Cymba Conchae Research Articles

Effects of Transcutaneous Auricular Vagus Nerve Stimulation on Cortical Excitability in Healthy Adults

ObjectiveVagus nerve stimulation (VNS) has recently been reported to exert additional benefits for functional recovery in patients with brain injury. However, the mechanisms underlying these effects have not yet been elucidated. This study examined the effects of transcutaneous auricular VNS (taVNS) on cortical excitability in healthy adults. Materials and MethodsWe recorded subthreshold and suprathreshold single- and paired-pulse motor-evoked potentials (MEPs) in the right-hand muscles of 16 healthy adults by stimulating the left primary motor cortex. Interstimulus intervals were set at 2 milliseconds and 3 milliseconds for intracortical inhibition (ICI), and 10 milliseconds and 15 milliseconds for intracortical facilitation (ICF). taVNS was applied to the cymba conchae of both ears for 30 minutes. The intensity of taVNS was set to a maximum tolerable level of 1.95 mA. MEPs were measured before stimulation, 20 minutes after the beginning of the stimulation, and 10 minutes after the cessation of stimulation. ResultsThe participants’ age was 33.25 ± 7.08 years, and nine of 16 were male. No statistically significant changes were observed in the mean values of the single-pulse MEPs before, during, or after stimulation. Although the ICF showed an increasing trend after stimulation, the changes in ICI and ICF were not significant, primarily because of the substantial interindividual variability. ConclusionsThe effect of taVNS on cortical excitability varied in healthy adults. An increase in ICF was observed after taVNS, although the difference was not statistically significant. Our findings contribute to the understanding of the mechanisms by which taVNS is effective in patients with brain disorders.

Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial

BackgroundVagus nerve stimulation is an investigational anti-inflammatory therapy targeting the nervous system to modulate immune activity. This study evaluated the efficacy and safety of transcutaneous auricular VNS (ta-VNS) in patients with pediatric-onset Crohn’s disease (CD) or ulcerative colitis (UC).MethodsParticipants were 10–21 years of age with mild/moderate CD or UC and fecal calprotectin (FC) > 200 ug/g within 4 weeks of study entry. Subjects were randomized to receive either ta-VNS targeting the cymba conchae of the external left ear, or sham stimulation, of 5 min duration once daily for a 2-week period, followed by a cross over to the alternative stimulation for an additional 2 weeks. At week 4, all subjects received ta-VNS of 5 min duration twice daily until week 16. Primary study endpoints were clinical remission, and a ≥ 50% reduction in FC level from baseline to week 16. Heart rate variability measurements and patient-reported outcome questionnaires were completed during interval and week 16 assessments.ResultsTwenty-two subjects were enrolled and analyzed (10 CD, 12 UC). Six of 10 with CD had a wPCDAI > 12.5 and 6/12 with UC had a PUCAI > 10 at baseline, correlating to mild to moderate symptom activity. Among the 12 subjects with active symptomatic disease indices at baseline, clinical remission was achieved in 3/6 (50%) with CD and 2/6 (33%) with UC at week 16. Despite all subjects having FC levels ≥ 200 within 4 weeks of enrollment, five subjects (4 UC, 1 CD) had FC levels < 200 at the baseline visit and were excluded from the FC analysis. Of the remaining 17, median baseline FC was 907 µg/g (IQR 411–2,120). At week 16, 11/17 (64.7%) of those with baseline FC ≥ 200 had a ≥ 50% reduction in FC (95% CI 38.3—85.8). In the UC subjects, there was an 81% median reduction in FC vs baseline (833 µg/g; p = 0.03) while in the CD subjects, median reduction in FC at 16 weeks was 51% (357 µg/g; p = 0.09). There were no safety concerns.ConclusionNoninvasive ta-VNS attenuated signs and symptoms in a pediatric cohort with mild to moderate inflammatory bowel disease.Trial RegistrationNCT03863704—Date of registration 3/4/2019.

Pupillary response to percutaneous auricular vagus nerve stimulation in alcohol withdrawal syndrome: A pilot trial

BackgroundAutonomic symptoms in alcohol withdrawal syndrome (AWS) are associated with a sympathetic-driven imbalance of the autonomic nervous system. To restore autonomic balance in AWS, novel neuromodulatory approaches could be beneficial. We conducted a pilot trial with percutaneous auricular vagus nerve stimulation (pVNS) in AWS and hypothesized that pVNS will enhance the parasympathetic tone represented by a reduction of pupillary dilation in a parasympatholytic pharmacological challenge. MethodsThirty patients suffering from alcohol use disorder, undergoing AWS, and stable on medication, were recruited in this open-label, single-arm pilot trial with repeated-measure design. Peripheral VNS (monophasic volt impulses of 1 msec, alternating polarity, frequency 1 Hz, amplitude 4 mV) was administered at the left cymba conchae for 72 h, followed by pupillometry under a tropicamide challenge. We assessed craving with a visual analog scale. We used pupillary mean as the dependent variable in a repeated-measures ANOVA (rmANOVA). ResultsA repeated-measures ANOVA resulted in a significant difference for pupillary diameter across time and condition (F(2,116) = 27.97, p < .001, ηp2 > .14). Tukey-adjusted post hoc analysis revealed a significant reduction of pupillary diameter after pVNS. Alcohol craving was significantly reduced after pVNS (p < .05, Cohen's d = 1.27). ConclusionOur study suggests that pVNS activates the parasympathetic nervous system in patients with acute AWS, and that this activation is measurable by pupillometry. To this end, pVNS could be beneficial as a supportive therapy for AWS. Potential confounding effects of anti-craving treatment should be kept in mind.

Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol

BackgroundOver 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5–15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI.DesignVINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI.DiscussionVINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT05514756. Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.)

An AAM-Based Identification Method for Ear Acupoint Area.

Ear image segmentation and identification is for the "observation" of TCM (traditional Chinese medicine), because disease diagnoses and treatment are achieved through the massaging of or pressing on some corresponding ear acupoints. With the image processing of ear image positioning and regional segmentation, the diagnosis and treatment of intelligent traditional Chinese medicine ear acupoints is improved. In order to popularize ear acupoint therapy, image processing technology has been adopted to detect the ear acupoint areas and help to gradually replace well-trained, experienced doctors. Due to the small area of the ear and the numerous ear acupoints, it is difficult to locate these acupoints based on traditional image recognition methods. An AAM (active appearance model)-based method for ear acupoint segmentation was proposed. The segmentation was illustrated as 91 feature points of a human ear image. In this process, the recognition effects of the ear acupoints, including the helix, antihelix, cymba conchae, cavum conchae, fossae helicis, fossae triangularis auriculae, tragus, antitragus, and earlobe, were divided precisely. Besides these, specially appointed acupoints or acupoint areas could be prominent in ear images. This method made it possible to partition and recognize the ear's acupoints through computer image processing, and maybe own the same abilities as experienced doctors for observation. The method was proved to be effective and accurate in experiments and can be used for the intelligent diagnosis of diseases.

Brief periods of transcutaneous auricular vagus nerve stimulation improve autonomic balance and alter circulating monocytes and endothelial cells in patients with metabolic syndrome: a pilot study

BackgroundThere is emerging evidence that the nervous system regulates immune and metabolic alterations mediating Metabolic syndrome (MetS) pathogenesis via the vagus nerve. This study evaluated the effects of transcutaneous auricular vagus nerve stimulation (TAVNS) on key cardiovascular and inflammatory components of MetS.MethodsWe conducted an open label, randomized (2:1), two-arm, parallel-group controlled trial in MetS patients. Subjects in the treatment group (n = 20) received 30 min of TAVNS with a NEMOS® device placed on the cymba conchae of the left ear, once weekly. Patients in the control group (n = 10) received no stimulation. Hemodynamic, heart rate variability (HRV), biochemical parameters, and monocytes, progenitor endothelial cells, circulating endothelial cells, and endothelial micro particles were evaluated at randomization, after the first TAVNS treatment, and again after 8 weeks of follow-up.ResultsAn improvement in sympathovagal balance (HRV analysis) was observed after the first TAVNS session. Only patients treated with TAVNS for 8 weeks had a significant decrease in office BP and HR, a further improvement in sympathovagal balance, with a shift of circulating monocytes towards an anti-inflammatory phenotype and endothelial cells to a reparative vascular profile.ConclusionThese results are of interest for further study of TAVNS as treatment of MetS.

Ear your heart: transcutaneous auricular vagus nerve stimulation on heart rate variability in healthy young participants.

Transcutaneous auricular vagus nerve stimulation (taVNS) stimulating the auricular branch of the vagus nerve along a well-defined neuroanatomical pathway, has promising therapeutic efficacy. Potentially, taVNS can modulate autonomic responses. Specifically, taVNS can induce more consistent parasympathetic activation and may lead to increased heart rate variability (HRV). However, the effects of taVNS on HRV remain inconclusive. Here, we investigated changes in HRV due to brief alteration periods of parasympathetic-vagal cardiac activity produced by taVNS on the cymba as opposed to control administration via the helix. We compared the effect of 10 min of active stimulation (i.e., cymba conchae) to sham stimulation (i.e., helix) on peripheral cardiovascular response, in 28 healthy young adults. HRV was estimated in the time domain and frequency domain during the overall stimulation. Although active-taVNS and sham-taVNS stimulation did not differ in subjective intensity ratings, the active stimulation of the cymba led to vagally mediated HRV increases in both the time and frequency domains. Differences were significant between active-taVNS and both sham-taVNS and resting conditions in the absence of stimulation for various HRV parameters, but not for the low-frequency index of HRV, where no differences were found between active-taVNS and sham-taVNS conditions. This work supports the hypothesis that taVNS reliably induces a rapid increase in HRV parameters when auricular stimulation is used to recruit fibers in the cymba compared to stimulation at another site. The results suggest that HRV can be used as a physiological indicator of autonomic tone in taVNS for research and potential therapeutic applications, in line with the established effects of invasive VNS. Knowledge of the physiological effect of taVNS short sessions in modulating cardiovagal processing is essential for enhancing its clinical use.

Meditative-based diaphragmatic breathing vs. vagus nerve stimulation in the treatment of fibromyalgia—A randomized controlled trial: Body vs. machine

Vagus nerve innervation via electrical stimulation and meditative-based diaphragmatic breathing may be promising treatment avenues for fibromyalgia. Explore and compare the treatment effectiveness of active and sham transcutaneous vagus nerve stimulation (tVNS) and meditative-based diaphragmatic breathing (MDB) for fibromyalgia. Participants enrolled from March 2019-October 2020 and randomly assigned to active tVNS (n = 28), sham tVNS (n = 29), active MDB (n = 29), or sham MDB (n = 30). Treatments were self-delivered at home for 15 min/morning and 15 min/evening for 14 days. Follow-up was at 2 weeks. Outpatient pain clinic in Oslo, Norway. 116 adults aged 18-65 years with severe fibromyalgia were consecutively enrolled and randomized. 86 participants (74%) had an 80% treatment adherence and 107 (92%) completed the study at 2 weeks; 1 participant dropped out due to adverse effects from active tVNS. Active tVNS is placed on the cymba conchae of the left ear; sham tVNS is placed on the left earlobe. Active MDB trains users in nondirective meditation with deep breathing; sham MDB trains users in open-awareness meditation with paced breathing. Primary outcome was change from baseline in ultra short-term photoplethysmography-measured cardiac-vagal heart rate variability at 2 weeks. Prior to trial launch, we hypothesized that (1) those randomized to active MDB or active tVNS would display greater increases in heart rate variability compared to those randomized to sham MDB or sham tVNS after 2-weeks; (2) a change in heart rate variability would be correlated with a change in self-reported average pain intensity; and (3) active treatments would outperform sham treatments on all pain-related secondary outcome measures. No significant across-group changes in heart rate variability were found. Furthermore, no significant correlations were found between changes in heart rate variability and average pain intensity during treatment. Significant across group differences were found for overall FM severity yet were not found for average pain intensity. These findings suggest that changes in cardiac-vagal heart rate variability when recorded with ultra short-term photoplethysmography in those with fibromyalgia may not be associated with treatment-specific changes in pain intensity. Further research should be conducted to evaluate potential changes in long-term cardiac-vagal heart rate variability in response to noninvasive vagus nerve innervation in those with fibromyalgia. https://clinicaltrials.gov/ct2/show/NCT03180554, Identifier: NCT03180554.

Non-invasive vagus nerve stimulation in a hungry state decreases heart rate variability

Vagus nerve signals from the gut to brain carry information about nutrients and drive food reward. Such signals are disrupted by consuming large amounts of high-calorie foods, necessitating greater food intake to elicit a similar neural response. Non‐invasive vagus nerve stimulation (nVNS) via a branch innervating the ear is a candidate treatment for obesity in humans. There is disagreement on the optimal location of nVNS in the ear for experimental and clinical studies. There are also no studies comparing nVNS in hungry and post-prandial states. We aimed to compare ear position(s) for nVNS and explore the effects of nVNS during hungry and post-prandial states on proxies for autonomic outflow (heart-rate variability) and efferent metabolism (gastric wave frequency and resting energy expenditure).In a within-subject design, 14 participants (10 women, on average 29.4 +/- 6.7 years old) received nVNS in four different locations (cymba conchae, tragus, earlobe, or tragus AND cymba conchae) on separate days. In each session, participants were asked to consume a palatable chocolate flavored milk. With electrography on the abdomen and indirect calorimetry in a canopy, we measured electro-cardiogram, electro-gastrogram and resting energy expenditure for 15 min before and at least 35 min after consumption of the palatable drink. We also collected ratings of the palatable drink and internal and other states.Pre-drink consumption (in a hungry state) we observed no differences in the effect of location of acute nVNS on resting energy expenditure and gastric wave measures. However, nVNS in cymba conchae decreases heart-rate variability (relative to sham) and ratings of how much participants want to consume the drink (relative to tragus AND cymba conchae and a trend relative to sham). After drink consumption and with continued nVNS, gastric wave frequency is unchanged, and resting energy expenditure increases regardless of stimulation location. Heart-rate variability decreases in all locations, except cymba conchae. We also observe a trend for an increase in gastric wave amplitude in late post-drink consumption time-points in cymba conchae. We observe no support for the combined stimulation of tragus AND cymba conchae being more effective than either of the individual locations.These results suggest that nVNS in the cymba conchae in a hungry state has a similar acute effect on vagal tone as food consumption: to decrease heart rate variability. This effect then negates the usual postprandial effects of a decrease in heart rate variability as seen in the other nVNS locations. These preliminary observations suggest that nVNS in cymba conchae may act primarily on vagal afferent autonomic (and only modestly on metabolic output) in a similar way as food consumption does.

Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

This study aimed to determine how transcutaneous vagus nerve stimulation (tVNS) alters autonomic nervous activity by comparing the effects of different tVNS frequencies and current intensities. We also investigated the sex-dependent autonomic response to tVNS. Thirty-five healthy adult participants were stimulated using a tVNS stimulator at the left cymba conchae while sitting on a reclining chair; tVNS-induced waveform changes were then recorded for different stimulus frequencies (Experiment 1: 3.0 mA at 100 Hz, 25 Hz, 10 Hz, 1 Hz, and 0 Hz (no stimulation)) and current intensities (Experiment 2: 100 Hz at 3.0 mA, 1.0 mA, 0.2 mA (below sensory threshold), and 0 mA (no stimulation)) using an electrocardiogram. Pulse widths were set at 250 µs in both experiment 1 and 2. Changes in heart rate (HR), root-mean-square of the difference between two successive R waves (RMSSD), and the ratio between low-frequency (LF) (0.04–0.15 Hz) and high-frequency (HF) (0.15–0.40 Hz) bands (LF/HF) in spectral analysis, which indicates sympathetic and parasympathetic activity, respectively, in heart rate variability (HRV), were recorded for analysis. Although stimulation at all frequencies significantly reduced HR (p = 0.001), stimulation at 100 Hz had the most pronounced effect (p = 0.001) in Experiment 1 and was revealed to be required to deliver at 3.0 mA in Experiment 2 (p = 0.003). Additionally, participants with higher baseline sympathetic activity experienced higher parasympathetic response during stimulation, and sex differences may exist in the autonomic responses by the application of tVNS. Therefore, our findings suggest that optimal autonomic changes induced by tVNS to the left cymba conchae vary depending on stimulating parameters and sex.

Clinical Application of Transcutaneous Auricular Vagus Nerve Stimulation

Transcutaneous auricular vagus nerve stimulation (taVNS) refers to stimulation of the vagus nerve through the skin of the left cymba conchae and is a unique strategy that is investigated as a useful therapeutic approach for a variety of conditions including epilepsy, depression, cardiac diseases, tinnitus, and migraine. A randomized double-blind clinical trial was performed in patients with drug-resistant epilepsy. Although several pilot studies were performed before this trial and showed that taVNS was safe, well tolerated, and feasible for long-term treatment, no statistically significant difference was observed between the high- and low-stimulation groups, and further studies are warranted to gain a deeper understanding of this subject. A tingling sensation or pain at the site of stimulation is the most common adverse effect associated with taVNS. Therefore, intermittent stimulation, ranging from 30 minutes to several hours, is provided during each session several times a day. Currently, taVNS is not approved for insurance coverage by the Japan Ministry of Health, Labour, and Welfare. Further studies and investigations are necessary in the near future.

Technical aspects and future approaches in transcutaneous vagus nerve stimulation (tVNS).

With the emergence of transcutaneous vagus nerve stimulation (tVNS) as a therapy option for a multitude of clinical indications, the development and improvement of the stimulators becomes an increasingly important point of focus. This paper aims to discuss electrotechnical and software-based improvements to the state-of-the-art stimulators, in order to reduce the experienced side effects of the subjects as well as to increase the efficacy of the stimulation. It was found that side effects such as erythema and pain at the stimulation site are caused by electrolysis at the site of stimulation, which can be reduced by maintaining a voltage below the decomposition voltage. This can be achieved by using electroactive materials and rare-earth fractal metal coatings on the electrode, or by stimulating at the chronaxie with a biphasic rectangular waveform and an in-built short circuit to avoid an after-potential. It is furthermore discussed how the currently most promising stimulation site, the cymba conchae, can technically be stimulated in a feasible and tolerable way for the subject. Utilizing the subjects individual pain threshold is also demonstrated as a good indicator for optimal stimulation, as stimulation just below the pain threshold activates Aα and Aβ-fibers, while being unable to polarize the smaller diameter Aδ and C-fibers responsible for pain signaling. Finally, an outlook to individualized tVNS therapy is given, by using evolution algorithms that utilize device and subject data to optimize stimulation parameters.

Auricular Transcutaneous Vagus Nerve Stimulation Acutely Modulates Brain Connectivity in Mice.

Brain electrical stimulation techniques take advantage of the intrinsic plasticity of the nervous system, opening a wide range of therapeutic applications. Vagus nerve stimulation (VNS) is an approved adjuvant for drug-resistant epilepsy and depression. Its non-invasive form, auricular transcutaneous VNS (atVNS), is under investigation for applications, including cognitive improvement. We aimed to study the effects of atVNS on brain connectivity, under conditions that improved memory persistence in CD-1 male mice. Acute atVNS in the cymba conchae of the left ear was performed using a standard stimulation protocol under light isoflurane anesthesia, immediately or 3 h after the training/familiarization phase of the novel object-recognition memory test (NORT). Another cohort of mice was used for bilateral c-Fos analysis after atVNS administration. Spearman correlation of c-Fos density between each pair of the thirty brain regions analyzed allowed obtaining the network of significant functional connections in stimulated and non-stimulated control brains. NORT performance was enhanced when atVNS was delivered just after, but not 3 h after, the familiarization phase of the task. No alterations in c-Fos density were associated with electrostimulation, but a significant effect of atVNS was observed on c-Fos-based functional connectivity. atVNS induced a clear reorganization of the network, increasing the inter-hemisphere connections and the connectivity of locus coeruleus. Our results provide new insights into the effects of atVNS on memory performance and brain connectivity extending our knowledge of the biological mechanisms of bioelectronics in medicine.

English MODULATION OF MELATONIN SECRETION WITH TRANSCUTANEOUS AURICULAR NERVE STIMULATION: A CASE STUDY

The main study objective was to test the hypothesis that selective electrical transcutaneous auricular nerve stimulation (tANS) under forenoon daylight conditions induces melatonin secretion in a 64-year-old male patient with angina pectoris, hypercholesterolomy and coronary artery disease, assuming that it has beneficial effects on accompanied insomnia (Regensburg Insomnia Scale (RIS) = 22 points, the total score ranges from 0 to 40). Silicone stimulation plugs, with two platinum stimulating cathodes each, were inserted into the left and right external ears. Afterwards, one-second-long pulse trains of cathodic, biphasic and current regulated stimulating pulses at stimulating charge density Cd of 50.88 µC/cm2 and frequency of 25 Hz, were delivered for 30 min to selected sites at the upper and lower part of the left and right Cymba Conchae (CC), respectively. The common anode was attached to the neck. The time gap between the pulse trains was measured by the patient using a tactile sensor and was about 250 ms. The results showed that selective tANS under forenoon daylight conditions increased melatonin saliva levels in all the trials accomplished in a patient. Precisely, the lowest increase was obtained in trials with lower right (LR) CC, while the highest increase was obtained in upper-right (UR) CC trials.

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets.

Transcutaneous auricular vagus nerve stimulation (taVNS) modulates central and peripheral neurophysiology. Specifically, taVNS increases heart rate variability (HRV) indicating a shift in autonomic function towards parasympathetic predominance. However, knowledge on the influence of stimulation parameters and targets is scarce. We hypothesized that the location and charge per phase of taVNS influences HRV. In thirteen healthy subjects, six different stimulation targets were investigated, i.e., cymba conchae, cavum conchae, outer tragus, inner tragus, crus helicis, and fossa triangularis. At each target, 24 parameter combinations were studied: Eight different electrical charges per phase were evaluated by investigating three pulse durations and eight charge-balanced current intensities, i.e., 100μs (0.250-2mA in steps of 0.250mA), 260μs (0.096-0.769mA in steps of 0.096mA), and 500μs (0.050-0.400mA in steps of 0.050mA). In a parallel group design, left and right taVNS were compared to each other. 30 bursts at each parameter combination were applied with a periodicity of 1Hz. Each burst consisted of five pulses applied at 25Hz. HRV increased in a charge-dependent way with significant differences between the right and left ear. The targets with the strongest effects were the cymba conchae and fossa triangularis, and to a lesser extent the inner tragus. HRV is suitable to define taVNS parameters and targets for research and therapeutic purposes. Bursts of taVNS with a pulse duration of 100μs and a current intensity of 2mA are comfortable for the participants and effective in increasing HRV when applied at specific auricular locations. These findings need to be replicated in larger cohorts, and with longer stimulation and off-periods between conditions. Since results may differ in conditions with an impaired autonomic tone, future studies should also consider aged and patient populations.

P072 Non-invasive Vagal Nerve Stimulation to Treat Crohn Disease and Ulcerative Colitis in Children and Young Adults: A Proof-of-Concept Clinical Trial.

Current inflammatory bowel disease (IBD) therapies are limited by incomplete efficacy, loss of response, side effects and high costs. Vagal nerve stimulation (VNS) is an investigational Bioelectronic Medicine therapy targeting the nervous system to treat IBD through an 'inflammatory reflex' that reduces systemic inflammation. Data in humans with IBD are promising but limited to two small studies using a cervically implanted VNS device in adults with Crohn disease (CD); no data exist to date using a non-invasive VNS modality in IBD. This study aimed to evaluate the efficacy and safety of transcutaneous auricular VNS (ta-VNS) in children and young adults with CD or ulcerative colitis (UC). IBD patients 10-21 years of age with mild/moderate CD or UC who did not achieve remission with conventional therapy, and a fecal calprotectin (FC) >200 ug/g within 4 weeks of study entry were enrolled. Subjects were randomized to receive either ta-VNS using a transcutaneous electrical nerve stimulator unit targeting the cymba conchae of the external left ear, or sham stimulation of the posterior lower leg, for 5 minutes once daily for a 2-week duration followed by a switch to the alternative stimulation for an additional 2 weeks. At week 4, all subjects were assigned to receive active ta-VNS for 5 minutes twice daily until week 16 so that all received 14 weeks of active ta-VNS by the end of the study. Primary study endpoint was defined as ∆FC ≥50% reduction from baseline to week 16. Secondary endpoints included improvement in weighted Pediatric Crohn Disease Activity Index (wPCDAI) or Pediatric Ulcerative Colitis Activity Index (PUCAI). Twenty-two subjects were enrolled (12 UC, 10 CD; median age 14.4 years [range 10-21] 54.5% male). Median baseline FC was 587 (range 18 - 3828, SD 1074). 5 subjects (4 UC, 1 CD) had FC levels 12.5 at baseline, 3 (50%) achieved clinical remission (wPCDAI ≤ 10) at week 16. In the full UC cohort (n = 12), baseline PUCAI ranged from 0-45. In the 6 with PUCAI > 10 at baseline, 2 (33%) achieved clinical remission at week 16. There were no safety concerns. Non-invasive ta-VNS reduced FC levels and improved symptoms in a pediatric cohort with mild/moderate IBD. Further research is needed to identify optimal electrical dose and settings to achieve peak anti-inflammatory effect and to identify the mechanistic principles for this therapy.

Technical Note: Modulation of fMRI brainstem responses by transcutaneous vagus nerve stimulation

Our increasing knowledge about gut-brain interaction is revolutionising the understanding of the links between digestion, mood, health, and even decision making in our everyday lives. In support of this interaction, the vagus nerve is a crucial pathway transmitting diverse gut-derived signals to the brain to monitor of metabolic status, digestive processes, or immune control to adapt behavioural and autonomic responses. Hence, neuromodulation methods targeting the vagus nerve are currently explored as a treatment option in a number of clinical disorders, including diabetes, chronic pain, and depression. The non-invasive variant of vagus nerve stimulation (VNS), transcutaneous auricular VNS (taVNS), has been implicated in both acute and long-lasting effects by modulating afferent vagus nerve target areas in the brain. The physiology of neither of those effects is, however, well understood, and evidence for neuronal response upon taVNS in vagal afferent projection regions in the brainstem and its downstream targets remain to be established.Therefore, to examine time-dependent effects of taVNS on brainstem neuronal responses in healthy human subjects, we applied taVNS during task-free fMRI in a single-blinded crossover design. During fMRI data acquisition, we either stimulated the left earlobe (sham), or the target zone of the auricular branch of the vagus nerve in the outer ear (cymba conchae, verum) for several minutes, both followed by a short ‘stimulation OFF’ period. Time-dependent effects were assessed by averaging the BOLD response for consecutive 1-minute periods in an ROI-based analysis of the brainstem.We found a significant response to acute taVNS stimulation, relative to the control condition, in downstream targets of vagal afferents, including the nucleus of the solitary tract, the substantia nigra, and the subthalamic nucleus. Most of these brainstem regions remarkably showed increased activity in response to taVNS, and these effect sustained during the post-stimulation period. These data demonstrate that taVNS activates key brainstem regions, and highlight the potential of this approach to modulate vagal afferent signalling. Furthermore, we show that carry-over effects need to be considered when interpreting fMRI data in the context of general vagal neurophysiology and its modulation by taVNS.

Randomized Cross Over Study Assessing the Efficacy of Non-invasive Stimulation of the Vagus Nerve in Patients With Axial Spondyloarthritis Resistant to Biotherapies: The ESNV-SPA Study Protocol.

Axial spondyloarthritis (SpA), is a major cause of chronic pain and disability that profoundly alters the quality of life of patients. Nearly half of patients with SpA usually develop drug resistance. Non-pharmacological treatments targeting inflammation are an attractive alternative to drug administration. Vagus nerve stimulation (VNS), by promoting a cholinergic anti-inflammatory reflex holds promise for treating inflammatory disease. Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of endotoxemia, sepsis, colitis, and other preclinical models of inflammatory diseases. It has been proposed that vagal efferent fibers release acetylcholine (Ach), which can interact with α7-subunit-containing nicotinic receptors expressed by tissue macrophages and other immune cells to rapidly inhibit the synthesis/release of pro-inflammatory cytokines such as TNFα, IL-1β, IL-6, and IL-18. External vagal nerve stimulation devices are now available that do not require surgery nor implantation to non-invasively stimulate the vagal nerve. This double-blind randomized cross-over clinical trial aims to study the change in SpA disease activity, according to Assessment in Ankylosing Spondylitis 20 (ASAS20) definition, after 12 weeks of non-invasive VNS treatment vs. non-specific dummy stimulation (control group). One hundred and twenty adult patients with drug resistant SpA, meeting the ASAS classification criteria, will be included in the study. Patients will be randomized into two parallel groups according to a cross over design: either active VNS for 12 weeks, then dummy stimulation for 12 weeks, or dummy stimulation for 12 weeks, then active VNS for 12 weeks. The two stimulation periods will be separated by a 4 weeks wash-out period. A transcutaneous auricular vagus nerve stimulator Tens Eco Plus SCHWA MEDICOTM France will be used in this study. The active VNS stimulation will be applied in the cymba conchae of the left ear upon the auricular branch of the vagus nerve, using low intensity (2–5 mA), once à week, during 1 h. Dummy stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at an irrelevant anatomical site: the left ear lobule. This multicenter study was registered on ClinicalTrials.gov: NCT04286373.

Brain-Heart Interaction During Transcutaneous Auricular Vagus Nerve Stimulation.

ObjectivesTranscutaneous auricular vagus nerve stimulation (taVNS) modulates brain activity and heart function. The induced parasympathetic predominance leads to an increase of heart rate variability (HRV). Knowledge on the corresponding cortical activation pattern is, however, scarce. We hypothesized taVNS-induced HRV increases to be related to modulation of cortical activity that regulates the autonomic outflow to the heart.Materials and MethodsIn thirteen healthy subjects, we simultaneously recorded 64-channel electroencephalography and electrocardiography during taVNS. Two taVNS stimulation targets were investigated, i.e., the cymba conchae and inner tragus, and compared to active control stimulation in the anatomical vicinity, i.e., at the crus helicis and outer tragus. We used intermitted stimulation bursts of 25 Hz applied at a periodicity of 1 Hz. HRV was estimated with different time-domain methodologies: standard deviation of RR (SDNN), the root mean squares of successive differences (RMSSD), the percentage of RR-intervals with at least 50 ms deviation from the preceding RR-interval (pNN50), and the difference of consecutive RR intervals weighted by their mean (rrHRV).ResultsThe stimulation-induced HRV increases corresponded to frequency-specific oscillatory modulation of different cortical areas. All stimulation targets induced power modulations that were proportional to the HRV elevation. The most prominent changes that corresponded to HRV increases across all parameters and stimulation locations were frontal elevations in the theta-band. In the delta-band, there were frontal increases (RMSSD, pNN50, rrHRV, SDNN) and decreases (SDNN) across stimulation sites. In higher frequencies, there was a more divers activity pattern: Outer tragus/crus helicis stimulation increased oscillatory activity with the most prominent changes for the SDNN in frontal (alpha-band, beta-band) and fronto-parietal (gamma-band) areas. During inner tragus/cymba conchae stimulation the predominant pattern was a distributed power decrease, particularly in the fronto-parietal gamma-band.ConclusionNeuro–cardiac interactions can be modulated by electrical stimulation at different auricular locations. Increased HRV during stimulation is correlated with frequency-specific increases and decreases of oscillatory activity in different brain areas. When applying specific HRV measures, cortical patterns related to parasympathetic (RMSSD, pNN50, rrHRV) and sympathetic (SDNN) modulation can be identified. Thus, cortical oscillations may be used to define stimulation locations and parameters for research and therapeutic purposes.

Folded Cymba Concha: Is It Large and Stable Enough for Caudal Septal Extension Graft in Asian Rhinoplasty?

Septal extension grafting (SEG) is used for nasal tip projection and positioning. Often, insufficient quadrangular cartilage is available for grafting in Asians and in most secondary cases, the septum is already harvested. We utilized the folded cymba concha as an alternative for caudal SEG (CSEG) by modifying a tongue-in-groove technique. To evaluate the physical validity of the cymba concha for CSEG and compare its outcomes with those of septal quadrangular cartilage. The mean length and width of 311 harvested consecutive folded cymba conchae were measured from intraoperative photographs. Data from 220 patients with >12 months of follow-up were retrospectively reviewed for clinical outcomes. Clinical demography was determined based on the need for additional spreader grafts. For clinical reliability, anthropometric photographs of patients in whom folded cymba conchae were used were compared with those in whom quadrangular cartilage was used. Mean lengths and widths of the folded cymba conchae in men and women were 24.2 ± 3.9 and 22.4 ± 3.7mm, and 7.8 ± 1.9 and 7.2 ± 1.9mm, respectively. Using the folded cymba concha graft significantly increased nasal tip projection by 28.9% and columellar-labial angle by 9.7%, improving both aspects postoperatively. Anthropometric comparison revealed no significant differences between folded cymba conchae and septal cartilage in terms of nasal tip projection (p = 0.264) and postoperative columellar-labial angle (p = 0.182). Folded cymba conchal cartilage can be a primary option for CSEG in Asian septorhinoplasty cases or for individuals with insufficient septal cartilage remnants.