Auricular Vagus Nerve Stimulation Research Articles

Efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with constipation-predominant irritable bowel syndrome: a single-center, single-blind, randomized controlled trial.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising therapy for irritable bowel syndrome (IBS). This clinical trial aims to evaluate the influence of taVNS on autonomic functions, rectal sensation, and acetylcholine (Ach) levels and to explore potential mechanisms involving gut microbiota and metabolic profiles. This study was a single-center, single-blind, randomized controlled trial executed at the First Affiliated Hospital of USTC, Anhui, China. Individual patients' IBS-C-related symptoms and mental health were assessed and scored using questionnaires at baseline and at week 4. Levels of Serum Ach and nitric oxide (NO), anorectal manometry, and heart rate variability (HRV) were assessed both prior to and following the therapy. Fecal samples from each group were assessed to compare the gut microbiota, short-chain fatty acids, and gut microbiota-derived tryptophan metabolites. Between September 2023 and May 2024, 40 participants (n=20 in both taVNS and sham-taVNS group) completed the four-week study by performing an intention-to-treat (ITT) analysis. No differences in all parameters between taVNS and sham-taVNS groups at the baseline was found. The taVNS significantly improved the VAS score (P < 0.001), IBS Severity Scoring System (IBS-SSS) (P < 0.001), weekly frequency of spontaneous bowel movements (SBMs) (P < 0.001), weekly frequency of complete SBMs (CSBMs) (P = 0.004), Bristol Stool Form Scale (BSFS) (P < 0.001), Hamilton Anxiety Scale (HAMA) (P < 0.001), Hamilton Depression Scale (HAMD) (P < 0.001), and IBS-QOL scores (P < 0.001). Furthermore, taVNS improved rectal sensation in IBS-C patients, including improvements in the threshold volume for initial sensation (P = 0.033), the urge to defecate (P = 0.022), and rectoanal inhibitory reflex (P = 0.002). Moreover, taVNS elevated serum levels of Ach (P = 0.005) and reduced NO (P = 0.016) while also enhancing vagal activity (P < 0.001) as determined by spectral analysis of HRV. Three individuals in the taVNS group and two in the control group had adverse consequences, which were manageable. Additionally, taVNS led to a significant rise in the level of the genus Bifidobacterium (P = 0.038), increased levels of acetic (P = 0.003), butyric (P = 0.011), and propionic acids (P = 0.005). It also decreased tryptophan metabolism content, including 3-hydroxyanthranilic acid (P = 0.007), anthranilic acid (P = 0.026) and L-tryptophan (P = 0.002). The study manifested that non-invasive taVNS effectively improved constipation and abdominal pain symptoms in IBS-C patients. The alleviation of IBS-C symptoms may be attributed to the integrative effects of taVNS on rectal functions, mediated through vagal, cholinergic, and multi-omics mechanisms.

Exploring the efficacy of Transcutaneous Auricular Vagus nerve stimulation (taVNS) in modulating local and systemic inflammation in experimental models of colitis

BackgroundCurrent inflammatory bowel disease (IBD) treatments often fail to achieve lasting remission and have adverse effects. Vagus nerve stimulation (VNS) offers a promising therapy due to its anti-inflammatory effects. Its invasive nature, however, has led to the development of non-invasive methods like transcutaneous auricular VNS (taVNS). This study assesses taVNS’s impact on acute colitis progression, inflammatory, anti-inflammatory, and apoptosis-related markers.MethodsMale C57BL/6 mice (11–12 weeks) were used for dextran sulfate sodium (DSS)- and dinitrobenzene sulfonic acid (DNBS)-induced colitis studies. The administration of taVNS or no stimulation (anesthesia without stimulation) for 10 min per mouse began one day before colitis induction and continued daily until sacrifice. Ulcerative colitis (UC)-like colitis was induced by administering 5% DSS in drinking water for 5 days, after which the mice were sacrificed. Crohn’s disease (CD)-like colitis was induced through a single intrarectal injection of DNBS/ethanol, with the mice sacrificed after 3 days. Disease activity index (DAI), macroscopic evaluations, and histological damage were assessed. Colon, spleen, and blood samples were analyzed via qRT-PCR and ELISA. One-way or two-way ANOVA with Bonferroni and Šídák tests were applied.ResultstaVNS improved DAI, macroscopic, and histological scores in DSS colitis mice, but only partially mitigated weight loss and DAI in DNBS colitis mice. In DSS colitis, taVNS locally decreased colonic inflammation by downregulating pro-inflammatory markers (IL-1β, TNF-α, Mip1β, MMP 9, MMP 2, and Nos2) at the mRNA level and upregulating anti-inflammatory TGF-β in non-colitic conditions at both mRNA and protein levels and IL-10 mRNA levels in both non-colitic and colitic conditions. Systemically, taVNS decreased splenic TNF-α in non-colitic mice and increased serum levels of TGF-β in colitic mice and splenic levels in non-colitic and colitic mice. Effects were absent in DNBS-induced colitis. Additionally, taVNS decreased pro-apoptotic markers (Bax, Bak1, and caspase 8) in non-colitic and colitic conditions and increased the pro-survival molecule Bad in non-colitic mice.ConclusionsThis study demonstrates that taVNS has model-dependent local and systemic effects, reducing inflammation and apoptosis in UC-like colitis while offering protective benefits in non-colitic conditions. These findings encourage further research into underlying mechanisms and developing adjunct therapies for UC.

Safety and effectiveness of transcutaneous auricular vagus nerve stimulation on patients with depersonalization-derealization disorder: study protocol for a randomized controlled trial

BackgroundDepersonalization-derealization disorder (DPD) is a complex psychiatric condition marked by profound and often relentless feelings of detachment from one’s self and surroundings. Transcranial electrical stimulation (taVNS) holds promise as a potential therapeutic approach for DPD. This study aims to investigate the safety and efficacy of taVNS in treating DPD.MethodsDPD patients were recruited as research subjects and randomly allocated to the experimental and control groups, with the former receiving active-taVNS treatment and the latter receiving sham stimulation treatment for 6 weeks. The efficacy of taVNS in treating DPD was evaluated by comparing scores for DPD symptoms, depression and anxiety symptoms, cognitive function, and social function before and after treatment between the two groups. The safety of taVNS in treating DPD was assessed by comparing general safety assessment results between the two groups of DPD patients.DiscussionThis study will assess taVNS as a potential treatment for DPD, evaluating its safety, efficacy, and impact on patient outcomes and societal burden.Trial registrationChinese Clinical Trial Registry, ChiCTR2300078183, Registered on 30 November, 2023, https://www.chictr.org.cn/showproj.html?proj=206119

Transcutaneous auricular vagus nerve stimulation as a potential therapy for attention deficit hyperactivity disorder: modulation of the noradrenergic pathway in the prefrontal lobe.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by developmental impairments, inattention, motor hyperactivity, and impulsivity. Currently, there is no effective intervention that can completely cure it. One of the pathogenic mechanisms of ADHD involves abnormalities in the norepinephrine (NE) pathway within the prefrontal cortex (PFC). In recent years, transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive neuromodulation technique, has demonstrated promising potential in the treatment of neurological and psychiatric disorders. However, its application in the management of ADHD remains relatively unexplored. Previous studies have shown that taVNS exerts therapeutic effects on attention, cognition, arousal, perception, and behavioral regulation primarily through activating the vagus nerve conduction pathway, specifically targeting the nucleus tractus solitarius - locus coeruleus - NE pathway. These findings have led to the hypothesis that taVNS may be an effective intervention for ADHD, with NE and its pathway playing a pivotal role in this context. Therefore, this review comprehensively examines the correlation between NE pathway alterations in the PFC and ADHD, the mechanism of action of taVNS, and the potential role of the NE pathway in treating ADHD with taVNS, aiming to provide a theoretical foundation for clinical applications.

Transcutaneous auricular vagus nerve stimulation attenuates stroke-heart syndrome: The role of parasympathetic activity

Stroke induces cardiac dysfunction, which increases poststroke mortality and morbidity. An imbalance in the autonomic nervous system resulting from brain injury may serve as the underlying mechanism. The present study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) attenuates poststroke cardiac dysfunction by activating the parasympathetic nervous system. Adult male mice were subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion surgery. The mice in the treatment group received repeated taVNS starting 60 min after the onset of cerebral ischemia. To assess whether the effects of taVNS were associated with parasympathetic activity, the MCAO mice in the atropine group received intraperitoneal injections of atropine to inhibit parasympathetic activity prior to taVNS. taVNS significantly increased the left ventricular ejection fraction (EF), attenuated myocardial apoptosis, reduced myocardial hypertrophy, and reduced fibrosis following stroke. The beneficial effects of taVNS on cardiac dysfunction were abolished by atropine administration. Heart rate variability (HRV) analysis and western blot analysis revealed that taVNS increased parasympathetic activity but decreased sympathetic dominance in mice with MCAO. Furthermore, the cardioprotective effects of taVNS were associated with muscarinic acetylcholine receptor activation, PI3K–Akt pathway modulation, and eNOS regulation in the heart. Therefore, taVNS alleviates cardiac dysfunction after stroke and is associated with activation of the parasympathetic nervous system.

Transcutaneous auricular vagus nerve stimulation for functional gastrointestinal disorders: From understanding to application

Abstract Functional gastrointestinal disorders (FGIDs) are debilitating diseases of the digestive system that severely impair an individual’s quality of life and impose a significant economic burden. However, the mechanisms underlying the pathogenesis of FGIDs and effective treatment options remain unclear. Transcutaneous auricular vagus nerve stimulation (taVNS), a novel neuromodulation therapy, has shown promising therapeutic outcomes in the treatment of FGIDs. This study conducted a comprehensive analysis of the development of taVNS and its relationship with vagus nerve stimulation and explored the clinical application of taVNS in managing FGIDs, including functional dyspepsia, irritable bowel syndrome, and functional constipation. Additionally, this study investigated the pathophysiological mechanisms of taVNS in FGIDs and reviewed its application as a holistic treatment approach, aiming to provide new insights into its therapeutic potential.

Investigating the modulation of gastric sensations and disposition toward food with taVNS.

Interoception, the perception of visceral sensations, is key for several survival functions, including those related to feeding behavior. Sensations of hunger and satiety are mediated by gastric signals transmitted via the vagus nerve to the Nucleus of Solitary Tract. Transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to modulate brain-viscera communication and to impact interoceptive processing in the cardiac domain. Yet, its effect on gastric interoception remains unclear. The aim of this study was to investigate taVNS' modulatory effects on gastric interoception using the Water Load Test-II (WLT-II) and its impact on food-related dispositions through a disposition and willingness to eat task (DWET). Participants underwent active or sham taVNS while performing the WLT-II and DWET. Results showed no significant difference in gastric interoceptive accuracy and amount of water ingested between taVNS groups. However, we found a significant reduction in food liking after the fullness phase of the WLT-II in the active (vs sham) taVNS group, suggesting an influence of vagal activation in the inhibition of food enjoyment when satiated. These findings suggest that, while taVNS may not directly enhance gastric interoceptive accuracy at a conscious level, it influences food-related dispositions, likely by modulating the processing of gastric signals. Further research exploring the intricate relationship between vagal modulation, interoceptive abilities and eating behaviors is warranted to elucidate the underlying mechanisms and, possibly, develop targeted interventions for eating disorders.

The effects of transcutaneous auricular vagus nerve stimulation (taVNS) on cholinergic neural networks in humans: A neurophysiological study

ObjectiveThe mechanisms of actions of transcutaneous auricular vagus nerve stimulation (taVNS) are still unclear, however the activity of the cholinergic system seems to be critical for the induction of VNS-mediated plasticity. Transcranial Magnetic Stimulation (TMS) is a well-suited, non-invasive tool to investigate cortical microcircuits involving different neurotransmitters. Herein, we evaluated the effect of taVNS on short-latency afferent inhibition (SAI), a TMS paradigm specifically measuring cholinergic neurotransmission. MethodsFifteen healthy subjects participated in this randomized placebo-controlled double-blind study. Each subject underwent two different sessions of 1-hour exposure to taVNS (real and sham) separated by a minimum of 48 h. Real taVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe. We evaluated SAI bilaterally over the motor cortex before and after exposure to taVNS. ResultsNo side effects were reported by any of the participants.Statistical analysis did not show any significant effect of taVNS on SAI. ConclusionsOur study demonstrated that cholinergic circuits explored by SAI are different from circuits engaged by taVNS. SignificanceSince the influence of VNS on cholinergic neurotransmission has been exhaustively demonstrated in animal models, further studies are mandatory to understand the actual impact of VNS on cholinergic circuits in humans.

The involvement of the dysfunctional insulin receptor signaling system in long COVID patients with diabetes and chronic pain and its implications for the clinical management using taVNS.

In clinical terms, chronic pain is the most prevalent sequela resulting from COVID-19, which is induced by the novel coronavirus (SARS-CoV-2), while type 2 diabetes mellitus (T2D) is the most common comorbidity. This triangular relationship can be attributed to the dysfunction of the insulin receptor signaling system (IRSS) in both central and peripheral systems. Patients with T2D are essentially more susceptible to SARS-CoV-2 infection due to the widespread expression of angiotensin converting enzyme 2 (ACE2) in their pancreatic beta cells, which serves as the cellular port for the SARS-CoV-2 to infect and enter the cell. This infection can exacerbate chronic pain and insulin resistance for various reasons. Peripherally, once infected, the virus can cause damage to peripheral nerves and pancreatic β-cells, further exacerbating pain and glucose metabolism conditions. Additionally, in the central nervous system, dysfunctional IRSS is closely linked to chronic pain. Over the past few years of the COVID-19 pandemic, an increasing body of evidence suggests that insulin and other medications currently used in clinical practice for hyperglycemia control may not be safe for treating these patients. Therefore, we need a proper approach for the treatment of chronic pain in long COVID patients, especially patients with T2D. This review presents evidence that transcutaneous auricular vagal nerve stimulation (taVNS) may provide a viable treatment option for chronic pain and metabolic dysfunction by improving the function of IRSS in both the central nervous system and peripheral tissues.

Safety and Preliminary Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation on Chronic Knee Pain: A Pilot Trial

ObjectiveTranscutaneous auricular vagus nerve stimulation (tVNS) may be an innovative treatment for symptoms of knee osteoarthritis (OA) due to possible shared pathological mechanisms between diminished parasympathetic function, central pain mechanisms, and knee pain. Thus, we sought to test the safety and preliminary efficacy of tVNS in people with knee OA. DesignA pilot trial in which participants received a 60-minute tVNS was conducted. At baseline, immediately after, and 15 minutes after tVNS, we assessed knee pain, pressure pain threshold (PPT), temporal summation (TS), conditioned pain modulation (CPM), and high-frequency power of heart rate variability (HF). We examined the extent to which these outcome measures changed after tVNS using linear mixed models. Results30 participants with knee OA were included, and all completed the intervention without any major side effects. Compared to baseline, knee pain was reduced by 1.27 (95% CI, -1.74, -0.80) immediately after and by 1.87 (-2.33, -1.40) 15 minutes after tVNS; CPM improved by 0.11 (0.04, 0.19) and 0.07 (-0.01, 0.15); and HF improved by 213.29 (-0.38, 426.96) and 234.17 (20.49, 447.84). PPT and TS were not changed after tVNS. ConclusionsOur preliminary data demonstrated that tVNS may be a safe pain-relieving treatment for people with knee OA. Our findings suggest that improvement of knee pain might be derived from improvement of parasympathetic function and central pain mechanisms as no local therapy was applied. A large study is needed to confirm that tVNS is a novel intervention to ameliorate knee pain in people with knee OA. Clinical Trial #ClinicalTrials.gov (NCT05625178)

Efficacy observation of combined transcutaneous vagus nerve stimulation and transcranial direct current stimulation on gait in 169 subacute stroke patients.

To investigate the combined effect of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation on improving lower limb function in stroke patients. Randomized controlled trial. Subacute stroke patients. 169 post-stroke hemiplegia patients were randomly divided into 4 groups (control, transcranial direct current stimulation, transcutaneous auricular vagus nerve stimulation, and transcutaneous auricular vagus nerve stimulation combined with transcranial direct current stimulation) and evaluated using the Fugl-Meyer Assessment-Lower Extremity (FMA-LL), Timed Up-and-Go (TUG) test, Modified Barthel Index (MBI), Berg Balance Scale (BBS), gait parameters, and surface electromyography (sEMG). Significant improvements in FMA-LL, MBI, BBS, TUG, gait parameters, and sEMG were noted in the intervention groups compared with the control, with the transcutaneous auricular vagus nerve stimulation combined with transcranial direct current stimulation group showing the most pronounced improvements. Differences in some outcomes were also notable between the transcutaneous auricular vagus nerve stimulation and transcranial direct current stimulation groups. The combination of transcutaneous auricular vagus nerve stimulation and transcranial direct current stimulation effectively enhances gait, balance, and daily living activities in subacute stroke patients. These benefits are likely due to transcutaneous auricular vagus nerve stimulation activating the solitary and trigeminal nuclei and transcranial direct current stimulation stimulating the motor cortex. Wearable gait analysis systems and electromyography are valuable in clinical gait assessment for these patients.

Transcutaneous auricular vagal nerve stimulation modulates blood glucose in ZDF rats via intestinal melatonin receptors and melatonin secretion.

Melatonin (MLT) and its receptor deficiency have been shown to be associated with type 2 diabetes mellitus (T2DM). Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive alternative intervention for patients suffering from hyperglycemia. Here, we aimed to investigate the role of taVNS on blood glucose modulation via intestinal melatonin receptors (MRs) and MLT secretion in hyperglycemia. Adult male Zucker diabetes fatty (ZDF) rats and Zucker lean (ZL) littermates were used. Forty ZDF rats were randomized into ZDF, taVNS, Px + taVNS and Lu + Px + taVNS groups (Px: pinealectomy, Lu: Luzindole). ZL rats served as a control group for comparison with ZDF rats without involvement in the taVNS intervention. Thirty min-taVNS interventions (2/15 Hz, 2 mA, 30 min/days) were administered once daily under anesthesia for 3 consecutive weeks in taVNS, Px + taVNS and Lu + Px + taVNS groups. Body weight and fasting blood glucose (FBG) were measured weekly in all rats, and real-time blood glucose was tested in the ZL and ZDF groups before, during and after the taVNS intervention. Plasma MLT concentration and the expression of MRs in the duodenum, jejunum and ileum were measured by the end of experiments. Compared with the ZL group, the level of FBG and body weight increased (all p < 0.01), plasma MLT secretion and the expression of MRs in duodenum, jejunum and ileum of ZDF rats decreased obviously (all p < 0.05), respectively. TaVNS can significantly reverse the hyperglycemia by regulating the non-pineal-derived MLT and MRs system in Px + taVNS group. Compared with the ZDF group, the expression of different intestinal MRs in the taVNS group was increased and more compactly arranged (both p < 0.05), the level of plasma MLT secretion was up-regulated (p < 0.01), and FBG and body weight were decreased (both p < 0.01). Meanwhile, after taVNS intervention in rats in the Px + taVNS group, we observed an increase in MLT secretion and the number of intestinal MRs compared with the taVNS group (all p > 0.05). In contrast, ZDF rats in which the pineal gland was excised by taVNS intervention and injected with the MRs antagonist Luzindole did not show these changes. The glucose reduction effect of taVNS may be related to regulating MLT levels and expressing intestinal MRs.

Transcutaneous Auricular Vagus Nerve Stimulation for Visually Induced Motion Sickness: An eLORETA Study

Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive form of electrical brain stimulation, has shown potent therapeutic potential for a wide spectrum of conditions. How taVNS influences the characterization of motion sickness – a long mysterious syndrome with a polysymptomatic onset – remains unclear. Here, to examine taVNS-induced effects on brain function in response to motion-induced nausea, 64-channel electroencephalography (EEG) recordings from 42 healthy participants were analyzed; collected during nauseogenic visual stimulation concurrent with taVNS administration, in a crossover randomized sham-controlled study. Cortical neuronal generators were estimated from the obtained EEG using exact low-resolution brain electromagnetic tomography (eLORETA). While both sham and taVNS increased insula activation during electrical stimulation, compared to baseline, taVNS additionally augmented middle frontal gyrus neuronal activity. Following taVNS, brain regions including the supramarginal, parahippocampal, and precentral gyri were activated. Contrasting sham, taVNS markedly increased activity in the middle occipital gyrus during stimulation. A repeated-measures ANOVA showed that taVNS reduced motion sickness symptoms. This reduction in symptoms correlated with taVNS-induced neural activation. Our findings provide new insights into taVNS-induced brain changes, during and after nauseogenic stimuli exposure, including accompanying behavioral response. Together, these findings suggest that taVNS has promise as an effective neurostimulation tool for motion sickness management.

Transcutaneous auricular vagus nerve stimulation improves cognitive decline by alleviating intradialytic cerebral hypoxia in hemodialysis patients: A fNIRS pilot study

Cognitive impairment is common in hemodialysis patients, possibly due to inadequate cerebral blood flow during hemodialysis. No effective non-pharmacological interventions are available. This study investigates the impact of hemodialysis-induced cerebral hypoxia on cognitive decline in hemodialysis patients and the potential of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-pharmacological intervention. A randomized controlled trial with 36 participants showed that cognitive performance and cerebral oxygenation in the dorsolateral prefrontal cortex (DLPFC) significantly declined in the sham group. In contrast, taVNS improved cognitive function by increasing cerebral oxygenation, with significant correlations to reaction times and MoCA scores. The study suggests that Hemodialysis-induced cerebral hypoxia may contribute to persistent cognitive decline in MHD patients. However, taVNS could be an effective intervention to prevent cognitive impairment in hemodialysis patients by alleviating cerebral hypoxia.

Transcutaneous auricular vagus nerve stimulation mitigates gouty inflammation by reducing neutrophil infiltration in BALB/c mice

Gouty inflammation, caused by uric acid crystal deposition, primarily affects tissues around the toe joints and triggers potent inflammatory responses. Current treatments focus on alleviating inflammation and pain using pharmaceutical agents, which can lead to side effects and complications. This has generated interest in non-pharmacological interventions, such as non-invasive vagus nerve stimulation (VNS). In this study, we explored the anti-inflammatory mechanisms of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of acute gout. Gouty inflammation was induced by injecting monosodium urate (MSU) crystals into the ankle joints of BALB/c mice. The effects of taVNS on the expression of inflammatory cytokines and chemokines in the ankle joint tissue were assessed using real-time quantitative PCR (qPCR), western blotting, histological assessments (H&E staining), and immunohistochemistry (IHC). The role of α7 nicotinic acetylcholine receptors (α7nAChR) was also evaluated by signal blocking. Our findings revealed that MSU significantly elevated gout-associated inflammatory cascades and mediators in the ankle joint. Notably, taVNS at 200 µA and 25 Hz effectively reduced these inflammatory responses, decreasing neutrophil infiltration and chemoattraction within the tissue. taVNS showed significant anti-inflammatory properties by suppressing neutrophil activity, offering a novel therapeutic approach for gout beyond conventional pharmacological methods. Additionally, taVNS holds potential for managing various chronic joint diseases. These results highlight taVNS as a promising non-pharmacological therapy for chronic inflammation.

Immediate modulatory effects of transcutaneous vagus nerve stimulation on patients with Parkinson's disease: a crossover self-controlled fMRI study.

Previous studies have evaluated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of Parkinson's disease (PD). However, the mechanism underlying the effect of taVNS on PD remains to be elucidated. This study aimed to investigate the immediate effects of taVNS in PD patients. This crossover self-controlled study included 50 PD patients. Each patient underwent three sessions of resting-state functional magnetic resonance imaging (rs-fMRI) under three conditions: real taVNS, sham taVNS, and no taVNS intervention. We analyzed whole-brain amplitude of low-frequency fluctuations (ALFF) from preprocessed fMRI data across different intervention conditions. ALFF values in altered brain regions were correlated with clinical symptoms in PD patients. Forty-seven participants completed the study and were included in the final analysis. Real taVNS was associated with a widespread decrease in ALFF in the right hemisphere, including the superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus (voxel p < 0.001, GRF corrected). The ALFF value in the right superior parietal lobule during real taVNS was negatively correlated with the Unified Parkinson's Disease Rating Scale Part III (r = -0.417, p = 0.004, Bonferroni corrected). TaVNS could immediately modulate the functional activity of brain regions involved in superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus. These findings offer preliminary insights into the mechanism of taVNS in treating PD and bolster confidence in its long-term therapeutic potential. TaVNS appears to reduce ALFF values in specific brain regions, suggesting a potential modulation mechanism for treating PD.

Acute transcutaneous auricular vagus nerve stimulation modulates presynaptic SV2A density in healthy rat brain: An invivo microPET study.

Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non-invasive form of VNS is transcutaneous auricular VNS (taVNS). Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive mechanisms of taVNS. We evaluated the acute effect of electrical stimulation of the left vagus nerve via the ear on brain synaptic vesicle glycoprotein 2A (SV2A) as a measure of presynaptic density and glucose metabolism in naïve rats. Female Sprague-Dawley rats were imaged with [11C]UCB-J (n = 11) or [18F]fluorodeoxyglucose ([18F]FDG) PET (n = 13) on two separate days, (1) at baseline, and (2) after acute unilateral left taVNS or sham stimulation (30 min). We calculated the regional volume of distribution (VT) for [11C]UCB-J and standard uptake values (SUV) for [18F]FDG. We observed regional reductions of [11C]UCB-J binding in response to taVNS ranging from 36% to 59%. The changes in taVNS compared to baseline were significantly larger than those induced by sham stimulation. The differences were observed bilaterally in the frontal cortex, striatum, and midbrain. The [18F]FDG PET uptake remained unchanged following acute taVNS or sham stimulation compared to baseline values. This proof-of-concept study shows for the first time that acute taVNS for 30 min can modulate invivo synaptic SV2A density in cortical and subcortical regions of healthy rats. Preclinical disease models and PET ligands of different targets can be a powerful combination to assess the therapeutic potential of taVNS.

Evaluating phasic transcutaneous vagus nerve stimulation (taVNS) with pupil dilation: the importance of stimulation intensity and sensory perception

The efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive method to modulate physiological markers of noradrenergic activity of the Locus Coeruleus (LC), such as pupil dilation, is increasingly more discussed. However, taVNS studies show high heterogeneity of stimulation effects. Therefore, a taVNS setup was established here to test different frequencies (10 Hz and 25 Hz) and intensities (3 mA and 5 mA) during phasic stimulation (3 s) with time-synchronous recording of pupil dilation in younger adults. Specifically, phasic real taVNS and higher intensity led to increased pupil dilation, which is consistent with phasic invasive VNS studies in animals. The results also suggest that the influence of intensity on pupil dilation may be stronger than that of frequency. However, there was an attenuation of taVNS-induced pupil dilation when differences in perception of sensations were considered. Specifically, pupil dilation during phasic stimulation increased with perceived stimulation intensity. The extent to which the effect of taVNS induces pupil dilation and the involvement of sensory perception in the stimulation process are discussed here and require more extensive research. Additionally, it is crucial to strive for comparable stimulation sensations during systematic parameter testing in order to investigate possible effects of phasic taVNS on pupil dilation in more detail.

TVNS alters inflammatory response in adult VPA-induced mouse model of autism: evidence for sexual dimorphism.

Autism is a neurodevelopmental disorder with limited treatment alternatives and which incidence is increasing. Some research suggests that vagus nerve simulation might lead to the reduction of certain symptom. Therefore, we aimed to examine the effect of bilateral transcutaneous auricular vagus nerve stimulation (tVNS) on the inflammatory response in an adult valproic acid (VPA) induced mouse (C57BL6) model of autism for the first time. The autism model was induced by oral VPA administration (600 mg·kg-1) to C57BL/6 pregnant mice on E12.5 days. The study included three groups: the VPA Transcutaneous Auricular Stimulation Group (VPA + tVNS), the VPA Control Group (VPA + sham), and the Healthy Control Group (Control + sham). Each group included 16 mice (8 M/8 F). Our results show that serum IL-1β and IL-6 levels were significantly higher in male VPA-exposed mice than controls. However, IL-1β was significantly lower, and IL-6, TNF- α, and IL-22 were not different in female VPA-exposed mice compared to the control group. Brain NLRP3 levels were significantly higher in both sexes in the VPA autism model (P < 0.05). tVNS application increased brain NLRP3 levels in both sexes and reduced serum IL-1β levels in male mice. We conclude that cytokine dysregulation is associated with the VPA-induced adult autism model, and the inflammatory response is more pronounced in male mice. tVNS application altered the inflammatory response and increased brain NLPR3 levels in both sexes. Further studies are needed to understand the beneficial or detrimental role of the inflammatory response in autism and its sexual dimorphism.

Effects of long-term transcutaneous auricular vagus nerve stimulation on circadian vagal activity in people with Prader-Willi Syndrome: A case-series

BackgroundPrader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder marked by disruptions in circadian rhythms and autonomic nervous system (ANS) activity, hyperphagia, and episodes of emotional outbursts. Previous trials suggest that both invasive and non-invasive vagus nerve stimulation (VNS) can reduce emotional outbursts in PWS, potentially through its effects on vagal activity. AimThis case series investigated the effects of transcutaneous auricular VNS (taVNS) on cardiac markers of circadian vagal activity, specifically heart rate variability (HRV) and heart rate (HR), and their potential links to improvements in emotional outbursts. MethodsFive individuals with PWS (mean age: 26.9 years; 3 males, 2 females) received four hours of daily taVNS for 12 months, followed by one month of two-hour daily sessions. Outcome measures included daily recording of emotional outbursts and every three months 24-h HRV and HR recordings. Mixed cosinor models were applied to analyze changes in circadian rhythms of HRV and HR. A linear mixed model was used to assess the predictive value of cardiac vagal activity on emotional outbursts. ResultsCircadian amplitudes of HRV and HR were significantly higher at the end of the treatment compared to baseline (all p’s < .01). There was a significant increase in the rhythm-adjusted mean of HRV (p < .01), while the rhythm-adjusted HR mean significantly decreased, both indicating increased cardiac vagal activity. Higher rhythm-adjusted mean HRV predicted a lower number of emotional outbursts. ConclusionThe results suggest that taVNS may be effective by targeting ANS activity in individuals with PWS, contributing to improvements in behavioral regulation.