Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation.

BackgroundAbdominal pain and constipation are 2 main symptoms in patients with constipation-predominant irritable bowel syndrome (IBS-C). This study aimed to investigate the effects and possible mechanisms of transcutaneous auricular vagal nerve stimulation (taVNS) in patients with IBS-C.MethodsForty-two patients with IBS-C were randomized into a 4-week sham-taVNS or taVNS treatment. The primary outcomes were complete spontaneous bowel movements per week (CSBMs/week) and visual analog scale (VAS) for abdominal pain. High-resolution anorectal manometry (HRAM) was performed to evaluate anorectal motor and sensory function. Cytokines and brain gut peptides were analyzed in blood samples. ECG was recorded for the assessment of autonomic function.ResultsCompared with sham-taVNS, (a) taVNS increased CSBMs/week (P = 0.001) and decreased VAS pain score (P = 0.001); (b) improved quality of life (P = 0.020) and decreased IBS symptom score (P = 0.001); (c) improved rectoanal inhibitory reflex (P = 0.014) and improved rectal sensation (P < 0.04); (d) decreased a number of proinflammatory cytokines and serotonin in circulation; and (e) enhanced vagal activity (P = 0.040). The vagal activity was weakly correlated with the CSBMs/week (r = 0.391; P = 0.010) and the VAS pain score (r = -0.347; P = 0.025).ConclusionsNoninvasive taVNS improves both constipation and abdominal pain in patients with IBS-C. The improvement in IBS-C symptoms might be attributed to the integrative effects of taVNS on intestinal functions mediated via the autoimmune mechanisms.Trial registrationwww.chictr.org.cn, no. ChiCTR2000029644.FundingNational Natural Science Foundation of China (grant no. 81970538 for FL).

Electrical Stimulation of the Greater Auricular Nerve to Reduce Postoperative Atrial Fibrillation.

BACKGROUND: Postoperative atrial fibrillation (POAF) occurs in up to 40% of patients undergoing cardiac surgery. Invasive stimulation of the vagal nerve previously demonstrated a reduced risk of POAF. Therefore, we examined the antiarrhythmic and anti-inflammatory effects of noninvasive low-level transcutaneous electrical stimulation (LLTS) of the greater auricular nerve in a pilot trial including patients undergoing cardiac surgery. METHODS: Patients were randomized into a sham (n=20) or a treatment group (n=20) for LLTS. After cardiac surgery, electrodes were applied in the triangular fossa of the ear. Stimulation (amplitude 1 mA, frequency 1 Hz for 40 minutes, followed by a 20 minutes break) was performed for up to 2 weeks after cardiac surgery. Heart rhythm was recorded continuously using an ECG during the observation period. CRP (C-reactive protein) and IL (interleukin)-6 plasma concentrations were measured immediately after surgery as well as on day 2 and 7 postsurgery. RESULTS: Patients receiving LLTS had a significantly reduced occurrence of POAF (4 of 20) when compared with controls (11 of 20, P=0.022) during a similar mean Holter recording period. The median duration of POAF was comparable between the treatment and the control group (878 [249; 1660] minutes versus 489 [148; 1775] minutes; P=0.661). No effect of LLTS on CRP or IL-6 levels was detectable. CONCLUSIONS: LLTS of the greater auricular nerve may be a potential therapy for POAF. We demonstrated the feasibility to conduct a randomized trial of neurostimulation as an outlay for a multisite clinical trial.

No modulation of pupil size and event-related pupil response by transcutaneous auricular vagus nerve stimulation (taVNS).

Transcutaneous auricular vagus nerve stimulation (taVNS) bears therapeutic potential for a wide range of medical conditions. However, previous studies have found substantial interindividual variability in responsiveness to taVNS, and no reliable predictive biomarker for stimulation success has been developed so far. In this study, we investigate pupil size and event-related pupil response as candidate biomarkers. Both measures have a direct physiological link to the activity of the locus coeruleus (LC), a brainstem structure and the main source of norepinephrine in the brain. LC activation is considered one of the key mechanisms of action of taVNS, therefore, we expected a clear increase of the pupillary measures under taVNS compared to sham (placebo) stimulation, such that it could serve as a prospective predictor for individual clinical and physiological taVNS effects in future studies. We studied resting pupil size and pupillary responses to target stimuli in an auditory oddball task in 33 healthy young volunteers. We observed stronger pupil responses to target than to standard stimuli. However, and contrary to our hypothesis, neither pupil size nor the event-related pupil response nor behavioral performance were modulated by taVNS. We discuss potential explanations for this negative finding and its implications for future clinical investigation and development of taVNS.

Transcutaneous auricular vagus nerve stimulation in treating major depressive disorder: A systematic review and meta-analysis.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS), as a noninvasive intervention, has beneficial effects on major depressive disorder based on clinical observations. However, the potential benefits and clinical role of taVNS in the treatment of major depressive disorder are still uncertain and have not been systematically evaluated. Therefore, we performed a systematic review and meta-analysis to evaluate the effectiveness and safety of taVNS in treating major depressive disorder. METHODS: Four electronic databases, namely, Embase, MEDLINE, the Cochrane Library and PsycINFO, were searched for all related trials published through May 1, 2018. We extracted the basic information and data of the included studies and evaluated the methodological quality with the Cochrane risk of bias tool and the nonrandomized studies-of interventions (ROBINS-I) tool. A meta-analysis of the comparative effects was conducted using the Review Manager 5.3 software. RESULTS: A total of 423 citations from the databases were searched, and 4 studies with 222 individuals were included in the meta-analysis. The taVNS technique could decrease 24-item HAMD scores more than the sham intervention (MD: -4.23, 95% CI: -7.15, -1.31; P = .005) and was also more effective in decreasing Self-Rating Depression Scale scores ((MD: -10.34, 95% CI: -13.48, -7.20; P < .00001), Beck Depression Inventory scores (MD: -10.3, 95% CI: -18.1, -2.5; P = .01) and Self-Rating Anxiety Scale scores (MD: -6.57, 95% CI: -9.30, -3.84; P < .00001). However, there was no significant difference in the Hamilton Anxiety Rating Scale scores between the taVNS and sham taVNS groups (MD: -1.12, 95% CI: -2.56, 0.32; P = .13). No obvious adverse effects of taVNS treatment were reported in the included studies. CONCLUSION: The results of the analysis preliminarily demonstrated that taVNS therapy can effectively ameliorate the symptoms of major depressive disorder, providing an alternative technique for addressing depression. However, more well-designed RCTs with larger sample sizes and follow-ups are needed in future studies to confirm our findings.

Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) can induce auditory and limbic cortices activation measured by fMRI.

The purpose of this study was to explore the central mechanism of transauricular vagus nerve stimulation (taVNS) to human by fMRI and to find a suitable taVNS site for potential tinnitus treatment. 24 healthy subjects aged between 28 and 38 years were enrolled in the experiment. 8 subjects were stimulated in the auricular acupoints Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) in the left ear, 8 subjects were stimulated at the anterior wall of the auditory canal and left lower limb as an anterior stimulation group; 8 persons who were arranged in a sham group received taVNS at the left ear lobe and tail of the helix. Functional magnetic resonance imaging (fMRI) data from the cortices was collected and an Alphasim analysis was performed. We found that taVNS at auricular acupoints CO10-12, TF4 can instantly and effectively generate blood oxygenation level dependent (BOLD) signal changes in the prefrontal, auditory and limbic cortices of healthy subjects by fMRI. When comparing the acupoints group and the sham group in the left brain, the signals from the prefrontal cortex, the auditory ascending pathway including superior temporal gyrus, middle temporal gyrus, thalamus and limbic system regions such as putamen, caudate, posterior cingulate cortex, amygdala and parahippocampal gyrus were increased under our stimulation. The difference of the BOLD signal in the left brain between acupoints group and anterior group was in the superior temporal gyrus. We could also find signal differences in several regions of right brain among the groups. In conclusion, taVNS at acupoints CO10-12, TF4 could activate the prefrontal, auditory and limbic cortices of healthy brain and this scheme could be a promising tool for tinnitus treatment.

Hind limb motoneurons activity during fictive locomotion or scratching induced by pinna stimulation, serotonin, or glutamic acid in brain cortex-ablated cats.

In brain cortex-ablated cats (BCAC), hind limb motoneurons activity patterns were studied during fictive locomotion (FL) or fictive scratching (FS) induced by pinna stimulation. In order to study motoneurons excitability: heteronymous monosynaptic reflex (HeMR), intracellular recording, and individual Ia afferent fiber antidromic activity (AA) were analyzed. The intraspinal cord microinjections of serotonin or glutamic acid effects were made to study their influence in FL or FS During FS, HeMR amplitude in extensor and bifunctional motoneurons increased prior to or during the respective electroneurogram (ENG). In soleus (SOL) motoneurons were reduced during the scratch cycle (SC). AA in medial gastrocnemius (MG) Ia afferent individual fibers of L6-L7 dorsal roots did not occur during FS Flexor digitorum longus (FDL) and MG motoneurons fired with doublets during the FS bursting activity, motoneuron membrane potential from some posterior biceps (PB) motoneurons exhibits a depolarization in relation to the PB (ENG). It changed to a locomotor drive potential in relation to one of the double ENG, PB bursts. In FDL and semitendinosus (ST) motoneurons, the membrane potential was depolarized during FS, but it did not change during FL Glutamic acid injected in the L3-L4 spinal cord segment favored the transition from FS to FL During FL, glutamic acid produces a duration increase of extensors ENGs. Serotonin increases the ENG amplitude in extensor motoneurons, as well as the duration of scratching episodes. It did not change the SC duration. Segregation and motoneurons excitability could be regulated by the rhythmic generator and the pattern generator of the central pattern generator.

Innervation of the Human Cavum Conchae and Auditory Canal: Anatomical Basis for Transcutaneous Auricular Nerve Stimulation.

The innocuous transcutaneous stimulation of nerves supplying the outer ear has been demonstrated to be as effective as the invasive direct stimulation of the vagus nerve for the treatment of some neurological and nonneurological disturbances. Thus, the precise knowledge of external ear innervation is of maximal interest for the design of transcutaneous auricular nerve stimulation devices. We analyzed eleven outer ears, and the innervation was assessed by Masson's trichrome staining, immunohistochemistry, or immunofluorescence (neurofilaments, S100 protein, and myelin-basic protein). In both the cavum conchae and the auditory canal, nerve profiles were identified between the cartilage and the skin and out of the cartilage. The density of nerves and of myelinated nerve fibers was higher out of the cartilage and in the auditory canal with respect to the cavum conchae. Moreover, the nerves were more numerous in the superior and posterior-inferior than in the anterior-inferior segments of the auditory canal. The present study established a precise nerve map of the human cavum conchae and the cartilaginous segment of the auditory canal demonstrating regional differences in the pattern of innervation of the human outer ear. These results may provide additional neuroanatomical basis for the accurate design of auricular transcutaneous nerve stimulation devices.

Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study.

BACKGROUND: Depression presents a significant burden to both patients and society. One treatment that has emerged is vagus nerve stimulation (VNS), an FDA-approved physical treatment for depressive disorders. However, the application of this intervention has been limited by the involvement of surgery and potential side effects. The aim of this study is to explore the effectiveness of stimulating the superficial branches of the vagus nerve as a solo treatment for MDD. METHODS: This is a nonrandomized, controlled study. The first cohort of patients (n=91) only received transcutaneous auricular VNS (taVNS) for 12 weeks. In the second cohort (n=69), patients first received 4 weeks of sham taVNS followed by 8 weeks of taVNS. All treatments were self-administered by the patients at home after they received training from the hospitals. The primary outcome measurement was the 24-item Hamilton Depression Rating Scale measured at weeks 0, 4, 8, and 12. Data analysis included a timelag analysis comparing (1) real and sham taVNS groups at week 4; (2) the real taVNS group at week 4 vs the sham taVNS group at week 8 (fourth week of real taVNS following 4 weeks of sham); and (3) the real taVNS group at week 8 vs the sham taVNS group at week 12 (eighth week of real taVNS following sham). RESULTS: After four weeks of treatment, MDD patients in the taVNS group showed greater improvement than patients in the sham taVNS group as indicated by Hamilton score changes as well as response and remission rates at week four. In addition, we also found that the clinical improvements continued until week 12 during taVNS. LIMITATIONS: Patients were not randomized in this study. CONCLUSIONS: Our results suggest that taVNS is a promising, safe, and cost-effective therapeutic method for mild and moderate MDD.

Modulation of Muscle Tone and Sympathovagal Balance in Cervical Dystonia Using Percutaneous Stimulation of the Auricular Vagus Nerve.

Primary cervical dystonia is characterized by abnormal, involuntary, and sustained contractions of cervical muscles. Current ways of treatment focus on alleviating symptomatic muscle activity. Besides pharmacological treatment, in severe cases patients may receive neuromodulative intervention such as deep brain stimulation. However, these (highly invasive) methods have some major drawbacks. For the first time, percutaneous auricular vagus nerve stimulation (pVNS) was applied in a single case of primary cervical dystonia. Auricular vagus nerve stimulation was already shown to modulate the (autonomous) sympathovagal balance of the body and proved to be an effective treatment in acute and chronic pain, epilepsy, as well as major depression. pVNS effects on cervical dystonia may be hypothesized to rely upon: (i) the alteration of sensory input to the brain, which affects structures involved in the genesis of motoric and nonmotoric dystonic symptoms; and (ii) the alteration of the sympathovagal balance with a sustained impact on involuntary movement control, pain, quality of sleep, and general well-being. The presented data provide experimental evidence that pVNS may be a new alternative and minimally invasive treatment in primary cervical dystonia. One female patient (age 50 years) suffering from therapy refractory cervical dystonia was treated with pVNS over 20 months. Significant improvement in muscle pain, dystonic symptoms, and autonomic regulation as well as a subjective improvement in motility, sleep, and mood were achieved. A subjective improvement in pain recorded by visual analog scale ratings (0-10) was observed from 5.42 to 3.92 (medians). Muscle tone of the mainly affected left and right trapezius muscle in supine position was favorably reduced by about 96%. Significant reduction of muscle tone was also achieved in sitting and standing positions of the patient. Habituation to stimulation leading to reduced stimulation efficiency was observed and counteracted by varying stimulation patterns. Experimental evidence is provided for significantly varied sympathovagal modulation in response to pVNS during sleep, assessed via heart rate variability (HRV). Time domain measures like the root mean square of successive normal to normal heart beat intervals, representing parasympathetic (vagal) activity, increased from 37.8 to 67.6 ms (medians). Spectral domain measures of HRV also show a shift to a more pronounced parasympathetic activity.

Transcutaneous electrical stimulation at auricular acupoints innervated by auricular branch of vagus nerve pairing tone for tinnitus: study protocol for a randomized controlled clinical trial.

BACKGROUND: Subjective tinnitus is a phantom sensation experienced in the absence of any source of sound. Its mechanism remains unclear, and no approved drugs are available. Vagus nerve stimulation (VNS) is an exciting new method to treat tinnitus, but direct electrical stimulation of the cervical vagus has disadvantages. This randomized controlled clinical trial aims to overcome these limitations by stimulating the auricular branch of vagus nerve (ABVN) on the outer ear. Since the ABVN is the only peripheral branch of the vagus nerve distributed on the ear's surface, it should be possible to achieve analogous efficacy to VNS by activating the central vagal pathways. However, researches have indicated that the curative effect lies in a combination of auditory and vagal nerve stimulation. Moreover, from traditional Chinese theory, auricular acupoints used to treat tinnitus are mainly in the regions supplied by the ABVN. Whether stimulation at the auricular acupoints is due to unintentional stimulation of vagal afferent fibers also needs evidence. METHODS/DESIGN: A total of 120 subjects with subjective tinnitus are randomized equally into four groups: (1) electrical stimulation at auricular acupoints (CO10, CO11, CO12, and TF4) innervated by the ABVN; (2) electrical stimulation at auricular acupoints (CO10, CO11, CO12, and TF4) innervated by ABVN pairing tones; (3) electrical stimulation at auricular acupoints innervated by non-ABVN pairing tones; (4) electrical acupuncture. Patients will be treated for 30 minutes every other day for 8 weeks. The primary outcome measure is the Tinnitus Handicap Inventory. The secondary outcome measure combines a visual analogue scale to measure tinnitus disturbance and loudness with the Hospital Anxiety and Depression Scale. Assessment is planned at baseline (before treatment) and in the 4th and 8th week, with further follow-up visits after termination of the treatment at the 12th week. Any adverse events will be promptly documented. DISCUSSION: Completion of this trial will help to confirm whether ABVN or the combination of ABVN and sound stimulus plays a more important role in treating tinnitus. Moreover, the result of this clinical trial will enhance our understanding of specific auricular acupoints. TRIAL REGISTRATION: Chinese Clinical Trials Register ChiCTR-TRC-14004940.

Modulatory effects of somatosensory electrical stimulation on neural activity of the dorsal cochlear nucleus of hamsters.

The effects of somatosensory electrical stimulation on the dorsal cochlear nucleus (DCN) activity of control and tone-exposed hamsters were investigated. One to three weeks after sound exposure and control treatment, multiunit activity was recorded at the surface of the left DCN before, during, and after electrical stimulation of the basal part of the left pinna. The results demonstrated that sound exposure induced hyperactivity in the DCN. In response to electrical stimulation, neural activity in the DCN of both control and exposed animals manifested four response types: S-S, suppression occurring during and after stimulation; E-S, excitation occurring during stimulation and suppression after; S-E, suppression occurring during stimulation and excitation after; and E-E, excitation occurring during and after stimulation. The results showed that there was a higher incidence of suppressive (up to 70%) than of excitatory responses during and after stimulation in both groups. In addition, there was a significantly higher degree of suppression after, rather than during stimulation. At high levels of electrical current, the degree of the induced suppression was generally higher during and after stimulation in exposed animals than in controls. The similarity of our results to those of previous clinical studies further supports the view that DCN hyperactivity is a direct neural correlate of tinnitus and that somatosensory electrical stimulation can be used to modulate DCN hyperactivity. Optimization of stimulation strategy through activating only certain neural pathways and applying appropriate stimulation parameters may allow somatosensory electrical stimulation to be used as an effective tool for tinnitus suppression.

Investigation of specificity of auricular acupuncture points in regulation of autonomic function in anesthetized rats.

Auricular acupuncture has been used for various autonomic disorders in clinical practice. It has been theorized that different auricular areas have distinct influence on autonomic functions. The present study aims to examine the effects of acupuncture stimulation at different auricular areas on cardiovascular and gastric responses. In male Sprague-Dawley rats anesthetized with pentobarbital sodium, five auricular areas, which were located at the apex of the helix (A(1)), the middle of the helix (A(2)), the tail of the helix (A(3)), the inferior concha (A(4)) and the middle of the antihelix (A(5)), had been selected for stimulation with manual acupuncture (MA) and different parameters of electroacupuncture (EA). A mild depressor response (6%-12% decrease from baseline) was evoked from A(1), A(3) and A(4) by MA and from all five areas by EA (100 Hz-1 mA). The biggest depressor response (-18.4+/-3.1 mmHg, p<0.001) was evoked from A(4). A small bradycardia was evoked by MA from A(4) and by EA at A(3), A(4) and A(5.) Increase in intragastric pressure (8-14 mmH(2)O) was evoked by MA from A(1), A(3) and A(4) and by EA at A(2.) These results show that similar patterns of cardiovascular and gastric responses could be evoked by stimulation of different areas of the auricle. The present results do not support the theory of a highly specific functional map in the ear. Rather, there is a similar pattern of autonomic changes in response to auricular acupuncture, with variable intensity depending on the area of stimulation.