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

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

Orally Ingested Self-Powered Stimulators for Targeted Gut-Brain Axis Electrostimulation to Treat Obesity and Metabolic Disorders.

Obesity is a significant health concern that often leads to metabolic dysfunction and chronic diseases. This study introduces a novel approach to combat obesity using orally ingested self-powered electrostimulators. These electrostimulators consist of piezoelectric BaTiO3 (BTO) particles conjugated with capsaicin (Cap) and aim to activate the vagus nerve. Upon ingestion by diet-induced obese (DIO) mice, the BTO@Cap particles specifically target and bind to Cap-sensitive sensory nerve endings in the gastric mucosa. In response to stomach peristalsis, these particles generate electrical signals. The signals travel via the gut-brain axis, ultimately influencing the hypothalamus. By enhancing satiety signals in the brain, this neuromodulatory intervention reduces food intake, promotes energy metabolism, and demonstrates minimal toxicity. Over a 3-week period of daily treatments, DIO mice treated with BTO@Cap particles show a significant reduction in body weight compared to control mice, while maintaining their general locomotor activity. Furthermore, this BTO@Cap particle-based treatment mitigates various metabolic alterations associated with obesity. Importantly, this noninvasive and easy-to-administer intervention holds potential for addressing other intracerebral neurological diseases.

Unmet needs of drugs for irritable bowel syndrome and inflammatory bowel diseases: interest of vagus nerve stimulation and hypnosis.

The gut and the brain communicate bidirectionally through the autonomic nervous system. The vagus nerve is a key component of this gut-brain axis, and has numerous properties such as anti-inflammatory, antinociceptive, anti-depressive effects. A perturbation of this gut-brain communication is involved in the pathogeny of functional digestive disorders, such as irritable bowel syndrome, and inflammatory bowel diseases. Stress plays a role in the pathogeny of these diseases, which are biopsychosocial models. There are presently unmet needs of pharmacological treatments of these chronic debilitating diseases. Treatments are not devoid of side effects, cost-effective, do not cure the diseases, can lose effects over time, thus explaining the poor satisfaction of patients, their lack of compliance, and their interest for non-drug therapies. The gut-brain axis can be targeted for therapeutic purposes in irritable bowel syndrome and inflammatory bowel disease through non-drug therapies, such as hypnosis and vagus nerve stimulation, opening up possibilities for responding to patient expectations.

Transcutaneous auricular vagus nerve stimulation for post-stroke depression: A double-blind, randomized, placebo-controlled trial.

BACKGROUND: It is a well-established fact that post-stroke depression (PSD) is a prevalent condition that affects a significant proportion of individuals who have suffered a stroke. Hence, our research endeavors to explore the safety, efficacy and the potential molecular mechanism of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of depression in PSD patients by conducting a double-blind, sham-controlled, randomized trial. METHODS: Patients who had experienced strokes and exhibited depressive symptoms, with a Hamilton Depression Scale (HAMD-17) score of ≥8 and met the DSM-IV criteria, were diagnosed with PSD. A volunteer sample of participants (N = 80) were randomly divided into either the ta-VNS group (which received ta-VNS in addition to conventional treatment) or the control group (which received conventional treatment only), in a 1:1 ratio. The effectiveness of the interventions was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17), Zung Self-Rating Depression Scale (SDS), and Barthel Index (BI) scores. Furthermore, Plasma BDNF, CREB1, and 5-HT levels were measured before and after treatment. RESULTS: The concomitant application of ta-VNS demonstrated a remarkable reduction in HAMD-17 and SDS scores, leading to noteworthy enhancements in patients' daily functioning, as evidenced by improved activities of daily living, at all assessed time points, in contrast to the control group (p < 0.0001). Notably, the ta-VNS group exhibited superior effects in modulating the measured neurotrophic biomarkers when compared to the control group (p < 0.05). CONCLUSIONS: The synergistic approach of combining ta-VNS with conventional treatment has demonstrated remarkable efficacy and tolerability in managing depression following a stroke.

Neurostimulation After Stroke.

Neural stimulation technology aids stroke survivors in regaining lost motor functions. This article explores its applications in upper and lower limb stroke rehabilitation. The authors review various methods to target the corticomotor system, including transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. In addition, the authors review the use of peripheral neuromuscular electrical stimulation for therapeutic and assistive purposes, including transcutaneous electrical nerve stimulation, neuromuscular electrical stimulation, and functional electrical stimulation. For each, the authors examine the potential benefits, limitations, safety considerations, and FDA status.

Involvement of the vagus nerve and hepatic gene expression in serum adiponectin concentrations in mice

Several humoral factors, such as adiponectin and urate, have been suggested to affect metabolic syndromes. Previously, we reported a reduction in blood adiponectin concentrations after a high-fructose diet partially via the vagus nerve in rats. Although a lithogenic diet (LD), i.e., supplementation of a normal control diet (CT) with 0.6% cholesterol and 0.2% sodium cholate, reduced blood adiponectin concentrations, the involvement of the vagus nerve in this mechanism remains unclear. To estimate the involvement of the vagus nerve in the regulation of blood adiponectin concentrations using an LD, male imprinting control region mice that had been vagotomized (HVx) or only laparotomized (Sham) were administered a CT or an LD for 10 weeks. Serum adiponectin concentrations in the Sham-LD, HVx-CT, and HVx-LD groups were reduced by half compared with the Sham-CT group. The hepatic mRNA levels of fibroblast growth factor 21 (Fgf21), which reportedly stimulates adiponectin secretion from white adipose tissue, were lower in the LD groups compared with the CT groups. HepG2 hepatoma cells showed that various bile acids reduced the mRNA expression of FGF21. Moreover, the LD increased serum urate concentrations and reduced hepatic expressions of the acyl-CoA oxidase 1 (Acox1) mRNA and glucokinase, suggesting insufficient regeneration of ATP from AMP. In conclusion, serum adiponectin concentration may be regulated via the vagus nerve in normal mice, whereas a reduction of hepatic Fgf21 mRNA by bile acids may also lower serum adiponectin levels. Moreover, the LD may promote hepatic AMP accumulation and subsequently increase the serum urate concentration in mice. (AU)

Transcutaneous auricular vagus nerve stimulation modulates the processing of interoceptive prediction error signals and their role in allostatic regulation.

It has recently been suggested that predictive processing principles may apply to interoception, defined as the processing of hormonal, autonomic, visceral, and immunological signals. In the current study, we aimed at providing empirical evidence for the role of cardiac interoceptive prediction errors signals on allostatic adjustments, using transcutaneous auricular vagus nerve stimulation (taVNS) as a tool to modulate the processing of interoceptive afferents. In a within-subject design, participants performed a cardiac-related interoceptive task (heartbeat counting task) under taVNS and sham stimulation, spaced 1-week apart. We observed that taVNS, in contrast to sham stimulation, facilitated the maintenance of interoceptive accuracy levels over time (from the initial, stimulation-free, baseline block to subsequent stimulation blocks), suggesting that vagus nerve stimulation may have helped to maintain engagement to cardiac afferent signals. During the interoceptive task, taVNS compared to sham, produced higher heart-evoked potentials (HEP) amplitudes, a potential readout measure of cardiac-related prediction error processing. Further analyses revealed that the positive relation between interoceptive accuracy and allostatic adjustments-as measured by heart rate variability (HRV)-was mediated by HEP amplitudes. Providing initial support for predictive processing accounts of interoception, our results suggest that the stimulation of the vagus nerve may increase the precision with which interoceptive signals are processed, favoring their influence on allostatic adjustments.

Cervical Manipulation and Koren Specific Technique Emotions Protocol in the Improvement of Intensive Nocturnal Dry Cough: A Case Report.

This report describes a 42-year-old female patient who presented with an intensive nocturnal dry cough persisting for over six months. Subsequent to the prolonged cough, she developed shoulder and neck discomfort, leading her to seek chiropractic care. The patient received cervical chiropractic adjustments combined with the Koren Specific Technique (KST) emotions protocol. The patient was mainly treated for her musculoskeletal complaint. However, after two treatment sessions, the patient's chronic cough showed significant improvement. Two weeks later, the cough had completely ceased, and her shoulder and neck discomfort had also improved. The cough symptoms did not reappear during the six-month follow-up. The mechanism of cough improvement remains unclear, whether it is due to spinal adjustments, the KST emotions protocol, their combined effects, or merely a placebo response. This report discusses the potential underlying mechanisms of the case improvement, suggesting a non-pharmacological adjunctive therapeutic approach that could be investigated further in future research.

Neuromodulation in migraine.

The International Neuromodulation Society defines therapeutic neuromodulation as the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body. Neuromodulation for the treatment of migraine is an evolving field offering further insight into the pathophysiology of migraine as well as advanced therapeutics. Central and peripheral neuronal targets have been explored in the efforts to reduce the frequency and severity of attacks. Invasive and noninvasive techniques have been developed, targeting either the central or peripheral nervous system. Noninvasive central neuromodulation techniques have the benefit of a low side effect profile in addition to higher level of evidence for use thanks to sham-controlled trials; however, these modalities are less clinically available for use. Noninvasive transcutaneous neuromodulation techniques that target the peripheral nervous system have provided devices that are available over the counter or by prescription. Several of these devices are effective for abortive and preventive treatment of migraine. Invasive techniques such as cranial nerve stimulation with implanted stimulator devices or spinal cord stimulation may be used for more aggressive management in patients refractory to other treatments. Overall, neuromodulation techniques can be particularly beneficial for medically complex or refractory patients, those that prefer nonmedication options, and those that have experienced adverse effects from medications.

Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome.

Limited treatment options have been shown to alter the natural course of constipation-predominant irritable bowel syndrome (IBS-C). Therefore, safer and more effective approaches are urgently needed. We investigated the effects of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of IBS-C. In the current study, C57BL/6 mice were randomly divided into normal control, IBS-C model control, sham-electrostimulation (sham-ES), taVNS, and drug treatment groups. The effects of taVNS on fecal pellet number, fecal water content, and gastrointestinal transit were evaluated in IBS-C model mice. We assessed the effect of taVNS on visceral hypersensitivity using the colorectal distention test. 16S rRNA sequencing was used to analyze the fecal microbiota of the experimental groups. First, we found that taVNS increased fecal pellet number, fecal water content, and gastrointestinal transit in IBS-C model mice compared with the sham-ES group. Second, taVNS significantly decreased the abdominal withdrawal reflex (AWR) score compared with the sham-ES group, thus relieving visceral hyperalgesia. Third, the gut microbiota outcomes showed that taVNS restored Lactobacillus abundance while increasing Bifidobacterium probiotic abundance at the genus level. Notably, taVNS increased the number of c-kit-positive interstitial cells of Cajal (ICC) in the myenteric plexus region in IBS-C mice compared with the sham-ES group. Therefore, our study indicated that taVNS effectively ameliorated IBS-C in the gut microbiota and ICC.

Heart rate variability and cold-induced vascular dilation after stimulation of two different areas of the ear: a prospective, single-blinded, randomized crossover study.

BACKGROUND: Both noninvasive transauricular vagus nerve stimulation (taVNS) and traditional medical practice (TMP), such as auriculotherapy, use the auricle as a starting point for stimulation, but with two different conceptual frameworks: taVNS depends on vagal afferences to account for its effects, whereas TMP requires stimulation of the ear with high topographical accuracy regardless of the afferent nerves. The aim of this study was to measure heart rate variability (HRV) and cold water-induced vasodilation (CIVD) after puncturing two different ear points with the same afference but that should have opposite effects according to TMP. METHODS: Ten healthy subjects were investigated in this single-blinded crossover study over three sessions. In the first session, sympathetic activation was performed via cold water immersion of the right hand, with recordings taken from multiple fingers. HRV was assessed in the time domain (square root of the mean squared differences of NN intervals (RMSSD)) and frequency domain (low (LF) and high frequencies (HF)). In the second and third sessions, the same skin immersion test was performed, and mechanical stimulation was applied to the ear at two different points on the internal surface of the antitragus, one with alleged parasympathetic activity and the other with alleged sympathetic activity. The stimulation was done with semipermanent needles. RESULTS: Stimulation of the point with alleged parasympathetic activity immediately resulted in a significant decrease in RMSSD in 75% of the subjects and in LF in 50% of the subjects, while stimulation of the point with alleged sympathetic activity resulted in an increase in HF and RMSSD in 50% of the subjects. Stimulation of these points did not affect the CIVD reflex. The 20 min cold water immersion induced an immediate decrease in LF and the LF/HF ratio and an increase in HF. The skin temperature of the nonimmersed medius significantly decreased when the contralateral hand was immersed, from 34.4 °C to 31.8 °C. CONCLUSIONS: Stimulation of two different ear points innervated by the same afferent nerves elicited different HRV responses, suggesting somatotopy and a vagal effect beyond vagal afferences. These results are not in accordance with the claims of TMP. TRIAL REGISTRATION: NCT04130893 (18/10/2019) clinicaltrials.com.

Effectiveness of transcutaneous vagus nerve stimulation (tVNS) on salicylate-induced tinnitus.

INTRODUCTION: Tinnitus is the most common symptom of auditory system disorders. It affects the quality of life of millions of people, but it is still incurable in most cases. Vagus nerve stimulation (VNS) therapy is a potential new treatment for subjective tinnitus. In this study, transcutaneous vagus nerve stimulation (tVNS) combined with tones was utilized to treat salicylate-induced tinnitus since salicylate is a reliable and convenient approach for rapidly inducing tinnitus. METHODS: Wistar rats were divided into acoustic stimulation alone (AS, n = 6), tVNS alone (n = 6), and tVNS with AS (n = 6) groups for behavioral and electrophysiological tests. They were assessed by auditory brainstem response (ABR), prepulse inhibition (PPI), gap prepulse inhibition of the acoustic startle (GPIAS), social interactions, and aggressive behavior tests at baseline and seven days' post-salicylate (175 mg/kg, twice a day) injection. RESULTS: The inhibition percentage of the GPIAS test was significantly reduced post-salicylate injection in the tVNS and AS alone groups, while it was not significant in the tVNS with AS group. There was no significant difference in the mean percentage of the GPIAS test between the tVNS groups (with or without AS) after salicylate injections. Social interactions were significantly different in the AS alone group pre- and post-salicylate injections, but they were not significant in other groups. Moreover, the results of aggressive behavior tests showed significantly increased post-salicylate injections in the AS alone group, while they were not significant in the tVNS groups (with or without AS). CONCLUSIONS: The current study revealed that the application of tVNS alone produced improved social interaction and mood and alleviated salicylate-induced tinnitus severity. Moreover, combining tVNS with acoustic stimulation can prevent salicylate-induced tinnitus.

Involvement of the vagus nerve and hepatic gene expression in serum adiponectin concentrations in mice.

Several humoral factors, such as adiponectin and urate, have been suggested to affect metabolic syndromes. Previously, we reported a reduction in blood adiponectin concentrations after a high-fructose diet partially via the vagus nerve in rats. Although a lithogenic diet (LD), i.e., supplementation of a normal control diet (CT) with 0.6% cholesterol and 0.2% sodium cholate, reduced blood adiponectin concentrations, the involvement of the vagus nerve in this mechanism remains unclear. To estimate the involvement of the vagus nerve in the regulation of blood adiponectin concentrations using an LD, male imprinting control region mice that had been vagotomized (HVx) or only laparotomized (Sham) were administered a CT or an LD for 10 weeks. Serum adiponectin concentrations in the Sham-LD, HVx-CT, and HVx-LD groups were reduced by half compared with the Sham-CT group. The hepatic mRNA levels of fibroblast growth factor 21 (Fgf21), which reportedly stimulates adiponectin secretion from white adipose tissue, were lower in the LD groups compared with the CT groups. HepG2 hepatoma cells showed that various bile acids reduced the mRNA expression of FGF21. Moreover, the LD increased serum urate concentrations and reduced hepatic expressions of the acyl-CoA oxidase 1 (Acox1) mRNA and glucokinase, suggesting insufficient regeneration of ATP from AMP. In conclusion, serum adiponectin concentration may be regulated via the vagus nerve in normal mice, whereas a reduction of hepatic Fgf21 mRNA by bile acids may also lower serum adiponectin levels. Moreover, the LD may promote hepatic AMP accumulation and subsequently increase the serum urate concentration in mice.

Making Sense of Vagus Nerve Stimulation for Stroke.

Implantable vagus nerve stimulation, paired with high-dose occupational therapy, has been shown to be effective in improving upper limb function among patients with stroke and received regulatory approval from the US Food and Drug Administration and the Centers for Medicare & Medicaid Services. Combining nonsurgical and surgical approaches of vagus nerve stimulation in recent meta-analyses has resulted in misleading reports on the efficacy of each type of stimulation among patients with stroke. This article aims to clarify the confusion surrounding implantable vagus nerve stimulation as a poststroke treatment option, highlighting the importance of distinguishing between transcutaneous auricular vagus nerve stimulation and implantable vagus nerve stimulation. Recent meta-analyses on vagus nerve stimulation have inappropriately combined studies of fundamentally different interventions, outcome measures, and participant selection, which do not conform to methodological best practices and, hence, cannot be used to deduce the relative efficacy of the different types of vagus nerve stimulation for stroke rehabilitation. Health care providers, patients, and insurers should rely on appropriately designed research to guide well-informed decisions.

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report.

OBJECTIVE: Transcutaneous auricular vagus nerve stimulation (taVNS) was performed in two patients suffering structural focal epilepsy with preserved intellectual ability to show the feasibility of taVNS for specific patient groups. CASE PRESENTATIONS: Patient 1 was a 24-year-old woman with frontal lobe epilepsy who had weekly hyperkinetic seizures despite multiple anti-seizure medications. Patient 2 was a 27-year-old woman with parietal lobe epilepsy and focal cortical dysplasia in the vicinity of the lipoma in the corpus callosum. She experienced weekly focal-impaired awareness seizures even with anti-seizure medication. taVNS was applied to the left earlobe of both patients at 1.5 mA, 25 Hz, 250 µs pulse width, and 30 s stimulation with 30 s rest for 4 h per day. Over an 8-week baseline and 20 weeks of stimulation, the rate of reduction in seizure frequency was evaluated, along with quality-of-life using the Short-Form 36-Item Health survey. RESULTS: At baseline, we measured up to 11 and 12 focal seizures per week in Patient 1 and 2, respectively, with both patients achieving seizure freedom after 4 and 20 weeks taVNS, respectively. Patient 1 and 2 were observed for 18 and 14 months, respectively, including the clinical trial and follow-up observation period. Quality-of-life ratings increased in both patients, and no significant adverse events occurred during the study period. During the maintenance period after 20 weeks, seizures remained absent in Patient 1, and seizures remained reduced in Patient 2. CONCLUSION: Our results demonstrate that taVNS may be a promising tool for structural focal epilepsy with preserved cognitive function. A multicenter double-blind clinical trial is needed to confirm the role of taVNS as an anti-seizure tool.

Locus coeruleus tyrosine hydroxylase positive neurons mediated the peripheral and central therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) in MRL/lpr mice.

OBJECTIVE: This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in MRL/lpr mice. METHODS: MRL/lpr mice were treated with taVNS for ten weeks. Locus coeruleus (LC) tyrosine hydroxylase positive (TH+) neurons were selectively lesioned by stereotactic injection of 6-hydroxydopamine (6-OHDA) or selectively activated by chemogenetic methods. Sympathetic denervation was conducted by intraperitoneal injection of 6-OHDA. RESULTS: TaVNS activated the TH + neurons in LC. TaVNS produced central therapeutic effects by reducing the number of hippocampal microglia, and increasing the number of surviving LC TH+ neurons in MRL/lpr mice. TaVNS also retarded the development of lymphadenectasis and splenomegaly, decreased the proportion of double-negative T (DNT) cells, and alleviated nephritis in MRL/lpr mice. The lesion of LC TH+ neurons eliminated both these central and peripheral therapeutic effects of taVNS, while chemogenetic activation of LC TH+ neurons mimicked most central and peripheral protective effects of taVNS in MRL/lpr mice. Furthermore, taVNS regulated the autonomic nervous system in MRL/lpr mice. CONCLUSION: This study provides direct evidence that taVNS can retard the development of peripheral and central symptoms of SLE, which is mediated by the LC TH+ neurons.

[Research advances in neuromodulation techniques for blood glucose regulation and diabetes intervention].

Diabetes and its complications that seriously threaten the health and life of human, has become a public health problem of global concern. Glycemic control remains a major focus in the treatment and management of patients with diabetes. The traditional lifestyle interventions, drug therapies, and surgeries have benefited many patients with diabetes. However, due to problems such as poor patient compliance, drug side effects, and limited surgical indications, there are still patients who fail to effectively control their blood glucose levels. With the development of bioelectronic medicine, neuromodulation techniques have shown great potential in the field of glycemic control and diabetes intervention with its unique advantages. This paper mainly reviewed the research advances and latest achievements of neuromodulation technologies such as peripheral nerve electrical stimulation, ultrasound neuromodulation, and optogenetics in blood glucose regulation and diabetes intervention, analyzed the existing problems and presented prospects for the future development trend to promote clinical research and application of neuromodulation technologies in the treatment of diabetes.

The effect of transcutaneous auricular vagus nerve stimulation on cycling ergometry and recovery in healthy young individuals.

BACKGROUND: It is aimed to examine the potential benefits and effects of the use of transcutaneous auricular vagus nerve stimulation (VNS) for sporting purposes on recovery, fatigue, and sportive performance level. METHODS: In this study, 90 people between the ages of 18-23 were participated. They were randomly divided into three groups as bilateral sham, unilateral left, and bilateral VNS. A 4-day protocol was applied to the participants. Cycling exercise was performed with maximum performance for 30 min under the same watt load. Pulse, systolic and diastolic blood pressure, distance, pain, fatigue, lactic acid level, and autonomic nervous system were evaluated. RESULTS: Within the groups, there was a statistically significant difference between the data (p < .05) except for the distance covered parameter. When we compare the groups, in addition to the distance traveled in all groups, there is no statistically significant difference in the 1st day 1st measurement and 2nd measurement data of all parameters (p > .05 When we compared the data according to days, there was a statistically significant difference between bilateral stimulation (BS) and unilateral stimulation, only pain and fatigue levels (p < .05). CONCLUSION: In our study, we saw that BS application gave positive results in reducing pain and fatigue due to cycling exercise compared to other applications. Similar results were obtained when we evaluated the data on a daily basis. We believe that VNS will be beneficial in reducing pain and fatigue, especially during and after the competition halftime.

Non-invasive neuromodulation: an emerging intervention for visceral pain in gastrointestinal disorders.

Gastrointestinal (GI) disorders, which extend from the esophagus to the anus, are the most common diseases of the GI tract. Among these disorders, pain, encompassing both abdominal and visceral pain, is a predominant feature, affecting the patients' quality of life and imposing a substantial financial burden on society. Pain signals originating from the gut intricately shape brain dynamics. In response, the brain sends appropriate descending signals to respond to pain through neuronal inhibition. However, due to the heterogeneous nature of the disease and its limited pathophysiological understanding, treatment options are minimal and often controversial. Consequently, many patients with GI disorders use complementary and alternative therapies such as neuromodulation to treat visceral pain. Neuromodulation intervenes in the central, peripheral, or autonomic nervous system by alternating or modulating nerve activity using electrical, electromagnetic, chemical, or optogenetic methodologies. Here, we review a few emerging noninvasive neuromodulation approaches with promising potential for alleviating pain associated with functional dyspepsia, gastroparesis, irritable bowel syndrome, inflammatory bowel disease, and non-cardiac chest pain. Moreover, we address critical aspects, including the efficacy, safety, and feasibility of these noninvasive neuromodulation methods, elucidate their mechanisms of action, and outline future research directions. In conclusion, the emerging field of noninvasive neuromodulation appears as a viable alternative therapeutic avenue for effectively managing visceral pain in GI disorders.