Transcutaneous auricular vagus nerve stimulation enhances short-latency afferent inhibition via central cholinergic system activation.

The present study examined the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on short-latency afferent inhibition (SAI), as indirect biomarker of cholinergic system activation. 24 healthy adults underwent intermittent taVNS (30 s on/30 s off, 30 min) or continuous taVNS at a frequency of 25 Hz (15 min) along with earlobe temporary stimulation (15 min or 30 min) were performed in random order. The efficiency with which the motor evoked potential from the abductor pollicis brevis muscle by transcranial magnetic stimulation was attenuated by the preceding median nerve conditioning stimulus was compared before taVNS, immediately after taVNS, and 15 min after taVNS. Continuous taVNS significantly increased SAI at 15 min post-stimulation compared to baseline. A positive correlation (Pearson coefficient = 0.563, p = 0.004) was observed between baseline SAI and changes after continuous taVNS. These results suggest that 15 min of continuous taVNS increases the activity of the cholinergic nervous system, as evidenced by the increase in SAI. In particular, the increase after taVNS was more pronounced in those with lower initial SAI. This study provides fundamental insight into the clinical potential of taVNS for cholinergic dysfunction.

The effectiveness of an osteopathic manual technique compared with a breathing exercise on vagal tone as indicated by heart rate variability, a crossover study.

INTRODUCTION: Parasympathetic nervous system (PSNS) function can be inferred by heart rate variability (HRV) providing indications about an individual's health. Manual therapy may influence PSNS function, however the research outcomes in this regard are equivocal. This study explored the PSNS effect of a measured breathing technique with suboccipital balanced ligamentous tension, an osteopathic manipulative therapy technique. METHODS: Healthy adult participants in this crossover study (n = 18) were randomly allocated into two groups with differing order of interventions. A 1:1 breathing rate of 6 breaths per minute maintained for 5 min was compared to the osteopathic intervention. HRV was measured for 5 min before and after each intervention and analysed using the root mean square of successive differences (RMSSD) between normal heartbeats and high frequency normalised units (HFnu). RESULTS: The RMSSD data demonstrated no significant difference between groups or within groups (p > 0.05) over time. HFnu results showed a significant between-group difference over the four time points (p = 0.004) with a medium effect size (ηp2 = 0.240), and no significant within-group difference (p > 0.05). DISCUSSION: The osteopathic intervention raised HRV to a small extent, however measured breathing lowered HRV. In the group that received the osteopathic technique first, HFnu values continued to rise post-osteopathic treatment possibly indicating an increasing parasympathetic effect over time. Recommendations for future studies include changing the breathing ratio to ensure parasympathetic response, take into account potential delayed effects of interventions, consider outcome measures less variable than HRV, and longer follow up times. CONCLUSION: This study suggests parasympathetic stimulation may occur with the application of suboccipital balanced ligamentous tension and sympathetic stimulation from measured breathing.

High-Frequency Heart Rate Variability Is Prospectively Associated With Sleep Complaints in a Healthy Working Cohort.

OBJECTIVE: Vagus nerve functioning, as indexed by high-frequency heart rate variability (HF-HRV), has been implicated in a wide range of mental and physical health conditions, including sleep complaints. This study aimed to test associations between HF-HRV measured during sleep (sleep HF-HRV) and subjective sleep complaints 4 years later. METHODS: One hundred forty-three healthy employees (91% male; MAge = 47.8 years [time 2], SD = 8.3 years) of an industrial company in Southern Germany completed the Jenkins Sleep Problems Scale, participated in a voluntary health assessment, and were given a 24-hour ambulatory heart rate recording device in 2007. Employees returned for a health assessment and completed the Jenkins Sleep Problems Scale 4 years later. RESULTS: Hierarchical regression analyses showed that lower sleep HF-HRV measured in 2007 was associated with higher self-reported sleep complaints 4 years later after controlling for covariates (rab,c = -0.096, b = -0.108, 95% CI, -0.298 to 0.081, ΔR2 = 0.009, p = .050). CONCLUSIONS: These data are the first to show that lower sleep HF-HRV predicted worse sleep 4 years later, highlighting the importance of vagus nerve functioning in adaptability and health.

Heart rate variability and vasovagal tone index in brachycephalic dogs.

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<0.05). In the evaluation of vagal sympathetic balance among all the dogs, there was a negative correlation between heart rate and HRV 10RR (r = - 0.7678; p < 0.0001), HRV 20RR (r = - 0.8548, p < 0.0001) and VVTI (r = - 0.2770; p = 0.0321). It can therefore be concluded that the dog's breed and morphology did not alter its electrocardiographic parameters or heart rate variability. The vagal tone index, which in other studies differed in brachycephalic dogs, showed no difference when compared separately in brachycephalic breeds.

Humanity's evolved nest and its relation to cardiac vagal regulation in the first years of life.

BACKGROUND: The Evolved Developmental Niche (EDN) is a millions-year-old developmental system that matches the maturational schedule of the offspring, optimizing health. Every animal has a developmental niche. AIMS: Humanity has fallen away from providing its EDN. Does it matter? STUDY DESIGN: Several components of humanity's EDN were reviewed (breastfeeding, positive touch, allomothers, responsive care, free play) in relation to cardiac vagal nerve regulation, a signal of healthy development. Focal subjects were young children. OUTCOME MEASURES: A review of research on the selected EDN components in relation to vagal nerve function was performed. Data were available for all but the allomother component, which is typically not measured by western researchers, although allomothers provide EDN components alongside parents. RESULTS: Apart from the lack of research on allomother effects, all these EDN components have been shown to influence cardiac vagal regulation in young children. CONCLUSIONS: Converging evidence suggests that providing the EDN in early life may not only support aspects of a child's primal health system, but bolster capacities for social health and wellness, the cornerstone of a positive life trajectory.

Brain histamine improves colonic hyperpermeability through the basal forebrain cholinergic neurons, adenosine A2B receptors and vagus nerve in rats.

Intestinal barrier dysfunction, leaky gut, is implicated in various diseases, including irritable bowel syndrome (IBS) and neurodegenerative conditions like Alzheimer's disease. Our recent investigation revealed that basal forebrain cholinergic neurons (BFCNs), critical for cognitive function, receive signals from butyrate and orexin, playing a role in regulating intestinal barrier function through adenosine A2B signaling and the vagus. This study explores the involvement and function of brain histamine, linked to BFCNs, in the regulation of intestinal barrier function. Colonic permeability, assessed by quantifying absorbed Evans blue in rat colonic tissue, showed that histamine did not affect increased colonic permeability induced by LPS when administered subcutaneously. However, intracisternal histamine administration improved colonic hyperpermeability. Elevating endogenous histamine levels in the brain with SKF91488, a histamine N-methyltransferase inhibitor, also improved colonic hyperpermeability. This effect was abolished by intracisternal chlorpheniramine, an histamine H1 receptor antagonist, not ranitidine, an H2 receptor antagonist. The SKF91488-induced improvement in colonic hyperpermeability was blocked by vagotomy, intracisternal pirenzepine (suppressing BFCNs activity), or alloxazine (an adenosine A2B receptor antagonist). Additionally, intracisternal chlorpheniramine injection eliminated butyrate-induced improvement in colonic hyperpermeability. These findings suggest that brain histamine, acting via the histamine H1 receptor, regulates intestinal barrier function involving BFCNs, adenosine A2B signaling, and the vagus. Brain histamine appears to centrally regulate intestinal barrier function influenced by butyrate, differentiating its actions from peripheral histamine in conditions like IBS, where mast cell-derived histamine induces leaky gut. Brain histamine emerges as a potential pharmacological target for diseases associated with leaky gut, such as dementia and IBS.

[Intraoperative neuromonitoring in surgery of cervical neurogenic tumors].

Objective: To investigate the application value of intraoperative motor nerve monitoring in cervical neurogenic tumor surgery. Methods: The efficacy of intraoperative neuromonitoring (IONM) was analyzed retrospectively in 18 patients, including 6 males and 12 females, aged from 15 to 74 years, treated in Affiliated Drum Tower Hospital, Medical School of Nanjing University from June 2019 to September 2022 who underwent total cystectomy of cervical neurogenic tumors under intraoperative nerve monitoring. Results: All 18 patients had complete tumor removal, including 8 patients with tumors from the vagus nerve and 10 patients with tumors from the brachial plexus nerve. Postoperative nerve functions were normal in patients with tumors from brachial plexus nerve, and incomplete vocal cord paralysis occurred in 2 patients with tumors from vagus vagus nerve. The total incidence of motor nerve injury was 11.1% (2/18). All patients were followed up for 6 to 45 months, with no tumor recurrence. Conclusion: Intraoperative neuromonitoring has significant values in surgery of cervical neurogenic tumors, which is helpful to remove completely the tumors on the basis of protecting the nerve functions to the maximum extent.

Impact of anesthesia on micromagnetic stimulation (µMS) of the vagus nerve.

To treat diseases associated with vagal nerve control of peripheral organs, it is necessary to selectively activate efferent and afferent fibers in the vagus. As a result of the nerve's complex anatomy, fiber-specific activation proves challenging. Spatially selective neuromodulation using micromagnetic stimulation(µMS) is showing incredible promise. This neuromodulation technique uses microcoils(µcoils) to generate magnetic fields by powering them with a time-varying current. Following the principles of Faraday's law of induction, a highly directional electric field is induced in the nerve from the magnetic field. In this study on rodent cervical vagus, a solenoidalµcoil was oriented at an angle to left and right branches of the nerve. The aim of this study was to measure changes in the mean arterial pressure (MAP) and heart rate (HR) followingµMS of the vagus. Theµcoils were powered by a single-cycle sinusoidal current varying in pulse widths(PW = 100, 500, and 1000µsec) at a frequency of 20 Hz. Under the influence of isoflurane,µMS of the left vagus at 1000µsec PW led to an average drop in MAP of 16.75 mmHg(n = 7). In contrast,µMS of the right vagus under isoflurane resulted in an average drop of 11.93 mmHg in the MAP(n = 7). Surprisingly, there were no changes in HR to either right or left vagalµMS suggesting the drop in MAP associated with vagusµMS was the result of stimulation of afferent, but not efferent fibers. In urethane anesthetized rats, no changes in either MAP or HR were observed uponµMS of the right or left vagus(n = 3). These findings suggest the choice of anesthesia plays a key role in determining the efficacy ofµMS on the vagal nerve. Absence of HR modulation uponµMS could offer alternative treatment options using VNS with fewer heart-related side-effects.

Vagus nerve stimulation modulates distinct acetylcholine receptors on B cells and limits the germinal center response.

Acetylcholine is produced in the spleen in response to vagus nerve activation; however, the effects on antibody production have been largely unexplored. Here, we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of VNS on T-dependent B cell responses. We observed lower titers of high-affinity IgG and fewer antigen-specific germinal center (GC) B cells. GC B cells from chronic VNS mice exhibited altered mRNA and protein expression suggesting increased apoptosis and impaired plasma cell differentiation. Follicular dendritic cell (FDC) cluster dispersal and altered gene expression suggested poor function. The absence of acetylcholine-producing CD4+ T cells diminished these alterations. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. α4 nAChR inhibited coligation of CD19 to the B cell receptor, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed to distinct effects of nAChRs on B cells.

Intracortical brain-heart interplay: An EEG model source study of sympathovagal changes.

The interplay between cerebral and cardiovascular activity, known as the functional brain-heart interplay (BHI), and its temporal dynamics, have been linked to a plethora of physiological and pathological processes. Various computational models of the brain-heart axis have been proposed to estimate BHI non-invasively by taking advantage of the time resolution offered by electroencephalograph (EEG) signals. However, investigations into the specific intracortical sources responsible for this interplay have been limited, which significantly hampers existing BHI studies. This study proposes an analytical modeling framework for estimating the BHI at the source-brain level. This analysis relies on the low-resolution electromagnetic tomography sources localization from scalp electrophysiological recordings. BHI is then quantified as the functional correlation between the intracortical sources and cardiovascular dynamics. Using this approach, we aimed to evaluate the reliability of BHI estimates derived from source-localized EEG signals as compared with prior findings from neuroimaging methods. The proposed approach is validated using an experimental dataset gathered from 32 healthy individuals who underwent standard sympathovagal elicitation using a cold pressor test. Additional resting state data from 34 healthy individuals has been analysed to assess robustness and reproducibility of the methodology. Experimental results not only confirmed previous findings on activation of brain structures affecting cardiac dynamics (e.g., insula, amygdala, hippocampus, and anterior and mid-cingulate cortices) but also provided insights into the anatomical bases of brain-heart axis. In particular, we show that the bidirectional activity of electrophysiological pathways of functional brain-heart communication increases during cold pressure with respect to resting state, mainly targeting neural oscillations in the δ $$ \delta $$ , ß $$ \beta $$ , and γ $$ \gamma $$ bands. The proposed approach offers new perspectives for the investigation of functional BHI that could also shed light on various pathophysiological conditions.

Mechanisms underlying the gut-brain communication: How enterochromaffin (EC) cells activate vagal afferent nerve endings in the small intestine.

How the gastrointestinal tract communicates with the brain, via sensory nerves, is of significant interest for our understanding of human health and disease. Enterochromaffin (EC) cells in the gut mucosa release a variety of neurochemicals, including the largest quantity of 5-hydroxytryptamine (5-HT) in the body. How 5-HT and other substances released from EC cells activate sensory nerve endings in the gut wall remains a major unresolved mystery. We used in vivo anterograde tracing from nodose ganglia to determine the spatial relationship between 5-HT synthesizing and peptide-YY (PYY)-synthesizing EC cells and their proximity to vagal afferent nerve endings that project to the mucosa of mouse small intestine. The shortest mean distances between single 5-HT- and PYY-synthesizing EC cells and the nearest vagal afferent nerve endings in the mucosa were 33.1 ± 14.4 µm (n = 56; N = 6) and 70.3 ± 32.3 µm (n = 16; N = 6). No morphological evidence was found to suggest that 5-HT- or PYY-containing EC cells form close morphological associations with vagal afferents endings, or varicose axons of passage. The large distances between EC cells and vagal afferent endings are many hundreds of times greater than those known to underlie synaptic transmission in the nervous system (typically 10-15 nm). Taken together, the findings lead to the inescapable conclusion that communication between 5-HT-containing EC cells and vagal afferent nerve endings in the mucosa of the mouse small intestinal occurs in a paracrine fashion, via diffusion. New and Noteworthy None of the findings here are consistent with a view that close physical contacts occur between 5-HT-containing EC cells and vagal afferent nerve endings in mouse small intestine. Rather, the findings suggest that gut-brain communication between EC cells and vagal afferent endings occurs via passive diffusion. The morphological data presented do not support the view that EC cells are physically close enough to vagal afferent endings to communicate via fast synaptic transmission.

Possible mechanisms of auricular acupoint stimulation in the treatment of migraine by activating auricular vagus nerve. / 从耳迷走神经探讨耳穴治疗偏头痛的可能机制.

Under the guidance of traditional Chinese medicine theory, the clinical research of auricular acupoint stimulation in the treatment of migraine has gained a lot, and the curative efficacy is definite, but its mechanism remains unclear. In the present paper, we discussed the efficacy of auricular acupoint stimulation including "transcutaneous auricular vagus nerve stimulation" (taVNS) in the treatment of migraine in recent years. Through bibliometric analysis, we screened out top 10 auricular acupoints (Shenmenï¼»TF4ï¼½, Pizhixiaï¼»AT4ï¼½, Jiaoganï¼»AH6aï¼½, Ganï¼»CO12ï¼½, Yidanï¼»CO11ï¼½, Neifenmiï¼»CO18ï¼½, Shenï¼»CO10ï¼½, Nieï¼»AT2ï¼½, Zhenï¼»AT3ï¼½ and Eï¼»AT1ï¼½) which were the most frequently used for migraine. Majority of these auricular acupoints just distributed in the region innervated by auricular vagus nerve. Thus, we thought that the analgesic effect of needling these auricular acupoints for migraine was produced by triggering the auricular vagus nerve, and concluded that the central mechanism underlying induction of analgesic effect by activating auricular vagus nerve may be achieved by activating the descending pain regulation pathway of the locus coeruleus nucleus and dorsal raphe nucleus. In addition, taVNS-induced 1) regulation of the activities of brain's default network and pain matrix, 2) activation of the cortical descending pain regulation pathway, and 3) inhibition of the neuroinflammatory response may also contribute to its ameliorating effect of migraine. This paper may provide ideas for the future research on the mechanism of auricular acupoint treatment of migraine.

Does vibrotactile stimulation of the auricular vagus nerve enhance working memory? A behavioral and physiological investigation.

BACKGROUND: Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact. OBJECTIVE: We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter. METHOD: This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control). RESULTS: In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d' compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d' with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham. CONCLUSION: Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory.

Online Bayesian optimization of vagus nerve stimulation.

Objective.In bioelectronic medicine, neuromodulation therapies induce neural signals to the brain or organs, modifying their function. Stimulation devices capable of triggering exogenous neural signals using electrical waveforms require a complex and multi-dimensional parameter space to control such waveforms. Determining the best combination of parameters (waveform optimization or dosing) for treating a particular patient's illness is therefore challenging. Comprehensive parameter searching for an optimal stimulation effect is often infeasible in a clinical setting due to the size of the parameter space. Restricting this space, however, may lead to suboptimal therapeutic results, reduced responder rates, and adverse effects.Approach. As an alternative to a full parameter search, we present a flexible machine learning, data acquisition, and processing framework for optimizing neural stimulation parameters, requiring as few steps as possible using Bayesian optimization. This optimization builds a model of the neural and physiological responses to stimulations, enabling it to optimize stimulation parameters and provide estimates of the accuracy of the response model. The vagus nerve (VN) innervates, among other thoracic and visceral organs, the heart, thus controlling heart rate (HR), making it an ideal candidate for demonstrating the effectiveness of our approach.Main results.The efficacy of our optimization approach was first evaluated on simulated neural responses, then applied to VN stimulation intraoperatively in porcine subjects. Optimization converged quickly on parameters achieving target HRs and optimizing neural B-fiber activations despite high intersubject variability.Significance.An optimized stimulation waveform was achieved in real time with far fewer stimulations than required by alternative optimization strategies, thus minimizing exposure to side effects. Uncertainty estimates helped avoiding stimulations outside a safe range. Our approach shows that a complex set of neural stimulation parameters can be optimized in real-time for a patient to achieve a personalized precision dosing.

Extracranial transport of brain lymphatics via cranial nerve in human.

Extracranial waste transport from the brain interstitial fluid to the deep cervical lymph node (dCLN) is not extensively understood. The present study aims to show the cranial nerves that have a role in the transport of brain lymphatics vessels (LVs), their localization, diameter, and number using podoplanin (PDPN) and CD31 immunohistochemistry (IHC) and Western blotting. Cranial nerve samples from 6 human cases (3 cadavers, and 3 autopsies) were evaluated for IHC and 3 autopsies for Western blotting. The IHC staining showed LVs along the optic, olfactory, oculomotor, trigeminal, facial, glossopharyngeal, accessory, and vagus nerves. However, no LVs present along the trochlear, abducens, vestibulocochlear, and hypoglossal nerves. The LVs were predominantly localized at the endoneurium of the cranial nerve that has motor components, and LVs in the cranial nerves that had sensory components were present in all 3 layers. The number of LVs accompanying the olfactory, optic, and trigeminal nerves was classified as numerous; oculomotor, glossopharyngeal, vagus, and accessory was moderate; and facial nerves was few. The largest diameter of LVs was in the epineurium and the smallest one was in the endoneurium. The majority of Western blotting results correlated with the IHC. The present findings suggest that specific cranial nerves with variable quantities provide a pathway for the transport of wastes from the brain to dCLN. Thus, the knowledge of the transport of brain lymphatics along cranial nerves may help understand the pathophysiology of various neurological diseases.

Stimulatory effect of methylglyoxal on capsaicin-sensitive lung vagal afferents in rats: role of TRPA1.

Methylglyoxal (MG), a reactive metabolic byproduct of glycolysis, is a causative of painful diabetic neuropathy. Patients with diabetes are associated with more frequent severe asthma exacerbation. Stimulation of capsaicin-sensitive lung vagal (CSLV) afferents may contribute to the pathogenesis of hyperreactive airway diseases such as asthma. However, the possibility of the stimulatory effect of MG on CSLV afferents and the underlying mechanisms remain unknown. Our results showed that intravenous injection of MG (25 mg/kg, MG25) in anesthetized, spontaneously breathing rats elicited pulmonary chemoreflexes characterized by apnea, bradycardia, and hypotension. The MG-induced apneic response was reproducible and dose dependent. MG25 no longer evoked these reflex responses after perineural capsaicin treatment of both cervical vagi to block C-fibers' conduction, suggesting that the reflexes were mediated through the stimulation of CSLV afferents. Pretreatment with HC030031 [an antagonist of transient receptor potential ankyrin subtype 1 protein (TRPA1)] or AP18 (another TRPA1 antagonist), but not their vehicle, markedly attenuated the apneic response induced by MG25. Consistently, electrophysiological results showed that pretreatment with HC030031 largely attenuated the intense discharge in CSLV afferents induced by injection of MG25 in open-chest and artificially ventilated rats. In isolated CSLV neurons, the perfusion of MG evoked an abrupt and pronounced increase in calcium transients in a concentration-dependent manner. This stimulatory effect on CSLV neurons was also abolished by HC030031 treatment but not by its vehicle. In conclusion, these results suggest that MG exerts a stimulatory effect on CSLV afferents, inducing pulmonary chemoreflexes, and such stimulation is mediated through the TRPA1 activation.NEW & NOTEWORTHY Methylglyoxal (MG) is implicated in the development of painful diabetic neuropathy. A retrospective cohort study revealed an increased incidence of asthma exacerbations in patients with diabetes. This study demonstrated that elevated circulating MG levels stimulate capsaicin-sensitive lung vagal afferents via activation of TRPA1, which in turn triggers respiratory reflexes. These findings provide new information for understanding the pathogenic mechanism of diabetes-associated hyperreactive airway diseases and potential therapy.

A vagal reflex evoked by airway closure.

Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes to maintain respiratory function1,2. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax or airway compression. Here we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, whereas ablating NEBs or vagal PVALB neurons eliminated gasping in response to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of Piezo2 in NEBs eliminated responses to airway closure. NEBs were dispensable for the Hering-Breuer inspiratory reflex, which indicated that discrete terminal structures detect airway closure and inflation. Similar to the involvement of Merkel cells in touch sensation3,4, NEBs are PIEZO2-expressing epithelial cells and, moreover, are crucial for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function.

A framework for the interpretation of heart rate variability applied to transcutaneous auricular vagus nerve stimulation and osteopathic manipulation.

Reports on autonomic responses to transcutaneous auricular vagus nerve stimulation (taVNS) and osteopathic manipulative techniques have been equivocal, partly due to inconsistent interpretation of heart rate variability (HRV). We developed a mechanistic framework for the interpretation of HRV based on a model of sinus node automaticity that considers autonomic effects on Phase 3 repolarization and Phase 4 depolarization of the sinoatrial action potential. The model was applied to HRV parameters calculated from ECG recordings (healthy adult humans, both genders) before (30 min), during (15 min), and after (30 min) a time control intervention (rest, n = 23), taVNS (10 Hz, 300 µs, 1-2 mA, cymba concha, left ear, n = 12), or occipitoatlantal decompression (OA-D, n = 14). The experimental protocol was repeated on 3 consecutive days. The model simulation revealed that low frequency (LF) HRV best predicts sympathetic tone when calculated from heart rate time series, while high frequency (HF) HRV best predicts parasympathetic tone when calculated from heart period time series. Applying our model to the HRV responses to taVNS and OA-D, revealed that taVNS increases cardiac parasympathetic tone, while OA-D elicits a mild decrease in cardiac sympathetic tone.

Short-Term Effects of Heart Rate Variability Biofeedback on Working Memory.

Drawing upon the well-documented impact of long-term heart rate variability biofeedback (HRVB) on psychophysiological responses, this study seeks to explore the short-term effects arising from a single HRVB session during and after paced breathing exercise. The research aligns with the neurovisceral integration model, emphasizing the link between heart rate variability (HRV) levels and cognitive performance. Therefore, a randomized controlled trial employing a between-subjects design was conducted with 38 participants. Each participant was assigned to either the paced breathing intervention group or the spontaneous breathing control group. The study assessed various parameters such as cardiac vagal tone, evaluated through vagally mediated HRV measures, and working memory, measured using the N-back task. Additionally, participants' affective states were assessed through self-reported questionnaires, specifically targeting attentiveness, fatigue, and serenity. The results notably reveal enhancements in the working memory task and an elevated state of relaxation and attention following the HRVB session, as evidenced by higher averages of correct responses, serenity and attentiveness scores. However, the findings suggest that this observed improvement is not influenced by changes in cardiac vagal tone, as assessed using a simple mediation analysis. In conclusion, this study presents promising insights into the impact of a single HRVB session, laying the foundation for future research advancements in this domain.