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

Abstract

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.

1. INTRODUCTION

Stimulating the auricular acupoint has a long history. For example, auricular acupuncture and physical oppression on auricular acupoint. Auricular acupuncture requires a disinfection then a tiny indermal needle is inserted into the skin of acupoints. Auricular pressure is a non-invasive treatment with small spherical spherical magnetic pellets or seeds fixed to the skin at the acupoints. Infection and skin rush is commonly found in traditional ear acupuncture therapy. Vagus nerve is thought to be the back door of the brain, one could hack into the brain and then debug the “brain program” by stimulating the peripheral branches of the vagus nerve. After that, dsyfunctions of brain were regulated. Recently, the connection between the ear and the rest of the body has been attracting more and more attention.¹

The concept of transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed, for taVNS and implantable cervical vagus nerve stimulation (iVNS) affect different vagus branches of nerve, and it is believed that taVNS and iVNS share a similar anatomical and physiological basis.² Namely, if taVNS have a similar efficacy to iVNS, it would be complementary replacement for iVNS. By applying electrical current to the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear, taVNS treats a disease non-invasively, this makes it possible that taVNS could break through the limitation of indications. Here, we comprehensively review current clinical trials of iVNS and taVNS, then made a comparison of their current indications and efficacy.

2. THE EFFICACY OF IVNS AND TAVNS WERE CONFIRMED IN EPILEPSY AND DEPRESSION

2.1. Epilepsy

IVNS is strongly recommended for drug-resistant epilepsy patients who have little improvement after craniotomy.³ A double-blind randomized prospective study (E03 study) showed iVNS reduced the seizure frequency in patients with focal seizure in 1994. In this study, 31 patients receiving high iVNS experienced a mean seizure frequency percentage reduction of 30.9%, while the 36 patients in the control group received low VNS, showing a reduction of 11.3% after 12 weeks treatment.⁴ In the following trial⁵ (E05 study) which expanded the sample size of E03 study, patients with generalized tonic-clonic seizures were recruited, it was found iVNS could also relieve comprehensive seizure. The E05 study shows patients who received real iVNS (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency, while in the control group, patients shown a 15% reduction (102 patients, ages 15 to 60 years). Safety and tolerance of iVNS were also confirmed. FDA approved iVNS for refractory epilepsy in adults in 1997. The efficacy and safety of iVNS were further confirmed in children with epilepsy.⁶

Existing evidence suggests that taVNS is effective in treating drug-resistant epilepsy. In a clinical trial, seizure frequency reduced 34.0% after 20 weeks of taVNS treatment. The study indicates similar antiepileptic efficacy of taVNS to iVNS.⁷,8 Another study showed that 16 weeks taVNS achieved a total of 12.0% completely remission in patients with refractory epilepsy. Furthermore, it was found that the patients’ mental alertness and language communication were also improved.⁹ However, patients with post-stroke epilepsy does no benefit from four-weeks’ taVNS therapy.¹⁰

2.2. Major depressive disorder

Stimulating the peripheral branches of the vagus nerve would modulate emotional-related brain regions.¹¹ Patients who are sensitive to electroconvulsive therapy (ECT) would have a better response to iVNS, suggesting that the three treatments share a common acting mechanism.^12-14 The ten-weeks response rate of iVNS for major depressive disorder (MDD) is 30.5%.¹⁵ A large sample (759 cases) study shows that iVNS would have a higher long-term response rate (67.6% vs 40.9%) and a higher remission rate (43.3% vs 25.7%)¹⁴ than conventional drug therapy. Although, some scholars still argue that the clinical evidence of iVNS in treating depression is not sufficiently.¹⁶

2.3. The respective advantages of taVNS and iVNS in the treatment of epilepsy and MDD

Diffferent from taVNS, the efficacy of iVNS on different subtypes of epilepsy syndrome were wildly explored. IVNS is effective against Lennox-Gastaut syndrome,¹⁷ Angelman syndrome,¹⁸ Lafora body disease.¹⁹ IVNS block 74% of patients with refractory epileptic status and super-refractory epileptic status.²⁰ Similar results were obtained even in children with epileptic status.²¹ However, there are still few studies on distinctive subtypes of epilepsy syndrome and epileptic status until now.²² Further, long-term study shows a gradually increasing efficacy of iVNS in the subsequent years after implant,⁸ the observation time of existing taVNS studies is relatively short, and there are no long-term clinical reports either. In summary, taVNS requires stronger clinical evidence to validate its efficacy and safety before it would be a routine recommendation for refractory epilepsy.

IVNS is currently only approved for drug-resistant depression, different from iVNS, most antidepressant clinical trials of taVNS recruit patients with mild to moderate MDD. In a study, taVNS reduces the abnormal responses to negative facial stimuli in adolescent MDD patients.²³ Another randomised controlled trial with a sample size of recruit 160 mild-moderate MDD patients shows an 80% of the participants in the taVNS group improved after 12 weeks measured.⁹ Meta-analysi revealed that of taVNS could improve both subjective scale and objective scale for MDD.²⁴

3. THE POTENTIAL THERAPEUTIC EFFECTS WRE TESTED IN VAGUS-ASSOCIATE DISEASES

3.1. Cardiovascular system

Stimulating the vagus nerve increases vagal activity and reduces sympathetic activity.²⁵ IVNS increased both Left Ventricular Ejection Fraction (LVEF) and the 6-minutes walking distance in heart failure (HF) patients.²⁸ Decrease in death rate and acute HF were also revealed in another study.²⁹ However, due to the fact of surgery, iVNS was accompanied by a higher rate of adverse events.²⁸ Although some studies show that taVNS improves the spontaneous cardiac baroreflex sensitivity and cardiovascular autonomic response in healthy participants,^30,31 there is still no clinical trial evaluating the efficacy of taVNS on patients with HF. At this time, we still have few evidences to confirm curative effects of iVNS and taVNS in improves HF, taVNS may be appropriate to obtain some pre-trial evidence.²⁷

3.2. Neuropathy and psychosis

Stimulating the vagus nerve branches modulates the trigeminal nerve reflex.³² The reflex plays a crucial role in trigeminal neuralgia, cluster headaches.³³ TcVNS, another noninvasive VNS, has been approved for supplementary treatment for acute migraine and cluster headache.³⁴ A RCT has shown taVNS significantly reduced the attack frequency in patients with chronic migraine.³⁵

Stimulating the vagus nerve is a promising way to improve neurodegenerative diseases.³⁶ In animal studies, learning and memory were improved by iVNS, because iVNS can regulate the distribution of neurotransmitters.^{37,⇓,⇓-40} TaVNS have been shown to improve the aging-related emotional problems and sleep disorders in elderly people.⁴¹ Clinical trials also reveal tcVNS improves gait disorders in patients with Parkinson’s disease.^41,42

TaVNS improves tinnitus symptoms and tinitus related emotional problems.⁴³,44 Safety and efficacy of taVNS on tinnitus were confirmed in another study,⁴⁴ and the underlying mechanism of were explorers in a magnetoencephalography study, reveals that taVNS affects the activity of auditory neurons in tinnitus patients.⁴³

3.3. Endocrinium

Stimulating the vagus nerve could adjust the body’s metabolism. In animal studies, increased vagal activity is found to promote the glucagon-like peptide-1 secretion and regulate melatonin secretion.⁴⁵ Fasting blood glucose 2 h post meal and the patients’ glycosylated hemoglobin reduced after taVNS, indicates taVNS could arouse a long-term regular effect on blood glucose.⁴⁸ Furthermore, taVNS inhibits the development of diabetic neuropathy by regulating the level of central serotonin and its receptors.⁴⁷

3.4. What do the existing studies implicate for future research

Only exploratory studies or pre-trials with very small sample sizes showing they have potential therapeutic effects on HF, diabetes, neurological disease. Clinical studies are too few to confirm the effectiveness of taVNS in these diseases until now.

Although iVNS is effective in some critical and intractable conditions, the risk of iVNS in treating these diseases can not be ignored. The side effects may minimize the portential benefits. In contrast, a case report highlight the advantages of taVNS in some critical situations such as chronic disturbance of consciousness.⁴⁹ A removable taVNS could minimize the potential adverse reactions, therefore, taVNS can be an alternative to iVNS for patients who are intolerant of iVNS.

4. CONCLUSIONS

4.1. Why taVNS Might be a Tool For Screening Who is Sensitive to IVNS?

TaVNS is a portable, cheaper, and easier operating method of stimulating the vagus nerve. Current studies shows taVNS has a similar anatomical, neurophysiological basis to iVNS. Since taVNS can be removable, it could be used as a screening tool before iVNS operation to reduce the secondary operation caused by the poor effect in advance.

4.2. In which situation would taVNS come to be an Alternative Method for IVNS in the future?

The similarities in mechanism provide theoretical possibilities for taVNS to be an alternative to iVNS. IVNS directly effects on the cervical vagus nerve, which could arouse a stable continuous stimulation. While taVNS effect on the surface of auricular concha. What is crucial now is to verify wheather taVNS could achieve sufficient and stable effects on the vagus nerve.