First in-neonate use of non-invasive transcutaneous auricular vagus nerve stimulation: 18-month neurodevelopmental and sensory follow-up

Objective: Non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) paired with oral feeding is a novel intervention for infants with feeding delays that may improve feeding and help avoid a gastrostomy tube (Gtube). However, the long-term impact of this neurostimulation on infant's development remains unknown. We investigated the neurodevelopmental and sensory outcomes of infants who received taVNS paired with bottle feeding. Method(s): Twenty-one of 35 toddlers who participated in the open label trial of taVNS paired with one or two feeds a day for 2-3 weeks, underwent comprehensive developmental assessments at 18 months of age using Cognitive Adaptive Test, Clinical Linguistics and Auditory Milestone, and Peabody gross motor scores. Twelve of those assessed achieved full oral feeds ('responders') and 9 had G-tube placed for feeds ('non-responders'). Before COVID, 12 toddlers (5 responders, 7 non-responders) were also assessed in the home using the Bayley-III and Sensory Profile (SP-2) assessments. Area deprivation index (ADI) was used to measure resource poor environments and relate to test scores. We used Fishers exact test and Pearson correlation coefficients to compare neurodevelopmental and sensory performance in responders versus non-responders. Result(s): taVNS responders showed significantly better general sensory processing in SP-2 than did non-responders (p =0.04). There were no significant differences in Bayley-III or CAT/CLAMS/ASQ scores in areas of cognition, receptive language, fine motor, and gross motor skills in this small sample size, but are similar to published scores for preterm infants who received G-tubes. ADI was not significantly associated with neurodevelopmental scores. Conclusion(s): These results suggest that taVNS paired with feeding may have a potential long-term positive neurodevelopmental effect on sensory processing in neonates with poor feeding. The current open-label results need testing in randomized controlled trials of taVNS paired with oral feeding in developmentally delayed infants failing oral feeds. Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Neurodevelopment, taVNS, feeding, developmental delaysCopyright © 2023

Clinical applications of transcutaneous auricular neurostimulation for opioid use disorder and pain

Symposium title: Addressing chronic pain and the opioid epidemic using auricular neuromodulation Symposium description: Our proposed symposium integrates a diverse group of scientist and clinician experts (Drs. Cunningham, Wilkes, Khodaparast, Badran) who have committed to exploring the anti-nociceptive and opioid sparing effects of auricular neuromodulation to progress toward non-opioid interventions for chronic pain and opioid use disorders. The demand for chronic pain therapies has increased at an unprecedented rate over the last several decades, contributing in part to a surge in prescription and illicit opioid demand. Countless patients were escalated to prolonged, high-dose opioid regimens over years of treatment. By 2014, 5.4% of U.S. adults were estimated to use prescription opioids on a long-term basis. As the harms of opioid proliferation became increasingly clear, a dramatic paradigm shift occurred in which these drugs are now perceived as more dangerous than beneficial for chronic pain. New clinical guidelines highlight the risks of high-dose regimens as well as the limited benefits, particularly insufficient analgesia and hyperalgesia, associated with long-term use. According to this new perspective, the preferred therapeutic modality for many patients is to safely taper, or even completely stop, using opioids. Transcutaneous auricular neurostimulation (tAN) is a novel therapeutic paradigm that includes stimulation of both the auricular branch of the vagus nerve and auriculotemporal nerve (branch of trigeminal). tAN therapy results in clinically significant reductions in opioid withdrawal symptoms associated with opioid detoxification and tapering. Either adjunctive vagal or trigeminal stimulation modulates pain transmission suggesting overlapping common effector pathways, possibly targeting the endogenous opioid system, which could lead to a synergistic therapeutic benefit for pain. This symposium will explore the scientific basis for this hypothesis across targeted and interconnected topics, including fundamental neuropharmacological mechanisms underlying pain and opioids, clinical challenges of tapering opioids, managing opioid withdrawal symptoms with tAN, and the prospects for tAN to deliver a safe alternative treatment option for pain disorders. The United States is experiencing an epidemic for prescription and non-prescription opioids, which have continued to rise since the 1990s. During 2015, approximately 2.1 million people were severely dependent on prescription opioids, and 513,000 on heroin. In 2020, the Centers for Disease Control reported 93,331 substance use overdose deaths. The continuing increase in opioid-related deaths from 2015 (18%) to 2020 (60%) is partly attributed to the mental health crisis during the Covid-19 pandemic. Aside from pain mitigation, individuals with opioid use disorder (OUD) may be motivated to continue drug-seeking by both the positive reinforcement of the euphoric effects of opioids and the negative reinforcement of opioid withdrawal symptoms due to cessation. Alternative approaches for OUD are a major priority for government agencies given the substantial impact on health, social, and economic welfare. Transcutaneous auricular neurostimulation (tAN) is a non-invasive form of vagus and trigeminal neuromodulation that was recently proven to be an efficacious non-pharmacologic based treatment for reducing opioid withdrawal symptoms. In 2021, tAN therapy received FDA clearance as an adjunctive treatment for opioid withdrawal symptoms in adults. tAN therapy was also proven safe and effective in reducing symptoms of neonatal opioid withdrawal syndrome (NOWS) in neonates. tAN as an adjuvant was safe, well-tolerated, while facilitating the successful rapid weaning of oral morphine and decreasing length of stay in the neonatal ICU. Based on these preliminary findings, tAN therapy is currently in two NIH-funded pivotal clinical trials to: 1) evaluate the long-term effects of tAN on opioid use relapse prevention and cravings in adults with OUD, and 2) determine f tAN therapy can reduce withdrawal symptoms and reduce morphine length of treatment for neonates with NOWS. Lastly, we will explore how tAN could be utilized as neuromodulatory approach for opioid sparing, and ultimately pain mitigation. Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Vagus Nerve Stimulation, Opioid Use Disorder, Pain, NeurostimulationCopyright © 2023

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best.

A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.

Case Report: Auricular vagus nerve stimulation possibly alleviates COVID-19 disease on a high-risk patient.

Introduction: SARS-CoV-2 is a highly contagious virus that was identified as the cause of COVID-19 disease in early 2020. The infection is clinically similar to interstitial pneumonia and acute respiratory distress syndrome (ARDS) and often shows cardiovascular damage. Patients with cardiovascular risk factors are more prone to COVID-19 disease and their sequelae. Due to the anti-inflammatory effect and the improvement in pulmonary function, auricular vagus nerve stimulation (aVNS) therapy might alleviate a COVID-19 infection. Patient and Methods: A high-risk patient with cardiovascular diseases and Implantable Cardioverter Defibrillator (ICD), type 2 diabetes and peripheral arterial disease IV, according to Rutherford`s classification, became infected with COVID-19. The patient underwent wound surgery because of an infected necrosis with a methicillin-resistant Staphylococcus aureus (MRSA) of his small toe and was already on aVNS therapy to relieve his leg pain and improve microcirculation. AVNS was performed with the AuriStim device (Multisana GmbH, Austria), which stimulates vagally innervated regions of the auricle by administering electrical stimulation via percutaneous electrodes for 6 weeks. Results: The multimorbid high-risk patient, who was expected to go through a severe course of the COVID-19 disease, showed hardly any symptoms during ongoing aVNS therapy, while other family members, being much younger and healthy suffered from a more serious course with headache, pneumonia and general weakness. Conclusion: The auricular vagus nerve stimulation is a clinically tested and safe procedure and might represent an alternative and effective way of treating COVID-19 disease. Nevertheless, due to several limitations of this case report, randomized controlled studies are needed to evaluate the efficacy of aVNS therapy on COVID-19 disease.

Effect of Peripheral Neuromodulation on Headache in Post Covid-19 Survivors

Objective: The purpose of present study was to evaluate the impact of peripheral neuromodulation through vagus nerve stimulation on headache in Post COVID-19 survivors. Method(s): Thirty Post COVID-19 survivors from both genders (17 females and 13 males) aged from 20 to 40 years who suffered from Post COVID-19 headache were recruited and randomized into two groups of equal number. Subjects in group A (study group) received transcutaneous vagus nerve stimulation as well as the designed physiotherapy program whereas subjects in group B (control group) underwent placebo transcutaneous vagus nerve stimulation on vagus nerve in addition to the same designed physical therapy program. The treatment was carried-out for 5 sessions each week for four weeks. Visual analogue scale (VAS) was used to measure the intensity of headache pain whereas the headache disability index (HDI) was used to measure the disability resulted from headache. Result(s): The findings showed significant decline in VAS and HDI post treatment in study group (A) and control group (B) in comparison with that pretreatment (p<0.001). Between-group analysis showed no significant difference between the two groups pretreatment (p>0.05), whereas there was significant decline in VAS and HDI in study group in comparison with that of the control group posttreatment (p<0.05). Conclusion(s): peripheral neuromodulation is more effective in managing headache in post COVID-19 survivors. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19. METHODS: A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment. RESULTS: After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes. CONCLUSIONS: taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19. TRIALS REGISTRY: The Brazilian Registry of Clinical Trials (RBR-399t4g5).

Transcutaneous Auricular Vagus Nerve Stimulation Improves Inflammation but Does Not Interfere with Cardiac Modulation and Clinical Symptoms of Individuals with COVID-19: A Randomized Clinical Trial.

Transcranial auricular vagus nerve stimulation (taVNS) has shown effectiveness in reducing inflammation and depression. Thus, this study evaluated its effect on inflammation, cardiac autonomic modulation, and clinical symptoms in individuals affected by COVID-19. Methods: There were 52 randomized participants hospitalized with COVID-19 diagnosis who were to receive active (a-taVNS) or sham taVNS (s-taVNS) for 90 min twice a day for seven consecutive days. Interleukin 6 (IL-6), 10 (IL-10), cortisol, C-reactive protein (CRP), heart rate variability (HRV), and clinical symptoms were assessed before and after seven days of treatment. There were also seven- and fourteen-day follow-ups for clinical symptoms, including anxiety and depression levels, as well as a six-month follow-up for memory and attention levels. Results: There was significant reduction in CRP -23.9%, (95% CI -46.3 to -1.4) and IL-6 -37.7%, (95% CI -57.6 to -17.7) for the a-taVNS group. There were no changes in IL-10, cortisol levels, or in HRV results (p > 0.05) in both groups. There were no changes regarding clinical symptoms, except for a significant decrease in depression level (-2.85, 95% CI -5.44 to -0.27) in the a-taVNS group. Conclusion: taVNS showed effects on CRP, IL-6, and depression levels; however, it did not affect other clinical symptoms.

TIME TO SLOW DOWN: A DEEPER LOOK INTO REMDESIVIR-ASSOCIATED BRADYCARDIA

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: The use of remdesivir in critical care setting has been utilized treatment of covid, but not without risk. Many cases have reported severe cardiac effects with bradycardia being the most common. CASE PRESENTATION: The patient was a 15-year-old female with a history of asthma, hyperinsulinemia who required hospitalization for acute hypoxic respiratory failure secondary to COVID-19 pneumonia. She received ceftriaxone, azithromycin, and a 10-day course of remdesivir (RDV). On her third day of admission, the patient developed significant sinus bradycardic with heart rate nadir of 30-40 bpm but denied any symptoms. She completed her remdesivir course on day five of hospitalization and was discharged on day nine with a heart rate of 47 bpm. She later presented to ED the night of discharge following acute onset of lightheadedness and blurry vision at home secondary to orthostatic hypotension and bradycardia. Her pulse was 48 bpm, temperature 36.1 C, respirations 24/min, blood pressure 119/50 mmHg and SpO2 99% on room air. Her physical exam was unremarkable. EKG showed sinus bradycardia with a PR interval of 124 ms and QTc of 406 ms. Echocardiogram showed normal cardiac anatomy and function. Patient was diagnosed with persistent RDV-associated bradycardia and discharged home with a Holter monitor and cardiology follow-up. Bradycardia resolved by her follow-up visit two weeks later. DISCUSSION: According to the WHO pharmacovigilance database, bradycardia is a relatively new adverse effect and 3.6% of the 2,603 adverse effects reported since the onset of the pandemic, with 2 million RDV doses administered during this time [1]. The mechanism of RDV-associated bradycardia is proposed to be an effect of adenosine triphosphate, an active metabolite, which reduces SA node automaticity via stimulation of vagal nerve, as well as RDV cross-reactivity with mRNA polymerase, leading to cardiotoxicity that usually resolves within 24 hours of medication discontinuation. In our patient's case bradycardia did not resolve until eight days after discontinuation of medication [2]. Review of previously case reports does not identify any association with patient age but could be related to timing of when medication reaches therapeutic window, as many patients had onset of bradycardia on day 3 of treatment [3]. We report a pediatric case of severe acute COVID-19 who developed sinus bradycardia on day 3 of RDV treatment as previously described, but the bradycardia persisted long after the discontinuation of RDV. CONCLUSIONS: With over 50 thousand pediatric COVID-19 hospitalizations to date, this case serves as a timely reminder that medication side effects should be monitored closely, and that more research needs to be done into the effects of RDV on cardiac function in pediatric patients. Reference #1: Jung SY, Kim MS, Li H, Lee KH, Koyanagi A, Solmi M, Kronbichler A, Dragioti E, Tizaoui K, Cargnin S, Terrazzino S, Hong SH, Abou Ghayda R, Kim NK, Chung SK, Jacob L, Salem JE, Yon DK, Lee SW, Kostev K, Kim AY, Jung JW, Choi JY, Shin JS, Park SJ, Choi SW, Ban K, Moon SH, Go YY, Shin JI, Smith L. Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database. Clin Transl Sci. 2022 Feb;15(2):501-513. doi: 10.1111/cts.13168. Epub 2021 Oct 31. PMID: 34719115;PMCID: PMC8841455. Reference #2: Touafchia A, Bagheri H, Carrié D, Durrieu G, Sommet A, Chouchana L, Montastruc F. Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns. Clin Microbiol Infect. 2021 Feb 27;27(5):791.e5–8. doi: 10.1016/j.cmi.2021.02.013. Epub ahead of print. PMID: 33647441;PMCID: PMC7910147. Reference #3: Rau, Cornelius MPhil;Apostolidou, Sofia MD;Singer, Dominique MD, PhD;Avataneo, Valeria PhD;Kobbe, Robin MD Remdesivir, Sinus Bradycardia and Therapeutic Drug Monitoring in Children With Severe CO

A SLOW PACED BREATHING INTERVENTION TO REDUCE IL-6 IN PATIENTS WITH COVID-19-PNEUMONIA - A RANDOMIZED CONTROLLED TRIAL

Elevated pro-inflammatory cytokines such as interleukin-6 (IL-6) have been observed in patients with COVID-19 and are associated with adverse clinical outcomes. Systemic immune response is co-regulated via the vagally-mediated cholinergic anti-inflammatory reflex. Specifically, a reduced release of pro-inflammatory cytokines such as IL-6 from acetylcholine-synthesizing T-cells in response to Vagus nerve stimulation has been demonstrated in animal and human studies. A known non-invasive and cost-effective way to stimulate efferent vagal activity is slow-paced breathing. The primary aim of this RCT was to determine if high-dose breath-assisted reflex stimulation results in a reduction of systemic inflammatory levels in COVID-19 patients. 48 hospitalized COVID-19 patients with moderate to severe symptoms from two isolation wards were randomized to intervention (3x20min app-assisted slow-paced breathing @6BPM) or TAU control group at the University Medical Center Ulm (Germany) during March & May 2021 (BEAT-COVID-study;DRKS00023971). Morning samples of IL-6, protocol adherence and self-reported total practice time (TPT) were collected bi-daily. Mixed effect linear regression models were used to explore groupXtime differences as well as dose-response analysis. Models were adjusted for age, ward, and TAU protocols. A total of 40 patients (age 55±14;67% male) were included to the final analysis. Feasibility of the applied breathing protocol was good, oxygenation was stable and no adverse events occurred. Adherence was closely monitored and sufficient in 17 out of 25 IG patients. Primary reason for non-adherence was worsening of symptoms with transfer to ICU. Reduction rate in inflammatory markers were not statistically different between IG and CG. Investigating the effect of categorized TPT on next morning IL-6 levels in 25 IG patients from 112 intervention days revealed significant lower IL-6 values when TPT exceeded 40min (b= -0.898ln[pg/ml];p=0.043). This is equivalent to a ratio of 59.3% reduction in circulating IL-6 compared to days with TPT <10min. This is the first clinical RCT to study immediate anti-inflammatory effects of a slow-paced breathing protocol in hospitalized COVID-19 patients. Although no between group differences were found in the reduction rate of systemic inflammatory markers, promising dose-response effects were observed.

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics.

The COVID-19 pandemic seems endless with the regular emergence of new variants. Is the SARS-CoV-2 virus particularly evasive to the immune system, or is it merely disrupting communication between the body and the brain, thus pre-empting homeostasis? Retrospective analysis of the COVID-19 and AIDS pandemics, as well as prion disease, emphasizes the pivotal but little-known role of the 10th cranial nerve in health. Considering neuroimmunometabolism from the point of view of the vagus nerve, non-invasive bioengineering solutions aiming at monitoring and stimulating the vagal tone are subsequently discussed as the next optimal and global preventive treatments, far beyond pandemics.

EHRA 2022 Abstract

The proceedings contain 629 papers. The topics discussed include: digitalized ECG measure of p-wave duration predicts incident heart failure;diagnostic value of Peguero Lo Presti Electrocardiografic index for diagnosis of left ventricle hypertrophy in correlation with cardiovascular magnetic resonance;electrocardiography: an useful tool for prediction of the diagnosis and severity of pulmonary embolism;association between excessive supraventricular ectopic activity and future diagnosis of atrial fibrillation in patients with cryptogenic stroke;low-level vagus nerve stimulation during cardiac surgery: smart neuromodulation;a polymorphism in histidine-rich calcium binding protein as second hit in phospholamban cardiomyopathy;genetic predisposition according to the age at the onset of atrial fibrillation;familial clustering of unexplained heart failure - a Danish nationwide cohort study;and fever following covid-19 vaccination in subjects with Brugada syndrome: incidence and management.

Non-invasive Vagus Nerve Stimulation for COVID-19: Results From a Randomized Controlled Trial (SAVIOR I).

Background: Severe coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various biomarkers of inflammation. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156). Methods: Participants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-min doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events. Results: Of the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n = 47; SoC, n = 50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (i.e., all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study. Conclusions: nVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential use earlier in the course of COVID-19 and its potential to mitigate some of the symptoms associated with post-acute sequelae of COVID-19 is warranted.

Different Transcutaneous Auricular Vagus Nerve Stimulation Parameters Modulate the Anti-Inflammatory Effects on Lipopolysaccharide-Induced Acute Inflammation in Mice.

Vagus nerve stimulation (VNS) is considered a potential method for anti-inflammation due to the involvement of the VN in the cholinergic anti-inflammatory pathway (CAP) formation of a connection between the central nervous system and peripheral immune cells that help relieve inflammation. However, whether a non-invasive transcutaneous auricular VNS (taVNS) modulates the inflammation levels via altering the parameter of taVNS is poorly understood. This study aimed to determine the differential inhibitory effects of taVNS on lipopolysaccharide (LPS)-induced systemic inflammation using electrical stimulation parameters such as pulse frequency and time. The taVNS-promoted CAP activity significantly recovered LPS-induced tissue injuries (lung, spleen, and intestine) and decreased inflammatory cytokine levels and tissue-infiltrated immune cells. Interestingly, the anti-inflammatory capacity of taVNS with 15 Hz was much higher than that of taVNS with 25 Hz. When a cytokine array was used to investigate the changes of inflammation and immune response-related cytokines/chemokines expression in taVNS with 15 Hz or 25 Hz treatment in LPS-induced endotoxemia in mice, most of the expression of cytokines/chemokines associated with pro-inflammation was severely decreased in taVNS with 15 Hz compared to 25 Hz. This study demonstrated that the taVNS parameter could differentially modulate the inflammation levels of animals, suggesting the importance of taVNS parameter selection for use in feasible interventions for acute inflammation treatment.

Cholinergic anti-inflammatory pathway and COVID-19.

The cholinergic anti-inflammatory pathway (CAP) first described by Wang et al, 2003 has contemporary interest arising from the COVID-19 pandemic. While tobacco smoking has been considered an aggravating factor in the severity of COVID-19 infections, it has been suggested by some that the nicotine derived from tobacco could lessen the severity of COVID-19 infections. This spotlight briefly describes the CAP and its potential role as a therapeutic target for the treatment of COVID-19 infections using vagus nerve stimulation or selective alpha7 nicotinic acetylcholine receptor agonists.

Intermittent dual vagus neuromodulation improved glycemic control in swine model of type 2 diabetes

Background: Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2DM). Post COVID-19 with an increased rate of obesity, there is a growing need for treatments providing improved efficacy and compliance. Modulation of nerves innervating organs that regulate plasma glucose (PG) may be a novel method for treating T2DM. Standalone stimulation of the vagus nerve or vagotomy/treatments has mixed/undesirable results. Long term/4 hrs dual neuromodulation consisting of simulation of celiac fibers innervating the pancreas (increasing insulin release) w/ simultaneous reversible electrical blockade of neuronal hepatic fibers innervating the liver (preventing glucose release) in obese T2DM animal models enhanced glycemic control superior to standalone treatments. This long term neuromodulation requires considerable amount of energy. Here we tested if glycemic control could be preserved w/ intermittent short-term neuromodulation. Methods: We used a proprietary bio-electronic device & algorithm developed by ReShape Lifesciences Inc. comprising Stimulation (Stim) of the celiac nerve w/ a simultaneous reversible high frequency alternating current (HFAC)-induced blockade of the hepatic nerve. Experiments were conducted in an Alloxan treated swine model of T2DM. Area under the curve (area units = AU) of Oral Glucose Tolerance Tests (OGTTs) was used to quantify glycemic control. Results: 30 min of HFAC/Stim @ OGTT initiation increased glycemic control (Sham = 6711 ± 1442 AU, HFAC/Stim = 545 ± 1632 AU, p < 0.05). During OGTT in Sham there was a 36 ± 7 mg/dL & 35 ± 9 mg/dL increase in PG @ 30 & 60 min w/ 9 ± 9 mg/dL @ 4 hrs. W/ 30 min of HFAC/Stim the PG was -5 ± 11 mg/dL & 3 ± 20 mg/dL relative to baseline @ 30 & 60 min & -7 ± 8 mg/dL @ 4 hrs. Interestingly, fasting PG remained suppressed by 34 ± 7 mg/dL following cessation of HFAC/Stim for 48 hrs. Histopathology demonstrated healthy tissues. Conclusions: These studies suggest a novel, reversible & intermittent energy efficient neuromodulation for the treatment of T2DM.

Use of Transcutaneous Auricular Vagus Nerve Stimulation as an Adjuvant Therapy for the Depressive Symptoms of COVID-19: A Literature Review.

The coronavirus disease 2019 (COVID-19) comprises more than just severe acute respiratory syndrome. It also interacts with the cardiovascular, nervous, renal, and immune systems at multiple levels, increasing morbidity in patients with underlying cardiometabolic conditions and inducing myocardial injury or dysfunction. Transcutaneous auricular vagus nerve stimulation (taVNS), which is derived from auricular acupuncture, has become a popular therapy that is increasingly accessible to the general public in modern China. Here, we begin by outlining the historical background of taVNS, and then describe important links between dysfunction in proinflammatory cytokine release and related multiorgan damage in COVID-19. Furthermore, we emphasize the important relationships between proinflammatory cytokines and depressive symptoms. Finally, we discuss how taVNS improves immune function via the cholinergic anti-inflammatory pathway and modulates brain circuits via the hypothalamic-pituitary-adrenal axis, making taVNS an important treatment for depressive symptoms on post-COVID-19 sequelae. Our review suggests that the link between anti-inflammatory processes and brain circuits could be a potential target for treating COVID-19-related multiorgan damage, as well as depressive symptoms using taVNS.

Transcutaneous Auricular Vagus Nerve Stimulation (tAVNS) Delivered During Upper Limb Interactive Robotic Training Demonstrates Novel Antagonist Control for Reaching Movements Following Stroke.

Implanted vagus nerve stimulation (VNS) delivered concurrently with upper limb rehabilitation has been shown to improve arm function after stroke. Transcutaneous auricular VNS (taVNS) offers a non-invasive alternative to implanted VNS and may provide similar therapeutic benefit. There is much discussion about the optimal approach for combining VNS and physical therapy, as such we sought to determine whether taVNS administered during robotic training, specifically delivered during the premotor planning stage for arm extension movements, would confer additional motor improvement in patients with chronic stroke. Thirty-six patients with chronic, moderate-severe upper limb hemiparesis (>6 months; mean Upper Extremity Fugl-Meyer score = 25 ± 2, range 13-48), were randomized to receive 9 sessions (1 h in length, 3x/week for 3 weeks) of active (N = 18) or sham (N = 18) taVNS (500 ms bursts, frequency 30 Hz, pulse width 0.3 ms, max intensity 5 mA, ∼250 stimulated movements per session) delivered during robotic training. taVNS was triggered by the onset of a visual cue prior to center-out arm extension movements. Clinical assessments and surface electromyography (sEMG) measures of the biceps and triceps brachii were collected during separate test sessions. Significant motor improvements were measured for both the active and sham taVNS groups, and these improvements were robust at 3 month follow-up. Compared to the sham group, the active taVNS group showed a significant reduction in spasticity of the wrist and hand at discharge (Modified Tardieu Scale; taVNS = -8.94% vs. sham = + 2.97%, p < 0.05). The EMG results also demonstrated significantly increased variance for the bicep peak sEMG amplitude during extension for the active taVNS group compared to the sham group at discharge (active = 26.29% MVC ± 3.89, sham = 10.63% MVC ± 3.10, mean absolute change admission to discharge, p < 0.01), and at 3-month follow-up, the bicep peak sEMG amplitude was significantly reduced in the active taVNS group (P < 0.05). Thus, robot training improved the motor capacity of both groups, and taVNS, decreased spasticity. taVNS administered during premotor planning of movement may play a role in improving coordinated activation of the agonist-antagonist upper arm muscle groups by mitigating spasticity and increasing motor control following stroke. Clinical Trial Registration: www.ClinicalTrials.gov, identifier (NCT03592745).

Validation and Reliability of a Novel Vagus Nerve Neurodynamic Test and Its Effects on Heart Rate in Healthy Subjects: Little Differences Between Sexes.

BACKGROUND: The vagus nerve (VN), also called the pneumogastric nerve, connects the brainstem to organs contained in the chest and abdomen. Physiologically, VN stimulation can rapidly affect cardiac activity and heart rate (HR). VN neuropathy can increase the risk of arrhythmias and sudden death. Therefore, a selective test of VN function may be very useful. Since peripheral neurodynamic tests (NDT) are reliable for the assessment of neuropathies in somatic nerves, we aimed to validate a novel NDT to assess VN activity, namely, the VN-NTD. METHODS: In this cross-sectional double-blind, sex-balanced study, 30 participants (15 females) completed a checklist of autonomic dysfunction symptoms. During the VN-NDT administration, HR and symptoms (i.e., mechanical allodynia) were monitored in parallel to a real-time ultrasonography imaging (USI) and motion capture analysis of the neck. The VN-NDT impact on HR and its accuracy for autonomic symptoms reported in the last 7 days were tested. RESULTS: The VN-NDT induced a significant HR reduction of about 12 and 8 bpm in males and females [t(1, 119) = 2.425; p < 0.017; ηp 2 = 0.047, 95% confidence interval (CI): 0.93-9.18], respectively. No adverse events were observed during VN-NDT. A substantial interexaminer agreement between the evaluators in symptoms induction by VN-NDT was detected [F(1, 119) = 0.540; p = 0.464; ηp 2 = 0.005, low effect]. Notably, mechanical allodynia accuracy for gastrointestinal dysfunctions was excellent (p < 0.05; 95% CI: 0.52-0.73; p < 0.001; 95% CI: 0.81-0.96). CONCLUSIONS: The novel VN-NDT is a valid and accurate test capable of detecting VN activation with high sensitivity. Data provided are suitable for both sexes as a hallmark of HR variation due to VN normal response. The proposed VN-NDT may be reliable as daily routine neurological examination tests for the evaluation of neuropathic signs related to neuroinflammation of the VN. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT04192877.