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Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.

SIGNIFICANCE: Information about the spatial organization of fibers within a nerve is crucial to our understanding of nerve anatomy and its response to neuromodulation therapies. A serial block-face microscopy method [three-dimensional microscopy with ultraviolet surface excitation (3D-MUSE)] has been developed to image nerves over extended depths ex vivo. To routinely visualize and track nerve fibers in these datasets, a dedicated and customizable software tool is required. AIM: Our objective was to develop custom software that includes image processing and visualization methods to perform microscopic tractography along the length of a peripheral nerve sample. APPROACH: We modified common computer vision algorithms (optic flow and structure tensor) to track groups of peripheral nerve fibers along the length of the nerve. Interactive streamline visualization and manual editing tools are provided. Optionally, deep learning segmentation of fascicles (fiber bundles) can be applied to constrain the tracts from inadvertently crossing into the epineurium. As an example, we performed tractography on vagus and tibial nerve datasets and assessed accuracy by comparing the resulting nerve tracts with segmentations of fascicles as they split and merge with each other in the nerve sample stack. RESULTS: We found that a normalized Dice overlap ( Dice norm ) metric had a mean value above 0.75 across several millimeters along the nerve. We also found that the tractograms were robust to changes in certain image properties (e.g., downsampling in-plane and out-of-plane), which resulted in only a 2% to 9% change to the mean Dice norm values. In a vagus nerve sample, tractography allowed us to readily identify that subsets of fibers from four distinct fascicles merge into a single fascicle as we move ∼ 5    mm along the nerves length. CONCLUSIONS: Overall, we demonstrated the feasibility of performing automated microscopic tractography on 3D-MUSE datasets of peripheral nerves. The software should be applicable to other imaging approaches. The code is available at https://github.com/ckolluru/NerveTracker.

Lack of liver regenerative capacity is the primary cause of hepatic failure and even mortality in patients undergoing hepatectomy, with no effective intervention strategies currently available. Therefore, identifying efficacious interventions to enhance liver regeneration is pivotal for optimizing clinical outcomes. Recent studies have demonstrated that vagotomy exerts an inhibitory effect on liver regeneration following partial hepatectomy, thereby substantiating the pivotal role played by the vagus nerve in the process of liver regeneration. In recent years, electroacupuncture (EA) has emerged as a non‐invasive technique for stimulating the vagus nerve. However, EA on hepatic regeneration remains uncertain. In this study, a 70% partial hepatectomy (PH) mouse model is utilized to investigate the effects of EA on acute liver regeneration and elucidate its underlying molecular mechanisms. It is observed that EA at ST36 acutely activated cholinergic neurons in the dorsal motor nucleus of the vagus nerve (DMV), resulting in increased release of acetylcholine from hepatic vagal nerve endings and subsequent activation of IL‐6 signaling in liver macrophages. Ultimately, these events promoted hepatocyte proliferation and facilitated liver regeneration. These findings provide insights into the fundamental brain‐liver axis mechanism through which EA promotes liver regeneration, offering a novel therapeutic approach for post‐hepatectomy liver regeneration disorders. [ABSTRACT FROM AUTHOR]

Abnormal brain aging is suggested in epilepsy. Given the brain network dysfunction in epilepsy, the white matter tracts, which primarily interconnect brain regions, could be of special importance. We focused on white matter brain aging in diverse forms of epilepsy and comorbid psychosis. We obtained brain diffusion tensor imaging (DTI) data at 3 T-MRI in 257 patients with epilepsy and 429 healthy subjects. The tract-based fractional anisotropy values of the healthy subjects were used to build a brain-age prediction model, and we calculated the brain-predicted age difference (brain-PAD: predicted age—chronological age) of all subjects. As a result, almost all epilepsy categories showed significantly increased brain-PAD (p < 0.001), including temporal lobe epilepsy (TLE) with no MRI-lesion (+ 4.2 yr), TLE with hippocampal sclerosis (+ 9.1 yr), extratemporal focal epilepsy (+ 5.1 yr), epileptic encephalopathy or progressive myoclonus epilepsy (+ 18.4 yr), except for idiopathic generalized epilepsy (IGE). Patients with psychogenic non-epileptic seizures also presented increased brain-PAD. In TLE, interictal psychosis significantly raised brain-PAD by 8.7 years. In conclusion, we observed increased brain aging in most types of epilepsy, which was generally consistent with brain morphological aging results in previous studies. Psychosis may accelerate brain aging in TLE. These findings may suggest abnormal aging mechanisms in epilepsy and comorbid psychotic symptoms. [ABSTRACT FROM AUTHOR]

Background: Vagal atrophy is a hallmark of Parkinson's disease (PD) and has been found to be associated with autonomic dysfunction, while analyses of the vagus nerve (VN) in atypical Parkinsonian syndromes (APS) have not yet been performed. We here investigate the characteristics of the VN in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and, in a second step, its potential as a possible biomarker for orthostatic dysregulation. Objectives: The aim was to compare the VN pathology in MSA and PSP with healthy individuals and patients with PD as a differentiating factor and to further analyse the correlation of the VN with clinical parameters and cardiovascular response. Design: We conducted a monocentric, cross-sectional cohort study in 41 APS patients and compared nerve ultrasound (NUS) parameters with 90 PD patients and 39 healthy controls. Methods: In addition to a detailed neurological history and examination, several clinical severity and motor scores were obtained. Autonomic symptoms were reported in the Scales for Outcomes in Parkinson's Disease – Autonomic questionnaire. Further scores were used to detect other non-motor symptoms, quality of life and cognition. Additionally, we performed a head up tilt test (HUTT) and NUS of the VN. We conducted correlation analyses of the VN cross-sectional area (CSA) with clinical scores and the heart rate and blood pressure variability parameters of the HUTT. Results: The examination demonstrated a high prevalence of abnormal autonomic response in both MSA (90%) and PSP (80%). The VN CSA correlated with spectral parameters of the HUTT, which are associated with sympatho-vagal imbalance. In addition, the CSA of the VN in patients with PD and PSP were significantly smaller than in healthy controls. In MSA, however, there was no marked vagal atrophy in comparison. Conclusion: The occurrence of autonomic dysfunction was high in MSA and PSP, which underlines its impact on these syndromes. Our findings indicate a connection between vagal pathology and autonomic dysfunction and might contribute to a better comprehension of APS. To further evaluate the clinical relevance and the VN as a possible marker of autonomic dysfunction in APS, prospective longitudinal observations are necessary. [ABSTRACT FROM AUTHOR]

Seizures produce autonomic symptoms, mainly sympathetic but also parasympathetic in origin. Within this context, the vagus nerve is a key player as it carries information from the different organs to the brain and vice versa. Hence, exploiting vagal neural traffic for seizure detection might be a promising tool to improve the efficacy of closed-loop Vagus Nerve Stimulation. This study developed a VENG detection algorithm that effectively detects seizures by emphasizing the loss of spontaneous rhythmicity associated with respiration in acute intrahippocampal Kainic Acid rat model. Among 20 induced seizures in six anesthetized rats, 13 were detected (sensitivity: 65%, accuracy: 92.86%), with a mean VENG-detection delay of 25.3 ± 13.5 s after EEG-based seizure onset. Despite variations in detection parameters, 7 out of 20 seizures exhibited no ictal VENG modifications and remained undetected. Statistical analysis highlighted a significant difference in Delta, Theta and Beta band evolution between detected and undetected seizures, in addition to variations in the magnitude of HR changes. Binomial logistic regression analysis confirmed that an increase in delta and theta band activity was associated with a decreased likelihood of seizure detection. This results suggest the possibility of distinct seizure spreading patterns between the two groups which may results in differential activation of the autonomic central network. Despite notable progress, limitations, particularly the absence of respiration recording, underscore areas for future exploration and refinement in closed-loop stimulation strategies for epilepsy management. This study constitutes the initial phase of a longitudinal investigation, which will subsequently involve reproducing these experiments in awake conditions with spontaneous recurrent seizures. [ABSTRACT FROM AUTHOR]

• Feeding induced increases in the amplitudes of jejunal myoelectrical signals. • The feeding-induced increase was abolished by vagotomy. • The feeding-induced increase was abolished by posterior insular cortical inhibition. • Feeding changed the autonomic activity. • These changes were abolished by posterior insular cortical inhibition. The gastrointestinal tract exhibits coordinated muscle motility in response to food digestion, which is regulated by the central nervous system through autonomic control. The insular cortex is one of the brain regions that may regulate the muscle motility. In this study, we examined whether, and how, the insular cortex, especially the posterior part, regulates gastrointestinal motility by recording jejunal myoelectrical signals in response to feeding in freely moving male rats. Feeding was found to induce increases in jejunal myoelectrical signal amplitudes. This increase in the jejunal myoelectrical signals was abolished by vagotomy and pharmacological inhibition of the posterior insular cortex. Additionally, feeding induced a decrease and increase in sympathetic and parasympathetic nervous activities, respectively, both of which were eliminated by posterior insular cortical inhibition. These results suggest that the posterior insular cortex regulates jejunal motility in response to feeding by modulating autonomic tone. [ABSTRACT FROM AUTHOR]

Background: Transcutaneous electrostimulation of the auricular branch of the vagal nerve (taVNS) has the propensity to reach diffuse neuromodulatory networks, which are dysfunctional in Parkinson's disease (PD). Previous studies support the use of taVNS as an add‐on treatment for gait in PD. Objectives: We assessed the effect of taVNS at 25 Hz (taVNS25), taVNS at 100 Hz (taVNS100), and sham earlobe stimulation (sVNS) on levodopa responsive (arm swing velocity, arm range of motion, stride length, gait speed) and non‐responsive gait characteristics (arm range of motion asymmetry, anticipatory postural adjustment [APA] duration, APA first step duration, APA first step range of motion), and turns (first turn duration, double 360° turn duration, steps per turn) in advanced PD. Methods: In our double blind sham controlled within‐subject randomized trial, we included 30 PD patients (modified Hoehn and Yahr stage, 2.5–4) to assess the effect of taVNS25, taVNS100, and sVNS on gait characteristics measured with inertial motion sensors during the instrumented stand and walk test and a double 360° turn. Separate generalized mixed models were built for each gait characteristic. Results: During taVNS100 compared to sVNS arm swing velocity (P = 0.030) and stride length increased (P = 0.027), and APA duration decreased (P = 0.050). During taVNS25 compared to sVNS stride length (P = 0.024) and gait speed (P = 0.021) increased and double 360° turn duration decreased (P = 0.039). Conclusions: We have found that taVNS has a frequency specific propensity to improve stride length, arm swing velocity, and gait speed and double 360° turn duration in PD patients. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Non-recurrent laryngeal nerve (NRLN) is an anatomic variation seen in about 0.52–0.7% patients, generally on right side. It exits the vagus nerve having a direct route to the larynx, unlike usual recurrent laryngeal nerve, supplying intrinsic laryngeal muscles except cricothyroid. It is sited over left side on extremely rare occasions, that is, 0.04% of the cases. Some cases of NRLN co-exists with aberrant right subclavian artery which courses behind the esophagus, also known as 'arteria lusoria'. Here we present a case of 60-years old patient, diagnosed as goiter presented to us in june 2023 at the department of head and neck surgery at a tertiary care setup of Karachi Pakistan. Intra-operatively, non-recurrent nerve was encountered, whose association was found with arteria lusoria, observed in pre-operative CT-scan. The nerve was saved and no post-operative complications were seen in patient. The association of arteria lusoria in this case emphasize its importance in predicting NRLN via pre-operative imaging techniques which can prevent its injury intra-operatively. [ABSTRACT FROM AUTHOR]

We present a case report describing an unexpected anomaly encountered during a total thyroidectomy for a patient with papillary carcinoma of the left lobe of the thyroid with retrosternal extension. Intraoperatively, we discovered that the left lobe of the thyroid gland had extended posteriorly, invading the carotid space and displacing the carotid sheath anteriorly. The vagus nerve was identified as a cord-like structure abutting the anterior surface of the tumor, in close relation to the strap muscles. This case highlights the importance of careful dissection and identification of anatomical structures during thyroidectomy procedures to avoid inadvertent nerve injury. We discuss the significance of meticulous dissection-wide exposure and advocate for greater awareness and vigilance among surgeons. [ABSTRACT FROM AUTHOR]

• Electrical stimulation of the dorsal motor nucleus of the vagus inhibits inflammation with no heart rate effects. • This approach beneficially alters cytokine levels in mice with experimental sepsis. • This approach also improves survival in experimental sepsis. The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis. Anesthetized male 8–10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days. Either left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice. For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN. [ABSTRACT FROM AUTHOR]

Outcomes following vagus nerve stimulation (VNS) improve over years after implantation in children with drug‐resistant epilepsy. The added value of deep brain stimulation (DBS) instead of continued VNS optimization is unknown. In a prospective, non‐blinded, randomized patient preference trial of 18 children (aged 8–17 years) who did not respond to VNS after at least 1 year, add‐on DBS resulted in greater seizure reduction compared with an additional year of VNS optimization (51.9% vs. 12.3%, p = 0.047). Add‐on DBS also resulted in less bothersome seizures (p = 0.03), but no change in quality of life. DBS may be considered earlier for childhood epilepsy after non‐response to VNS. ANN NEUROL 2024;96:405–411 [ABSTRACT FROM AUTHOR]

(1) Background: We examined the effect of the acute administration of olive oil (EVOO), linseed oil (GLO), soybean oil (SO), and palm oil (PO) on gastric motility and appetite in rats. (2) Methods: We assessed food intake, gastric retention (GR), and gene expression in all groups. (3) Results: Both EVOO and GLO were found to enhance the rate of stomach retention, leading to a decrease in hunger. On the other hand, the reduction in food intake caused by SO was accompanied by delayed effects on stomach retention. PO caused an alteration in the mRNA expression of NPY, POMC, and CART. Although PO increased stomach retention after 180 min, it did not affect food intake. It was subsequently verified that the absence of an autonomic reaction did not nullify the influence of EVOO in reducing food consumption. Moreover, in the absence of parasympathetic responses, animals that received PO exhibited a significant decrease in food consumption, probably mediated by lower NPY expression. (4) Conclusions: This study discovered that different oils induce various effects on parameters related to food consumption. Specifically, EVOO reduces food consumption primarily through its impact on the gastrointestinal tract, making it a recommended adjunct for weight loss. Conversely, the intake of PO limits food consumption in the absence of an autonomic reaction, but it is not advised due to its contribution to the development of cardiometabolic disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Healthcare workers (HCWs) have been significantly impacted by the pandemic. Elderly health care workers carry out a variety of duties at work and have years of clinical expertise. Anxiety and insomnia are among the more commonly encountered problems in senior physicians and other geriatric medical professional populations. OBJECTIVE: The study aims to determine the effect of vagal nerve stimulation on anxiety and sleep disturbances among geriatric medical professionals. METHODS: 42 participants were enrolled in this study based on the inclusion and exclusion criteria. The participants were divided into two groups using the closed envelope approach, and they took part in therapy sessions lasting 30 minutes, three times per week for a period of four weeks. The Experimental group A received non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) and Control group A received Jacobson's progressive muscle relaxation technique. RESULTS: With a p value of 0.001, taVNS stimulation significantly improved sleep quality and reduced anxiety after 4 weeks. The post-intervention assessment revealed a highly significant improvement in Group A, with a T value of 251 (p < 0.001). CONCLUSION: The findings suggest that taVNS may be an effective intervention for addressing anxiety and sleep issues in geriatric medical professionals. These results contribute to the exploration of non-invasive strategies to enhance the well-being of healthcare professionals working in demanding environments. [ABSTRACT FROM AUTHOR]

Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, in vitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons. [ABSTRACT FROM AUTHOR]

Objective: Endotracheal tube (ETT) surface electrodes are used to monitor the vagus nerve (VN), recurrent laryngeal nerve (RLN), and external branch of the superior laryngeal nerve (EBSLN) during thyroid and parathyroid surgery. Alternative nerve monitoring methods are desirable when intubation under general anesthesia is not desirable or possible. In this pilot study, we compared the performance of standard ETT electrodes to four different noninvasive cutaneous recording electrode types (two adhesive electrodes and two needle electrodes) in three different orientations. Methods: The VN was stimulated directly during thyroid and parathyroid surgery using a Prass stimulator probe. Electromyographic (EMG) responses for each patient were recorded using an ETT plus one of the following four cutaneous electrode types: large‐foot adhesive, small‐foot adhesive, long‐needle and short‐needle. Each of the four electrode types was placed in three orientations: (1) bilateral, (2) ipsilateral mediolateral, and (3) ipsilateral craniocaudal. Results: Four surgical cases were utilized for data collection with the repetitive measures obtained in each subject. Bilateral electrode orientation was superior to ipsilateral craniocaudal and ipsilateral mediolateral orientations. Regardless of electrodes type, all amplitudes in the bilateral orientation were >100 μV. When placed bilaterally, the small‐foot adhesive and the long‐needle electrodes obtained the highest EMG amplitudes as a percentage of ETT amplitudes. Conclusion: Cutaneous electrodes could potentially be used to monitor the VN during thyroid and parathyroid procedures. Different electrode types vary in their ability to record amplitudes and latencies. Bilateral orientation improves EMG responses in all electrode types. Additional validation of cutaneous electrodes as an alternative noninvasive method to monitor the VN is needed. [ABSTRACT FROM AUTHOR]

Maintenance of autonomic homeostasis is continuously calibrated by sensory fibers of the vagus nerve and sympathetic chain that convey compound action potentials (CAPs) to the central nervous system. Lipopolysaccharide (LPS) intravenous challenge reliably elicits a robust inflammatory response that can resemble systemic inflammation and acute endotoxemia. Here, we administered LPS intravenously in nine healthy subjects while recording ventral cervical magnetoneurography (vcMNG)-derived CAPs at the rostral Right Nodose Ganglion (RNG) and the caudal Right Carotid Artery (RCA) with optically pumped magnetometers (OPM). We observed vcMNG RNG and RCA neural firing rates that tracked changes in TNF-α levels in the systemic circulation. Further, endotype subgroups based on high and low IL-6 responders segregate RNG CAP frequency (at 30-120 min) and based on high and low IL-10 response discriminate RCA CAP frequency (at 0-30 min). These vcMNG tools may enhance understanding and management of the neuroimmune axis that can guide personalized treatment based on an individual's distinct endophenotype. Ventral cervical magnetoneurography responses after LPS administration temporally aligned with the changes in TNF-α levels, making it a potential sensitive bioindicator of the neuroimmune axis for clinical use. [ABSTRACT FROM AUTHOR]

Background Methods Key Results Conclusions and Inferences Diarrhea is commonly associated with irritable bowel syndrome, inflammatory bowel disease, microscopic colitis, and other gastrointestinal dysfunctions. Spontaneously occurring idiopathic chronic diarrhea is frequent in rhesus macaques, but has not been used as a model for the investigation of diarrhea or its treatment. We characterized this condition and present preliminary data demonstrating that left vagal nerve stimulation provides relief.Stool consistency scores were followed for up to 12 years. Inflammation was assessed by plasma C‐reactive protein, [18F]fluorodeoxyglucose (FDG) uptake, measured by positron emission tomography (PET), multiplex T cell localization, endoscopy and histology. The vagus was stimulated for 9 weeks in conscious macaques, using fully implanted electrodes, under wireless control.Macaques exhibited recurrent periods of diarrhea for up to 12 years, and signs of inflammation: elevated plasma C‐reactive protein, increased bowel FDG uptake and increased mucosal T helper1 T‐cells. The colon and distal ileum were endoscopically normal, and histology revealed mild colonic inflammation. Application of vagal nerve stimulation to conscious macaques (10 Hz, 30 s every 3 h; 24 h a day for 9 weeks) significantly reduced severity of diarrhea and also reduced inflammation, as measured by FDG uptake and C‐reactive protein.These macaques exhibit spontaneously occurring diarrhea with intestinal inflammation that can be reduced by VNS. The data demonstrate the utility of this naturally occurring primate model to study the physiology and treatments for chronic diarrhea and the neural control circuits influencing diarrhea and inflammation that are not accessible in human subjects. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Although >30% of epilepsy patients have drug‐resistant epilepsy (DRE), typically those with generalized or multifocal disease have not traditionally been considered surgical candidates. Responsive neurostimulation (RNS) of the centromedian (CM) region of the thalamus now appears to be a promising therapeutic option for this patient population. We present outcomes following CM RNS for 13 patients with idiopathic generalized epilepsy (IGE) and eight with multifocal onsets that rapidly generalize to bilateral tonic–clonic (focal to bilateral tonic–clonic [FBTC]) seizures.A retrospective review of all patients undergoing bilateral CM RNS by the senior author through July 2022 were reviewed. Electrodes were localized and volumes of tissue activation were modeled in Lead‐DBS. Changes in patient seizure frequency were extracted from electronic medical records.Twenty‐one patients with DRE underwent bilateral CM RNS implantation. For 17 patients with at least 1 year of postimplantation follow‐up, average seizure reduction from preoperative baseline was 82.6% (SD = 19.0%, median = 91.7%), with 18% of patients Engel class 1, 29% Engel class 2, 53% Engel class 3, and 0% Engel class 4. There was a trend for average seizure reduction to be greater for patients with nonlesional FBTC seizures than for other patients. For patients achieving at least Engel class 3 outcome, median time to worthwhile seizure reduction was 203.5 days (interquartile range = 110.5–343.75 days). Patients with IGE with myoclonic seizures had a significantly shorter time to worthwhile seizure reduction than other patients. The surgical targeting strategy evolved after the first four subjects to achieve greater anatomic accuracy.Patients with both primary and rapidly generalized epilepsy who underwent CM RNS experienced substantial seizure relief. Subsets of these patient populations may particularly benefit from CM RNS. The refinement of lead targeting, tuning of RNS system parameters, and patient selection are ongoing areas of investigation. [ABSTRACT FROM AUTHOR]

Background: Premature Ventricular Complexes (PVCs) are very common in clinical practice, with frequent PVCs (more than 30 beats per hour) or polymorphic PVCs significantly increasing the risk of mortality. Previous studies have shown that vagus nerve stimulation improves ventricular arrhythmias. Stimulation of the auricular distribution of the vagus nerve has proven to be a simple, safe, and effective method to activate the vagus nerve. Transcutaneous au ricular vagus nerve stimulation (taVNS) has shown promise in both clinical and experimental setting for PVCs; however, high-quality clinical studies are lacking, resulting in insufficient evidence of efficacy. Methods: The study is a prospective, randomized, parallel-controlled trial with a 1:1 ratio between the two groups. Patients will be randomized to either the treatment group (taVNS) or the control group (Sham-taVNS) with a 6-week treatment and a subsequent 12-week follow-up period. The primary outcome is the proportion of patients with a ≥ 50% reduction in the number of PVCs monitored by 24-hour Holter. Secondary outcomes include the proportion of patients with a ≥ 75% reduction in PVCs, as well as the changes in premature ventricular beats, total heartbeats, and supraventricular premature beats recorded by 24-hour Holter. Additional assessments compared score changes in PVCs-related symptoms, as well as the score change of self-rating anxiety scale (SAS), self-rating depression scale (SDS), and 36-item short form health survey (SF-36). Discussion: The TASC-V trial will help to reveal the efficacy and safety of taVNS for frequent PVCs, offering new clinical evidence for the clinical practice. Trial registration: Clinicaltrials.gov: NCT04415203 (Registration Date: May 30, 2020). [ABSTRACT FROM AUTHOR]

Introduction: Chronic anxiety is a statemarked by sustained activation of the masseter muscle, manifesting in both mental and physical strain. This prolonged tension can significantly impact mental wellbeing and cognitive abilities, posing a risk for a range of health complications. This double-blind, randomized, controlled clinical trial investigated the impact of transcutaneous auricular vagus nerve stimulation (TAVNS) on masseter muscle activity, pressure pain threshold (PPT), and anxiety levels in university students with elevated anxiety. Methods: Forty-two participants meeting inclusion criteria were randomly assigned to either active TAVNS or sham TAVNS groups. Various parameters, including masseter muscle electromyographic (EMG) signals, PPT, and Beck Anxiety Inventory (BAI) scores, were assessed before pretreatment, immediately after the intervention week, and 2 weeks follow-up. Results: Active TAVNS significantly reduced both left and right masseter activation during resting mandibular position, persisting for 2 weeks post-intervention. Additionally, TAVNS induced a lasting decrease in both left and right masseter PPT, indicative of altered pain perception. Notably, BAI scores showed a substantial reduction, emphasizing TAVNS as a potential intervention for anxiety, with effects maintained at the 2-week follow-up. Discussion: This study provides comprehensive insights into the multifaceted effects of TAVNS on physiological and psychological aspects associated with anxiety in university students. The promising results underscore TAVNS as a potential neuromodulatory intervention for anxiety-related conditions, warranting further research and clinical exploration. [ABSTRACT FROM AUTHOR]

Bioelectronic therapies modulating the vagus nerve are promising for cardiovascular, inflammatory, and mental disorders. Clinical applications are however limited by side-effects such as breathing obstruction and headache caused by non-specific stimulation. To design selective and functional stimulation, we engineered VaStim, a realistic and efficient in-silico model. We developed a protocol to personalize VaStim in-vivo using simple muscle responses, successfully reproducing experimental observations, by combining models with trials conducted on five pigs. Through optimized algorithms, VaStim simulated the complete fiber population in minutes, including often omitted unmyelinated fibers which constitute 80% of the nerve. The model suggested that all Aα-fibers across the nerve affect laryngeal muscle, while heart rate changes were caused by B-efferents in specific fascicles. It predicted that tripolar paradigms could reduce laryngeal activity by 70% compared to typically used protocols. VaStim may serve as a model for developing neuromodulation therapies by maximizing efficacy and specificity, reducing animal experimentation. Advancements in bioelectronic therapies offer new hope for treating various disorders. Here, the authors present an accurate, subject-specific model of vagus nerve stimulation for enhancing efficacy and reducing side effects. [ABSTRACT FROM AUTHOR]

Tinnitus, characterized by phantom sound perception, is a highly disruptive disorder lacking definitive and effective treatments. Its intricate neural mechanisms are not fully understood. Transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated potential as a substitute or supplementary treatment by activating central vagal pathways. However, standardized therapeutic protocols and objective tests to assess efficacy are lacking. Therefore, taVNS shows promise as a therapy for tinnitus, and treatment protocols should be optimized in future clinical trials. [ABSTRACT FROM AUTHOR]

The vagus nerve regulates metabolic homeostasis and mediates gut–brain communication. We hypothesized that vagus nerve dysfunction, induced by truncated vagotomy (VGX) or carotid artery occlusion (AO), would disrupt gut–brain communication and exacerbate metabolic dysregulation, neuroinflammation, and cognitive impairment. This study aimed to test the hypothesis in gerbils fed a high-fat diet. The gerbils were divided into four groups: AO with VGX (AO_VGX), AO without VGX (AO_NVGX), no AO with VGX (NAO_VGX), and no AO without VGX (NAO_NVGX). After 5 weeks on a high-fat diet, the neuronal cell death, neurological severity, hippocampal lipids and inflammation, energy/glucose metabolism, intestinal morphology, and fecal microbiome composition were assessed. AO and VGX increased the neuronal cell death and neurological severity scores associated with increased hippocampal lipid profiles and lipid peroxidation, as well as changes in the inflammatory cytokine expression and brain-derived neurotrophic factor (BDNF) levels. AO and VGX also increased the body weight, visceral fat mass, and insulin resistance and decreased the skeletal muscle mass. The intestinal morphology and microbiome composition were altered, with an increase in the abundance of Bifidobacterium and a decrease in Akkermansia and Ruminococcus. Microbial metagenome functions were also impacted, including glutamatergic synaptic activity, glycogen synthesis, and amino acid biosynthesis. Interestingly, the effects of VGX were not significantly additive with AO, suggesting that AO inhibited the vagus nerve activity, partly offsetting the effects of VGX. In conclusion, AO and VGX exacerbated the dysregulation of energy, glucose, and lipid metabolism, neuroinflammation, and memory deficits, potentially through the modulation of the gut–brain axis. Targeting the gut–brain axis by inhibiting vagus nerve suppression represents a potential therapeutic strategy for ischemic stroke. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that vagus nerve stimulation can modulate heart rate variability (HRV). However, there is a lack of mechanistic studies in healthy subjects assessing the effects of bilateral transcutaneous auricular vagus nerve stimulation (taVNS) on HRV. Our study aims to investigate how taVNS can influence the HRV response, including the influence of demographic variables in this response. Methods: Therefore, we conducted a randomized controlled study with 44 subjects, 22 allocated to active and 22 to sham taVNS. Results: Our results showed a significant difference between groups in the high-frequency (HF) metric. Active taVNS increased the HF metric significantly as compared to sham taVNS. Also, we found that age was a significant effect modifier of the relationship between taVNS and HF-HRV, as a larger increase in HF-HRV was seen in the older subjects. Importantly, there was a decrease in HF-HRV in the sham group. Conclusions: These findings suggest that younger subjects can adapt and maintain a constant level of HF-HRV regardless of the type of stimulation, but in the older subjects, only the active taVNS recipients were able to maintain and increase their HF-HRV. These results are important because they indicate that taVNS can enhance physiological regulation processes in response to external events. [ABSTRACT FROM AUTHOR]

The neurovisceral integration model proposes that information flows bidirectionally between the brain and the heart via the vagus nerve, indexed by vagally mediated heart rate variability (vmHRV). Voluntary reduction in breathing rate (slow‐paced breathing, SPB, 5.5 Breathing Per Minute (BPM)) can enhance vmHRV. Additionally, prefrontal transcranial direct current stimulation (tDCS) can modulate the excitability of the prefrontal region and influence the vagus nerve. However, research on the combination of SPB and prefrontal tDCS to increase vmHRV and other cardiac (heart rate (HR) and blood pressure) and peripheral (skin conductance) indices is scarce. We hypothesized that the combination of 20 min of SPB and prefrontal tDCS would have a greater effect than each intervention in isolation. Hence, 200 participants were divided into four groups: active tDCS with SPB, active tDCS with 15 BPM breathing, sham tDCS with SPB, and sham tDCS with 15 BPM breathing. Regardless of the tDCS condition, the 5.5 BPM group showed a significant increase in vmHRV over 20 minutes and significant decreases in HR at the first and second 5‐min epochs of the intervention. Regardless of breathing condition, the active tDCS group exhibited higher HR at the fourth 5‐min epoch of the intervention than the sham tDCS group. No other effects were observed. Overall, SPB is a robust technique for increasing vmHRV, whereas prefrontal tDCS may produce effects that counteract those of SPB. More research is necessary to test whether and how SPB and neuromodulation approaches can be combined to improve cardiac vagal tone. [ABSTRACT FROM AUTHOR]

Upper limb impairment is common after stroke, with a significant impact on the stroke survivor's function, social participation and quality of life. Clinical guidelines are needed to inform clinical practise, tailor interventions to improve outcomes and address unresolved research questions. This review contributes to the evidence guiding clinical practise for upper limb motor recovery after stroke by summarising the recommendations from the UK rehabilitation guidelines (National Institute for Health and Care Excellence (NICE) and the Intercollegiate Stroke Working Party (ISWP)) and the European Stroke Organisation (ESO) guidelines, all published in 2023. All three guidelines target researchers, clinical practitioners, stroke survivors and their social networks. An important feature in all three guidelines was therapeutic intensity, with all guidelines recommending increased therapeutic intensity. Unlike the ESO, the NICE and ISWP additionally include specific research recommendations. While the NICE guidelines seem more holistic and target a wider audience, the three guidelines are complimentary. We recommend that a future consensus statement should be developed in partnership between all three organisations, agreeing on scope and using the same terminology, on recommendations to improve stroke rehabilitation in the UK and Europe. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patients and are associated with side effects that may limit their use. The vagus nerve (VN) provides a direct communication conduit between the CNS and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the VN (VNS) shows efficacy in ameliorating pathology in several CNS and autoimmune disorders. We therefore investigated the impact of VNS in a rat experimental autoimmune encephalomyelitis (EAE) model of MS. In this study, VNS-mediated neuroimmune modulation is demonstrated to effectively decrease EAE disease severity and duration, infiltration of neutrophils and pathogenic lymphocytes, myelin damage, blood-brain barrier disruption, fibrinogen deposition, and proinflammatory microglial activation. VNS modulates expression of genes that are implicated in MS pathogenesis, as well as those encoding myelin proteins and transcription factors regulating new myelin synthesis. Together, these data indicate that neuroimmune modulation via VNS may be a promising approach to treat MS, that not only ameliorates symptoms but potentially also promotes myelin repair (remyelination). [ABSTRACT FROM AUTHOR]

Background: Maternal exposure to inflammation is one of the causes of autism spectrum disorder (ASD). Electrical stimulation of the vagus nerve exerts a neuroprotective effect via its anti-inflammatory action. We thus investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) can enhance social abilities in a mouse model of ASD induced by maternal immune activation (MIA). Methods: ASD mouse model were constructed by intraperitoneal injection of polyinosinic: polycytidylic acid (poly (I:C)). TaVNS with different parameters were tested in ASD mouse model and in C57BL/6 mice, then various behavioral tests and biochemical analyses related to autism were conducted. ASD model mice were injected with an interleukin (IL)-17a antibody into the brain, followed by behavioral testing and biochemical analyses. Results: TaVNS reduced anxiety, improved social function, decreased the number of microglia, and inhibited M1 polarization of microglia. Additionally, taVNS attenuated the expression of the IL-17a protein in the prefrontal cortex and blood of ASD model mice. To examine the possible involvement of IL-17a in taVNS-induced neuroprotection, we injected an IL-17a antibody into the prefrontal cortex of ASD model mice and found that neutralizing IL-17a decreased the number of microglia and inhibited M1 polarization. Furthermore, neutralizing IL-17a improved social function in autism model mice. Conclusion: Our study revealed that reduced neuroinflammation is an important mechanism of taVNS-mediated social improvement and neuroprotection against autism. This effect of taVNS could be attributed to the inhibition of the IL17a pathway. [ABSTRACT FROM AUTHOR]

Background: Long COVID, also known as Post-COVID-19 syndrome, is characterized by multisystemic symptoms that persists for weeks to years beyond acute infection. It disproportionately affects women and those with preexisting anxiety/depression, conditions more prevalent in females. The vagus nerve, with its extensive innervation and regulation of critical bodily functions, has become a focal point for therapeutic interventions. Transcutaneous vagus nerve stimulation (t-VNS) has emerged as a promising non-invasive treatment for COVID-19 conditions. Methods: This pilot study assessed the efficacy of t-VNS in 24 female Long COVID patients (45.8  ±  11.7  years old; 20.2  ±  7.1  months since infection), who underwent a 10-day  t-VNS intervention at home (30  min/session, twice a day). Cognition was considered the primary outcome, with anxiety, depression, sleep, fatigue, and smell as secondary outcomes. Outcomes were measured at baseline, post-intervention, and 1-month follow-up. Results: Significant improvements were observed in various cognitive functions, anxiety, depression, and sleep at post-intervention, with benefits remaining or progressing at 1-month follow-up. Improvements in fatigue were delayed, reaching statistical significance at 1-month follow-up compared to baseline. No significant changes were noted in olfactory performance. Conclusion: This pilot study provides preliminary evidence supporting the potential of t-VNS as a therapeutic intervention for female Long COVID patients. The encouraging results justify further rigorous investigation through larger, randomized controlled trials to confirm the efficacy of t-VNS, assess its generalizability to male cohorts, and explore biological markers to inform personalized treatment approaches. Our findings support the allocation of resources to conduct such trials and advance the understanding of t-VNS as a potential treatment for Long COVID. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder that affects approximately 10.5 million children worldwide. Approximately 33% of affected patients exhibit resistance to all available antiseizure medications, but the underlying mechanisms are unknown and there is no effective treatment. Increasing evidence has shown that an abnormal gut microbiota may be associated with epilepsy. The gut microbiota can influence the function of the brain through multiple pathways, including the neuroendocrine, neuroimmune, and autonomic nervous systems. This review discusses the interactions between the central nervous system and the gastrointestinal tract (the brain-gut axis) and the role of the gut microbiota in the pathogenesis of epilepsy. However, the exact gut microbiota involved in epileptogenesis is unknown, and no consistent results have been obtained based on current research. Moreover, the target that should be further explored to identify a novel antiseizure drug is unclear. The role of the gut microbiota in epilepsy will most likely be uncovered with the development of genomics technology. [ABSTRACT FROM AUTHOR]

Encoding artificial perceptions through brain stimulation, especially that of higher cognitive functions such as speech perception, is one of the most formidable challenges in brain-computer interfaces (BCI). Brain stimulation has been used for functional mapping in clinical practices for the last 70 years to treat various disorders affecting the nervous system, including epilepsy, Parkinson's disease, essential tremors, and dystonia. Recently, direct electrical stimulation has been used to evoke various forms of perception in humans, ranging from sensorimotor, auditory, and visual to speech cognition. Successfully evoking and fine-tuning artificial perceptions could revolutionize communication for individuals with speech disorders and significantly enhance the capabilities of brain-computer interface technologies. However, despite the extensive literature on encoding various perceptions and the rising popularity of speech BCIs, inducing artificial speech perception is still largely unexplored, and its potential has yet to be determined. In this paper, we examine the various stimulation techniques used to evoke complex percepts and the target brain areas for the input of speech-like information. Finally, we discuss strategies to address the challenges of speech encoding and discuss the prospects of these approaches. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) affects millions of individuals worldwide, leading to considerable social and economic costs. Despite advancements in pharmacological treatments, achieving remission remains a key challenge, with a substantial number of patients showing resistance to existing therapies. This resistance is often associated with elevated levels of proinflammatory cytokines, suggesting a connection between inflammation, MDD pathophysiology, and treatment efficacy. The observation of increased immune activation in about a quarter of patients with MDD resulted in the distinction between inflammatory and noninflammatory endotypes. Although anti-inflammatory treatments show promise in alleviating depression-like symptoms, responses are heterogeneous, thus highlighting the importance of identifying distinct inflammatory endotypes to tailor effective therapeutic strategies. The intestinal microbiome emerges as a crucial modulator of mental health, mediating its effects partially through different immune pathways. Microbiota-derived short-chain fatty acids (SCFAs) significantly impact innate and adaptive immune cells, regulating their differentiation, function, and cellular response. Furthermore, gut-educated immune cells reach the border regions of the central nervous system (CNS), regulating glial cell functions. Although the CNS modulates immune responses via efferent parts of the vagus nerve, afferent tracts concurrently transport information on peripheral inflammation back to the brain. This bidirectional communication is particularly relevant in depression, allowing for therapeutic stimulation of the vagus nerve in the context of inflammatory depression endotypes. In this review, we explore the intricate relationship between inflammation and depression, discuss how inflammatory signals are translated into depressive-like symptoms, and highlight immune-modulating therapeutic avenues. [ABSTRACT FROM AUTHOR]

Electrical stimulation mapping (ESM) is used to locate the brain areas supporting language directly within the human cortex to minimize the risk of functional decline following epilepsy surgery. ESM is completed by utilizing subdural grid or depth electrodes (stereo‐electroencephalography [sEEG]) in combination with behavioral evaluation of language. Despite technological advances, there is no standardized method of assessing language during pediatric ESM. To identify current clinical practices for pediatric ESM of language, we surveyed neuropsychologists in the Pediatric Epilepsy Research Consortium. Results indicated that sEEG is used for functional mapping at >80% of participating epilepsy surgery centers (n = 13/16) in the United States. However, >65% of sites did not report a standardized protocol to map language. Survey results indicated a clear need for practice recommendations regarding ESM of language. We then utilized PubMed/Medline and PsychInfo to identify 42 articles that reported on ESM of language, of which 18 met inclusion criteria, which included use of ESM/signal recording to localize language regions in children (<21 years) and a detailed account of the procedure and language measures used, and region‐specific language localization outcomes. Articles were grouped based on the language domain assessed, language measures used, and the brain regions involved. Our review revealed the need for evidence‐based clinical guidelines for pediatric language paradigms during ESM and a standardized language mapping protocol as well as standardized reporting of brain regions in research. Relevant limitations and future directions are discussed with a focus on considerations for pediatric language mapping. [ABSTRACT FROM AUTHOR]

Objective: To identify the most common locations of cluster headache pain from an international, non–clinic‐based survey of participants with cluster headache, and to compare these locations to other cluster headache features as well as to somatotopic maps of peripheral, brainstem, thalamic, and cortical areas. Background: Official criteria for cluster headache state pain in the orbital, supraorbital, and/or temporal areas, yet studies have noted pain extending beyond these locations, and the occipital nerve appears relevant, given the effectiveness of suboccipital corticosteroid injections and occipital nerve stimulation. Furthermore, cranial autonomic features vary between patients, and it is not clear if the trigeminovascular reflex is dermatome specific (e.g., do patients with maxillary or V2 division pain have more rhinorrhea?). Finally, functional imaging studies show early activation of the posterior hypothalamus in a cluster headache attack. However, the first somatosensory area to be sensitized is unclear; the first area can be hypothesized based on the complete map of pain locations. Methods: The International Cluster Headache Questionnaire was an internet‐based cross‐sectional survey that included a clickable pain map of the face. These data were compared to several other datasets: (1) a meta‐analysis of 22 previous publications of pain location in cluster headache (consisting of 6074 patients); (2) four cephalic dermatome maps; (3) participants' survey responses for demographics, autonomic features, and effective medications; and (4) previously published somatotopic maps of the brainstem, thalamus, primary somatosensory cortex, and higher order somatosensory cortex. Results: One thousand five hundred eighty‐nine participants completed the pain map portion of the survey, and the primary locations of pain across all respondents was the orbital, periorbital, and temporal areas with a secondary location in the lower occiput; these primary and secondary locations were consistent with our meta‐analysis of 22 previous publications. Of the four cephalic dermatomes (V1, V2, V3, and a combination of C2‐3), our study found that most respondents had pain in two or more dermatomes (range 85.7% to 88.7%, or 1361–1410 of 1589 respondents, across the four dermatome maps). Dermatomes did not correlate with their respective autonomic features or with medication effectiveness. The first area to be sensitized in the canonical somatosensory pathway is either a subcortical (brainstem or thalamus) or higher order somatosensory area (parietal ventral or secondary somatosensory cortices) because the primary somatosensory cortex (area 3b) and somatosensory area 1 have discontinuous face and occipital regions. Conclusions: The primary pain locations in cluster headache are the orbital, supraorbital, and temporal areas, consistent with the official International Classification of Headache Disorders criteria. However, activation of the occiput in many participants suggests a role for the occipital nerve, and the pain locations suggest that somatosensory sensitization does not start in the primary somatosensory cortex. Plain Language Summary: Cluster headache (CH) pain is often thought to be located in or around the eye; however, multiple studies have documented pain elsewhere, and procedures that target nerves in the back of the head can help CH. In this large survey (1604 respondents) with a clickable pain map of the face, we found that (1) most respondents had pain extending beyond the area of the eye, and (2) the pain location did not correlate with autonomic symptoms, medication effectiveness, or other CH features. Cluster headache pain beyond the eye is common, and based on the pattern of areas activated, we hypothesized which parts of the brain's somatosensory system may be activated first in cluster attacks. [ABSTRACT FROM AUTHOR]

The importance of psychopathy for perpetration and maintenance of intimate partner violence (IPV) has been speculated. However, less is known about whether psychopathy would explain a psychophysiological response (cardiorespiratory and electrodermal) of IPV perpetrators dealing with acute stressors. Therefore, we first aimed to assess whether IPV perpetrators (n = 58) showed differences in psychopathic traits and their psychophysiological response to acute stress compared to nonviolent men (n = 53). Second, we examined in both groups whether psychopathic traits would explain a psychophysiological response when dealing with acute laboratory stress. Our results revealed that IPV perpetrators differed from controls in all the psychopathic traits, scoring higher on all psychopathy scales. Moreover, IPV perpetrators showed lower total respiratory sinus arrhythmia (RSA) levels than controls. Finally, regarding high total psychopathy scores, factor 1 and affective facet entailed low RSA levels in both groups and scoring high in lifestyle facet of factor 2 explained reduced heart rate (HR) changes in response to acute stress in both groups. All these results highlighted that a reduced vagal tone could be characteristic of psychopathic traits, especially for the affective facet of psychopathy. Therefore, it would be important to incorporate biological markers in combination with psychological measurements to clearly diagnose IPV perpetrators before starting intervention programs. This would increase our ability to improve IPV intervention therapeutic targets and reduce risk of recidivism. [ABSTRACT FROM AUTHOR]

Objectives: The author discusses current otolaryngological procedures employing the palatopharyngeus muscle, based on the surgical anatomy of the muscle and its neural supply. These techniques should be deeply revised for more conservative, anatomically-based maneuvers. Methods: Revision of anatomical and surgical research and comments with the provision of a primary concept. Results: The palatopharyngeus muscle is innervated by the pharyngeal plexus (the vagus and the accessory nerves) with additional fibers from the lesser palatine nerves. The innervation enters the muscle mainly through its lateral border. Conclusions: The palatopharyngeus muscle has a fundamental role in swallowing and speech. The muscle helps other dilators to maintain upper airway patency. Sphincter pharyngoplasty should be revised as regards its role as a sphincter. Palatopharyngeal procedures for OSA employing the palatopharyngeus muscle should follow the conservative, anatomically-based, and non-neural ablation concept. Level of evidence: 4. [ABSTRACT FROM AUTHOR]

Higher magnetic field strength introduces stronger magnetic field inhomogeneities in the brain, especially within temporal lobes, leading to image artifacts. Particularly, T2-weighted fluid-attenuated inversion recovery (FLAIR) images can be affected by these artifacts. Here, we aimed to improve the FLAIR image quality in temporal lobe regions through image processing of multiple contrast images via machine learning using a neural network. Thirteen drug-resistant MR-negative epilepsy patients (age 29.2 ± 9.4y, 5 females) were scanned on a 7 T MRI scanner. Magnetization-prepared (MP2RAGE) and saturation-prepared with 2 rapid gradient echoes, multi-echo gradient echo with four echo times, and the FLAIR sequence were acquired. A voxel-wise neural network was trained on extratemporal-lobe voxels from the acquired structural scans to generate a new FLAIR-like image (i.e., deepFLAIR) with reduced temporal lobe inhomogeneities. The deepFLAIR was evaluated in temporal lobes through signal-to-noise (SNR), contrast-to-noise (CNR) ratio, the sharpness of the gray-white matter boundary and joint-histogram analysis. Saliency mapping demonstrated the importance of each input image per voxel. SNR and CNR in both gray and white matter were significantly increased (p < 0.05) in the deepFLAIR's temporal ROIs, compared to the FLAIR. The gray-white matter boundary sharpness was either preserved or improved in 10/13 right-sided temporal regions and was found significantly increased in the ROIs. Multiple image contrasts were influential for the deepFLAIR reconstruction with the MP2RAGE second inversion image being the most important. The deepFLAIR network showed promise to restore the FLAIR signal and reduce contrast attenuation in temporal lobe areas. This may yield a valuable tool, especially when artifact-free FLAIR images are not available. • 7 T FLAIR often suffers from signal dropout in temporal lobes. • A subject-specific neural network to reduce the artifacts in post-processing. • The network reconstructs per voxel the FLAIR signal from other structural scans. • Improved SNR and CNR were observed in the attenuated regions. • Further developments may yield deepFLAIR a helpful tool to combat signal dropout. [ABSTRACT FROM AUTHOR]

• Vagotomy mitigates Salmonella-induced systemic infection and anxiety-like behavior. • Vagotomy alleviates the Salmonella-induced gut inflammation and neuroinflammation. • Vagotomy enhanced GABA production and related microbes abundance in the infected mice. • Vagotomy relies on GABA production to alleviate gut inflammation. The vagus nerve, a pivotal link within the gut-brain axis, plays a critical role in maintaining homeostasis and mediating communication between the gastrointestinal tract and the brain. It has been reported that gastrointestinal infection by Salmonella typhimurium (S. typhimurium) triggers gut inflammation and manifests as anxiety-like behaviors, yet the mechanistic involvement of the vagus nerve remains to be elucidated. In this study, we demonstrated that unilateral cervical vagotomy markedly attenuated anxiety-like behaviors induced by S. typhimurium SL1344 infection in C57BL/6 mice, as evidenced by the open field test and marble burying experiment. Furthermore, vagotomy significantly diminished neuronal activation within the nucleus of the solitary tract and amygdala, alongside mitigating aberrant glial cell activation in the hippocampus and amygdala. Additionally, vagotomy notably decreases serum endotoxin levels, counters the increase in splenic Salmonella concentration, and modulates the expression of inflammatory cytokines—including IL-6, IL-1β, and TNF-α—in both the gastrointestinal tract and brain, with a concurrent reduction in IL-22 and CXCL1 expression. This intervention also fostered the enrichment of beneficial gut microbiota, including Alistipes and Lactobacillus species, and augmented the production of gamma-aminobutyric acid (GABA) in the gut. Administration of GABA replicated the vagotomy's beneficial effects on reducing gut inflammation and anxiety-like behavior in infected mice. However, blockade of GABA receptors with picrotoxin abrogated the vagotomy's protective effects against gut inflammation, without influencing its impact on anxiety-like behaviors. Collectively, these findings suggest that vagotomy exerts a protective effect against infection by promoting GABA synthesis in the colon and alleviating anxiety-like behavior. This study underscores the critical role of the vagus nerve in relaying signals of gut infection to the brain and posits that targeting the gut-brain axis may offer a novel and efficacious approach to preventing gastrointestinal infections and associated behavioral abnormalities. [ABSTRACT FROM AUTHOR]

• Gastric schwannomas originate from the gastrointestinal plexus and are a rare type of schwannomas occurring in the gastrointestinal tract. Such surgery is very likely to damage the corresponding gastric innervation and cause adverse reactions. • Postoperative gastroparesis syndrome is a kind of gastric neuromuscular dysfunction characterized by delayed gastric emptying. At present, the clinical treatment of gastroparesis has certain limitations, and the effect is usually not good. • Electroacupuncture can accelerate the recovery process of patients with gastroparesis after gastric neurinoma surgery, which is shown to increase the tolerance of patients to oral feeding, accelerate the passage of contrast agent through pyloric sinus, and ultimately shorten the length of hospital stay of patients. The patient was well accepted and well tolerated. We identified the potential role of electroacupuncture (EA) as an alternative therapy to traditional Chinese medicine (TCM) in a rare case of postoperative gastroparesis after gastric schwannoma (GS). A 31-year-old woman presented with impaired gastric emptying after gastrectomy for GS and was diagnosed with postoperative gastroparesis syndrome (PGS). The symptoms were slightly relieved after routine placement of the jejunal tube; however, symptoms such as dietary intolerance and impaired gastric emptying persisted. After the consultation, the patient agreed to undergo EA therapy. The patient was able to tolerate oral intake after seven days of EA treatment, and the frequency and amount of food intake increased. The jejunal tube was removed at the outpatient follow-up two weeks after discharge, and the patient resumed a semi-liquid diet and was able to eat small amounts of rice. Reexamination of the upper digestive tract angiography showed that part of the contrast agent passed through the pyloric sinus, which showed improvement. EA stimulation increased tolerance to transoral feeding in patients with postoperative gastroparesis and facilitated the passage of contrast agents through the pyloric sinus. No adverse effects were observed during treatment, and the treatment was well accepted and tolerated by patients. A review article noted the benefits of acupuncture for gastrointestinal disorders but lacked high-quality evidence to support this. 1 Therefore, the therapeutic role of EA needs to be further elucidated to provide high-quality evidence-based medical evidence for its clinical use. [ABSTRACT FROM AUTHOR]

Introduction: Swallowing impairment is a crucial issue that can lead to aspiration, pneumonia, and malnutrition. Animal models are useful to reveal pathophysiology and to facilitate development of new treatments for dysphagia caused by many diseases. The present study aimed to develop a new dysphagia model with reduced pharyngeal constriction during pharyngeal swallowing. Methods: We analyzed the dynamics of pharyngeal swallowing over time with the pharyngeal branches of the vagus nerve (Ph-X) bilaterally or unilaterally transected, using videofluoroscopic assessment of swallowing in guinea pigs. We also evaluated the detailed anatomy of the pharyngeal constrictor muscles after the denervation. Results: Videofluoroscopic examination of swallowing showed a significant increase in the pharyngeal area during swallowing after bilateral and unilateral sectioning of the Ph-X. The videofluoroscopy also showed significantly higher pharyngeal transit duration for bilateral and unilateral section groups. The thyropharyngeal muscle on the sectioned side was significantly thinner than that on the intact side. In contrast, the thickness of the cricopharyngeal muscles on the sectioned and intact sides were not significantly different. The mean thickness of the bilateral thyropharyngeal muscles showed a linear correlation to the pharyngeal area and pharyngeal transit duration. Discussion: Data obtained in this study suggest that denervation of the Ph-X could influence the strength of pharyngeal contraction during pharyngeal swallowing in relation to thickness of the pharyngeal constrictor muscles, resulting in a decrease in bolus speed. This experimental model may provide essential information (1) for the development of treatments for pharyngeal dysphagia and (2) on the mechanisms related to the recovery process, reinnervation, and nerve regeneration following injury and swallowing impairment possibly caused by medullary stroke, neuromuscular disease, or surgical damage from head and neck cancer. [ABSTRACT FROM AUTHOR]

Background: Chronic low back pain (CLBP) is a frequent disease. It is a critical health concern that can influence functional capacity by restricting living activities. Objectives: The current study is to investigate the effects of transcutaneous vagus nerve stimulation (TVNs) in the management of CLBP. Methods: We searched the databases on Google Scholar, PubMed, Web of Science, Cochrane, and Pedro for randomized clinical trial (RCT) studies published in any language that looked at the effectiveness of TVNs in people with chronic LBP. The inclusion criteria were PICO. Participants in the research were people (≥ 18 years) diagnosed with persistent low back pain for more than 3 months. Study quality was assessed using Cochrane ROB 2. Results: Our database search found 1084 RCT. A number of studies that were not necessary for the issue were removed, and the overall outcome was six trials. Risk of bias (ROB) evaluations at the study level (derived from outcomes) are reported. In the six studies, two (33.3%) had an overall uncertain ROB (i.e., some concerns), whereas one (16.7%) had a high overall ROB. Three trials (50%) had a low overall RoB. Conclusion: There is still no evidence to support the use of transcutaneous vagus nerve stimulation as a viable therapeutic rehabilitation strategy. Therefore, we recommend high-quality trials and long-term follow-up to evaluate disability, quality of life, and pain outcomes in these patients. [ABSTRACT FROM AUTHOR]

Background: The autonomic nervous system plays a vital role in regulating physiological functions. Transcutaneous auricular vagus nerve stimulation (taVNS) is a method that provides insights into autonomic nerve modulation. This paper presents a research protocol investigating proof of mechanism for the impact of taVNS on autonomic functions and aims to both deepen theoretical understanding and pave the way for clinically relevant applications. Methods: This protocol employs a single-blind, randomized cross-over design involving 10 healthy male participants. Simultaneous assessment of both the afferent and efferent aspects of the vagus nerve will be performed by integrating physiological measures, magnetic resonance imaging, and a questionnaire survey. Electrocardiogram will be measured to assess changes in heart rate, as a primary outcome, and heart rate variability. Active taVNS and sham stimulation will be compared, which ensures precision and blinding. Electrical stimulation will be applied to the left concha cymba and the left lobule for the active and sham conditions, respectively. The specific parameters of taVNS involve a pulse width of 250 µs, a frequency of 25 Hz, and a current adjusted to the perception threshold (0.1 mA ≤ 5 mA), delivered in cycles of 32 s on and 28 s off. Conclusions: This research investigates proof of mechanism for taVNS to elucidate its modulatory effects on the central and peripheral components of the autonomic nervous system. Beyond theoretical insights, the findings will provide a foundation for designing targeted neuromodulation strategies, potentially benefiting diverse patient populations experiencing autonomic dysregulation. By elucidating the neural mechanisms, this study contributes to the evolution of personalized and effective clinical interventions in the field of neuromodulation. Trial Registration: JRCT, jRCTs032220332, Registered 13 September 2022; https://jrct.niph.go.jp/latest-detail/jRCTs032220332. [ABSTRACT FROM AUTHOR]

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has garnered attention for stroke rehabilitation, with studies demonstrating its benefits when combined with motor rehabilitative training or delivered before motor training. The necessity of concurrently applying taVNS with motor training for post-stroke motor rehabilitation remains unclear. We aimed to investigate the necessity and advantages of applying the taVNS concurrently with motor training by an electromyography (EMG)-triggered closed-loop system for poststroke rehabilitation. Methods: We propose a double-blinded, randomized clinical trial involving 150 stroke patients assigned to one of three groups: concurrent taVNS, sequential taVNS, or sham control condition. In the concurrent group, taVNS bursts will synchronize with upper extremity motor movements with EMG-triggered closed-loop system during the rehabilitative training, while in the sequential group, a taVNS session will precede the motor rehabilitative training. TaVNS intensity will be set below the pain threshold for both concurrent and sequential conditions and at zero for the control condition. The primary outcome measure is the Fugl-Meyer Assessment of Upper Extremity (FMA-UE). Secondary measures include standard upper limb function assessments, as well as EMG and electrocardiogram (ECG) features. Ethics and dissemination: Ethical approval has been granted by the Medical Ethics Committee, affiliated with Zhujiang Hospital of Southern Medical University for Clinical Studies (2023-QX-012-01). This study has been registered on ClinicalTrials (NCT05943431). Signed informed consent will be obtained from all included participants. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings. Discussion: This study represents a pioneering effort in directly comparing the impact of concurrent taVNS with motor training to that of sequential taVNS with motor training on stroke rehabilitation. Secondly, the incorporation of an EMG-triggered closed-loop taVNS system has enabled the automation and individualization of both taVNS and diverse motor training tasks--a novel approach not explored in previous research. This technological advancement holds promise for delivering more precise and tailored training interventions for stroke patients. However, it is essential to acknowledge a limitation of this study, as it does not delve into examining the neural mechanisms underlying taVNS in the context of post-stroke rehabilitation. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: Compression of the vagus nerve by a pharyngeal mass is a well-documented condition that can result in sinus node dysfunction (SND). However, there is scarce literature on extrinsic vagal nerve compression from a tonsillar abscess. Case Report: A 59-year-old woman with a history of asthma and chronic throat discomfort presented to the Emergency Department with bradycardia, palpitations, and voice changes. Following a shellfish allergy hospitalization, an otolaryngology evaluation revealed an enlarged right tonsil, recommending tonsillectomy, but scheduling challenges persisted. The patient reported mild throat pain, dysphagia, hoarseness, rhinorrhea, and exertional dyspnea and was admitted for the evaluation of peritonsillar mass. She was found to be bradycardic with a heart rate of 47, with an electrocardiogram revealing SND. Albuterol and ipratropium nebulizers, as well as dexamethasone and pantoprazole, were initiated. With this treatment, the patient symptomatically improved with a new heart rate of 68. She was discharged with outpatient appointments, but was unfortunately lost to follow-up. Conclusions: This case reveals sinus node dysfunction resulting from extrinsic vagal nerve compression by a tonsillar abscess. Pressure on the vagus nerve can trigger bradycardia and low blood pressure, possibly due to compensatory overfiring of afferent vagal nerve signals from local mass effect. Early recognition and antibiotic treatment are essential to prevent cardiac complications. Clinicians must remain vigilant for such extrinsic causes, particularly in patients with chronic sore throat and cardiac symptoms. Further research and case reports are needed to deepen our understanding of this rare yet significant association. [ABSTRACT FROM AUTHOR]

Background: Vagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. Achieving a better understanding of the relationship between VNS parameters and neural and physiological responses is therefore necessary to enable the design of personalized dosing procedures and improve precision and efficacy of VNS therapies. Methods: We used biomarkers from recorded evoked fiber activity and short-term physiological responses (throat muscle, cardiac and respiratory activity) to understand the response to a wide range of VNS parameters in anaesthetised pigs. Using signal processing, Gaussian processes (GP) and parametric regression models we analyse the relationship between VNS parameters and neural and physiological responses. Results: Firstly, we illustrate how considering multiple stimulation parameters in VNS dosing can improve the efficacy and precision of VNS therapies. Secondly, we describe the relationship between different VNS parameters and the evoked fiber activity and show how spatially selective electrodes can be used to improve fiber recruitment. Thirdly, we provide a detailed exploration of the relationship between the activations of neural fiber types and different physiological effects. Finally, based on these results, we discuss how recordings of evoked fiber activity can help design VNS dosing procedures that optimize short-term physiological effects safely and efficiently. Conclusion: Understanding of evoked fiber activity during VNS provide powerful biomarkers that could improve the precision, safety and efficacy of VNS therapies. [ABSTRACT FROM AUTHOR]

Guarana (GUA), a Brazilian seed extract, contains caffeine and other bioactive compounds that may have psychoactive effects. To assess the acute effects of GUA compared to a low dose of caffeine (CAF) on cognitive and mood parameters, twenty participants completed a double-blind, crossover experiment where they ingested capsules containing the following: (1) 100 mg CAF, (2) 500 mg GUA containing 130 mg caffeine, or (3) placebo (PLA). Cognitive tests (Simon and 2N-Back Task) were performed at the baseline (pre-ingestion) and 60 min after ingestion. The response time for the cognitive tests and heart rate variability were unaffected (p > 0.05) by treatment, although 2N-Back was overall faster (p = 0.001) across time. The accuracy in the 2N-Back Task showed a significant interaction effect (p = 0.029) due to higher post-ingestion versus pre-ingestion levels (p = 0.033), but only with the PLA. The supplements also had no effect on cognitive measures following physical fatigue (n = 11). There was an interaction effect on perceived mental energy, where the pre-ingestion of GUA had lower mental pep ratings compared to post-ingestion (p = 0.006) and post-exercise (p = 0.018) levels. Neither the acute ingestion of GUA nor low dose of CAF influenced cognitive performance or provided consistent benefit on mood or mental workload through vagal modulation. Additional investigations are beneficial to determining the lowest effective dose for CAF or GUA to influence mood and/or cognitive performance. [ABSTRACT FROM AUTHOR]

Enteric neuropathies are characterized by abnormalities of gut innervation, which includes the enteric nervous system, inducing severe gut dysmotility among other dysfunctions. Most of the gastrointestinal tract is innervated by the vagus nerve, the efferent branches of which have close interconnections with the enteric nervous system and whose afferents are distributed throughout the different layers of the digestive wall. The vagus nerve is a key element of the autonomic nervous system, involved in the stress response, at the interface of the microbiota‐gut‐brain axis, has anti‐inflammatory and prokinetic properties, modulates intestinal permeability, and has a significant capacity of plasticity and regeneration. Targeting these properties of the vagus nerve, with vagus nerve stimulation (or non‐stimulation/ pharmacological methods), could be of interest in the therapeutic management of enteric neuropathies. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is a neuromodulatory therapy that has been FDA approved for the treatment of various disorders, including but not limited to, movement disorders (e.g., Parkinson's disease and essential tremor), epilepsy, and obsessive-compulsive disorder. Computational methods for estimating the volume of tissue activated (VTA), coupled with brain imaging techniques, form the basis of models that are being generated from retrospective clinical studies for predicting DBS patient outcomes. For instance, VTA models are used to generate target-and network-based probabilistic stimulation maps that play a crucial role in predicting DBS treatment outcomes. This review defines the methods for calculation of tissue activation (or modulation) including ones that use heuristic and clinically derived estimates and more computationally involved ones that rely on finite-element methods and biophysical axon models. We define model parameters and provide a comparison of commercial, open-source, and academic simulation platforms available for integrated neuroimaging and neural activation prediction. In addition, we review clinical studies that use these modeling methods as a function of disease. By describing the tissue-activation modeling methods and highlighting their application in clinical studies, we provide the neural engineering and clinical neuromodulation communities with perspectives that may influence the adoption of modeling methods for future DBS studies. [ABSTRACT FROM AUTHOR]

Background: Treatment of disorders of consciousness (DOC) poses a huge challenge for clinical medicine. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation method, which shows potential in improving recovery of DOC. However, the evidence came from single-center, small-sample randomized controlled trial, which is insufficient to form a conclusion. Thereby, we propose a prospective, multicenter, doubleblind, stratified, two-arm randomized controlled trial protocol to investigate the efficacy and safety of bilateral synchronous taVNS for treatment of DOC. Methods: We aim to recruit 382 patients with prolonged DOC, and divide them into an active stimulation group and a sham stimulation group. The patients in the active stimulation group will receive bilateral synchronous taVNS with a 200  μs pulse width, 20  Hz frequency, and personal adjusted intensity. The sham stimulation group will wear the same stimulator but without current output. Both groups will receive treatment for 30  min per session, twice per day, 6 days per week lasting for 4 weeks. The clinical assessment including Coma Recovery Scale-Revised (CRS-R), Full Outline of Unresponsiveness (FOUR), Glasgow Coma Scale (GCS), and Extended Glasgow Outcome Scale (GOS-E) will be conducted to evaluate its efficacy. Heart rate variability (HRV), blood pressure, and adverse events will be recorded to evaluate its safety. Discussion: These results will enable us to investigate the efficacy and safety of taVNS for DOC. This protocol will provide multicenter, large-sample, highquality Class II evidence to support bilateral synchronous taVNS for DOC, and will advance the field of treatment options for DOC [ABSTRACT FROM AUTHOR]