstrated that the process of feature selection enhanced classification performance and facilitated representation learning.

Transcutaneous electrical vagus nerve stimulation to suppress premature ventricular complexes (TREAT PVC): study protocol for a multi-center, double-blind, randomized controlled trial

BackgroundThe autonomic nervous system can be responsible for the initiation and maintenance of arrhythmias. Low-level tragus stimulation (LLTS), a noninvasive form of autonomic neuromodulation, has been shown to be effective in treating atrial fibrillation. We intended to treat frequent premature ventricular complexes (PVCs) with LLTS.Methods and designThe present study will be a prospective multicenter, double-blind, randomized, controlled trial to assess the antiarrhythmic effects of LLTS on frequent PVCs in patients without structured heart disease (SHD). A total of 100 patients with PVC burden > 10% will be randomly assigned to the active or sham LLTS in 1:1 fashion and receive the proposed intervention for 6 months. The primary outcome is PVC burden at 6 months as assessed by 10 days of continuous ambulatory electrocardiographic monitoring. Secondary outcomes include heart rate variability (HRV), quality of life, skin sympathetic nerve activity, and inflammatory markers. Adverse events will also be recorded.DiscussionThe present trial will be the first to evaluate the effect of LLTS on frequent PVCs on patients without SHD. LLTS may serve as a low-cost, minimal-risk, and non-invasive alternative to conventional antiarrhythmic therapy.Trial registrationClinicalTrial.gov NCT04909528. Registered on 17 June 2021. World health organization trial registration data set was shown in Supplementary Table 1.

Voltammetry in the spleen assesses real-time immunomodulatory norepinephrine release elicited by autonomic neurostimulation

BackgroundThe noradrenergic innervation of the spleen is implicated in the autonomic control of inflammation and has been the target of neurostimulation therapies for inflammatory diseases. However, there is no real-time marker of its successful activation, which hinders the development of anti-inflammatory neurostimulation therapies and mechanistic studies in anti-inflammatory neural circuits.MethodsIn mice, we performed fast-scan cyclic voltammetry (FSCV) in the spleen during intravenous injections of norepinephrine (NE), and during stimulation of the vagus, splanchnic, or splenic nerves. We defined the stimulus-elicited charge generated at the oxidation potential for NE (~ 0.88 V) as the “NE voltammetry signal” and quantified the dependence of the signal on NE dose and intensity of neurostimulation. We correlated the NE voltammetry signal with the anti-inflammatory effect of splenic nerve stimulation (SpNS) in a model of lipopolysaccharide- (LPS) induced endotoxemia, quantified as suppression of TNF release.ResultsThe NE voltammetry signal is proportional to the estimated peak NE blood concentration, with 0.1 μg/mL detection threshold. In response to SpNS, the signal increases within seconds, returns to baseline minutes later, and is blocked by interventions that deplete NE or inhibit NE release. The signal is elicited by efferent, but not afferent, electrical or optogenetic vagus nerve stimulation, and by splanchnic nerve stimulation. The magnitude of the signal during SpNS is inversely correlated with subsequent TNF suppression in endotoxemia and explains 40% of the variance in TNF measurements.ConclusionsFSCV in the spleen provides a marker for real-time monitoring of anti-inflammatory activation of the splenic innervation during autonomic stimulation.

Electrical stimulation of the auricular branch of the vagus nerve potentiates analgesia induced by physical exercise in mice with peripheral inflammation.

This study evaluated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) associated with physical exercise, i.e., swimming, in mice with peripheral inflammation. The pain model was induced by intraplantar (i.pl.) injection of Freund's complete adjuvant (CFA). Sixty-four male Swiss mice (35-40 g) received an i.pl. of CFA and underwent behavioral tests, i.e., mechanical hyperalgesia, edema, and paw temperature tests. Additionally, cytokine levels, specifically interleukin-6 (IL-6) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay. Mice were treated with swimming exercise for 30 min alone or associated with different time protocols (10, 20, or 30 min) of stimulation in the left ear with random frequency during four consecutive days. pVNS for 20 min prolonged the antihyperalgesic effect for up to 2 h, 24 h after CFA injection. pVNS for 30 min prolonged the antihyperalgesic effect for up to 7 h, 96 h after CFA injection. However, it did not alter the edema or temperature at both analyzed times (24 and 96 h). Furthermore, the combination of pVNS plus swimming exercise, but not swimming exercise alone, reduced IL-6 levels in the paw and spinal cord, as well as IL-10 levels in the spinal cord. pVNS potentiates the analgesic effect induced by swimming, which may be, at least in part, mediated by the modulation of inflammatory cytokines in the periphery (paw) and central nervous system (spinal cord). Therefore, the combination of these therapies may serve as an important adjunctive treatment for persistent inflammatory pain.

Vagus nerve stimulation and acetylcholinesterase inhibitor donepezil provide cardioprotection against trastuzumab-induced cardiotoxicity in rats by attenuating mitochondrial dysfunction

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Cholinergic anti-inflammatory pathway mediates diesel exhaust PM2.5-induced pulmonary and systemic inflammation

Previous research has indicated that the cholinergic anti-inflammatory pathway (CAP) can regulate the duration and intensity of inflammatory responses. A wide range of research has demonstrated that PM2.5 exposure may induce various negative health effects via pulmonary and systemic inflammations. To study the potential role of the CAP in mediating PM2.5-induced effects, mice were treated with vagus nerve electrical stimulation (VNS) to activate the CAP before diesel exhaust PM2.5 (DEP) instillation. Analysis of pulmonary and systemic inflammations in mice demonstrated that VNS significantly reduced the inflammatory responses triggered by DEP. Meanwhile, inhibition of the CAP by vagotomy aggravated DEP-induced pulmonary inflammation. The flow cytometry results showed that DEP influenced the CAP by altering the Th cell balance and macrophage polarization in spleen, and in vitro cell co-culture experiments indicated that this DEP-induced change on macrophage polarization may act via the splenic CD4+ T cells. To further confirm the effect of alpha7 nicotinic acetylcholine receptor (α7nAChR) in this pathway, mice were then treated with α7nAChR inhibitor (α-BGT) or agonist (PNU282987). Our results demonstrated that specific activation of α7nAChR with PNU282987 effectively alleviated DEP-induced pulmonary inflammation, while specific inhibition of α7nAChR with α-BGT exacerbated the inflammatory markers. The present study suggests that PM2.5 have an impact on the CAP, and CAP may play a critical function in mediating PM2.5 exposure-induced inflammatory response. Availability of data and materialsThe datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

ID: 208947 Ultrashort Microscopic Magnetic Vagal Stimulation

Electrical stimulation of the cervical vagus nerve is an emerging treatment field for various central nervous system disorders. Invasive electrical Vagus nerve stimulation (VNS) is an FDA-approved add-on treatment to medication for refractory partial-onset seizures in patients 12 years of age and older. However, only approximately 40-50% of patients experience a marked seizure reduction of 50% or more than seizures before treatment [1]. The effects of VNS on neurotransmitter systems, including the noradrenergic system originating from the locus coeruleus and the serotonergic system from the dorsal raphe nucleus, have been reported in experimental settings. The therapeutic effect of VNS in the brain is linked to the stimulation of large diameter afferent fibers. These large myelinated afferent fibers, terminating in the nucleus tractus solitarius in the brainstem, are assumed to deliver the therapeutic effect through further projections into the other brain areas. Non-selective stimulation results in inadvertent activation of efferent fibers that innervate a wide range of peripheral organs resulting in adverse effects [2] with a rare but severe risk of bradyarrhythmia and asystole.

Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice

Deficiency of coagulation factor VIII in hemophilia A disrupts clotting and prolongs bleeding. While the current mainstay of therapy is infusion of factor VIII concentrates, inhibitor antibodies often render these ineffective. Because preclinical evidence shows electrical vagus nerve stimulation accelerates clotting to reduce hemorrhage without precipitating systemic thrombosis, we reasoned it might reduce bleeding in hemophilia A. Using two different male murine hemorrhage and thrombosis models, we show vagus nerve stimulation bypasses the factor VIII deficiency of hemophilia A to decrease bleeding and accelerate clotting. Vagus nerve stimulation targets acetylcholine-producing T lymphocytes in spleen and α7 nicotinic acetylcholine receptors (α7nAChR) on platelets to increase calcium uptake and enhance alpha granule release. Splenectomy or genetic deletion of T cells or α7nAChR abolishes vagal control of platelet activation, thrombus formation, and bleeding in male mice. Vagus nerve stimulation warrants clinical study as a therapy for coagulation disorders and surgical or traumatic bleeding.

Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation

BackgroundThe liver is an important immunological organ and liver inflammation is part of the pathophysiology of non-alcoholic steatohepatitis, a condition that may promote cirrhosis, liver cancer, liver failure, and cardiovascular disease. Despite dense innervation of the liver parenchyma, little is known about neural regulation of liver function in inflammation. Here, we study vagus nerve control of the liver response to acute inflammation.MethodsMale C57BL/6 J mice were subjected to either sham surgery, surgical vagotomy, or electrical vagus nerve stimulation followed by intraperitoneal injection of the TLR2 agonist zymosan. Animals were euthanized and tissues collected 12 h after injection. Samples were analyzed by qPCR, RNAseq, flow cytometry, or ELISA.ResultsHepatic mRNA levels of pro-inflammatory mediators Ccl2, Il-1β, and Tnf-α were significantly higher in vagotomized mice compared with mice subjected to sham surgery. Differences in liver Ccl2 levels between treatment groups were largely reflected in the plasma chemokine (C–C motif) ligand 2 (CCL2) concentration. In line with this, we observed a higher number of macrophages in the livers of vagotomized mice compared with sham as measured by flow cytometry. In mice subjected to electrical vagus nerve stimulation, hepatic mRNA levels of Ccl2, Il1β, and Tnf-α, and plasma CCL2 levels, were significantly lower compared with sham. Interestingly, RNAseq revealed that a key activation marker for hepatic stellate cells (HSC), Pnpla3, was the most significantly differentially expressed gene between vagotomized and sham mice. Of note, several HSC-activation associated transcripts were higher in vagotomized mice, suggesting that signals in the vagus nerve contribute to HSC activation. In support of this, we observed significantly higher number of activated HSCs in vagotomized mice as compared with sham as measured by flow cytometry.ConclusionsSignals in the cervical vagus nerve controlled hepatic inflammation and markers of HSC activation in zymosan-induced peritonitis.

The ghrelin agonist, HM01 activates central vagal and enteric cholinergic neurons and reverses gastric inflammatory and ileus responses in rats.

Electrical vagal stimulation alleviates abdominal surgery (AS)-induced intestinal inflammation. Ghrelin receptors (GHS-Rs) are expressed in the brain and peripheral tissues. We investigated the influence of HM01, an orally active ghrelin agonist crossing the blood-brain barrier, on AS-induced gastric inflammation and emptying (GE) in rats. HM01 (6mg/kg) or saline pretreatment was administered per orally (po) or intraperitoneally (ip). We assessed GE, gastric cytokine mRNA, and Fos positive cells in the dorsal motor nucleus of the vagus (DMN) and gastric corpus myenteric plexus (MP) in sham (anesthesia alone) and AS groups. The transcripts of GHS-R1 variants were determined in the medulla oblongata and gastric corpus of naïve rats. In vehicle pretreated rats, HM01 (ip) significantly increased the number of Fos immunoreactive cells in the MP and DMN in 55% and 52% of cholinergic neurons respectively. Hexamethonium did not modify HM01-induced Fos expression in the DMN while reducing it in the MP by 2-fold with values still significantly higher than that in control groups. AS upregulated gastric IL-1β and TNFα expression and inhibited GE by 66.6%. HM01 (po) abolished AS-induced gastric ileus and increased cytokine expression and elevated IL-10 by 4.0-fold versus vehicle/sham. GHS-R1a mRNA level was 5.4-fold higher than the truncated GHS-R1b isoform in the brain medulla and 40-fold higher in the gastric submucosa/muscle layers than in the mucosa. Peripheral HM0 activates central vagal and myenteric cholinergic pathways that may influence both central and peripheral targets to prevent AS-induced gastric inflammatory and ileus.

Electrical Stimulation of the Auricular Branch Vagus Nerve Using Random and Alternating Frequencies Triggers a Rapid Onset and Pronounced Antihyperalgesia via Peripheral Annexin A1-Formyl Peptide Receptor 2/ALX Pathway in a Mouse Model of Persistent Inflammatory Pain.

This study evaluated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) by comparing the effects of alternating and random frequencies in an animal model of persistent inflammatory hyperalgesia. The model was induced by Freund's complete adjuvant (CFA) intraplantar (i.pl.) injection. Mice were treated with different protocols of time (10, 20, or 30min), ear laterality (right, left or both), and frequency (alternating or random). Mechanical hyperalgesia was evaluated, and some groups received i.pl. WRW4 (FPR2/ALX antagonist) to determine the involvement. Edema, paw surface temperature, and spontaneous locomotor activity were evaluated. Interleukin-1β, IL-6, IL-10, and IL4 levels were verified by enzyme-linked immunosorbent assay. AnxA1, FPR2/ALX, neutrophil, M1 and M2 phenotype macrophage, and apoptotic cells markers were identified using western blotting. The antihyperalgesic effect pVNS with alternating and random frequency effect is depending on the type of frequency, time, and ear treated. The pVNS random frequency in the left ear for 10min had a longer lasting antihyperalgesic effect, superior to classical stimulation using alternating frequency and the FPR2/ALX receptor was involved in this effect. There was a reduction in the levels of pro-inflammatory cytokines and an increase in the immunocontent of AnxA1 and CD86 in mice paw. pVNS with a random frequency in the left ear for 10min showed to be optimal for inducing an antihyperalgesic effect. Thus, the random frequency was more effective than the alternating frequency. Therefore, pVNS may be an important adjunctive treatment for persistent inflammatory pain.

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect

Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles—a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses. However, it remains unclear if placement can alter the balance between intended effect and limiting side effect. We used an FDA investigational device exemption approved six-contact epineural cuff to deliver VNS in pigs and quantified how epineural electrode location impacts on- and off-target VNS activation. Detailed post-mortem histology was conducted to understand how the underlying neuroanatomy impacts observed functional responses. Here we report the discovery and characterization of clear neuroanatomy-dependent differences in threshold and saturation for responses related to both effect (change in heart rate) and side effect (neck muscle contractions). The histological and electrophysiological data were used to develop and validate subject-specific computation models of VNS, creating a well-grounded quantitative framework to optimize electrode location-specific activation of nerve fibers governing intended effect versus unwanted side effect.

Effects on heart rate from direct current block of the stimulated rat vagus nerve

Objective. Although electrical vagus nerve stimulation has been shown to augment parasympathetic control of the heart, the effects of electrical conduction block have been less rigorously characterized. Previous experiments have demonstrated that direct current (DC) nerve block can be applied safely and effectively in the autonomic system, but additional information about the system dynamics need to be characterized to successfully deploy DC nerve block to clinical practice. Approach. The dynamics of the heart rate (HR) from DC nerve block of the vagus nerve were measured by stimulating the vagus nerve to lower the HR, and then applying DC block to restore normal rate. DC block achieved rapid, complete block, as well as partial block at lower amplitudes. Main Results. Complete block was also achieved using lower amplitudes, but with a slower induction time. The time for DC to induce complete block was significantly predicted by the amplitude; specifically, the amplitude expressed as a percentage of the current required for a rapid, 60 s induction time. Recovery times after the cessation of DC block could occur both instantly, and after a significant delay. Both blocking duration and injected charge were significant in predicting the delay in recovery to normal conduction. Significance. While these data show that broad features such as induction and recovery can be described well by the DC parameters, more precise features of the HR, such as the exact path of the induction and recoveries, are still undefined. These findings show promise for control of the cardiac autonomic nervous system, with potential to expand to the sympathetic inputs as well.

Abstract 11205: Pharmacological and Non-Pharmacological Parasympathomimetic Interventions Prevent Trastuzumab-Induced Cardiotoxicity Through Attenuating Impaired Mitochondrial Function

Introduction: Although the use of trastuzumab (Trz) has effectively reduced the mortality rate in breast cancer patients, Trz-induced cardiotoxicity (TIC) has become a serious complication. Parasympathetic activations via either electrical vagus nerve stimulation (VNS) device or acetylcholinesterase inhibitor donepezil (DPZ), have been shown to exert cardioprotection in various heart diseases. However, the cardioprotective effects of VNS and DPZ on left ventricular (LV) function, autonomic function, and mitochondrial function in TIC rats are unknown. Hypothesis: Both VNS and DPZ protect the heart against TIC by reducing LV dysfunction, sympathovagal imbalance, and mitochondrial dysfunction. A combination of VNS and DPZ treatment exerts a better benefit than either single intervention. Methods: Adult male Wistar rats (N=25) were subjected to VNS device implantation. Then, rats were assigned into five groups (N=5/group), including (i) control without VNS (C), (ii) Trz (4 mg/kg/day, I.P., 7 days), (iii) Trz+DPZ (5 mg/kg/day, P.O., 7 days) (TrzD), (iv) Trz with VNS (TrzV), and (v) Trz+DPZ with VNS (TrzVD). LV function and heart rate variability (HRV) were performed. All hearts were collected to determine mitochondrial reactive oxygen species (ROS) levels and mitochondrial morphology. Results: Trz rats had a reduced LV ejection fraction, impaired HRV as shown by increased LF/HF ratio, and mitochondrial dysfunction shown by increased ROS levels and dysmorphology (Figures 1A-D). Treatment with either DPZ, VNS, or the combined treatment exerted similar cardioprotection via reducing sympathovagal imbalance and mitochondrial injury, leading to improved LV function, (Figures 1A-D). Conclusions: Promoting parasympathetic activity using VNS, DPZ, or the combined treatment similarly protected the heart against TIC via improving HRV, mitochondrial function, and mitochondrial morphology, suggesting a novel potential strategy for patients receiving Trz.

Effect of transcutaneous auricular vagus nerve stimulation on post-stroke dysphagia.

It has been proved that electrical vagus nerve stimulation can promote the recovery of motor function after stroke. There were no trials on the use of transcutaneous auricular electrical vagus nerve stimulation (ta-VNS) in patients with dysphagia after acute stroke. Our aim was to confirm whether ta-VNS can promote the recovery of swallowing function in these acute stroke patients with dysphagia. We conducted a sham-controlled, double-blinded, parallel pilot study in 40 acute stroke patients randomly assigned to receive ta-VNS or sham ta-VNS combined with conventional rehabilitation training. The intensity of ta-VNS treatment was adjusted according to the patient's tolerance, 30min each time, twice a day, five times a week, with a total course of 3weeks. In the sham group, the parameters were the same except energy output. Swallowing function was assessed with Modified Mann assessment of swallowing ability (MASA), functional communication measure swallowing test (FCM), and the Rosenbek leakage/aspiration scale (RAS) according to swallowing video fluoroscopic (SVF) before the intervention (baseline, T0), immediately after the intervention (T1) and 4weeks after the intervention (T2). After treatment, ta-VNS group statistically and clinically had larger change of MASA, FCM, and RAS scores compared with control group (P < 0.05) and this improvement continued at least 4weeks after the end of treatment. There were no serious adverse events occurred during the whole intervention. The transcutaneous auricular electrical vagus nerve stimulation is effective as a novel and noninvasive treatment strategy for patients with dysphagia after acute stroke. No: kelunshen No. 63 in 2020.