Search Results (74)

The vagus nerve (innervating the gut from esophagus to proximal colon) and sacral nerve (innervating distal colon and rectum) are key parasympathetic regulators of gastrointestinal (GI) function. While vagus nerve stimulation (VNS) has shown therapeutic potential in upper GI disorders, its role in modulating distal colon and rectal function remains poorly understood. This study investigated the effects and mechanisms of VNS on distal colon transit and rectal tone in rats. Adult male Sprague Dawley rats were implanted with stimulation electrodes at the cervical or auricular vagal afferent nerve. VNS was applied with varying frequencies, pulse widths, and amplitudes. Rectal tone was assessed using a barostat device, and distal colon transit was evaluated using bead expulsion. Nitrergic and cholinergic contributions were examined using L-NAME and nNOS expression, and acetylcholine ELISA and ChAT expression, respectively. Central pathways were investigated by immunofluorescence staining of c-fos and ChAT in the nucleus tractus solitarius (NTS). Sacral efferent pathway was assessed by chemogenetic inhibition of the dorsal motor nucleus of the vagus (DMV) and Barrington nucleus (BN/PMC). VNS (5 Hz, 0.1 and 0.5 ms, 0.5 mA) significantly increased rectal volume, indicating relaxation, and accelerated distal colon transit. L-NAME abolished VNS-induced rectal relaxation, while nNOS expression in the rectum was upregulated, confirming nitrergic mediation. Distal colon transit was associated with increased acetylcholine release and ChAT expression, highlighting cholinergic involvement. VNS enhanced c-fos and ChAT-positive neurons in the NTS, suggesting central integration of vagal afferent signals. Chemogenetic inhibition of DMV and BN attenuated rectal relaxation, indicating that VNS effects are mediated via a vagal–NTS–sacral pathway. VNS modulates distal colon transit and rectal tone through coordinated nitrergic and cholinergic signaling and central vagal-to-sacral circuits. These findings reveal functional crosstalk between vagal and sacral parasympathetic pathways and provide mechanistic insight into potential VNS therapy for lower GI disorders. Full article

Background: Long COVID, or post-COVID-19 condition (PCC), affects around 36% of individuals following SARS-CoV-2 infection, manifesting as persistent fatigue, cognitive dysfunction, and dysautonomia among its hallmark features. Affecting an estimated 400 million individuals globally, it imposes an annual economic burden exceeding $1 trillion, yet no pharmacological therapy has demonstrated consistent efficacy in adequately powered randomized controlled trials. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a candidate intervention targeting the autonomic dysfunction and neuroinflammation responsible for PCC pathophysiology. Methods: We conducted a PRISMA 2020-compliant systematic review (PROSPERO: CRD420261287286) searching PubMed, Scopus, Cochrane, and Web of Science databases from inception to January 2026 for studies evaluating any form of VNS in adults with Long COVID. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, the JADAD scale, and the PEDro scale. Certainty of evidence was evaluated using the GRADE framework. Narrative synthesis followed SWiM guidelines. Results: Five studies (n = 154 participants) (three randomized controlled trials (RCTs) and two single-arm studies) met inclusion criteria. Three of five studies (60%) were rated high overall risk of bias; only two RCTs achieved “some concerns.” The only adequately double-blinded RCT found no significant between-group differences across all outcomes. Paradoxically, in the best-powered RCT (Percin et al.), sham stimulation produced significantly greater fatigue improvement than active taVNS, despite active taVNS producing significant HRV increases consistent with cardiac autonomic modulation. All efficacy outcomes were rated “very low” certainty (GRADE); safety was rated “low” certainty. Conclusions: Currently available evidence supporting the use of taVNS for Long COVID remains limited, and the absence of reliable target engagement markers in the included studies constrains confidence in this approach. Nonetheless, the physiological rationale remains sound, and the favorable safety profile across all included studies supports the feasibility of future investigation. However, given that positive findings were confined to inadequately controlled studies, enthusiasm for further research should be directed first toward mechanistic clarification and rigorous dose-finding work. Large-scale, double-blind, sham-controlled trials incorporating validated markers of vagal engagement are required before taVNS can be firmly recommended for COVID-19 sequelae management. Full article

Background and Objectives: Coronavirus disease 2019 (COVID-19) is characterized by excessive inflammatory responses, including the so-called cytokine storm, which contributes substantially to morbidity and mortality in hospitalized patients. The vagus nerve, through the cholinergic anti-inflammatory pathway, represents a theoretically attractive therapeutic target for modulating systemic inflammation. Vagus nerve stimulation (VNS) has emerged as a potential adjunctive treatment for COVID-19, with several randomized controlled trials (RCTs) investigating its efficacy on inflammatory biomarkers and clinical outcomes. The quality of this evidence base has not been rigorously evaluated. This systematic review critically appraises all available RCT evidence for VNS in hospitalized COVID-19 patients. Materials and Methods: We systematically searched PubMed, Scopus, Cochrane (CENTRAL), and Web of Science from database inception to January 2026, for RCTs evaluating any form of VNS (invasive, non-invasive, cervical, or auricular) in hospitalized patients with confirmed acute COVID-19. Two reviewers independently screened titles, abstracts, and full texts according to pre-specified eligibility criteria. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, with assessments initially performed using multiple artificial intelligence tools and subsequently validated by the authors in accordance with PRISMA 2020 guidelines. Given substantial heterogeneity and high risk of bias, narrative synthesis was performed rather than meta-analysis. Also, GRADE assessment was performed. Results: From 437 records identified, six RCTs comprising 221 patients met the inclusion criteria. Five trials (83%) were rated as high risk of bias, primarily due to inadequate blinding, substantial baseline imbalances, significant missing data and extensive multiple testing without statistical correction. The single double-blind trial with a credible sham control (Rangon et al.) found null results across all outcomes, including clinical progression, ICU transfer, and mortality, while the five “high” risk-of-bias trials generally reported positive findings on various inflammatory markers and clinical outcomes. One trial (Corrêa et al.) measured heart rate variability as a direct indicator of vagal activation and found no change despite claiming anti-inflammatory effects, contradicting the proposed mechanism of action. Significant cognitive findings from an interim analysis (Uehara et al., n = 21) disappeared in the larger completed trial (Corrêa et al., n = 52), providing empirical demonstration of false positive findings in small, underpowered studies. Conclusions: Currently available evidence supporting the use of VNS for acute COVID-19 remains scarce; however, the physiological rationale remains sound, although the absence of reliable target engagement markers in the included studies limits confidence in this treatment method. Large-scale, double-blind, sham-controlled trials are required before VNS can be firmly recommended for COVID-19 management. Full article

Non-invasive vagus nerve stimulation (nVNS) is gaining attention as a promising approach to modulate emotional, cognitive, and autonomic processes. This exploratory study analyzed the short-term effects of manual vagal maneuver (MVM), applied to the left or the right side of the neck (carotid region), on emotional regulation, cognitive performance, and cardiac autonomic activity in healthy young females. Sixty participants, divided equally into three groups (left MVM, right MVM, and control), completed attentional tasks under their respective conditions. Heart rate variability (HRV), cardiac coherence, self-reported emotional states, and task performance were measured. The preliminary findings of this pilot study offer mixed evidence: while both stimulation groups seem to show significant improvements in attentional performance, only left-sided MVM was associated with increased cardiac coherence and elevated perceived emotional dominance. No significant changes were observed in HRV indices across groups, highlighting potential limitations of current physiological markers in capturing subtle autonomic modulation. These preliminary findings from a pilot study suggest that, in young healthy women, stimulation—particularly on the left side—may have a potential to enhance cognitive and affective functioning, even though no detectable changes were observed in conventional HRV metrics. Given the small sample size and other important methodological limitations, such as the single-session design, these results should be interpreted with caution, and replication in larger, more rigorous studies is necessary. Full article

For decades, researchers have explored the therapeutic potential of the vagus nerve through vagus nerve stimulation (VNS). Initially developed for epilepsy, VNS has since been applied to treat resistant depression, stroke recovery, and inflammatory conditions. Transcutaneous VNS (tVNS) now offers a noninvasive alternative, fueling clinical trials in disorders ranging from rheumatoid arthritis and migraines to long COVID-19. Mechanistic studies suggest that afferent and efferent vagal fibers modulate immune responses, mood regulation, and neurotransmitter systems. The SPARC initiative has accelerated mapping of vagal circuits, enabling more precise approaches to stimulation. Despite progress, the results remain mixed: while some patients experience lasting symptom relief, others respond no better than to placebo. Depression studies, in particular, highlight both the promise and the complexity of VNS, as inflammation, motivation circuits, and gut–brain signaling emerge as key modulators. Next-generation closed-loop devices and circuit-specific targeting may improve efficacy and reduce adverse effects. VNS research thus lies at the intersection of neuromodulation, psychiatry, and immunology—offering hope for hard-to-treat conditions, yet demanding rigorous trials to separate myths from medicine. In this article, we review the current clinical and experimental applications of tVNS, analyze its mixed efficacy across psychiatric, immunological, and neurological disorders, and highlight the mechanistic insights, stimulation parameters, and emerging technologies that may shape next-generation therapies. Full article

Development of new therapeutic approaches and strategies for common neuropsychiatric disorders, including Major Depressive Disorder, anxiety disorders, and Post-Traumatic Stress Disorder, represent a significant global health challenge. Recent research indicates that emotional dysregulation and persistent inflammation are closely linked and serve as key pathophysiological features of these conditions. Emotional dysregulation is mechanistically coupled to locus coeruleus and norepinephrine (LC-NE) or noradrenergic system activity. Stemming from chronic stress, persistently elevated activity of the LC-NE system leads to hypervigilance, anxious states, and depressed mood. Concurrently, these symptoms are marked by systemic inflammation as indicated by elevated pro-inflammatory cytokines, and central neuroinflammation indicated by microglial activation in brain regions and networks involved in mood regulation and emotional control. In turn, chronic inflammation increases sympathetic tone and LC-NE activity resulting in a vortex of psychoneuroimmunological dysfunction that worsens mental health. Transcutaneous auricular vagus nerve stimulation (taVNS) in a non-invasive neuromodulation method uniquely positioned to address both noradrenergic dysfunction and chronic inflammation in neuropsychiatric applications. Evidence spanning the past decade demonstrates taVNS works via two complementary mechanisms. An ascending pathway engages vagal afferents projecting to the LC-NE system in the brain stem, which has been shown to modulate cortical arousal, cognitive function, mood, and stress responses. Through descending circuits, taVNS also modulates the cholinergic anti-inflammatory pathway to suppress the production of pro-inflammatory cytokines like TNF-α and IL-6 mitigating poor health outcomes caused by inflammation. By enhancing both central brain function and peripheral immune responses, taVNS has shown significant potential for recalibrating perturbed affective-cognitive processing. The present article describes and discusses recent evidence suggesting that taVNS offers a promising network-based paradigm for restoring psychoneuroimmunological homeostasis in common neuropsychiatric conditions. Full article

It has been demonstrated that prolonged exposure to stress engenders a plethora of neuropsychiatric, immune and metabolic disorders. However, its pathophysiology transcends the conventional hypothalamic–pituitary–adrenal (HPA) axis. This review addresses the central question of how integrated neural and microbial pathways regulate stress responses and resilience. We present a model in which the parasympathetic nervous system (particularly the vagus nerve) and the gut microbiota interact to form a bidirectional neuroimmune network that modulates the HPA axis, immune function, neurotransmitter balance, and metabolic adaptation. Key molecular pathways include nitric oxide synthesis via the classical nitric oxide synthase (NOS)-dependent and microbiota-mediated nitrate–nitrite routes, inducible nitric oxide synthase (iNOS) regulation, nuclear factor erythroid 2-related factor 2 (Nrf2) signalling, lysosomal function, autophagy and the cholinergic anti-inflammatory reflex. Other pathways include the gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signalling, polyamine metabolism and peroxisome proliferator-activated receptor gamma (PPARγ). Intermittent hypoxia training (IHT) enhances mitochondrial function, oxidative stress responses, autonomic balance and gut microbiota composition. This promotes parasympathetic activity and stress resilience that is tailored to the individual. These adaptations support the concept of personalised stress response profiles based on hypoxic adaptability. Clinical implications include combining IHT with vagus nerve stimulation, probiotics, dietary strategies, and stress reduction techniques. Monitoring vagal tone and microbiota composition could also serve as predictive biomarkers for personalised interventions in stress-related disorders. This integrative framework highlights the therapeutic potential of targeting the parasympathetic system and the gut microbiota to modulate stress. Full article

Motility disorders, particularly gastroparesis, are prevalent complications following solid organ transplantation, significantly impacting quality of life, nutritional status, graft survival, and mortality. This comprehensive review synthesises evidence from PubMed, Scopus, and Embase databases on pathophysiology, clinical manifestations, diagnosis, management, and prognostic factors across transplant types. Mechanisms include vagal nerve injury (highest in lung transplants, prevalence 40–91%), immunosuppressive effects (e.g., tacrolimus accelerates motility; mycophenolate impairs it), surgical trauma, microbiome dysbiosis (reduced Firmicutes/Bacteroidetes ratio), and metabolic factors like post-transplant diabetes (OR 5.17 in kidney recipients). Pediatric and thoracic recipients face the highest risks, with lung transplant gastroparesis conferring a 2.7-fold increased mortality/retransplantation hazard (p < 0.05). Diagnosis relies on gastric emptying scintigraphy (gold standard, sensitivity 85–95%) and wireless motility capsules (100% sensitivity for delay), while management encompasses prokinetics (60–80% response), endoscopic G-POEM (85% success), gastric electrical stimulation (100% quality-of-life improvement in series), and nutritional support. Prognostic factors include younger age (better intervention response), aetiology (anatomical worse than metabolic), and early therapy success. Outcomes vary: lung recipients experience severe impacts on chronic allograft dysfunction (83% oesophageal motility abnormalities correlate with 66–67% rejection). Future directions emphasise microbiome therapies, AI predictive models (AUC 0.85), and wearables for continuous monitoring. Multidisciplinary approaches are essential to balance immunosuppression with GI management, addressing ethical dilemmas like drug interactions and access disparities. Ultimately, early screening and personalised interventions can mitigate complications, enhancing long-term transplant success. Full article

Cardiomyopathies affect over 3 million individuals globally, with conventional treatments exhibiting up to 60% resistance and 25% 30-day readmission rates. This review synthesizes the current evidence on the role of neuro-immune interactions in the pathogenesis of cardiomyopathy and evaluates emerging therapies targeting this axis. We systematically examined clinical trials and mechanistic and multi-omics data across cardiomyopathy phenotypes, focusing on autonomic-immune dysregulation. Sympathetic overactivation, present in approximately 85% of patients, correlates with elevated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and contributes significantly to therapeutic non-response. Concurrent parasympathetic withdrawal impairs cholinergic anti-inflammatory pathways, as reflected by reduced heart rate variability and baroreflex sensitivity. At the molecular level, shared mechanisms include inflammasome activation, neuroimmune synaptic signaling, and neurogenic inflammation. Emerging therapies targeting this axis are promising. Vagus nerve stimulation, as demonstrated in the INOVATE-HF trial, improves functional outcomes, whereas IL-1β antagonists reduce cardiovascular events by 15–20% in the context of inflammatory diseases. Bioelectronic interventions, such as transcutaneous vagal nerve stimulation and baroreflex activation therapy, offer noninvasive dual-modulatory strategies that address both neural and immune pathways, positioning the neuroimmune axis as a central driver of cardiomyopathy, regardless of etiology. The integration of genetic and metabolomic profiling may enable precision therapies targeting neuroimmune circuits, thereby overcoming the limitations of hemodynamic-focused care. This mechanistic framework shifts the therapeutic paradigm from symptomatic relief to targeted modulation of pathogenic pathways, with implications for millions of patients with cardiomyopathy and broader inflammatory cardiovascular disorders. Full article

Background/Objectives: A combination of sympathoexcitation and parasympathetic withdrawal contributes to the occurrence of ventricular arrhythmias, sudden cardiac death, and progression of heart failure after myocardial injury. As a result, vagal nerve stimulation has been under investigation as a potential option to increase cardiac vagal tone, but the results of clinical trials have been mixed. Prior studies have suggested that the vagal ganglia and nerves may contain sympathetic neurons that express tyrosine hydroxylase (TH), which, if stimulated, could potentially mitigate the effects of vagal nerve stimulation. The goal of the current study was to better characterize these neurons. Methods: Immunohistochemical staining was performed to evaluate for the presence of TH-expressing neurons in the inferior vagal (nodose) ganglia from six pigs. Additional staining was performed for dopamine beta-hydroxylase (DBH), which is required for the production of norepinephrine (NE), to determine if these neurons are indeed sympathetic and capable of releasing NE. Analysis of stellate ganglia was also performed, given that these ganglia are known to provide sympathetic innervation to the heart and release NE in the myocardium. Results: While nearly all TH-expressing neurons in the stellate ganglia expressed DBH, confirming that they can produce or release NE, none of the TH-expressing neurons in the vagal ganglia expressed DBH, demonstrating that these are dopaminergic but not noradrenergic neurons. Conclusions: TH-expressing neurons in the vagal ganglia previously reported to be potentially “sympathetic” do not express DBH and are, therefore, not capable of synthesizing NE. Full article

Behavioral issues in domestic dogs represent a significant welfare concern affecting both canines and their caregivers, with prevalence rates reported to range from 34 to 86% across the population. Current treatment options, including selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, often present limitations including adverse effects and delayed efficacy. This randomized, placebo-controlled (maltodextrin) study investigated the effects of a novel Lactiplantibacillus plantarum strain (LP815^TM) on canine behavioral concerns through gut–brain axis modulation. Home-based dogs (n = 40) received either LP815^TM (n = 28) or placebo (n = 12) daily for 4 weeks, with behavioral changes assessed using the comprehensive Canine Behavioral Assessment & Research Questionnaire (C-BARQ) and continuous activity monitoring. After the intervention period, dogs receiving LP815^TM showed significant improvements in aggression (p = 0.0047) and anxiety (p = 0.0005) compared to placebo controls. These findings were corroborated by objective activity data, which demonstrated faster post-departure settling, reduced daytime sleep, and improved sleep consistency in the treatment group. Throughout >1120 administered doses, no significant adverse events were reported, contrasting favorably with pharmaceutical alternatives. The concordance between our findings and previous research using different L. plantarum strains suggests a consistent biological mechanism, potentially involving GABA production and vagal nerve stimulation. These results indicate that LP815^TM represents a promising, safe alternative for addressing common canine behavioral concerns with potential implications for improving both canine welfare and the human–animal bond. Full article

Vagal nerve stimulators (VNSs) improve seizure control in up to half of the patients who have them implanted. In non-responding patients, VNS removal may be necessary. Removal is traditionally accomplished through two incisions. We present our experience removing VNSs through a single incision. Background/Objectives: To determine if VNS removal can be safely performed through a single incision. Methods: The medical records of 73 consecutive patients who underwent VNS removal at our institution from 2012 to 2024 were reviewed. Patients were divided into single-incision and two-incision treatment groups. Operative time and surgical complications were compared between groups. Results: A total of 73 patients underwent VNS removal during the study timeframe. Forty-eight VNS removals were accomplished via a single incision, while 25 required both incisions. Time in the operating room was roughly half as long for single-incision removal vs. two-incision removal (29.4 min, range 11–84 vs. 74.2 min, range 33–203); however, single incision was initially attempted in all cases. In two of the incision cases, the neck dissection resulted in an injury to the internal jugular (IJ) vein. In one case, the IJ was repaired and the lead wire removed. In a second case, the IJ could not be repaired, and a segment of lead wire was retained. In a third case, a short length of lead wire was discovered after a single-incision removal and a second procedure was necessary for removal. There were no significant differences in the rates of transient vocal cord weakness, cough, and/or dysphagia between both treatment groups (p = 0.7368), and there were no cases of permanent nerve palsy. Conclusions: VNS removal can be safely accomplished via a single incision in most cases. Successful single-incision procedures may be shorter than the two-incision approach. Attempted VNS removal via a single incision may result in increased incidence of transient hoarseness, dysphagia, and/or cough, but may result in reduced rates of permanent injury or IJ injury. Full article

Background and Objectives: This study aimed to discuss positional changes in the sternocleidomastoid (SCM) muscle and vagus nerve with head position, their effect on the surgical path, positional variations, the selection of an appropriate position for surgery, their effects on the surgical procedure, and complications by using peroperative ultrasonography. Materials and Methods: Vagal nerve stimulation surgery patients over the age of 18 years were included. Peroperative ultrasonography images were scanned, and changes in head position and anatomical and positional variations in the SCM muscle and vagus nerve at the surgical incision level were examined. Results: SCM localization was most frequently observed in the lateral aspect of the carotid sheath (n:16) in neutral position, while it was mostly observed in the medial aspect of the carotid sheath (n:16) at a 15 degree rotation. The vagus nerve was mostly observed between the jugular vein and carotid artery in neutral position (n:21), and it was observed at the same position at a 15 degree rotation (n:17). The positional change of the SCM muscle with head position was found to be statistically significant (p < 0.001), while the positional change of the vagus nerve was not (p:0.198). Conclusions: The SCM muscle closes the surgical path with head rotation by either deviating over the carotid sheath or increasing its deviation. In addition to its anatomical variations, the vagus nerve shows different positional changes with head rotation. Deciding on the head position in vagal nerve stimulation surgery, using peroperative ultrasonography rather than a routine position, may be effective in reducing surgical time and possible complications. Full article

Patients with type 2 diabetes mellitus (T2DM) predominantly experience mortality due to cardiovascular diseases (CVD), particularly in low- and middle-income nations. Among these, heart failure (HF) is the most severe cardiovascular complication in terms of prognosis and management. Despite advancements in individualized glycemic control and cardiovascular risk management, including the development of novel glucose- and lipid-lowering agents, the prevalence of HF in T2DM patients remains persistently high. This indicates that factors beyond hyperglycemia significantly contribute to the heightened risk of HF associated with T2DM. This review examines critical factors influencing CVD risk in T2DM, particularly the roles of reduced heart rate variability (HRV), a marker of autonomic dysfunction, and chronic inflammation, both of which play pivotal roles in HF pathogenesis. Recent evidence highlights the potential of vagus nerve activation to modulate these risk factors, underscoring its capacity to reduce T2DM-related cardiovascular complications. Specifically, we discuss the therapeutic promise of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive intervention to enhance vagal tone, decrease systemic inflammation, and improve cardiovascular outcomes in T2DM. By addressing the interplay among HRV, microvascular disease, and inflammation, this review provides a comprehensive perspective on the potential utility of taVNS in managing HF in T2DM. Full article

Background: The ongoing conflict in Ukraine has forced numerous migrants into neighboring countries, many suffering from pre-existing or newly acquired physical and mental health conditions. Addressing these complex challenges in humanitarian settings requires innovative, evidence-based interventions that are cost-effective and easy to administer. Drawing upon research highlighting the vagus nerve’s role in regulating well-being, we hypothesized that vagal nerve activation could offer a promising therapeutic approach. Method: We conducted a proof-of-concept study in which 21 Ukrainian forced migrants were trained in a biofeedback-guided paced breathing intervention designed to stimulate the vagus nerve and promote self-regulation of stress response systems. Changes in pain perception, perceived stress, blood pressure, and heart rate were assessed before and after the vagal breathing intervention using a t-test. Correlations were examined at baseline. Results: Statistically significant improvements were observed in all measures except systolic blood pressure, providing preliminary evidence for the efficacy of vagal nerve activation in alleviating stress-related health symptoms. Conclusions: This study demonstrates the feasibility and therapeutic potential of a vagal nerve-activating intervention in a humanitarian setting. These findings warrant replication in larger, controlled trials. If substantiated, this low-cost, scalable intervention could help mitigate health burdens among forced migrant populations worldwide. Full article