Auricular Branch Of The Vagus Research Articles

Brainstem neuronal responses to transcutaneous auricular and cervical vagus nerve stimulation in rats.

Transcutaneous auricular vagus nerve stimulation (taVNS) targets subcutaneous axons in the auricular branch of the vagus nerve at the outer ear. Its non-invasive nature makes it a potential treatment for various disorders. taVNS induces neuromodulatory effects within the nucleus of the solitary tract (NTS), and due to its widespread connectivity, the NTS acts as a gateway to elicit neuromodulation in both higher-order brain regions and other brainstem nuclei (e.g. spinal trigeminal nucleus; Sp5). Our objective was to examine stimulation parameters on single-neuron electrophysiological responses in α-chloralose-anaesthetized Sprague-Dawley rats within NTS and Sp5. taVNS was also compared to traditional cervical VNS (cVNS) on single neuronal activation. Specifically, electrophysiological extracellular recordings were evaluated for a range of frequency and intensity parameters (20-250Hz, 0.5-1.0mA). Neurons were classified as positive, negative or non-responders based on increased activity, decreased activity or no response during stimulation, respectively. Frequency-dependent analysis showed that 20 and 100Hz generated the highest proportion of positive responders in NTS and Sp5 with 1.0mA intensities eliciting the greatest magnitude of response. Comparisons between taVNS and cVNS revealed similar parameter-specific activation for caudal NTS neuronal populations; however, individual neurons showed different activation profiles. The latter suggests that cVNS and taVNS send afferent input to NTS via different neuronal pathways. This study demonstrates differential parameter-specific taVNS responses and begins an investigation of the mechanisms responsible for taVNS modulation. Understanding the neuronal pathways responsible for eliciting neuromodulatory effects will enable more tailored taVNS treatments in various clinical disorders. KEY POINTS: Transcutaneous auricular vagus nerve stimulation (taVNS) offers a non-invasive alternative to invasive cervical vagus nerve stimulation (cVNS) by activating vagal afferents in the ear to induce neuromodulation. Our study evaluated taVNS effects on neuronal firing patterns in the nucleus of the solitary tract (NTS) and spinal trigeminal nucleus (Sp5) and found that 20 and 100Hz notably increased neuronal activity during stimulation in both nuclei. Increasing taVNS intensity not only increased the number of neurons responding in Sp5 but also increased the magnitude of response, suggesting a heightened sensitivity to taVNS compared to NTS. Comparisons between cVNS and taVNS revealed similar overall activation but different responses on individual neurons, indicating distinct neural pathways. These results show parameter-specific and nuclei-specific responses to taVNS and confirm that taVNS can elicit responses comparable to cVNS at the neuronal level, but it does so through different neuronal pathways.

Transcutaneous vagal nerve stimulation during lower body negative pressure

BackgroundPara-sympathetic vagal activation has profound influence on heart rate and other cardiovascular parameters. We tested the hypothesis that transcutaneous Vagal Nerve Stimulation (tVNS) through the auricular branch of the vagus nerve would attenuate the normal sympathetic response to central blood volume reduction by lower body negative pressure (LBNP). Method10 healthy volunteers (6 female; age 21 ± 2 years; weight 62 ± 13 kg; height 167 ± 12 cm) were included in this cross-over design trial. After 15 min rest in supine position, subjects underwent three 15-min periods of 30 mmHg LBNP intervention with and without cyclic tVNS stimulation. Continuous cardiovascular parameters (Nexfin) were recorded. ResultsOverall tVNS did not convincingly attenuate sympathetic response to central hypovolemia. Deactivation of the tVNS during LBNP resulted in increased MAP at 2.3 ± 0.5 mmHg (P < 0.001). Comparing the cyclic actual active stimulation periods to periods with pause during tVNS intervention showed a decrease in HR by 72.9 ± 11.2 to 70.2 ± 11.6 bpm (mean ± SD; P < 0.05), and concomitant increases in SV (86.0 ± 12.1 to 87.2 ± 12.6 mL; P < 0.05), MAP (82.9 ± 6.3 to 84.0 ± 6.2 mmHg; P < 0.05) and TPR (1116.0 ± 111.1 to 1153 ± 104.8 dyn*s/cm5; P < 0.05). ConclusiontVNS in 30 s cycles during LBNP can selectively attenuate HR, prompting a compensatory augmented sympathetic response. It would appear the method used in this study at least, has an isolated cardiac inhibitory effect probably mediated by augmented vagal activity on the sinoatrial or atrio-ventricular node, possibly in combination with reduced activity in the sympathetic cardiac nerve.

Neuroregulatory Effects of Microcone Patch Stimulation on the Auricular Branch of the Vagus Nerve and the Prefrontal Cortex: A Feasibility Study.

Background: The primary purpose of this study was to preliminarily examine the effects of autonomic nervous system activity on the dorsolateral prefrontal cortex. Recent studies have examined approaches to modulating autonomic activity using invasive and non-invasive methods, but the effects of changes in autonomic activity during cognitive tasks on the dorsolateral prefrontal cortex have not been fully investigated. The purpose of this preliminary investigation was to examine changes in autonomic activity and blood oxygen saturation in the dorsolateral prefrontal cortex during reading tasks induced by vagus nerve stimulation using a microcone patch. Methods: A cohort of 40 typically developing adults was enrolled in this study. We carefully examined changes in autonomic nervous system activity and blood oxygen saturation in the dorsolateral prefrontal cortex during a reading task in two conditions: with and without microcone patch stimulation. Results: Significant changes in brain activation in the dorsolateral prefrontal cortext due to microcone patch stimulation were confirmed. In addition, hierarchical multiple regression analysis revealed specific changes in reading task-related blood oxygen saturation in the dorsolateral prefrontal region during microcone patch stimulation. Conclusions: It should be recognized that this study is a preliminary investigation and does not have immediate clinical applications. However, our results suggest that changes in autonomic nervous system activity induced by external vagal stimulation may affect activity in specific reading-related regions of the dorsolateral prefrontal cortex. Further research and evaluation are needed to fully understand the implications and potential applications of these findings.

Transcutaneous Auricular Vagus Nerve Stimulation Alleviates Monobenzone-Induced Vitiligo in Mice.

Vitiligo is a complex skin disorder that involves oxidative stress and inflammatory responses and currently lacks a definitive cure. Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive method for targeting the auricular branch of the vagus nerve and has gained widespread attention for potential intervention in the autonomic nervous system. Although previous research has suggested that vagus nerve stimulation can potentially inhibit inflammatory responses, its specific role and mechanisms in vitiligo treatment remain unknown. This study aimed to explore the therapeutic effects of taVNS in a mouse model of vitiligo induced by monobenzone. Initially, a quantitative assessment of the treatment effects on vitiligo mice was conducted using a scoring system, revealing that taVNS significantly alleviated symptoms, particularly by reducing the depigmented areas. Subsequent immunohistochemical analysis revealed the impact of taVNS treatment on melanocyte granules, mitigating pigment loss in the skin of monobenzone-induced vitiligo mice. Further analysis indicated that taVNS exerted its therapeutic effects through multiple mechanisms, including the regulation of oxidative stress, enhancement of antioxidant capacity, promotion of tyrosine synthesis, and suppression of inflammatory responses. The conclusions of this study not only emphasize the potential value of taVNS in vitiligo therapy, but also lay a foundation for future research into the mechanisms and clinical applications of taVNS.

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial

BackgroundLow-level transcutaneous stimulation of the auricular branch of the vagus nerve at the tragus is antiarrhythmic and anti-inflammatory in animals and humans. Preliminary studies show that transcutaneous vagus nerve stimulation (tVNS) is beneficial in animal models of postural tachycardia syndrome (POTS). ObjectivesIn this study the authors conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of tVNS on POTS over a 2-month period relative to sham stimulation. MethodstVNS (20 Hz, 1 mA below discomfort threshold) was delivered using an ear clip attached to either the tragus (active; n = 12) or the ear lobe (sham; n = 14) for 1 hour daily over a 2-month period. Postural tachycardia was assessed during the baseline and 2-month visit. Heart rate variability based on 5-minute electrocardiogram, serum cytokines, and antiautonomic autoantibodies were measured at the respective time points. ResultsMean age was 34 ± 11 years (100% female; 81% Caucasian). Adherence to daily stimulation was 83% in the active arm and 86% in the sham arm (P > 0.05). Postural tachycardia was significantly less in the active arm compared with the sham arm at 2 months (mean postural increase in heart rate 17.6 ± 9.9 beats/min vs 31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower in the active arm compared with the sham arm at 2 months (P < 0.05). Heart rate variability was better in the active arm. No device-related side effects were observed. ConclusionsOur results support the emerging paradigm of noninvasive neuromodulation to treat POTS. Mechanistically, this effect appears to be related to reduction of antiautonomic autoantibodies and inflammatory cytokines, and improvement in autonomic tone. Further studies are warranted. (Autoimmune Basis for Postural Tachycardia Syndrome; NCT05043051).

Exploration of transcutaneous vagus nerve stimulation as a treatment option for adjuvant cancer and heart failure therapy

Vagus nerve stimulation (VNS) has gained prominence in the treatment of various clinical disorders such as migraine, depression, and tinnitus. Based on increased scientific knowledge of the VNS and insights into the vagus nerve (VN) function and anatomy/conduction, robust treatment approaches have been developed. There are both noninvasive and invasive VNS (iVNS) techniques. Currently, only iVNS techniques are approved by the US Food and Drug Administration (FDA). In contrast, transcutaneous VNS (tVNS) is a new treatment option that is receiving increasing attention. The tVNS application uses the cutaneous distribution of afferent VN fibers in the auricle, the auricular branch of the VN (ABVN), or in the neck, the cervical branch of the VN (CBVN). However, the tVNS technique has not yet been sufficiently researched in its application and mode of action to be used clinically on a large scale. Moreover, the stimulation parameters of the VN vary widely in different studies. Despite the growing number of research papers on this topic, more coherence in neurostimulation research and neuroanatomical basis is needed. The aim of this review is to highlight new clinical treatment options based on existing clinically applied treatment options. In this article, current clinical applications of tVNS are analyzed and important stimulation parameters are highlighted. Based on this data, useful new tVNS therapies are recommended. The focus will be placed on the study of inflammatory processes associated with cancer and on applications to cardiovascular events such as heart failure.

Electrical stimulation of the auricular branch of the vagus nerve potentiates analgesia induced by physical exercise in mice with peripheral inflammation.

This study evaluated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) associated with physical exercise, i.e., swimming, in mice with peripheral inflammation. The pain model was induced by intraplantar (i.pl.) injection of Freund's complete adjuvant (CFA). Sixty-four male Swiss mice (35-40 g) received an i.pl. of CFA and underwent behavioral tests, i.e., mechanical hyperalgesia, edema, and paw temperature tests. Additionally, cytokine levels, specifically interleukin-6 (IL-6) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay. Mice were treated with swimming exercise for 30 min alone or associated with different time protocols (10, 20, or 30 min) of stimulation in the left ear with random frequency during four consecutive days. pVNS for 20 min prolonged the antihyperalgesic effect for up to 2 h, 24 h after CFA injection. pVNS for 30 min prolonged the antihyperalgesic effect for up to 7 h, 96 h after CFA injection. However, it did not alter the edema or temperature at both analyzed times (24 and 96 h). Furthermore, the combination of pVNS plus swimming exercise, but not swimming exercise alone, reduced IL-6 levels in the paw and spinal cord, as well as IL-10 levels in the spinal cord. pVNS potentiates the analgesic effect induced by swimming, which may be, at least in part, mediated by the modulation of inflammatory cytokines in the periphery (paw) and central nervous system (spinal cord). Therefore, the combination of these therapies may serve as an important adjunctive treatment for persistent inflammatory pain.

Simulation of the auricular branch of the vagus nerve by acupuncture in women with fibromyalgia with severe pain and other functional and emotional problems: study protocol for a randomized, controlled, double-blind clinical trial

Simulation of the auricular branch of the vagus nerve by acupuncture in women with fibromyalgia with severe pain and other functional and emotional problems: study protocol for a randomized, controlled, double-blind clinical trial

Management of auricular transcutaneous neuromodulation and electro-acupuncture of the vagus nerve for chronic migraine: a systematic review.

Migraine is a type of primary headache that is accompanied by symptoms such as nausea, vomiting, or sensitivity to light and sound. The aim of this study was to conduct a systematic review on the effectiveness of non-invasive neuromodulation, auricular transcutaneous vagus nerve stimulation (at-VNS), and electro-ear acupuncture of the vagus nerve in patients with migraine headaches. Six databases were searched from inception to 15 June 2022 for clinical trials, in which at least one group received any form of non-invasive neuromodulation of the vagus nerve for managing migraine with outcomes collected on pain intensity and related disability. Data, including participants, interventions, blinding strategy, outcomes, and results, were extracted by two reviewers. The methodological quality was assessed with the PEDro scale, ROB, and Oxford scale. The search identified 1,117 publications with nine trials eligible for inclusion in the review. The methodological quality scores ranged from 6 to 8 (mean: 7.3, SD: 0.8) points. Low-quality evidence suggests some positive clinical effects for the treatment of chronic migraine with 1 Hz with at-VNS and ear-electro-acupuncture compared with the control group at post-treatment. Some of the studies provided evidence of the relationship between chronic migraine and a possible positive effect as a treatment with at-VNS and the neurophysiological effects using fMRI. Six of the studies provided evidence using fMRI of the relationship between chronic migraine and a possible positive effect as a treatment with at-VNS and the neurophysiological effects. Regarding all included studies, the level of evidence with the Oxford scale was level 1 (11.17%), six studies were graded as level 2 (66.66%), and two studies were graded as level 3 (22.2%). With the PEDro score, five studies got a low methodological score < 5 and only four got a score superior to 5, being highly methodological quality studies. For ROB, most of the studies were high risk and only a few of them received a low risk of bias. The pain intensity, migraine attacks, frequency, and duration were measured by three studies with positive results at post-treatment. And only 7% reported adverse events using at-VNS. All studies reported results at a post-treatment period in their respective main outcomes. And all studies with fMRI provided strong evidence of the relationship between the Locus Coeruleus, Frontal Cortex, and other superior brain areas with the auricular branch of the Vagus nerve with at-VNS. Some positive effects regarding the effect of non-invasive neuromodulation, auricular transcutaneous vagus nerve stimulation (at-VNS), and electro-ear acupuncture of the vagus nerve on migraine is reported in the current literature, but there are not enough data to obtain strong conclusions. This systematic review was registered in the PROSPERO database (registration number: CRD42021265126).

Daith Ear Piercing in The Treatment of Migraine

We report the initial results from an ongoing study of Daith ear piercing undertaken in collaboration with experienced piercers at a long-established national chain of piercing studios. Daith piercing passes through the cartilage of the crus helix, an area innervated by the auricular branch of the vagus nerve. Historically, Daith piercing was cosmetic, but has become increasingly popular after unexpected improvement in migraine was first noticed in 1992. Since then, many migraine sufferers have sought a Daith piercing from cosmetic piercing studios and their reports of improvements continue. Apart from isolated case histories there has been no medical investigation. Electrical stimulation of the vagus nerve is an established treatment for migraine and epilepsy that is recognised by NICE in the UK. We hypothesize that the piercing stimulates the vagus nerve by mechanical or inflammatory irritation.

Transcutaneous auricular vagus nerve stimulation would be an alternative to implantable cervical vagus nerve stimulation in some situation.

Implantable cervical vagus nerve stimulation (iVNS) is a representative and promising neuromodulation. However, the invasive nature restricts its application. Traditional auricular acupuncture treatment has a long history. The auricular branch of the vagus nerve (ABVN) is a branch on the surface of the ear. Some studies demonstrates that transcutaneous auricular vagus nerve stimulation (taVNS) would achieve similar effects as iVNS. TaVNS and iVNS share a common anatomical basis and acting mechanism. In this article, we made a comparison between iVNS and taVNS in indications and efficacy. The recent studies have revealed similar clinical efficacy of taVNS, taVNS would expand the indication of iVNS. High-quality clinical evidences are needed before taVNS become be an alternative of iVNS.

LB-456640-4 NONINVASIVE VAGUS NERVE STIMULATION IN POSTURAL TACHYCARDIA SYNDROME: A RANDOMIZED CLINICAL TRIAL

Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the tragus (LLTS) is anti-arrhythmic and anti-inflammatory in animals and humans. Preliminary animal studies show that LLTS is beneficial in animal models of postural tachycardia syndrome (POTS).

Transcutaneous electrical stimulation of auricular branch of the vagus nerve effectively and rapidly modulates the EEG patterns in patients with possible electrographic status epilepticus.

Invasive vagal nerve stimulation (iVNS) is a known treatment approach for patients with refractory epilepsy. Transcutaneous auricular vagus nerve stimulation (tVNS) was developed to overcome the side effects and surgical complications of iVNS. tVNS is proven beneficial in refractory epilepsy. The effectiveness of tVNS, however, has never been studied in patients with Status Epilepticus. In this study, we explored the effect of tVNS in three patients with possible electrographic status epilepticus. To compare the EEG pattern before, during and after tVNS in three patients with possible electrographic status epilepticus. Three consecutive patients with possible electrographic status epilepticus were included after due consenting process. In addition to the standard care, tVNS was applied on the left ear over the cymba concha in two sessions, 6 h apart, with each session for 45 min. Continuous EEG monitoring was performed as standard of care and the findings before, during and after tVNS were documented. The duration of status epilepticus at the time of inclusion of Patients 1, 2, and 3 was 6 weeks, 7 days, and 5 days respectively. All were in coma and on multiple antiseizure medications. Patient 1 and 3 were on anesthetic infusions. Before stimulation, one patient had burst suppression pattern and two had generalized periodic discharges at 1 Hz frequency. We observed a significant reduction/resolution of ongoing EEG patterns in all three patients during the stimulation. The abnormal patterns re-emerged approximately 20 min post cessation of tVNS. No stimulation-related side effects were detected. There was no change in clinical status, but all three patients had severe underlying conditions. Transcutaneous auricular Vagus Nerve Stimulation (tVNS) is a potential noninvasive adjuvant therapy that can modulate EEG patterns in patients with Status epilepticus. Larger studies in early SE are needed to assess its clinical benefits.

The Effect of Short-Term Transcutaneous Electrical Stimulation of Auricular Vagus Nerve on Parameters of Heart Rate Variability

Many previous studies have demonstrated that transcutaneous vagus nerve stimulation (VNS) has the potential to exhibit therapeutic effects similar to its invasive counterpart. An objective assessment of VNS requires a reliable biomarker of successful vagal activation. Although many potential biomarkers have been proposed, most studies have focused on heart rate variability (HRV). Despite the physiological rationale for HRV as a biomarker for assessing vagal stimulation, data on its effects on HRV are equivocal. To further advance this field, future studies investigating VNS should contain adequate methodological specifics that make it possible to compare the results between studies, to replicate studies, and to enhance the safety of study participants. This article describes the design and methodology of a randomized study evaluating the effect of short-term noninvasive stimulation of the auricular branch of the vagus nerve on parameters of HRV. Primary records of rhythmograms of all the subjects, as well as a dataset with clinical, instrumental, and laboratory data of all the current study subjects are in the public domain for possible secondary analysis to all interested researchers. The physiological interpretation of the obtained data is not considered in the article.

Transcutaneous auricular vagus nerve stimulation may elicit anti-inflammatory actions through activation of the hypothalamic-pituitary-adrenal axis in humans

Introduction: Since the discovery of the cholinergic anti-inflammatory pathway, vagus nerve stimulation (VNS) has been suggested as a treatment option for chronic inflammatory conditions. This pathway relies on efferent vagal nerve fibers. Invasive cervical VNS activates afferent and efferent vagal nerve fibers and, thus, has the potential to directly activate the cholinergic anti-inflammatory pathway. In contrast, transcutaneous auricular VNS (taVNS) activates the auricular branch of the vagus nerve that is purely afferent and projects to the nucleus of the solitary tract. Thus, any anti-inflammatory actions of taVNS are unlikely to result from a direct activation of the cholinergic anti-inflammatory pathway. The objective of this study was to investigate alternative mechanisms by which taVNS may elicit anti-inflammatory effects. The hypothesis was tested that taVNS activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in adrenal cortisol secretion that will then modulate circulatory immune cell numbers. Methods: The study was approved by the appropriate authorities (IRB# 0054_2019 and NCT04177264). Study participants were healthy adults (n=19, 6 male, 13 female). On three consecutive days either taVNS (left ear, 10 Hz, 1-2 mA, 300 μs pulse width) or sham-taVNS (stimulator off) was applied for 10 minutes. A blood sample was drawn at the end of the third day. Plasma cortisol was determined by ELISA (K003-H1W, Arbor Assays, MI). Circulating T-helper cells (CD3+, CD4+), cytotoxic T-cells (CD3+, CD8+), B-cells (CD19+), monocytes (CD14+, CD11b+), and natural killer (NK, CD3-, CD56+) cells were counted using flow cytometry. Statistical significance was assumed at P&lt;0.05 and trends are reported for P&lt;0.15 based on unpaired t-tests. Results: Plasma cortisol levels tended to be higher following taVNS (72.5±9.5 ng/mL) compared to sham-taVNS (52.3±3.8 ng/mL, P=0.09). Following taVNS, the relative number of circulatory B cells was lower (0.48±0.11 % vs. 0.82±0.11 %, P&lt;0.05), while the number of circulatory monocytes was higher (2.21±0.32 % vs 1.58±0.16 %, P=0.06) compared to sham-taVNS. T-helper cells, cytotoxic T cells, and NK cells were not significantly affected by taVNS. In conclusion, the higher plasma cortisol levels following taVNS together with the higher number of circulatory monocytes and lower number of B cells suggest that taVNS elicits anti-inflammatory actions through activation of the HPA axis, because it is known that cortisol increases circulatory monocytes and reduces B cells. The decrease in B cells following taVNS gives rise to the intriguing hypothesis that taVNS may prevent secondary treatment failure to biologic drugs in chronic inflammatory conditions by reducing production of anti-drug antibodies. Funding: This study was supported by a grant from the American Osteopathic Association (Grant No.: 19137759). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Electroacupuncture of the cymba concha alleviates p-chlorophenylalanine-induced insomnia in mice.

Insomnia is the most common sleep disorder and is often comorbid with mental and physical diseases. The present study was designed to investigate the hypnotic effect of electroacupuncture (EA) of the cymba concha to stimulate the auricular branch of the vagus nerve (ABVN). Mice were intraperitoneally injected with p-chlorophenylalanine (PCPA, 300 mg/kg·d) for 2 days to induce insomnia and subsequently received EA or manual acupuncture (MA) of the cymba concha for 30 min once daily for 5 consecutive days, or no treatment. The phenobarbital-induced sleep test was used to analyze the hypnotic effects and the open field test was used to analyze the locomotor activities and anxiolytic effects of EA/MA of the cymba concha. In addition, the levels of gamma-aminobutyric acid (GABA) and glutamate (Glu) in the hypothalamus and peripheral blood were determined by enzyme-linked immunosorbent assay (ELISA). PCPA injection significantly decreased sleep duration, increased sleep latency and induced anxiety-like behaviors in mice. In PCPA-insulted mice, EA of the cymba concha improved the sleep disturbance by significantly prolonging sleep duration, while no change in sleep latency was observed. Moreover, EA of the cymba concha improved PCPA-induced anxiety-like behaviors without decreasing locomotor activities in the open field test. EA of the cymba concha increased the level of GABA in the hypothalamus and peripheral blood, while Glu concentrations remained unchanged. These findings indicate that EA of the region innervated by the ABVN upregulates GABA levels in the hypothalamus and ameliorates the symptoms of insomnia and anxiety, suggesting that EA of the cymba concha might have potential value as an intervention for insomnia.

Immediate effects and duration of a short and single application of transcutaneous auricular vagus nerve stimulation on P300 event related potential.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neuromodulatory technique that stimulates the auricular branch of the vagus nerve. The modulation of the locus coeruleus-norepinephrine (LC-NE) network is one of the potential working mechanisms of this method. Our aims were 1-to investigate if short and single applications of taVNS can modulate the P300 cognitive event-related potential (ERP) as an indirect marker that reflects NE brain activation under control of the LC, and 2-to evaluate the duration of these changes. 20 healthy volunteers executed an auditory oddball paradigm to obtain P300 and reaction time (RT) values. Then a 7 min active or sham taVNS period was initiated and simultaneously a new P300 paradigm was performed. We successively repeated the paradigm on 4 occasions with different time intervals up to 56 min after the stimulation onset. During active taVNS an immediate and significant effect of increasing the amplitude and reducing the latency of P300, as well as a shortening in the RT was observed. This effect was prolonged in time up to 28 min. The values then returned to pre-stimulation levels. Sham stimulation did not generate changes. Our results, demonstrate differential facilitating effects in a concrete time window after taVNS. Literature about the modulatory effect of taVNS over P300 ERP shows a wide spread of results. There is not a standardized system for taVNS and currently the great heterogeneity of stimulation approaches concerning targets and parameters, make it difficult to obtain conclusions about this relationship. Our study was designed optimizing several stimulation settings, such as a customized earbud stimulator, enlarged stimulating surface, simultaneous stimulation over the cymba and cavum conchae, a Delayed Biphasic Pulse Burst and current controlled stimulation that adjusted the output voltage and guaranteed the administration of a preset electrical dose. Under our stimulation conditions, targeting vagal nerve fibers via taVNS modulates the P300 in healthy participants. The optimal settings of modulatory function of taVNS on P300, and their interdependency is insufficiently studied in the literature, but our data provides several easily optimizable parameters, that will produce more robust results in future.

Transauricular vagus nerve stimulation for patients with disorders of consciousness: A randomized controlled clinical trial.

Disorders of consciousness (DoCs) are a frequent complication of brain injury disease, and effective treatments are currently lacking. Transauricular vagus nerve stimulation (tVNS) has been proposed as a promising therapeutic method for neurological disorders such as epilepsy and depression. In our previous study, we demonstrated that vagus nerve stimulation promoted recovery in rats with DoCs caused by traumatic brain injury. However, the clinical effect of vagus nerve stimulation on consciousness disorders is unclear. We aimed to investigate the therapeutic efficacy and safety of tVNS in patients with DoCs. We conducted a randomized, double-blinded, sham-controlled trial. Patients (N = 60) with DoCs, including minimally conscious state (MCS) and vegetative state/unresponsive wakefulness syndrome, were enrolled and randomized to groups receiving either active or sham tVNS. A frequency of 20 Hz and pulse wave of 200 us was used in the active-tVNS protocol, which was performed in the auricular branch of the vagus nerve in the left outer ear. The sham-tVNS protocol was the same as the active-tVNS protocol although without current input. Both groups of patients also received conventional treatments. Consciousness was evaluated according to the Coma Recovery Scale-Revised before and after the 4-week intervention. We also recorded the type and number of behavioral responses. Safety was primarily assessed according to the incidence of treatment-emergent adverse events. Each patient's heart rate and blood pressure were monitored during all treatment sessions. Ultimately, 57 patients completed the study: 28 patients underwent active tVNS and 29 patients underwent sham tVNS. No significant differences were observed in Coma Recovery Scale-Revised scores between the active- and sham-tVNS groups before the tVNS sessions. Compared with patients in the sham-tVNS group (9.28 ± 4.38), patients with DoCs treated with active tVNS showed improved consciousness (10.93 ± 4.99), although not statistically significant. Further analysis revealed obvious differences between patients with MCS receiving active and sham tVNS, but no significant difference in patients with vegetative state/unresponsive wakefulness syndrome in both groups. All side effects were considered common medical conditions with no obvious correlation to tVNS. These preliminary data provide early evidence that tVNS may be an effective and safe approach for promoting the recovery of consciousness, especially in patients with MCS. https://www.chictr.org.cn/edit.aspx?pid=175938&htm=4, identifier: ChiCTR2200066629.

Anatomy of small canals around the jugular foramen: Special reference to Jacobson's and Arnold's nerves.

The jugular foramen harbors anatomically complex bony, venous and neural structures. It is closely associated with small canals including the mastoid, tympanic, and cochlear canaliculi, and the stylomastoid foramen. The minute intraosseous branches of Arnold's and Jacobson's nerves (<1 mm in length) remain difficult to study with current imaging techniques, and cadaveric dissection is the most reliable approach. Our aim was to examine the variations of Jacobson's and Arnold's canaliculi and nerves and to provide detailed cadaveric graphics. To reveal the anatomical structures of small canals around the jugular foramen, 25 sides of dry skulls and 14 sides of cadaveric heads were examined. Intraosseous branches varied more in Arnold's nerve than Jacobson's nerve. In our cadaveric dissection, all specimens formed a single canal for Jacobson's nerve connecting the jugular foramen to the tympanic cavity. The intraosseous course of Arnold's nerve varied in its communication with the facial nerve. A descending branch crossing the facial nerve was identified in five of 14 sides, an ascending branch in 13. In two specimens, an ascending branch clearly reached the base of the stapedius muscle. Classical anatomical studies of cadavers remain a supplementary tool for analyzing these tiny structures. The present study confirms Gray's findings of 1913. Variations of these nerves could be even more complex than previously reported. Our study provides additional information regarding the anatomy of Jacobson's and Arnold's nerves.

Exploratory Investigation of the Effects of Tactile Stimulation Using Air Pressure at the Auricular Vagus Nerve on Heart Rate Variability.

To explore the effects of tactile stimulation using air pressure at the auricular branch of the vagus nerve on autonomic activity in healthy individuals. Three types of tactile stimulation were used in this study: continuous low-amplitude, continuous high-amplitude, and pulsed airflow. The tactile stimulations were provided to the cymba concha to investigate autonomic activity in 22 healthy participants. The mean heart rate (HR) and parameters of HR variability, including the standard deviation of R-R intervals (SDNN) and root mean square of successive R-R interval differences (RMSSD) were compared at baseline, stimulation, and recovery periods. Two-way repeated measures ANOVA indicated a significant main effect of time on HR (p=0.001), SDNN (p=0.003), and RMSSD (p<0.001). These parameters showed significant differences between baseline and stimulation periods and baseline and recovery periods in the post-hoc analyses. There were no significant differences in the changes induced by stimulation type and the interaction between time and stimulation type for all parameters. One-way repeated measures ANOVA showed that HR, SDNN, and RMSSD did not differ significantly among the three time periods during sham stimulation. Parasympathetic activity can be enhanced by auricular tactile stimulation using air pressure, targeting the cymba concha. Further studies are warranted to investigate the optimal stimulation parameters for potential clinical significance.