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Augmented vagal signaling may be therapeutic in hypertension. Most studies to date have used stimulation of the cervical vagal branches. Here, we investigated the effects of chronic intermittent electric stimulation of the ventral subdiaphragmatic vagal nerve branch (sdVNS) on long-term blood pressure, immune markers, and gut microbiota in the spontaneously hypertensive rat (SHR), a rodent model of hypertension characterized by vagal dysfunction, gut dysbiosis, and low-grade inflammation. We evaluated the effects of sdVNS on transcriptional networks in the nucleus of the solitary tract (NTS), a major cardioregulatory brain region with direct gut vagal projections. Male juvenile SHRs were implanted with radiotelemetry transmitters and vagal nerve cuffs for chronic intermittent electric sdVNS, applied three times per day for 7 consecutive weeks followed by 1 wk of no stimulation. Blood pressure was measured once a week using telemetry in the sdVNS group as well as age-matched sham-stimulated SHR controls. At the endpoint, colonic and circulating inflammatory markers, corticosterone, and circulating catecholamines were investigated. Bacterial 16 s sequencing measured gut bacterial abundance and composition. RNA sequencing evaluated the effects of sdVNS on transcriptional networks in the NTS. SHRs that received sdVNS exhibited attenuated development of hypertension compared with sham animals. No changes in peripheral inflammatory markers, corticosterone, or catecholamines and no major differences in gut bacterial diversity and composition were observed following sdVNS, apart from decreased abundance of Defluviitaleaceale bacterium detected in sdVNS SHRs compared with sham animals. RNA sequencing revealed significant sdVNS-dependent modulation of select NTS transcriptional networks, including catecholaminergic and corticosteroid networks. NEW & NOTEWORTHY We show that stimulation of the ventral subdiaphragmatic vagal nerve branch may be a promising potential approach to treating hypertension. The data are especially encouraging given that rodents received only 30 min per day of intermittent stimulation therapy and in view of the potential of long-term blood pressure effects that are not stimulus-locked. [ABSTRACT FROM AUTHOR]

Abstract Brachycephalic breeds of dogs, most of which show signs of the brachycephalic syndrome may have greater parasympathetic stimulation than other breeds, leading to higher values of heart rate variability and vagal tone index. The aim of this study was to establish a computerized electrocardiographic study and an assessment of the vagus sympathetic balance through heart rate variability and vagal tone index of five brachycephalic breeds compared to mesocephalic dogs. Sixty dogs were used, divided into groups made up of Boxers, English Bulldogs, French Bulldogs, Pugs, Shih-Tzu and no defined breed mesocephalic dogs. Statistical analysis was carried out using the Shapiro-Wilk test, Kruskal-Wallis and Dunn’s test or ANOVA and Bonferroni (p

Introduction: Various types of vagus nerve stimulation are employed in the treatment of a range of conditions, including depression, anxiety, epilepsy, headache, tinnitus, atrial fibrillation, schizophrenia, and musculoskeletal pain. The objective of this study was to apply vagal stimulation to the neck area using standardised cold, and then analyse the level of vascular access discomfort experienced by individuals who underwent venous cannulation from the dorsal side of the hand prior to anaesthesia. Materials and Methods: A total of 180 patients, aged 18–75, who were scheduled to undergo elective surgery, were categorised into three distinct groups: the Sham group (Group S), the Control group (Group K), and the Cold group (Group M), with each group consisting of 60 individuals. Bilateral cold application to the lateral side of the neck was performed prior to the commencement of vascular access in Group M patients, followed by the subsequent opening of vascular access. The alterations in heart rate among patients was assessed subsequent to the application of cold and following the establishment of vascular access. The participants were instructed to assess their level of vascular access pain on a numerical pain scale (NRS) ranging from 0 to 10. Results: A statistically significant difference (p = 0.035) was seen when comparing the pain ratings of patients during vascular access. The study revealed that the NRS values exhibited a statistically significant decrease in Group M compared to both Group K (p = 0.038) and Group S (p = 0.048). Group M had a higher prevalence of individuals experiencing mild pain compared to other groups, and the difference was statistically significant (p = 0.029). In Group M, the average heart rate following vagal stimulation exhibited a statistically significant decrease compared to the average heart rate observed at the beginning of the study (p < 0.05). Upon comparing the original heart rate measurements with the heart rate values following vascular access, it was observed that there was an elevation in heart rate for both Group S and Group K. Conversely, Group M exhibited a decrease in heart rate after vascular access when compared to the initial heart rate values. Conclusions: In the present investigation, it was discovered that the application of cold to the neck region resulted in a drop in heart rate among the patients, which persisted throughout the process of vascular access. Furthermore, the level of pain experienced by these individuals was reduced during vascular access procedures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Suctioning of the posterior pharynx immediately after birth during neonatal resuscitation can produce a vagal response resulting in bradycardia or apnea. The feasibility of delaying any airway suctioning and avoiding deep suctioning has not been studied. OBJECTIVES: To test the hypothesis that newborn resuscitation is feasible with the following two guidelines: 1) avoiding any suctioning until the infant establishes spontaneous respiration, and 2) avoiding the use of deep suction with catheters. STUDY DESIGN: A quality improvement project was implemented using these two guidelines. Infants' mouth was cleaned with a dry cloth. No suction was started until infants establish spontaneous breathing. Then, bulb suction was used to clear secretions from the sides of the mouth and the nose without reaching the back of the pharynx. Deep suction using catheters was not used. Neonatal staff and physicians received biweekly training to support these changes. Resuscitation data before and after the practice change were compared. RESULTS: A total of 999 sequential cases were compared; of them 501 and 498 infants were resuscitated before and after the implementation of the new practice, respectively. Suction before spontaneous breathing occurred in 12.4% in the first cohort. There were no differences between groups except for less use of oxygen with the new guidelines (12.4% vs 4.4%, P < 0.001). CONCLUSION: Avoidance of any suction prior to spontaneous breathing and not applying deep suction with catheters are feasible during newborn resuscitation. These practices are associated with decreased exposure to oxygen in the delivery room. [ABSTRACT FROM AUTHOR]

Suspension laryngoscopy is a commonly performed procedure for effective laryngeal microsurgery (LMS). Although it is associated with few adverse events, cardiac complications such as severe arrhythmia induced by exaggerated vagal tone may arise during this procedure. Here, I present the case of a 52-year-old female patient who presented with a suspected thyroid follicular neoplasm and enlarged cervical lymph nodes. LMS was planned to remove a vocal fold polyp before the thyroid surgery. The patient was placed in a Boyce-Jackson position, and suspension laryngoscopy was performed. However, several sinus pauses were detected whenever external laryngeal manipulation (ELM) was performed to improve surgical field exposure, which was presumed to be attributed to vagal stimulation or reflex induced by numerous external and internal factors during laryngeal manipulation. The suspected mechanism was the direct stimulation of the vagus nerve termed the laryngo-cardiac reflex, or carotid sinus reflex, a type of baroreceptor reflex. When the first episode of sinus pause occurred, the effect-site target concentration of propofol was unadjusted after checking the bispectral index level indicating an adequate anesthetic depth, but ELM was discontinued. When the second episode occurred, ELM could not be stopped until good laryngeal visualization was achieved. Then, the patient received 0.2 mg of intravenous glycopyrrolate. Her heart rate returned within the normal range whenever ELM was not applied. When performing suspension laryngoscopy, the head and neck positioning, the procedure itself and laryngeal manipulation may act as external factors that could induce an exaggerated vagal response. Further, patients with head and neck tumors have various internal factors, such as tumor itself, cervical lymphadenopathy or postirradiation fibrosis, which can affect the carotid sinus and deteriorate the vagal response. Therefore, careful preoperative evaluation is required to identify these internal factors in advance and take proper care to minimize the additional influence of external factors. [ABSTRACT FROM AUTHOR]

The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links the nervous and immune systems. Initially, the pathway was discovered based on the observation that vagal nerve stimulation (VNS) reduced the systemic inflammatory response in septic animals. Subsequent studies form a foundation for the leading hypothesis about the central role of the spleen in CAP activation. VNS evokes noradrenergic stimulation of ACh release from T cells in the spleen, which in turn activates α7nAChRs on the surface of macrophages. α7nAChR-mediated signaling in macrophages reduces inflammatory cytokine secretion and modifies apoptosis, proliferation, and macrophage polarization, eventually reducing the systemic inflammatory response. A protective role of the CAP has been demonstrated in preclinical studies for multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn’s disease, ulcerative colitis, endometriosis, and potentially COVID-19, sparking interest in using bioelectronic and pharmacological approaches to target α7nAChRs for treating inflammatory conditions in patients. Despite a keen interest, many aspects of the cholinergic pathway are still unknown. α7nAChRs are expressed on many other subsets of immune cells that can affect the development of inflammation differently. There are also other sources of ACh that modify immune cell functions. How the interplay of ACh and α7nAChR on different cells and in various tissues contributes to the anti-inflammatory responses requires additional study. This review provides an update on basic and translational studies of the CAP in inflammatory diseases, the relevant pharmacology of α7nAChR-activated drugs and raises some questions that require further investigation.

Coronary reperfusion therapy has played a pivotal role for reducing mortality and heart failure after acute myocardial infarction. Although several adjunctive approaches have been studied for reducing infarct size further, both ischemia–reperfusion injury and microvascular obstruction are still major contributors to both early and late clinical events after acute myocardial infarction. The progress in the field of cardioprotection has found several promising proof‐of‐concept preclinical studies. However, translation from bench to bedside has not been very successful. This comprehensive review discusses the importance of infarct size as a driver of clinical outcomes post‐acute myocardial infarction and summarizes recent novel device‐based approaches for infarct size reduction. Device‐based interventions including mechanical cardiac unloading, myocardial cooling, coronary sinus interventions, supersaturated oxygen therapy, and vagal stimulation are discussed. Many of these approaches can modify ischemic myocardial biology before reperfusion and offer unique opportunities to target ischemia–reperfusion injury.

Simple Summary: Adropin plays an important role in the regulation of energy homeostasis and metabolism. It enhances glucose tolerance, improves insulin resistance, ameliorates lipid metabolism, and has antihyperlipidemic activity. It has previously been detected in various organs, including the pancreas. Our aim was to investigate whether adropin affects pancreas exocrine secretion. The influence of different doses of adropin was tested in basal and stimulated conditions (CCK-8 and vagal stimulation). In addition, the effect of adropin has been studied under vagotomy and capsaicin deafferentation conditions. Our results indicate that adropin inhibits pancreas exocrine secretion both in the basal and stimulated conditions, whereas vagotomy and deafferentation abolish the pancreas responses to adropin. Based on the obtained results, it can be assumed that the effect of adropin on the pancreas is related to an indirect vagal mechanism. Nevertheless, this hypothesis requires further verification. The aim was to investigate the potential effect of adropin (ADR) on pancreatic–biliary juice (PBJ) secretion (volume, protein content, trypsin activity) in a rat model. The animals were divided into control and five experimental groups: adropin, CCK-8 (CCK-8 stimulation), capsaicin (capsaicin deactivation of afferents), vagotomy (vagotomy procedure), and vagal stimulation (vagal nerve stimulation). The experiment consisted of four phases, during which vehicle (0.9% NaCl) and three ADR boluses (5, 10, and 20 µg/kg BW) were administered i.v. every 30 min. PBJ samples were collected from each rat at 15 min intervals after boluses. Exogenous ADR failed to affect the pancreatic responses after vagotomy and the capsaicin pretreatment and reduced the PBJ volume, protein outputs, and trypsin activity in the adropin, CCK-8, and vagal stimulation groups in a dose-dependent manner. In all these groups, volume of PBJ was reduced only by the highest dose of ADR (p < 0.001 for adropin group and p < 0.01 for CCK-8 and vagal stimulation groups), and the protein outputs were reduced by the administration of ADR 10 µg/kg BW (adropin and CCK-8 groups, p < 0.01 in both cases) and 20 µg/kg BW (p < 0.001 for adropin and CCK-8 groups, p < 0.01 for vagal stimulation group). The 10 µg/kg BW dose of ADR reduced the trypsin output in the CCK-8 group (p < 0.01), and the highest ADR dose reduced the trypsin output in the CCK-8 (p < 0.001) and vagal stimulation (p < 0.01) groups. In conclusion, adropin in the analyzed doses exhibits the negative feedback pathway. This mechanism seems to participate in the regulation of pancreatic juice secretion via an indirect vagal mechanism. [ABSTRACT FROM AUTHOR]

Objective: Possible effects of the vagus inhibition and stimulation on the hypothalamic nuclei, myenteric plexes and the vagus nerve were investigated. Methods: The female rats divided to the inhibition (INH), stimulation (STI) and, sham (SHAM) groups were fed with high fat diet (including 40% of energy from animal fat). After nine weeks, the rats were allowed to recover for 4 weeks in INH group. In STI group, the left vagus nerve stimulated (30 Hz/500 msn/30 sec.) starting 2nd post operative day for 5 minutes during 4 weeks. Healthy female rats used as control (CONT). Then, tissue samples were analyzed by biochemical, histological and stereological methods. Results: The mean number of the neurons in the arcuate nucleus of the INH group was significantly less; but, that is significantly more in the STI group compared to the other groups. The neuronal density of ventromedial nucleus in the STI group was higher; while the density in the INH group was lower than the other groups. In the dorsomedial nucleus, neuron density of the INH group was lower than the other groups. In terms of the myenteric plexus volumes, that of the INH group was lowest. The myelinated axon number in the INH group was significantly highest. The myelin sheath thickness and axon area of the INH group was significantly lower than the other groups. Discussion: The results of the study show that the vagal inhibition is more effective than the vagal stimulation on the weight loss in the obesity. [ABSTRACT FROM AUTHOR]

Introduction Vagal nerve stimulation (VNS) is an adjuvant therapy used in the treatment of patients with refractory epilepsy who are not candidates for resective surgery or who have limited results after surgical procedures. Currently, there is enough evidence to support its use in patients with various types of epilepsy. Therefore, the present study was conducted to explore the possibility of optimizing therapy by reducing the consumption of the system's battery. Methods The prospective and double-blind analysis consisted in the evaluation of 6 patients submitted to VNS implantation for 3 months, followed by adjustment of the stimulation settings and continuity of follow-up for another month. The standard protocol was replaced by another with a frequency value of 20 Hz instead of 30 Hz to increase battery life. The safety of this procedure was evaluated through the assessment of two main variables: seizures and side effects. Results The stimulation at 20 Hz showed 68% reduction in the incidence of seizures (p = 0.054) as well as low incidence of side effects. Conclusion The present study suggests that the reduction of the stimulation frequency from 30 to 20 Hz is a safe procedure, and it does not compromise the effectiveness of therapy.

The cardiac autonomic nervous system plays an important role in the genesis and maintenance of atrial fibrillation. Although, pulmonary vein isolation is the cornerstone in today's approach to atrial fibrillation ablation, a considerable proportion of patients will recur with atrial arrhythmias following this procedure, especially in the non-paroxysmal forms. The pulmonary vein isolation indirectly targets and ablate the ganglionated plexi. This might ultimately enhance the efficacy of the procedure, but an optimal ablation strategy and a reliable method to confirm and quantify the efficacy of vagal denervation following the procedure might be necessary, thus leading to significantly better results. [ABSTRACT FROM AUTHOR]

The intrinsic cardiac nervous system represents the final site of signal integration for neurotransmission to the myocardium to enable local control of cardiac performance. The electrophysiological characteristics and ganglionic transmission of adult mouse intrinsic cardiac ganglion (ICG) neurons were investigated using a whole‐mount ganglion preparation of the excised right atrial ganglion plexus and intracellular microelectrode recording techniques. The passive and active electrical properties of ICG neurons and synaptic transmission including synaptic response strength and efficacy as a function of stimulation frequency were examined. The resting membrane potential and input resistance of ICG neurons were −47.9 ± 4.0 mV and 197.2 ± 81.5 MΩ, respectively. All neurons had somatic action potentials with overshoots of >+15 mV and after‐hyperpolarizations having an average of 10 mV amplitude and ~45 ms half duration. Phasic discharge activities were recorded from the majority of neurons studied and several types of excitatory synaptic responses were recorded following inputs from the vagus or interganglionic nerve trunk(s). Most postganglionic neurons (>75%) received a strong, suprathreshold synaptic input and reliably followed high‐frequency repetitive nerve stimulation up to at least 50 Hz. Nerve‐evoked synaptic transmission was blocked by extracellular Cd2+, ω‐conotoxin CVIE, or α‐conotoxin RegIIA, a selective α3‐containing nicotinic acetylcholine receptor antagonist. Synaptic transmission and the electrical properties of murine ICG neurons contribute to the pattern of discharge which regulates chronotropic, dromotropic, and inotropic elements of cardiac function. [ABSTRACT FROM AUTHOR]

Abstract The intrinsic cardiac nervous system represents the final site of signal integration for neurotransmission to the myocardium to enable local control of cardiac performance. The electrophysiological characteristics and ganglionic transmission of adult mouse intrinsic cardiac ganglion (ICG) neurons were investigated using a whole‐mount ganglion preparation of the excised right atrial ganglion plexus and intracellular microelectrode recording techniques. The passive and active electrical properties of ICG neurons and synaptic transmission including synaptic response strength and efficacy as a function of stimulation frequency were examined. The resting membrane potential and input resistance of ICG neurons were −47.9 ± 4.0 mV and 197.2 ± 81.5 MΩ, respectively. All neurons had somatic action potentials with overshoots of >+15 mV and after‐hyperpolarizations having an average of 10 mV amplitude and ~45 ms half duration. Phasic discharge activities were recorded from the majority of neurons studied and several types of excitatory synaptic responses were recorded following inputs from the vagus or interganglionic nerve trunk(s). Most postganglionic neurons (>75%) received a strong, suprathreshold synaptic input and reliably followed high‐frequency repetitive nerve stimulation up to at least 50 Hz. Nerve‐evoked synaptic transmission was blocked by extracellular Cd2+, ω‐conotoxin CVIE, or α‐conotoxin RegIIA, a selective α3‐containing nicotinic acetylcholine receptor antagonist. Synaptic transmission and the electrical properties of murine ICG neurons contribute to the pattern of discharge which regulates chronotropic, dromotropic, and inotropic elements of cardiac function.

The aim was to investigate the potential effect of adropin (ADR) on pancreatic–biliary juice (PBJ) secretion (volume, protein content, trypsin activity) in a rat model. The animals were divided into control and five experimental groups: adropin, CCK-8 (CCK-8 stimulation), capsaicin (capsaicin deactivation of afferents), vagotomy (vagotomy procedure), and vagal stimulation (vagal nerve stimulation). The experiment consisted of four phases, during which vehicle (0.9% NaCl) and three ADR boluses (5, 10, and 20 µg/kg BW) were administered i.v. every 30 min. PBJ samples were collected from each rat at 15 min intervals after boluses. Exogenous ADR failed to affect the pancreatic responses after vagotomy and the capsaicin pretreatment and reduced the PBJ volume, protein outputs, and trypsin activity in the adropin, CCK-8, and vagal stimulation groups in a dose-dependent manner. In all these groups, volume of PBJ was reduced only by the highest dose of ADR (p < 0.001 for adropin group and p < 0.01 for CCK-8 and vagal stimulation groups), and the protein outputs were reduced by the administration of ADR 10 µg/kg BW (adropin and CCK-8 groups, p < 0.01 in both cases) and 20 µg/kg BW (p < 0.001 for adropin and CCK-8 groups, p < 0.01 for vagal stimulation group). The 10 µg/kg BW dose of ADR reduced the trypsin output in the CCK-8 group (p < 0.01), and the highest ADR dose reduced the trypsin output in the CCK-8 (p < 0.001) and vagal stimulation (p < 0.01) groups. In conclusion, adropin in the analyzed doses exhibits the negative feedback pathway. This mechanism seems to participate in the regulation of pancreatic juice secretion via an indirect vagal mechanism.

Aims: Microvolt T-wave alternans (TWA), an oscillation in T-wave morphology of the electrocardiogram (ECG), has been associated with increased susceptibility to ventricular tachy-arrhythmias, while vagus nerve stimulation has shown promising anti-arrhythmic effects in in vivo and ex vivo animal studies. We aimed to examine the effect of non-invasive, acute low-level tragus stimulation (LLTS) on TWA in patients with ischemic cardiomyopathy and heart failure.Methods: 26 patients with ischemic cardiomyopathy (left ventricular ejection fraction

Background Low‐level tragus stimulation (LLTS) has been shown to significantly reduce atrial fibrillation (AF) burden in patients with paroxysmal AF. P‐wave alternans (PWA) is believed to be generated by the same substrate responsible for AF. Hence, PWA may serve as a marker in guiding LLTS therapy. We investigated the utility of PWA in guiding LLTS therapy in patients with AF. Methods and Results Twenty‐eight patients with AF were randomized to either active LLTS or sham (earlobe stimulation). LLTS was delivered through a transcutaneous electrical nerve stimulation device (pulse width 200 μs, frequency 20 Hz, amplitude 10–50 mA), for 1 hour daily over a 6‐month period. AF burden over 2‐week periods was assessed by noninvasive continuous ECG monitoring at baseline, 3 months, and 6 months. A 5‐minute control ECG for PWA analysis was recorded during all 3 follow‐up visits. Following the control ECG, an additional 5‐minute ECG was recorded during active LLTS in all patients. At baseline, acute LLTS led to a significant rise in PWA burden. However, active patients receiving chronic LLTS demonstrated a significant reduction in both PWA and AF burden after 6 months (P

Aims: Microvolt T-wave alternans (TWA), an oscillation in T-wave morphology of the electrocardiogram (ECG), has been associated with increased susceptibility to ventricular tachy-arrhythmias, while vagus nerve stimulation has shown promising anti-arrhythmic effects in in vivo and ex vivo animal studies. We aimed to examine the effect of non-invasive, acute low-level tragus stimulation (LLTS) on TWA in patients with ischemic cardiomyopathy and heart failure. Methods: 26 patients with ischemic cardiomyopathy (left ventricular ejection fraction <35%) and chronic stable heart failure, previously implanted with an automatic implantable cardioverter defibrillator (ICD) device with an atrial lead (dual chamber ICD or cardiac resynchronization therapy defibrillator), were enrolled in the study. Each patient sequentially received, (1) Sham LLTS (electrode on tragus, but no stimulation delivered) for 5 min; (2) Active LLTS at two different frequencies (5 and 20 Hz, 15 min each); and (3) Active LLTS, during concomitant atrial pacing at 100 bpm at two different frequencies (5 and 20 Hz, 15 min each). LLTS was delivered through a transcutaneous electrical nerve stimulation device (pulse width 200 μs, frequency 5/20 Hz, amplitude 1 mA lower than the discomfort threshold). TWA burden was assessed using continuous ECG monitoring during sham and active LLTS in sinus rhythm, as well as during atrial pacing. Results: Right atrial pacing at 100 bpm led to significantly heightened TWA burden compared to sinus rhythm, with or without LLTS. Acute LLTS at both 5 and 20 Hz, during sinus rhythm led to a significant rise in TWA burden in the precordial leads (p < 0.05). Conclusion: Acute LLTS results in a heart-rate dependent increase in TWA burden. [ABSTRACT FROM AUTHOR]

Abstract Sinus node (SN) function is an important prognostic factor of atrial fibrillation (AF). However, AF ablation guideline has not recommended SN function test before ablation. SN function testing before AF ablation in patients with tachycardia‐bradycardia syndrome should be beneficial to determine further therapy strategies and prognosis.

The cardiac autonomic nervous system plays an important role in the genesis and maintenance of atrial fibrillation. Although, pulmonary vein isolation is the cornerstone in today’s approach to atrial fibrillation ablation, a considerable proportion of patients will recur with atrial arrhythmias following this procedure, especially in the non-paroxysmal forms. The pulmonary vein isolation indirectly targets and ablate the ganglionated plexi. This might ultimately enhance the efficacy of the procedure, but an optimal ablation strategy and a reliable method to confirm and quantify the efficacy of vagal denervation following the procedure might be necessary, thus leading to significantly better results.

Abstract Background/objective Changes in brain metabolism has been investigated thoroughly during unilateral cervical chronic vagal stimulation in epileptic or depressive patients. Bilateral stimulation of the abdominal vagus (aVNS) has received less attention despite the reduction in body weight and an altered feeding behavior in obese animals that could be clinically relevant in obese individuals. Our study aims to examine the changes in brain glucose metabolism (CMRglu) induced by aVNS in obese adult miniature pigs. Dopamine (DAT) and serotonin transporters (SERT) were also quantified to further understand the molecular origins of the alterations in brain metabolism. Subjects/methods Pairs of stimulating electrodes were implanted during laparoscopy on both abdominal vagal trunks in 20 obese adult’s miniature pigs. Half of the animals were permanently stimulated while the remaining were sham stimulated. Two months after the onset of stimulation, dynamic 18FDG PET and 123I-ioflupane SPECT were performed. Food intake, resting energy expenditure and fat deposition were also assessed longitudinally. Results Food intake was halved and resting energy expenditure was increased by 60% in aVNS group compared to sham. The gain in body weight was also 38% less in aVNS group compared to sham. Brain metabolic connectivity increased between numerous structures including striatum, mid-brain, amygdala and hippocampus. On the contrary, increased CMRglu were restricted to the thalamus, the periaqueducal grey and the amygdala. DAT binding potential was decreased by about one third in the striatum while SERT was about doubled in the midbrain. Conclusions Our findings demonstrated that aVNS reduced weight gain as a consequence of diminished daily food intake and increased resting energy expenditure. These changes were associated with enhanced connectivity between several brain areas. A lower striatal DAT together with a doubled mid-brain SERT were likely causative for these changes.

The autonomic nervous system (ANS) regulates the cardiovascular system. A growing body of experimental and clinical evidence confirms significant dysfunction of this regulation during sepsis and septic shock. Clinical guidelines do not currently include any evaluation of ANS function during the resuscitation phase of septic shock despite the fact that the severity and persistence of ANS dysfunction are correlated with worse clinical outcomes. In the critical care setting, the clinical use of ANS-related hemodynamic indices is currently limited to preliminary investigations trying to predict and anticipate imminent clinical deterioration. In this review, we discuss the evidence supporting the concept that, in septic shock, restoration of ANS-mediated control of the cardiovascular system or alleviation of the clinical consequences induced by its dysfunction (e.g., excessive tachycardia, etc.), may be an important therapeutic goal, in combination with traditional resuscitation targets. Recent studies, which have used standard and advanced monitoring methods and mathematical models to investigate the ANS-mediated mechanisms of physiological regulation, have shown the feasibility and importance of monitoring ANS hemodynamic indices at the bedside, based on the acquisition of simple signals, such as heart rate and arterial blood pressure fluctuations. During the early phase of septic shock, experimental and/or clinical studies have shown the efficacy of negative-chronotropic agents (i.e., beta-blockers or ivabradine) in controlling persistent tachycardia despite adequate resuscitation. Central α-2 agonists have been shown to prevent peripheral adrenergic receptor desensitization by reducing catecholamine exposure. Whether these new therapeutic approaches can safely improve clinical outcomes remains to be confirmed in larger clinical trials. New technological solutions are now available to non-invasively modulate ANS outflow, such as transcutaneous vagal stimulation, with initial pre-clinical studies showing promising results and paving the way for ANS modulation to be considered as a new potential therapeutic target in patients with septic shock. [ABSTRACT FROM AUTHOR]

Prevention of weight regain following successful weight loss is a major challenge in the treatment of obesity, irrespective of the weight reduction method used. The majority of individuals regain the lost weight over time; thus, achieving long-term sustainability in weight loss remains an unresolved issue. A compensatory adaptation to the weight loss methods occurs in several body organs and partly explains the lack of sustainable effect. Variability is inherent in many biological systems, and patterns of variability constitute a body mechanism that is active at several levels, starting from the genes and cellular pathways through to the whole-organ level. This study aimed to describe a platform that introduces individually tailored variability in vagal nerve stimulation and dietary regimen to ensure prolonged and sustainable weight loss and prevent weight regain. The platform is intended to provide a method that can overcome the body's compensatory adaptation mechanisms while ensuring a prolonged beneficial effect. [ABSTRACT FROM AUTHOR]

• There is a strong and bidirectional association between depression and CVD. • Sex influences the relationship between depression and cardiac autonomic dysfunction. • Depressed women, despite a greater vagal tone, experience a higher risk of CVD. • tVNS determines a bottom-up neuromodulation. • rTMS, tDCS and tVNS promote the remodelling of depression-damaged neuronal circuits. Depression is a well-established stress-related risk factor for several diseases, mainly for those with cardiovascular outcomes. The mechanisms that link depression disorders with cardiovascular diseases (CVD) include dysfunctions of the autonomic nervous system. Heart rate variability analysis is a widely-used non-invasive method that can simultaneously quantify the activity of the two branches of cardiac autonomic neural control and provide insights about their pathophysiological alterations. Recent scientific literature suggests that sex influences the relationship between depressive symptoms and cardiac autonomic dysfunction. Moreover, a few studies highlight a possible sex paradox: depressed women, despite a greater vagal tone, experience a higher risk of adverse cardiovascular events than depressed men. Although there are striking sex differences in the incidence of depression, scanty data on this topic are available. Lastly, studies on the heart-brain axis bidirectionality and the role of sex are fundamental not only to clarify the biological bases of depression-CVD comorbidity, but also to develop alternative therapies, where vagus nerve appears to be a promising target of non-invasive neuromodulation techniques. [ABSTRACT FROM AUTHOR]

The native immune system is the main component of defense against pathogen, injury and trauma. Vagal fibers contain sensory and motor components controlling different functions such as heart frequency and digestion. There are lots of reasons this nervous based antiinflammatory pathway is useful, the cholinergic anti-inflammatory pathway, which is fast, separate and localized in tissue where the injury originated and can induce humoral systemic anti-inflammatory response which has a number of usefull effects on a number of heart diseases. [ABSTRACT FROM AUTHOR]

The glossopharyngeal nerve, via the carotid sinus nerve (CSN), presents baroreceptors from the internal carotid artery (ICA) and chemoreceptors from the carotid body. Although neurons in the nodose ganglion were labelled after injecting tracer into the carotid body, the vagal pathway to these baro‐ and chemoreceptors has not been identified. Neither has the glossopharyngeal intracranial afferent/sensory pathway that connects to the brainstem been defined. We investigated both of these issues in male Sprague–Dawley rats (n = 40) by injecting neural tracer wheat germ agglutinin‐horseradish peroxidase into: (i) the peripheral glossopharyngeal or vagal nerve trunk with or without the intracranial glossopharyngeal rootlet being rhizotomized; or (ii) the nucleus of the solitary tract right after dorsal and ventral intracranial glossopharyngeal rootlets were dissected. By examining whole‐mount tissues and brainstem sections, we verified that only the most rostral rootlet connects to the glossopharyngeal nerve and usually four caudal rootlets connect to the vagus nerve. Furthermore, vagal branches may: (i) join the CSN originating from the pharyngeal nerve base, caudal nodose ganglion, and rostral or caudal superior laryngeal nerve; or (ii) connect directly to nerve endings in the middle segment of the ICA or to chemoreceptors in the carotid body. The aortic depressor nerve always presents and bifurcates from either the rostral or the caudal part of the superior laryngeal nerve. The vagus nerve seemingly provides redundant carotid baro‐ and chemoreceptors to work with the glossopharyngeal nerve. These innervations confer more extensive roles on the vagus nerve in regulating body energy that is supplied by the cardiovascular, pulmonary and digestive systems. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study was to evaluate the contribution in the acute loss in vagal innervation after ablation with the second generation cryoballoon (CB-A) in each distinct pulmonary vein (PV) by means of external cardiac vagal stimulation (ECVS) by positioning a catheter in the internal jugular vein in a cohort of 60 patients. Methods: Sixty patients, 50 starting from the left superior pulmonary vein (LSPV) and 10 from the right superior pulmonary vein with symptomatic paroxysmal atrial fibrillation (PAF), having undergone ECVS before the first and after each PV ablation by means of CB-A ablation, were included. Results: The ECVS performed pre-ablation provoked cardioinhibitory responses in all cases with mean pause duration of 10251.83 ms ± 2826.23 ms. At the end of the procedure, the vagal reactions (VR) were significantly diminished. Specifically, compared against the initial pause, responses were 8957.06 ± 2711.66 ms (p < 0.01) after left superior PV, 10017.36 ± 9127.0 ms (p = 0.88) after left inferior PV, 6020.16 ± 3780.709 ms (p < 0.001) after right inferior PV and 1687.5 ± 2183.7 ms (p < 0.001) after right superior PV. Noteworthy, if starting with ablation in the RSPV, VR was immediately reduced by 90.34%, 990.7 ± 379.78 ms (p < 0.001) as compared to baseline response. Conclusions: Although not directly targeting the ganglion plexuses, AF ablation with the CB-A causes a significant acute loss in parasympathetic innervation. The RSPV showed to be associated with the most significant reduction of acute loss in parasympathetic innervation. [ABSTRACT FROM AUTHOR]

Vanillylmandelic acid, a catecholamine end-metabolite, has been shown to have several biological properties in previous studies, despite considered biologically inactive. We examined the potential effects of vanillylmandelic acid on the ischemic heart following myocardial infarction and reperfusion on a rat model. Thirty-four female Wistar rats were randomized into two groups, control and experimental. They were anesthetized and subjected to myocardial infarction through left anterior descending artery ligation. A previously studied dose of vanillylmandelic acid (10 mg/kg) was administered and the following parameters were studied during ischemia and reperfusion: a) mortality b) severity of ventricular tachyarrhythmias c) premature ventricular contractions and d) heart rate. Administration of vanillymandelic acid significantly reduced the severity of ventricular tachyarrhythmias and mortality rate during reperfusion, while it did not affect any other of the parameters studied. In conclusion, reperfusion injury was blunted through vanillylmandelic acid administration, which seems to be mediated by parasympathetic activation. [ABSTRACT FROM AUTHOR]

Key points: Vagal reflexes slow heart rate and can change where the heartbeat originates within the sinoatrial node (SAN). The mechanisms responsible for this process – termed leading pacemaker (LP) shift – have not been investigated fully.We used optical mapping to measure the effects of baroreflex, chemoreflex and carbachol on pacemaker entrainment and electrical conduction across the SAN.All methods of stimulation triggered shifts in LP site from the central SAN to one or two caudal pacemaker regions. These shifts were associated with reduced current generation capacity centrally and increased electrical load caudally.Previous studies suggest LP shift is a rate‐dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. However, our findings indicate the LP region is defined by both pacemaker rate and capacity to drive activation.Shifts in LP site provide an important homeostatic mechanism for rapid switches in heart rate. Reflex vagal activity causes abrupt heart rate slowing with concomitant caudal shifts of the leading pacemaker (LP) site within the sinoatrial node (SAN). However, neither the mechanisms responsible nor their dynamics have been investigated fully. Therefore, the objective of this study was to elucidate the mechanisms driving cholinergic LP shift. Optical maps of right atrial activation were acquired in a rat working heart–brainstem preparation during baroreflex and chemoreflex stimulation or with carbachol. All methods of stimulation triggered shifts in LP site from the central SAN to caudal pacemaker regions, which were positive for HCN4 and received uniform cholinergic innervation. During baroreflex onset, the capacity of the central region to drive activation declined with a decrease in amplitude and gradient of optical action potentials (OAPs) in the surrounding myocardium. Accompanying this decline, there was altered entrainment in the caudal SAN as shown by decreased conduction velocity, OAP amplitude, gradient and activation time. Atropine abolished these responses. Chemoreflex stimulation produced similar effects but central capacity to drive activation was preserved before the LP shift. In contrast, carbachol produced a prolonged period of reduced capacity to drive and altered entrainment. Previous studies suggest LP shift is a rate‐dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. Our findings indicate that cholinergic LP shifts are also determined by altered electrical source‐to‐sink balance in the SAN. We conclude that the LP region is defined by both rate and capacity to drive atrial activation. Key points: Vagal reflexes slow heart rate and can change where the heartbeat originates within the sinoatrial node (SAN). The mechanisms responsible for this process – termed leading pacemaker (LP) shift – have not been investigated fully.We used optical mapping to measure the effects of baroreflex, chemoreflex and carbachol on pacemaker entrainment and electrical conduction across the SAN.All methods of stimulation triggered shifts in LP site from the central SAN to one or two caudal pacemaker regions. These shifts were associated with reduced current generation capacity centrally and increased electrical load caudally.Previous studies suggest LP shift is a rate‐dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. However, our findings indicate the LP region is defined by both pacemaker rate and capacity to drive activation.Shifts in LP site provide an important homeostatic mechanism for rapid switches in heart rate. [ABSTRACT FROM AUTHOR]

Paroxysmal supraventricular tachycardia (SVT) is a common emergency department presentation. Vagal maneuvers are commonly tried to terminate SVT but are often unsuccessful in terminating the dysrhythmia. The use of adenosine, while often successful, is associated with a number of side effects and is often disliked by patients with recurrent episodes of SVT. We report on a 44-year-old woman with a past medical history of SVT who presented to the emergency department (ED) due to a recurrence of her SVT. The patient had no intravenous access and preferred not to receive adenosine. The patient received intranasal stimulation with a nasopharyngeal swab used for COVID-19 testing for 5–10 s. After less than 10 s, the patient converted to a sinus rhythm. She was successfully discharged from the ED after 1 h of observation and no recurrence of her SVT. [ABSTRACT FROM AUTHOR]

Controlled breathing maneuver is being widely applied for cardiovascular autonomic control evaluation and cardiac vagal activation through reduction of breathing rate (BR). However, this maneuver presented contradictory results depending on the protocol and the chosen BR. These variations may be related to the individual intrinsic profile baseline sympathetic tonus, as described before by others. In this study, we evaluated the effect of controlled breathing maneuver on cardiovascular autonomic control in 26 healthy subjects allocated into two protocols: (1) controlled breathing in three different rates (10, 15, and 20 breaths/min) and (2) controlled breathing in rates normalized by the individual spontaneous breathing rate (SBR) at 100, 80, 70, and 50%. Our results showed autonomic responses favorable to vagal modulation with the lower BR maneuvers. Nevertheless, while this activation was variable using the standard protocol, all participants of the normalized protocol demonstrated an increase of vagal modulation at 80% BR (HFnu 80 = 67.5% vs. 48.2%, p < 0.0001). These results suggest that controlled breathing protocols to induce vagal activation should consider the SBR, being limited to values moderately lower than the baseline.

Sinus node (SN) function is an important prognostic factor of atrial fibrillation (AF). However, AF ablation guideline has not recommended SN function test before ablation. SN function testing before AF ablation in patients with tachycardia‐bradycardia syndrome should be beneficial to determine further therapy strategies and prognosis. [ABSTRACT FROM AUTHOR]

Background: Fibromyalgia and complex regional pain syndrome (CRPS) are both chronic pain syndromes with pathophysiologic mechanisms related to autonomic nervous system dysregulation and central sensitization. Both syndromes are considered difficult to treat with conventional pain therapies. Case presentations: Here we describe a female veteran with fibromyalgia and a male veteran with CRPS, both of whom failed multiple pharmacologic, physical and psychological therapies for pain, but responded to percutaneous electrical neural field stimulation (PENFS) targeted at the auricular branches of the cranial nerves. Discussion: While PENFS applied to the body has been previously described for treatment of localized pain, PENFS effects on cranial nerve branches of the ear is not well-known, particularly when used for regional and full-body pain syndromes such as those described here. PENFS of the ear is a minimally-invasive, non-pharmacologic therapy that could lead to improved quality of life and decreased reliance on medication. However, further research is needed to guide clinical application, particularly in complex pain patients.

Controlled breathing maneuver is being widely applied for cardiovascular autonomic control evaluation and cardiac vagal activation through reduction of breathing rate (BR). However, this maneuver presented contradictory results depending on the protocol and the chosen BR. These variations may be related to the individual intrinsic profile baseline sympathetic tonus, as described before by others. In this study, we evaluated the effect of controlled breathing maneuver on cardiovascular autonomic control in 26 healthy subjects allocated into two protocols: (1) controlled breathing in three different rates (10, 15, and 20 breaths/min) and (2) controlled breathing in rates normalized by the individual spontaneous breathing rate (SBR) at 100, 80, 70, and 50%. Our results showed autonomic responses favorable to vagal modulation with the lower BR maneuvers. Nevertheless, while this activation was variable using the standard protocol, all participants of the normalized protocol demonstrated an increase of vagal modulation at 80% BR (HFnu 80 = 67.5% vs. 48.2%, p < 0.0001). These results suggest that controlled breathing protocols to induce vagal activation should consider the SBR, being limited to values moderately lower than the baseline. [ABSTRACT FROM AUTHOR]

Background: Both vagal (VS) and sympathetic (SS) stimulations can increase atrial fibrillation (AF) inducibility, with VS being known as more arrhythmogenic in normal hearts. Heart failure (HF) results in autonomic dysfunction (characterized by sympathetic activation and vagal withdrawal) and is associated with an increased AF incidence. This study investigated whether failing hearts, compared with normal control hearts, respond differently to autonomic stimulation-induced AF arrhythmogenesis and the effect of dantrolene on SS-enhanced AF in HF.Methods and Results: A rat myocardial infarction (MI) HF model was used. In experiment 1, AF inducibility was compared in 9 MI-HF rats versus 10 sham-control animals at baseline, during VS, and during SS with isoproterenol infusion. In experiment 2, dantrolene treatment (n = 8) was compared with placebo-control (n = 9) on SS-induced AF inducibility in HF. Compared with the sham-control, baseline AF inducibility was higher in the MI-HF group. AF inducibility was augmented in both groups by autonomic stimulation. However, under VS the increased magnitude was less in the MI-HF group (49% ± 11% vs 80% ± 10%; P = .029), but under SS was significantly more (53% ± 8% vs 6% ± 7%; P < .001), compared with sham-control. Dantrolene significantly attenuated SS-enhanced AF in HF (69% ± 6% vs 29% ± 9%; P = .006).Conclusions: Failing hearts are less sensitive to VS, but more vulnerable to SS-induced AF compared with normal-control hearts. Dantrolene can significantly attenuate SS-enhanced AF in HF, indicating that cardiac ryanodine receptor dysfunction may play a critical role in SS-enhanced AF in HF, and stabilizing leaky ryanodine receptor with the use of dantrolene may be a new treatment option in this condition. [ABSTRACT FROM AUTHOR]

Epilepsy is the second rated neurological disorder in the world with over 50 million patients and about 2 million new cases each year. One third of the epileptic patients are pharmaco-resistant. Thus, vagal stimulation becomes a viable treatment option which allows for better control of the frequency of the seizures, as well as an improvement in the quality of life in patients diagnosed with this condition. [ABSTRACT FROM AUTHOR]