Search Results (139)

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

The heart is innervated by the autonomic nervous system (ANS), which plays a role in regulating the heart rate. Cross-country mountain biking (MTBXC) is a sport with high physiological demands, where the autonomic nervous system plays a significant role. The main objective of this study was to analyze the asymmetry of heart rate in Colombian National Team mountain bikers, sub-23 category, during a 20 min cardiovascular autonomic profile test. Method: The cardiovascular autonomic profile was measured through heart rate variability during a 20 min test, divided into eight phases (supine, controlled ventilation at 10 cycles/min, controlled ventilation at 12 cycles/min, postural change, orthostasis, Ruffier test, 1 min recovery, and final recovery) in a group of n = 10 MTB cyclists from the National Sub-23 Team, including 5 males and 5 females. Results: The results for the male athletes were as follows: age: 19 ± 1 years; VO2max: 67.5 mL/kg/min; max power: 355 W; HRmax: 204 bpm. The results for the female athletes were as follows: age: 19 ± 1 years; VOmax: 58.5 mL/kg/min; max power: 265 W; HRmax: 194 bpm. Both genders showed the expected autonomic behavior in each phase. Asymmetrical propagation of heart rate was observed, with a greater deceleration pattern after postural changes and effort and a symmetrical acceleration pattern in these two phases. Discussion: Athletes exhibit increased vagal response compared to non-athletes. Mountain bikers show rapid heart rate reduction after exertion. Conclusion: This study demonstrates how mountain bikers exhibit increased heart rate deceleration following sympathetic stimuli. Full article

Background/Objectives: Bruxism has been associated with dysregulation of the autonomic nervous system (ANS). Visceral manual therapy (VMT) has shown beneficial effects on the vagal tone and modulation of ANS activity. This study aimed to evaluate the immediate and short-term effects of VMT in individuals with clinically based bruxism. Methods: A single-blind randomized controlled trial was conducted including 24 individuals with clinically based bruxism. Participants received two sessions of either VMT or a sham placebo technique. Outcome measures included heart rate variability (HRV), both normal-to-normal intervals (HRV-SDNN), and the root mean square of successive normal-to-normal intervals (HRV-RMSSD), as well as muscle tone and stiffness and pressure pain thresholds (PPTs). Measurements were made at T1 (baseline), T2 (post-first intervention), T3 (pre-second intervention), T4 (post-second intervention), and T5 (4-week follow-up). Results: A significant time*group interaction was observed for HRV-SDNN (p = 0.04, η² = 0.12). No significant changes were found for muscle tone or stiffness. PPTs significantly increased at C4 after the second session (p = 0.049, η² = 0.16) and at the left temporalis muscle after the first session (p = 0.01, η² = 0.07). Conclusions: The findings suggest that two sessions of VMT may lead to significant improvements in HRV-SDNN compared to the placebo, suggesting a modulatory effect on autonomic function. No consistent changes were observed for the viscoelastic properties of the masticatory muscles. Isolated improvements in pressure pain sensitivity were found at C4 and the left temporalis muscle. Further research with larger sample sizes and long-term follow-up is needed to determine the clinical relevance of VMT in the management of signs and symptoms in individuals with bruxism. 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: Chronic pain is closely associated with dysregulation of the autonomic nervous system, often reflected by reduced heart rate variability (HRV). While observational studies have demonstrated this association, the extent to which pain interventions modulate HRV and the impact of individual factors on HRV changes remain unclear. Objective: To evaluate the impact of pain interventions on HRV parameters through meta-analysis of randomized controlled trials (RCTs), and to examine whether intervention type and individual factors such as body mass index (BMI) moderate HRV responses. Methods: We conducted a systematic review of 23 RCTs and a meta-analysis of 21 RCTs (1262 subjects) involving patients with acute and chronic pain. HRV outcomes were extracted pre- and post-intervention. Both between-group (active vs. sham/control) and one-group (pre-post within active group) analyses were performed for time-domain indices—standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), and percentage of successive normal-to-normal intervals > 50 ms (pNN50)—and frequency-domain indices—high-frequency (HF) and low-frequency (LF) components. Meta-regressions tested moderators including BMI, age, and pain phenotype. The protocol was registered in PROSPERO (CRD42023448264). Results: Twenty-three RCTs involving 1262 participants with a wide range of pain conditions were included. Meta-analysis of time-domain HRV parameters showed a trend toward improvement: SDNN (g = 0.435, p = 0.059) approached significance, while RMSSD (g = 0.361, p = 0.099) and pNN50 (g = 0.222, p = 0.548) showed smaller, non-significant effects. Frequency-domain analysis revealed a significant moderate reduction in the LF/HF ratio (g = −0.378, p = 0.003), suggesting a shift toward parasympathetic dominance. HF and LF showed small, non-significant changes. One-group meta-analysis confirmed significant improvements in vagally mediated HRV, with large effects for RMSSD (g = 1.084, p < 0.001) and HF (g = 0.622, p < 0.001), and a moderate effect for SDNN (g = 0.455, p = 0.004). Meta-regression identified BMI as a significant moderator: higher BMI was associated with attenuated improvements in HF and RMSSD and a slight shift toward sympathetic predominance. Conclusions: Pain interventions can significantly modulate autonomic function, as reflected in HRV improvements, particularly in vagally mediated indices. These effects are influenced by patient characteristics such as BMI. HRV may serve as a valuable biomarker for both treatment efficacy and autonomic recovery in pain management. In this context, HRV highlights its role as a biomarker for pain dysregulation and compensatory failure, reflecting shared top-down modulation between nociception and autonomic regulation. Full article

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons, leading to the rapid decline of motor function. In recent years, dysfunction of the autonomic nervous system (ANS) has also been increasingly recognized as a contributing factor in various neurodegenerative diseases, including ALS. This study is the second publication from our ALS research cohort at Kaunas Clinics. Our previous work examined ultrasonographic changes in the phrenic nerve as a supplementary diagnostic approach for ALS. Materials and Methods: In the present study, we investigated ultrasonographic alterations of the vagus nerve within the same ALS cohort, aiming to explore correlations with ANS involvement. We performed high-resolution ultrasonography of the vagus nerve (VN), collected clinical data, conducted heart rate monitoring, and evaluated respiratory function. Results: We prospectively included 32 ALS patients meeting “Gold Coast” criteria and 64 age- and sex-matched control patients. The average onset of ALS was 57.97 ± 9.22 years, and the duration of the disease was15.41 ± 9.04 months. For ALS patients, we found significantly reduced vagus nerve cross-sectional area (CSA) at the level of the carotid artery bifurcation bilaterally compared to controls (right VN 1.86 ± 0.21 vs. 2.07 ± 0.18 mm², p < 0.001; left VN 1.69 ± 0.21 vs. 1.87 ± 0.21 mm², p < 0.001). Reduced values of the left VN positively correlated with the reduced values of FEV1% and sO₂. Conclusions: Our findings revealed a significant bilateral reduction in vagus nerve size in ALS patients compared to controls, suggesting that vagal atrophy may serve as a potential marker of autonomic dysfunction in ALS. Full article

Background: Heart rate variability (HRV) provides both linear and nonlinear autonomic proxies that can be informative of health status in fibromyalgia (FM), where sympatho-vagal abnormalities are common. This retrospective observational study aims to: 1. detect differences in correlation dimension (D2) between FM patients and healthy controls (HCs); 2. correlate D2 with standard HRV parameters; 3. correlate the degree of HRV changes using a global composite parameter called HRV grade, derived from three linear indices (SDNN = intervals between normal sinus beats; RMSSD = mean square of successive differences; total power), with FM clinical outcomes; 4. correlate all linear and nonlinear HRV parameters with clinical variables in patients. Methods: N = 85 patients were considered for the analysis and compared to 35 healthy subjects. According to standard diagnostic protocol, they underwent a systematic HRV protocol with a 5-min paced breathing task. Disease duration, pain intensity, mood, sleep, fatigue, and quality of life were assessed. Non-parametric tests for independent samples and pairwise correlations were performed using JMP (all p < 0.001). Results: Mann-Whitney U found a significant difference in D2 values between FM patients and HCs (p < 0.001). In patients, D2 was associated with all HRV standard indices (all p < 0.001) and FM impairment (FIQ = −0.4567; p < 0.001). HRV grade was also associated with FM impairment (FIQ = 0.5058; p < 0.001). Conclusion: Combining different HRV measurements may help understand the correlates of autonomic dysregulation in FM. Specifically, clinical protocols could benefit from the inclusion and validation of D2 and HRV parameters to target FM severity and related dysautonomia. Full article

Long COVID, characterized by persistent symptoms following COVID-19 infection, significantly impacts individuals’ health and daily functioning due to fatigue and pain. Focusing on pain, this review addresses nociplastic and chronic pain conditions. Interventions designed to reduce inflammation, oxidative stress, and enhance vagal activity may offer a promising approach to managing post-pandemic pain. This review presents individual components of food supplements with demonstrated efficacy in one or more pain conditions, focusing on their proposed mechanisms and clinical activity in pain, including their use in post-COVID-19 pain when available. Many of these substances have a long history of safe use and may offer an alternative to long-term analgesic drug treatment, which is often associated with potential side effects. This review also explores the potential for synergistic effects when combining these substances with each other or with conventional analgesics, considering the advantages for both patients and the healthcare system in using these substances as adjunctive or primary therapies for pain symptoms related to long COVID. While preclinical scientific literature provides a mechanistic basis for the action of several food supplements on pain control mechanisms and signaling pathways, clinical experience, particularly in the field of long COVID-associated pain, is still limited. However, the reviewed literature strongly suggests that the use of food supplements in long COVID-associated pain is an attainable goal, provided that rigorous clinical trials are conducted. 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

Background: The beat-by-beat fluctuation of heart rate (HR) in its temporal sequence (HR dynamics) provides information on HR regulation by the autonomic nervous system (ANS) and its dysregulation in pathological states. Commonly, linear analyses of HR and its variability (HRV) are used to draw conclusions about pathological states despite clear statistical and translational limitations. Objective: The main aim of this study was to compare linear and nonlinear HR measures, including detrended fluctuation analysis (DFA), based on ECG recordings by radiotelemetry in C57BL/6N mice to identify pathological HR dynamics. Methods: We investigated different behavioral and a wide range of pharmacological interventions which alter ANS regulation through various peripheral and/or central mechanisms including receptors implicated in psychiatric disorders. This spectrum of interventions served as a reference system for comparison of linear and nonlinear HR measures to identify pathological states. Results: Physiological HR dynamics constitute a self-similar, scale-invariant, fractal process with persistent intrinsic long-range correlations resulting in physiological DFA scaling coefficients of α~1. Strongly altered DFA scaling coefficients (α ≠ 1) indicate pathological states of HR dynamics as elicited by (1) parasympathetic blockade, (2) parasympathetic overactivation and (3) sympathetic overactivation but not inhibition. The DFA scaling coefficients are identical in mice and humans under physiological conditions with identical pathological states by defined pharmacological interventions. Conclusions: Here, we show the importance of tonic vagal function for physiological HR dynamics in mice, as reported in humans. Unlike linear measures, DFA provides an important translational measure that reliably identifies pathological HR dynamics based on altered ANS control by pharmacological interventions. Central ANS dysregulation represents a likely mechanism of increased cardiac mortality in psychiatric disorders. Full article

This paper presents a study undertaken to evaluate the sensor systems that were shortlisted to be used in the development of a portable respiratory-gated transcutaneous auricular vagus nerve stimulation (taVNS) system. To date, all published studies assessing respiratory-gated taVNS have been performed in controlled laboratory environments. This limitation arises from the reliance on non-portable sensing equipment, which poses significant logistical challenges. Therefore, we recognised a need to develop a portable sensor system for future research, enabling participants to perform respiratory-gated stimulation conveniently from their homes. This study aimed to measure the accuracy of an in-ear and a fingertip-based photoplethysmography (PPG) sensor in measuring cardiac vagal tone relevant heart rate variability (HRV) parameters of root mean square of successive R-R interval differences (RMSSDs) and the high-frequency (HF) component of HRV. Thirty healthy participants wore the prototype sensor equipment and the gold standard electrocardiogram (ECG) equipment to record beat-to-beat intervals simultaneously during 10 min of normal breathing and 10 min of deep slow breathing (DSB). Additionally, a stretch sensor was evaluated to measure its accuracy in detecting exhalation when compared to the gold standard sensor. We used Bland–Altman analysis to establish the agreement between the prototypes and the ECG system. Intraclass correlation coefficients (ICCs) were calculated to establish consistency between the prototypes and the ECG system. For the stretch sensor, the true positive rate (TPR), false positive rate (FPR), and false negative rate (FNR) were calculated. Results indicate that while ICC values were generally good to excellent, only the fingertip-based sensor had an acceptable level of agreement in measuring RMSSDs during both breathing phases. Only the fingertip-based sensor had an acceptable level of agreement during normal breathing in measuring HF-HRV. The study highlights that a high correlation between sensors does not necessarily translate into a high level of agreement. In the case of the stretch sensor, it had an acceptable level of accuracy with a mean TPR of 85% during normal breathing and 95% during DSB. The results show that the fingertip-based sensor and the stretch sensor had acceptable levels of accuracy for use in the development of the respiratory-gated taVNS system. Full article

Background: Transient receptor potential vanilloid subtype 4 (TRPV4) is a Ca²⁺-permeable non-selective cation channel that is involved in the development of cough hypersensitivity. Purinergic 2 receptors (P2X) belong to a class of adenosine triphosphate (ATP)-gated non-selective cation channels that also play an important role in cough hypersensitivity. Nevertheless, little is known about the interaction between them for cough hypersensitivity. The present study was designed to clarify the roles of TRPV4 and ATP-P2X receptors in cough hypersensitivity, and to explore the possible involvement of ATP-P2X receptors in the development of cough hypersensitivity mediated by TRPV4. Design and Method: This study aims to establish a guinea pig model of citric acid-induced enhanced cough to confirm the effects of the TRPV4-mediated purinergic signaling pathway on cough sensitivity by testing the number of coughs, the release of ATP, and the expressions of P2X and TRPV4 receptors in the tracheal carina and vagal ganglion; recording the activity of cellular currents with the whole-cell patch clamp technique; and detecting changes in intracellular calcium flow in the vagus nerve cells. Results: The number of coughs in the TRPV4 agonist GSK1016790A-treated control group was elevated compared with that in the control group, whereas the number of coughs in the TRPV4 antagonist HC067047-treated model group was significantly reduced compared with that in the chronic cough group. When the individuals in the chronic cough group were treated with A317491, PSB12062, and A804598 (P2X3,4,7 antagonists), the number of coughs was significantly decreased. This suggests that TRPV4 and P2X3, P2X4, and P2X7 receptors have an effect on cough hyper-responsiveness in guinea pigs with chronic cough. Enzyme-linked immunosorbent assay results suggested that TRPV4 antagonist and P2X3,4,7 antagonist could differentially reduce the levels of inflammatory factor SP and CGRP in alveolar lavage fluid, and TRPV4 antagonist could reduce the ATP content in the alveolar lavage fluid of guinea pigs in the model. Western blot and immunohistochemistry results showed that, in the tracheal carina and vagal ganglion, the TRPV4 and P2X3,4,7 expression was elevated in the chronic cough group compared with the control group, and could be significantly inhibited by TRPV4 antagonist. Vagus ganglion neurons were isolated, cultured, identified, and subjected to whole-cell membrane clamp assay. When ATP was given extracellularly, a significant inward current was recorded in the examined cells of individuals in the chronic cough and control groups, and the inward current induced by ATP was higher in the chronic cough group relative to the control group. This inward current (I_ATP) was differentially blocked by P2X3, P2X4, and P2X7 antagonists. Further studies revealed that TRPV4 agonists potentiated ATP-activated currents, and the potentiated currents could still be inhibited by P2X3, P2X4, and P2X7 receptor antagonists, whereas TRPV4 inhibitors partially blocked ATP-activated currents. It is suggested that TRPV4 affects P2X3, P2X4, and P2X7 receptor-mediated ATP-activated currents. Calcium imaging also showed that TRPV4 agonists induced different degrees of calcium inward currents in the vagal neurons of the chronic cough and the control group, and the calcium inward currents were more significant in the model group. Conclusions: The TRPV4-mediated purinergic signaling pathway was identified to be involved in the development of cough hypersensitivity in guinea pigs with chronic cough; i.e., TRPV4 can lead to the release of airway epithelial ATP, which can stimulate P2X receptors on the cough receptor, and further activate the sensory afferent nerves in the peripheral airway, leading to increased cough sensitivity. Full article

Cardioneuroablation is a rapidly developing procedure for the treatment of vagally mediated bradyarrhythmias. However, the lack of multicenter, randomized trials prevents it from being included in bradyarrhythmia treatment guidelines. So far, only one small, randomized study has been published assessing the effectiveness of this method in the treatment of reflex syncope. This is a brief review of ongoing randomized trials evaluating the effectiveness and safety of cardioneuroablation for the treatment of functional bradyarrhythmias. Full article

The rising burden of type 2 diabetes mellitus (T2DM) is a growing global public health problem, particularly prominent in developing countries. The early detection of T2DM and prediabetes is vital for reversing the outcome of disease, allowing early intervention. In the past decade, various microbiome–metabolome studies have attempted to address the question of whether there are any common microbial patterns that indicate either prediabetic or diabetic gut microbial signatures. Because current studies have a high methodological heterogeneity and risk of bias, we have selected studies that adhered to similar design and methodology. We performed a systematic review to assess if there were any common changes in microbiome belonging to diabetic, prediabetic and healthy individuals. The cross-sectional studies presented here collectively covered a population of 65,754 people, with 1800 in the 2TD group, 2770 in the prediabetic group and 61,184 in the control group. The overall microbial diversity scores were lower in the T2D and prediabetes cohorts in 86% of the analyzed studies. Re-programming of the microbiome is potentially one of the safest and long-lasting ways to eliminate diabetes in its early stages. The differences in the abundance of certain microbial species could serve as an early warning for a dysbiotic gut environment and could be easily modified before the onset of disease by changes in lifestyle, taking probiotics, introducing diet modifications or stimulating the vagal nerve. This review shows how metagenomic studies have and will continue to identify novel therapeutic targets (probiotics, prebiotics or targets for elimination from flora). This work clearly shows that gut microbiome intervention studies, if performed according to standard operating protocols using a predefined analytic framework (e.g., STORMS), could be combined with other similar studies, allowing broader conclusions from collating all global cohort studies efforts and eliminating the effect-size statistical insufficiency of a single study. Full article