Re: 귀에서 자극하는 미주신경 자극기 탐구!!

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Front Neurosci. 2020; 14: 284.

Published online 2020 Apr 28. doi: 10.3389/fnins.2020.00284

PMCID: PMC7199464

PMID: 32410932

Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice

Jonathan Y. Y. Yap,1,† Charlotte Keatch,2,† Elisabeth Lambert,3,4 Will Woods,3 Paul R. Stoddart,1,2 and Tatiana Kameneva2,4,5,*

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Abstract

Several studies have illustrated that transcutaneous vagus nerve stimulation (tVNS) can elicit therapeutic effects that are similar to those produced by its invasive counterpart, vagus nerve stimulation (VNS). VNS is an FDA-approved therapy for the treatment of both depression and epilepsy, but it is limited to the management of more severe, intervention-resistant cases as a second or third-line treatment option due to perioperative risks involved with device implantation. In contrast, tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. Although it has been shown that tVNS elicits hypo- and hyperactivation in various regions of the brain associated with anxiety and mood regulation, the mechanism of action and influence of stimulation parameters on clinical outcomes remains predominantly hypothetical. Suppositions are largely based on correlations between the neurobiology of the vagus nerve and its effects on neural activity. However, tVNS has also been investigated for several other disorders, including tinnitus, migraine and pain, by targeting the vagus nerve at sites in both the ear and the neck. As most of the described methods differ in the parameters and protocols applied, there is currently no firm evidence on the optimal location for tVNS or the stimulation parameters that provide the greatest therapeutic effects for a specific condition. This review presents the current status of tVNS with a focus on stimulation parameters, stimulation sites, and available devices. For tVNS to reach its full potential as a non-invasive and clinically relevant therapy, it is imperative that systematic studies be undertaken to reveal the mechanism of action and optimal stimulation modalities.

여러 연구에 따르면 

경피적 미주신경 자극(tVNS)이 침습적 방법인 

미주신경 자극(VNS)과 유사한 치료 효과를 이끌어낼 수 있는 것으로 나타났습니다. 

VNS는 

우울증과 뇌전증 치료를 위해 FDA 승인을 받은 치료법이지만, 

장치 이식과 관련된 수술 전후 위험으로 인해 2차 또는 3차 치료 옵션으로서 

더 심각하고 개입에 저항하는 사례의 관리에만 제한적으로 사용됩니다. 

반면, 

tVNS는 

특정 위치에 표면 전극을 통해 전류를 가하는 비침습적 기술로, 

가장 일반적으로 목의 미주신경의 귀가지 auricular branch of the vagus nerve  (ABVN)와 

미주신경의 경추 가지 cervical branch of the vagus nerve 를 표적으로 합니다. 

tVNS가 불안 및 기분 조절과 관련된 뇌의 다양한 영역에서 저활성화 및 과활성화를 유도하는 것으로 밝혀졌지만, 그 작용 메커니즘과 자극 매개변수가 임상 결과에 미치는 영향은 주로 가설에 머물러 있습니다. 이러한 가정은 주로 미주 신경의 신경생물학과 신경 활동에 미치는 영향 사이의 상관관계에 근거하고 있습니다. 

그러나 귀와 목의 미주 신경을 표적으로 삼아 이명, 편두통, 통증 등 여러 다른 질환에 대해서도 tVNS가 연구되고 있습니다. 설명된 대부분의 방법은 적용되는 매개변수와 프로토콜이 다르기 때문에, 현재 특정 질환에 가장 큰 치료 효과를 제공하는 tVNS의 최적 위치나 자극 매개변수에 대한 확실한 증거는 없습니다. 

이 리뷰에서는 

자극 매개변수, 

자극 부위 및 사용 가능한 장치에 중점을 두고 

tVNS의 현재 상태를 소개합니다. 

tVNS가 비침습적이고 임상과 관련된 치료법으로서 잠재력을 최대한 발휘하려면 작용 메커니즘과 최적의 자극 양식을 밝히기 위한 체계적인 연구가 필수적입니다.

Keywords: vagus nerve, vagus nerve stimulation, transcutaneous, neuromodulation, neurostimulation

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1. Introduction

Vagus nerve stimulation (VNS) is an FDA-approved treatment for both pharmacoresistant depression and epilepsy and can produce clinically meaningful antidepressant and anti-seizure effects (Nemeroff et al., 2006; Johnson and Wilson, 2018). More than 100,000 VNS devices had been implanted in more than 70,000 patients globally by 2013 (Labiner and Ahern, 2007). The implantable device consists of an electrode, which is wrapped around the left vagus nerve, and an implantable unit, positioned below the collarbone and containing the battery and pulse generator.

Device implantation is predominantly performed on an outpatient basis under general anesthetic, but some patients may require overnight stay if extended observation is necessary. Despite being a minimally invasive procedure, the surgery is inherently risky due to the location of implantation, with electrode placement requiring dissection of the vagus nerve from the carotid artery. Potential adverse events arising from the surgical intervention include bradyarrhythmias during device placement, the development of peritracheal hematoma (due to surgical trauma), and other respiratory complications, including vocal cord dysfunction and dyspnea (due to nerve trauma). VNS can also cause changes to breathing patterns during sleep, resulting in an increase in the number of obstructive apneas and hypopneas (Marzec et al., 2003; Fahy, 2010), and can, albeit rarely, produce late-onset bradyarrhythmias and severe asystolia due to atrium-ventricular block (Iriarte et al., 2009). These potential adverse events limit the intervention's applicability to those who are resistant to conventional therapeutic strategies, and total device and procedural costs amount to around AU $50,000 (Lehtimäki et al., 2013), a price that is prohibitively high for many, as it is a non-subsidized treatment.

Transcutaneous vagus nerve stimulation (tVNS) is a method that has been developed to overcome these limitations, and the potential widespread accessibility of the technology adds to its appeal as a possible first-line treatment option. Anatomical studies of the ear suggest that the tragus, concha, and cymba concha are the places on the human body where there are cutaneous afferent vagus nerve distributions (Figure 1) (Peuker and Filler, 2002), and it is believed that stimulation of these afferent fibers should produce therapeutic effects that are similar to those of regular VNS (Hein et al., 2012; Rong et al., 2012; Stefan et al., 2012). Similarly non-invasive stimulation of the cervical branch of the vagus nerve has received popularity due to minimal side effects, low cost, and morbidity associated with the technique (Goadsby et al., 2014; Grazzi et al., 2014; Kinfe et al., 2015b). In this review, we refer to both auricular and cervical nerve stimulation as tVNS.

1. 소개
미주신경 자극(VNS)은 약물 내성 우울증과 간질 모두에 대해 FDA 승인을 받은 치료법으로 임상적으로 의미 있는 항우울 및 항발작 효과를 나타낼 수 있습니다(Nemeroff et al., 2006; Johnson and Wilson, 2018). 2013년까지 전 세계적으로 70,000명 이상의 환자에게 100,000개 이상의 VNS 장치가 이식되었습니다(Labiner and Ahern, 2007). 이식형 장치는 왼쪽 미주 신경을 감싸는 전극과 쇄골 아래에 위치하며 배터리와 펄스 발생기를 포함하는 이식형 장치로 구성됩니다.

장치 이식은 주로 전신 마취 하에 외래에서 시행되지만, 일부 환자는 장기간 관찰이 필요한 경우 하룻밤 입원이 필요할 수 있습니다. 최소 침습적 시술임에도 불구하고 경동맥에서 미주 신경을 절개해야 하는 전극 삽입 위치로 인해 수술은 본질적으로 위험합니다. 수술로 인해 발생할 수 있는 부작용으로는 장치 삽입 중 서맥 부정맥, (수술 외상으로 인한) 기관 주위 혈종 발생, 성대 기능 장애 및 호흡곤란(신경 외상으로 인한) 등 기타 호흡기 합병증이 있습니다. 또한 VNS는 수면 중 호흡 패턴에 변화를 일으켜 폐쇄성 무호흡과 저호흡의 수를 증가시킬 수 있으며(Marzec 등, 2003; Fahy, 2010), 드물기는 하지만 심방-심실 차단으로 인해 서맥 부정맥과 심한 무수축을 유발할 수 있습니다(Iriarte 등, 2009). 이러한 잠재적 부작용으로 인해 기존 치료 전략에 내성이 있는 환자에게는 시술 적용이 제한되며, 총 기기 및 시술 비용이 약 5만 호주 달러(Lehtimäki 등, 2013)에 달해 보조금이 지급되지 않는 치료법이기 때문에 많은 환자에게는 턱없이 높은 가격입니다.

경피 미주신경 자극(tVNS)은

이러한 한계를 극복하기 위해 개발된 방법이며,

이 기술의 잠재적인 광범위한 접근성은 가능한 1차 치료 옵션으로서의 매력을 더합니다.

귀에 대한 해부학적 연구에 따르면

이소골, 이소골, 심바이소골은

인체에서 피부 구심성 미주신경 분포가 있는 곳이며(그림 1)(Peuker and Filler, 2002),

이러한

구심성 섬유를 자극하면

일반 VNS와 유사한 치료 효과가 나타날 것으로 여겨집니다(Hein et al., 2012; Rong et al., 2012; Stefan et al., 2012).

마찬가지로

미주신경의 경추 분지에 대한 비침습적 자극은

이 기술과 관련된 최소한의 부작용, 저렴한 비용 및 이환율로 인해 인기를 얻고 있습니다(Goadsby 등, 2014; Grazzi 등, 2014; Kinfe 등, 2015b).

이 리뷰에서는

귀신경 자극과 경추 신경 자극을

모두 tVNS라고 합니다.

Figure 1

(A) Ear regions with innervation by the cutaneous auricular branch of the vagus nerve (ABVN). (B) Nerves in the neck region including cervical branch of the vagus nerve.

The potential of tVNS is not limited to the treatment of depression and epilepsy, with the technology being investigated for a variety of disorders including headache, tinnitus, atrial fibrillation, post-error slowing, prosocial behavior, associative memory, schizophrenia, and pain (Laqua et al., 2014; Hasan et al., 2015; Hyvärinen et al., 2015; Jacobs et al., 2015; Nesbitt et al., 2015; Sellaro et al., 2015a,b; Stavrakis et al., 2015).

Despite the breadth of research being undertaken, many questions remain regarding the most effective stimulation sites and parameters. As many of the described methods differ in the parameters and protocols applied, there is currently no firm evidence regarding the optimal location for stimulation to achieve the greatest clinical effects let alone an understanding of the neurophysiological mechanisms. Therefore, this critical review aims to explore the reported studies in tVNS with a view to promoting more systematic approaches that might help to translate the technique into mainstream clinical practice.

In comparison to tVNS, the invasive approach to VNS has been the subject of a number of recent reviews. For example, a review of functional neuroimaging studies in VNS confirmed that invasive stimulation causes changes in various brain regions and at different levels (Chae et al., 2003). A review of VNS with a focus on depression is presented in Müller et al. (2018). Recent advances in devices for VNS have been covered in Mertens et al. (2018). Similarly, applications and potential mechanisms of VNS have been discussed in some detail (Groves and Brown, 2005; Yuan and Silberstein, 2016a,b).

The few reviews that specifically focus on tVNS are very recent. A systematic review of the safety and tolerability of tVNS was presented in Redgrave et al. (2018), while two companion papers have focused on the physiological and engineering perspectives of tVNS (Kaniusas et al., 2019a,b). Whereas, Kaniusas et al. (2019a,b) outlined current research directions in auricular vagus nerve stimulation, this review takes a more critical approach and explores fundamental limitations of study design protocols that may lead to difficulties in translating current research into the clinic. We have also reviewed cervical vagus nerve stimulation in addition to auricular applications.

The review presented here focuses on a mechanistic understanding of tVNS, with a detailed description of stimulation parameters, sites of stimulation, and devices used in current research. We review current publications investigating the effect of electrode placement on auricular vagus nerve stimulation recruitment and corresponding neural activations, papers studying the effect of stimulation parameters (waveform, polarity, frequency, pulse width, duty cycle, and current), and manuscripts exploring the neurophysiological mechanisms of tVNS. We also consider whether tVNS can be used for closed-loop control of neural activity. We outline fundamental gaps in our understanding that need to be overcome in order to maximize efficacy, minimize risk, and thus support the successful translation of tVNS into mainstream clinical practice.

두통, 이명, 심방 세동, 오류 후 둔화, 친사회적 행동, 연상 기억, 정신 분열증, 통증 등 다양한 장애에 대한 연구가 진행 중이며, tVNS의 잠재력은 우울증과 간질 치료에만 국한되지 않습니다(Laqua et al, 2014; 하산 외, 2015; 하이베리넨 외, 2015; 제이콥스 외, 2015; 네스빗 외, 2015; 셀라로 외, 2015a,b; 스타브라키스 외, 2015).

광범위한 연구가 진행되고 있음에도 불구하고 가장 효과적인 자극 부위와 매개변수에 관한 많은 의문이 남아 있습니다. 설명된 많은 방법이 적용되는 매개변수와 프로토콜이 다르기 때문에, 현재 신경생리학적 메커니즘에 대한 이해는 물론 가장 큰 임상 효과를 얻을 수 있는 최적의 자극 위치에 대한 확실한 증거는 없습니다. 따라서 이 비판적 검토는 이 기술을 주류 임상 진료로 전환하는 데 도움이 될 수 있는 보다 체계적인 접근법을 촉진하기 위해 tVNS에 대해 보고된 연구를 살펴보는 것을 목표로 합니다.
tVNS와 비교하여, VNS에 대한 침습적 접근 방식은 최근 여러 리뷰의 주제였습니다. 예를 들어, VNS의 기능적 신경 영상 연구를 검토한 결과 침습적 자극이 다양한 뇌 영역과 다양한 수준에서 변화를 일으킨다는 사실이 확인되었습니다(Chae et al., 2003). 우울증에 초점을 맞춘 VNS에 대한 리뷰는 Müller 등(2018)에 나와 있습니다. VNS를 위한 기기의 최근 발전은 Mertens 등(2018)에서 다루었습니다. 마찬가지로 VNS의 응용과 잠재적 메커니즘에 대해서도 자세히 논의되었습니다(Groves and Brown, 2005; Yuan and Silberstein, 2016a,b).

tVNS에 특별히 초점을 맞춘 리뷰는 매우 최근의 것입니다. tVNS의 안전성과 내약성에 대한 체계적인 검토는 Redgrave 등(2018)에서 발표되었으며, 두 편의 동반 논문은 tVNS의 생리적 및 공학적 관점에 초점을 맞췄습니다(Kaniusas 등, 2019a,b). Kaniusas 등(2019a,b)은 귀 미주신경 자극의 현재 연구 방향을 개괄적으로 설명한 반면, 이 리뷰에서는 보다 비판적인 접근 방식을 취하고 현재 연구를 임상에 적용하는 데 어려움을 초래할 수 있는 연구 설계 프로토콜의 근본적인 한계를 탐구합니다. 또한 귀에 적용하는 것 외에 경추 미주신경 자극에 대해서도 검토했습니다.

여기에 제시된 리뷰는 자극 매개변수, 자극 부위 및 현재 연구에 사용된 장치에 대한 자세한 설명과 함께 tVNS에 대한 기계적인 이해에 초점을 맞추고 있습니다. 전극 배치가 귀 미주신경 자극 모집과 그에 따른 신경 활성화에 미치는 영향을 조사한 최신 논문, 자극 파라미터(파형, 극성, 주파수, 펄스 폭, 듀티 사이클 및 전류)의 효과를 연구한 논문, tVNS의 신경생리학적 메커니즘을 탐구한 원고를 검토합니다. 또한 신경 활동의 폐쇄 루프 제어에 tVNS를 사용할 수 있는지 여부도 고려합니다. 우리는 효능을 극대화하고 위험을 최소화하여 tVNS를 주류 임상으로 성공적으로 전환하기 위해 극복해야 할 근본적인 이해의 격차를 설명합니다.

2. Transcutaneous Vagus Nerve Stimulation (tVNS)

2.1. Anatomical Considerations

Transcutaneous vagus nerve stimulation (tVNS) is based on the results of anatomical studies illustrating the path of the auricular branch of the vagus nerve (ABVN; Alderman's nerve; and Arnold's nerve), which originates from the superior ganglion of the vagus nerve from within the jugular foramen (Tekdemir et al., 1998), transversely passing through the facial canal, entering the small canal of the petrous bone, and emerging from the tympanomastoid fissure, proceeding to innervate the external acoustic meatus and auricle (Kiyokawa et al., 2014). As Peuker and Filler identify, the ABVN (Figure 2) is most prominently spread through the antihelix, tragus, cymba concha, and concha (Peuker and Filler, 2002). These are the places on the human body where there are cutaneous afferent vagus nerve distributions, and thus, as theoretically proposed by Ventureyra (2000), it is believed that direct stimulation of these nerve fibers should produce therapeutic effects similar to those of VNS. More recently, the original article by Peuker and Filler was the subject of some controversy due to different numbers being reported for tragus innervation by the ABVN in the main text and in the table (possibly a typing error) (Burger and Verkuil, 2018). Peuker and Filler (2002) later explained that the knowledge of auricular vagus nerve anatomy does not rest solely on this data, and other publications support the same findings (He et al., 2012).

2. 경피적 미주 신경 자극(tVNS)
2.1. 해부학적 고려 사항
경피적 미주 신경 자극(tVNS)은 경정공 내에서 미주 신경의 상부 신경절에서 시작하여 경정공(Tekdemir et al..., 1998)을 가로질러 안면관으로 들어가는 미주 신경의 귀가지(ABVN; Alderman's 신경; 및 Arnold 신경)의 경로를 보여주는 해부학적 연구 결과에 근거하고 있습니다, 1998), 안면관을 횡으로 통과하여 석골의 소관으로 들어가고 고실골 균열에서 나와 외부 청각 근육과 귓바퀴를 자극합니다 (Kiyokawa et al., 2014). Peuker와 Filler가 확인한 바와 같이, ABVN(그림 2)은 반나선, 트라구스, 심바콘차, 콘차를 통해 가장 두드러지게 퍼져 있습니다(Peuker and Filler, 2002). 이들은 인체에서 피부 구심성 미주 신경 분포가 있는 곳이며, 따라서 이론적으로 Ventureyra(2000)가 제안한 것처럼 이러한 신경 섬유를 직접 자극하면 VNS와 유사한 치료 효과를 낼 수 있을 것으로 여겨집니다. 최근에는 Peuker와 Filler의 원본 논문이 본문과 표에서 ABVN에 의한 삼차 신경 분포에 대해 다른 숫자가 보고되어(아마도 입력 오류일 수 있음) 논란의 대상이 되기도 했습니다(Burger and Verkuil, 2018). Peuker와 Filler(2002)는 나중에 귀 미주신경 해부학에 대한 지식이 이 데이터에만 의존하지 않으며 다른 출판물에서도 동일한 결과를 뒷받침한다고 설명했습니다(He et al., 2012).

Figure 2

Innervation of the auricular branch of the vagus nerve (ABVN). GAN, great auricular nerve; ATN, auriculotemporal nerve; STA, superficial temporal artery; LON, lesser occipital nerve; V, vessels. Adapted from Peuker and Filler (2002) with permission.

Transcutaneous cervical vagus nerve stimulation is another method that has been developed to non-invasively stimulate the vagus nerve with electrodes placed over the sternocleidomastoid muscle. This is a similar location to where the electrodes for VNS are positioned and is more reminiscent of Corning's initial approach. However, the vagus nerve's location within the carotid sheath (Figure 3), beneath the skin (2 mm), superficial fascia (3–6 mm), and sternocleidomastoid muscle (5–6 mm) (Seiden et al., 2013) can make selective transcutaneous stimulation of vagus nerve fibers difficult, with current product offerings most likely indiscriminately stimulating afferent and efferent fibers alike (Yuan and Silberstein, 2016b).

경피 경추 미주 신경 자극은 흉쇄유돌근 위에 전극을 배치하여 미주 신경을 비침습적으로 자극하기 위해 개발된 또 다른 방법입니다. 이는 VNS의 전극이 위치하는 위치와 유사하며 코닝의 초기 접근 방식과 더 유사합니다. 그러나 미주 신경이 경동맥 피복(그림 3), 피부 아래(2mm), 표재성 근막(3-6mm), 흉쇄유돌근(5-6mm) 내에 위치하기 때문에(Seiden et al., 2013) 미주 신경 섬유의 선택적 경피 자극이 어려울 수 있으며, 현재 제공되는 제품은 구심성 섬유와 원심성 섬유를 모두 무차별적으로 자극할 가능성이 높습니다(Yuan and Silberstein, 2016b).

Figure 3

Topography of vagus nerve anatomy in the neck. Blue arrows indicate vessels external to the epineurium. Adapted from Hammer et al. (2018) with permission.

Conventionally, the left vagus nerve has mostly been selected as the preferred stimulation site due to safety concerns arising from observations during animal studies showing that right-sided VNS results in a greater degree of bradycardia (Yuan and Silberstein, 2016b). This is due to the asymmetric innervation of the heart, where the right vagus nerve predominantly innervates the sinoatrial (SA) node and the left predominantly innervates the atrioventricular (AV) node (Ardell and Randall, 1986). As such, right VNS in dog studies activated the cardiac motor efferents innervating the SA node, causing bradycardia through a reduction of depolarization rates and providing credence to the belief that right-sided VNS should not be attempted in clinical settings (Krahl, 2012). However, the anatomy of the cervical vagus trunk differs between dogs and humans, and the location around which the VNS stimulation electrodes are wrapped (in humans) does not include the superior or inferior cardiac branches, thereby diminishing the risk of significant cardiac adverse events (Krahl, 2012). Despite this, the FDA-approved labeling for VNS devices specifies that “the VNS Therapy System is indicated for use only in stimulating the left vagus nerve in the neck area inside the carotid sheath. The VNS Therapy System is indicated for use only in stimulating the left vagus nerve below where the superior and inferior cervical cardiac branches separate from the vagus nerve. The safety and efficacy of the VNS Therapy System have not been established for stimulation of the right vagus nerve or of any other nerve, muscle, or tissue” (Depression Physician's Manual, 2005).

While limiting treatments to the left side may be warranted for VNS, due to the potential to directly stimulate the cardiac motor efferents innervating the SA node, there are questions as to whether the application of these conventional reservations to tVNS is justified. The cardiac effects seen through ABVN stimulation are mediated through a neural pathway that involves the nucleus tractus solitarii (NTS); this activates the dorsal motor nucleus, which then delivers processed signals to the heart surface bilaterally via the efferent cervical vagus nerves. Therefore, unlike cervical VNS, tVNS circumvents the risk of directly and asymmetrically stimulating cardiac motor efferent fibers, thus causing adverse cardiac events (Chen et al., 2015). As such, simply disregarding the therapeutic potential of bilateral ABVN stimulation, based on conventional preconceptions and parallels drawn from VNS, may be premature and warrants further investigation. Additionally, bilateral ABVN stimulation has been shown to be safe in pilot studies investigating tVNS as a complementary therapy for pediatric epilepsy (He et al., 2013).

2.2. Nerve Fiber Types

The vagus and its branches consist of around 80% sensory afferent and 20% motor afferent fibers (Yu et al., 2008). Nerve fibers can be further classified into one of three groups based on their diameter: the A group (consisting of Aα Aβ, Aγ, and Aδ), B group, and C group. The different nerve fiber types have different diameters and myelination thicknesses (Table 1), which corresponds to different conduction velocities, with thicker myelination typically linked to faster conduction velocities or signal propagation (Fix and Brueckner, 2009).

일반적으로 좌측 미주신경은 주로 우측 미주신경이 더 많은 서맥을 유발한다는 동물 연구 결과에서 관찰된 안전성 문제로 인해 선호되는 자극 부위로 선택되어 왔습니다(Yuan and Silberstein, 2016b). 이는 심장의 비대칭적인 신경 분포로 인해 오른쪽 미주 신경이 주로 방실(SA) 결절에, 왼쪽은 방실(AV) 결절에 주로 신경을 공급하기 때문입니다(Ardell and Randall, 1986). 따라서 개 연구에서 우측 VNS는 SA 결절을 자극하는 심장 운동 원동을 활성화하여 탈분극률을 감소시킴으로써 서맥을 유발하고 임상 환경에서 우측 VNS를 시도해서는 안 된다는 믿음에 신빙성을 부여했습니다(Krahl, 2012). 그러나 경부 미주신경줄기의 해부학적 구조는 개와 사람마다 다르며, VNS 자극 전극을 감싸는 위치(사람의 경우)에는 상심방 또는 하심방이 포함되어 있지 않아 중대한 심장 부작용의 위험이 감소합니다(Krahl, 2012). 그럼에도 불구하고 FDA가 승인한 VNS 기기 라벨에는 "VNS 치료 시스템은 경동맥 피복 안쪽 목 부위의 왼쪽 미주 신경을 자극하는 데만 사용하도록 명시되어 있습니다. VNS 치료 시스템은 미주 신경에서 상하 경부 심장 가지가 분리되는 부분 아래의 좌측 미주 신경을 자극하는 데만 사용하도록 되어 있습니다."라고 명시되어 있습니다. 오른쪽 미주 신경이나 다른 신경, 근육 또는 조직의 자극에 대한 VNS 치료 시스템의 안전성과 효능은 확립되지 않았습니다."(우울증 의사 매뉴얼, 2005).

좌측으로 치료를 제한하는 것은 VNS의 경우 SA 마디를 자극하는 심장 운동 신경을 직접 자극할 가능성이 있기 때문에 타당할 수 있지만, 이러한 기존의 유보 사항을 tVNS에 적용하는 것이 정당한지에 대해서는 의문이 있습니다. ABVN 자극을 통해 나타나는 심장 효과는 솔리타리핵(NTS)을 포함하는 신경 경로를 통해 매개되며, 이는 등쪽 운동핵을 활성화하여 처리된 신호를 원심성 경부 미주 신경을 통해 양측으로 심장 표면에 전달합니다. 따라서 경부 미주신경과는 달리 tVNS는 심장 운동 구심성 섬유를 직접적이고 비대칭적으로 자극하여 심장 부작용을 일으킬 위험을 피할 수 있습니다(Chen et al., 2015). 따라서 기존의 선입견과 VNS에서 도출된 유사점을 근거로 양측 ABVN 자극의 치료 가능성을 단순히 무시하는 것은 시기상조일 수 있으며 추가 조사가 필요합니다. 또한, 소아 뇌전증에 대한 보완 요법으로 tVNS를 조사하는 파일럿 연구에서 양측 ABVN 자극은 안전한 것으로 나타났습니다(He et al., 2013).

2.2. 신경 섬유 유형
미주신경과 그 가지들은 약 80%의 감각 구심성 섬유와 20%의 운동 구심성 섬유로 구성되어 있습니다(Yu et al., 2008). 신경 섬유는 직경에 따라 A 그룹(Aα Aβ, Aγ, Aδ로 구성), B 그룹, C 그룹의 세 가지 그룹 중 하나로 더 분류할 수 있습니다. 신경 섬유 유형에 따라 직경과 수초 두께가 다르며(표 1), 이는 서로 다른 전도 속도에 해당하며, 일반적으로 두꺼운 수초는 더 빠른 전도 속도 또는 신호 전달과 관련이 있습니다(Fix and Brueckner, 2009).

Table 1

Classification of nerve fibers.

Nerve fiberDiameterMyelinationConductionvelocityAfferent orTypeclassification(μm)(m/s)Efferent

Aα	13–20	Thick	80–120	Both	Sensory
					and Motor
Aβ	6–12	Medium	33–75	Both	Sensory
					and Motor
Aγ	5–8	Medium	4–24	Efferent	Motor
Aδ	1–5	Thin	3–30	Afferent	Sensory
B	<3	Thin	3–14	Afferent	Autonomic
C	0.2–1.5	None	0.5–2	Afferent	Sensory
					and Motor

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Adapted from Fix and Brueckner (2009).

A-group fibers are thick, myelinated, afferent, and efferent, and they also typically have diameters of around 1–22 μm and a conduction velocity of 5–120 m/s. They are typically found in both motor and sensory pathways. B fibers are only moderately myelinated, with diameters = 3 μ m and a conduction velocity ranging from 3 to 15 m/s. C fibers are non-myelinated, and they thus have slower conduction speeds of 2 m/s and thinner diameters of between 0.2 and 1.5 μm.

The cervical branch vagus nerve is made up of about 20% myelinated A and B fibers and 80% unmyelinated C fibers (Vonck et al., 2009). Contrary to earlier studies, which have suggested that C fiber recruitment during VNS was essential for seizure suppression, Kraus et al. (2007) showed that destruction of peripheral C fibers did not influence VNS-induced seizure suppression, and the therapeutic effects of VNS have thus been attributed to the maximal recruitment of thick afferent A and B nerve fibers (Evans et al., 2004). Minimal side effects suggest that stimulation of these fibers is well-tolerated (Helmers et al., 2012).

Similarly, Stefan et al. (2012) showed that tVNS does not elicit painful sensations in the participants, which suggests that afferent C axons and thin myelinated Aδ axons are not activated. A study by Mourdoukoutas et al. (2018) also investigated the fibers that can be activated by tVNS, and they found that at the typically used current of 10 mA, only A-axons and larger B-axons were activated; this is likely due to the diameter of their fibers, implying that C-fibers were too thin to be activated by the applied electrical stimulation.

At the cervical level, the vagus nerve mainly consists of small diameter unmyelinated C fibers (65–80%) and of a smaller portion of intermediate- diameter myelinated B fibers and large-diameter myelinated A fibers. A, B, and C fiber distributions within the carotid vagus nerve have been well-documented (Standring, 2015), enabling the development of computational models to determine the optimal current and pulse width parameters for VNS to activate the myelinated A and B afferent fibers (Helmers et al., 2012). Despite this, the optimal stimulation parameters for VNS are unknown, as the effects of other parameters, such as frequency and duty cycle, are observed post-synaptically in various structures of the brain. Given that these activations cannot be computationally modeled, clinical application and stimulation parameter selection of VNS relies on subjective benefits reported by patients.

In contrast, the distributions of the various nerve fiber types of the ABVN have not been investigated to the level of detail necessary for computational modeling. Therefore, the presence of various nerve fiber types remains speculative and eval‎uations of intervention efficacy have been based on subjectively experienced therapeutic benefits correlated with other primary and secondary outcomes, such as neuroimaging studies.

As with stimulation of the cervical branches of the vagus nerve with low level electrical currents, stimulation of the ABVN would be expected to activate thick myelinated fibers only and with no activation of the thin diameter unmyelinated C fibers. The ABVN is a general sensory fiber and is one of the few branches to contain no motor fibers. As such, the myelinated fibers found in the ABVN would be expected to be A-group sensory axons rather than B-group autonomic fibers. Only one study has determined the number of myelinated axons that are present in the ABVN (Safi et al., 2016). Around 50% of the myelinated axons were measured to have a diameter of between 2.5 and 4.4 μm, which suggests that they belong to the Aδ group. Nearly 20% of the axons were measured to have a diameter >7 μm, suggesting the fibers belong to the Aβ class. However, the ABVN contains almost six times less Aβ class nerve fibers than those found in the cervical branch of the vagus nerve. This number also varied greatly between individuals, which may explain why some individuals do not experience therapeutic effects after treatment with tVNS, and it may go some way to explain the anatomical basis behind the mechanism and effectiveness of tVNS (Butt et al., 2019).

A그룹 섬유는 굵고, 수초화되어 있으며, 구심성 및 원심성이며, 일반적으로 직경이 약 1-22 μm이고 전도 속도가 5-120 m/s입니다. 일반적으로 운동 경로와 감각 경로 모두에서 발견됩니다. B 섬유는 직경 = 3 μ m, 전도 속도가 3 ~ 15 m/s인 중간 정도의 수초화 섬유입니다. C 섬유는 수초화되지 않았기 때문에 전도 속도가 2m/s로 느리고 직경이 0.2~1.5μm로 더 얇습니다.
경추 가지 미주신경은 약 20%의 수초화된 A 및 B 섬유와 80%의 비수초화된 C 섬유로 구성되어 있습니다(Vonck et al., 2009). 발작 억제를 위해 VNS 중 C 섬유 모집이 필수적이라고 제안한 초기 연구와는 달리, 크라우스 등(2007)은 말초 C 섬유의 파괴가 VNS에 의한 발작 억제에 영향을 미치지 않으며, 따라서 VNS의 치료 효과는 두꺼운 구심성 A 및 B 신경 섬유의 최대 모집에 기인한다는 것을 보여주었습니다(Evans et al., 2004). 최소한의 부작용은 이러한 섬유의 자극이 잘 견뎌낸다는 것을 시사합니다(Helmers et al., 2012).
마찬가지로 Stefan 등(2012)은 tVNS가 참가자에게 고통스러운 감각을 유발하지 않는 것으로 나타났는데, 이는 구심성 C 축삭과 얇은 골수화된 Aδ 축삭이 활성화되지 않음을 시사합니다. 무두쿠타스 등(2018)의 연구에서도 tVNS로 활성화할 수 있는 섬유를 조사한 결과, 일반적으로 사용되는 전류 10mA에서는 A 축삭과 더 큰 B 축삭만 활성화되었으며, 이는 섬유의 직경으로 인해 C 섬유가 적용된 전기 자극에 의해 활성화되기에는 너무 가늘다는 것을 의미합니다.
경추 수준에서 미주신경은 주로 작은 직경의 수초화되지 않은 C 섬유(65~80%)와 중간 직경의 수초화 B 섬유 및 큰 직경의 수초화 A 섬유로 구성되어 있습니다. 경동맥 미주신경 내의 A, B, C 섬유 분포는 잘 문서화되어 있어(Standring, 2015), VNS가 수초화된 A 및 B 구심성 섬유를 활성화하기 위한 최적의 전류 및 펄스 폭 파라미터를 결정하는 계산 모델을 개발할 수 있었습니다(Helmers et al., 2012). 그럼에도 불구하고 주파수 및 듀티 사이클과 같은 다른 파라미터의 영향이 뇌의 다양한 구조에서 시냅스 후 관찰되기 때문에 VNS에 대한 최적의 자극 파라미터는 알려져 있지 않습니다. 이러한 활성화는 계산적으로 모델링할 수 없기 때문에 VNS의 임상 적용 및 자극 파라미터 선택은 환자가 보고한 주관적인 효과에 의존합니다.

반면, ABVN의 다양한 신경 섬유 유형의 분포는 전산 모델링에 필요한 세부 수준까지 조사되지 않았습니다. 따라서 다양한 신경 섬유 유형의 존재는 여전히 추측에 불과하며 중재 효과에 대한 평가는 신경 영상 연구와 같은 다른 일차 및 이차 결과와 연관된 주관적으로 경험한 치료 효과에 근거해 이루어졌습니다.

낮은 수준의 전류로 미주신경의 경추 가지를 자극할 때와 마찬가지로, ABVN을 자극하면 두꺼운 수초 섬유만 활성화되고 얇은 직경의 비수초 C 섬유는 활성화되지 않을 것으로 예상됩니다. ABVN은 일반적인 감각 섬유이며 운동 섬유를 포함하지 않는 몇 안 되는 가지 중 하나입니다. 따라서 ABVN에서 발견되는 수초화된 섬유는 B군 자율 섬유가 아닌 A군 감각 축삭일 것으로 예상됩니다. ABVN에 존재하는 수초화 축삭의 수를 결정한 연구는 단 한 건뿐입니다(Safi et al., 2016). 골수화 축삭의 약 50%는 직경이 2.5~4.4 μm인 것으로 측정되었으며, 이는 Aδ 그룹에 속하는 것으로 추정됩니다. 축삭의 약 20%는 직경이 7μm를 초과하는 것으로 측정되어 섬유가 Aβ 계열에 속하는 것으로 나타났습니다. 그러나 ABVN에는 미주신경의 경부 가지에서 발견되는 것보다 거의 6배 적은 Aβ 계열 신경 섬유가 포함되어 있습니다. 이 수치는 또한 개인마다 크게 달라서 일부 개인이 tVNS 치료 후 치료 효과를 경험하지 못하는 이유를 설명할 수 있으며, tVNS의 메커니즘과 효과에 대한 해부학적 근거를 설명하는 데 어느 정도 도움이 될 수 있습니다(Butt et al., 2019).

2.3. tVNS for Common Health Conditions

2.3.1. Depression 

The mechanism behind the therapeutic anti-depressive effects of VNS and tVNS is still unknown. In 2007, Kraus et al. investigated the acute brain activations of healthy subjects following tVNS through functional magnetic resonance imaging (fMRI), showing hypoactivation of the amygdala, hippocampus, parahippocampal gyrus, and middle and superior temporal gyrus, and hyperactivation in the insula, precentral gyrus, and thalamus (Kraus et al., 2007). These cortical areas are connected both directly and indirectly to the nucleus tractus solitarii (NTS), which receives greatest afferent vagus input. The NTS relays incoming sensory information to the brain via an automatic feedback loop, direct projections to the reticular formation in the medulla, and ascending projections to the amygdala, insula, hypothalamus, thalamus, orbitofrontal cortex, and other limbic regions involved in anxiety and mood regulation via the parabrachial nucleus and the locus coeruleus (Mohr et al., 2011). It is hypothesized that hypoactivation of the amygdala suppresses the hyperactive limbic brain areas, as seen in patients with depression (Mayberg, 1997), through projections from the amygdala to the amygdala–hippocampus–entorhinal cortex of the limbic system (Kraus et al., 2007).

These results are consistent with the acute diminished activity of the limbic system found during VNS (Henry et al., 1998; Chae et al., 2003; Mohr et al., 2011). Interestingly, changes in regional cerebral blood flow induced by VNS are similar to those found in depressed patients treated with selective serotonin reuptake inhibitors (fluoxetine) (Mayberg et al., 2000), either in the amygdala, hippocampus, or parahippocampus (Nemeroff et al., 2006). fMRI studies of patients with depression, following 1 month of tVNS, showed increased functional connections between the default mode network and the precuneus, rostral anterior cingulate cortex, and medial prefrontal cortex. This has also been associated with a reduction in depression severity (Fang et al., 2016) and is similar to results illustrating the therapeutic effects of transcranial magnetic stimulation (Fitzgerald et al., 2006).

Activation of the central nervous system via electrical stimulation of peripheral nerves has become known as the “bottom-up” mechanism, which is a hypothesis based on the neurobiology of the vagus nerve and its effects on neural activity. This is in contrast to the well-known “top-down” mechanism of strategies, such as electroconvulsive therapy and transcranial magnetic stimulation, where the stimulus is applied to central brain structures and subsequently propagates to peripheral sites (Shiozawa et al., 2014). In both human and animal studies, VNS has been shown to elicit changes in neurotransmitters associated with the pathophysiology of depression, including serotonin, norepinephrine, GABA, and glutamate (Ben-Menachem et al., 1995; Krahl et al., 1998; Walker et al., 1999; Dorr and Debonnel, 2006; Manta et al., 2009).

Hein et al. (2012) illustrated the antidepressant effects of 2 weeks of tVNS using an add-on study design, which resulted in significantly improved outcomes on the Beck Depression Inventory (BDI; 27.0–14.0 points). However, no significant changes were observed on the Hamilton Depression Rating Scale (HAMD). Very little information was provided regarding the stimulation parameters that were used; 1.5 Hz unipolar rectangular waves and currents were individually adjusted to maximal but not painful intensities (0–600 mA). In a single blinded clinical trial conducted by Fang et al. (2016) investigating the antidepressant effects of tVNS as a solo treatment, significant improvement was not only seen on the HAMD (28.5–15.0) but also on the Self-Rating Anxiety Scale (SAS; 56.56–42.83) and the Self-Rating Depression Scale (SDS; 66.33–50.56). It is implied that these therapeutic effects may be due to modulation of the resting state functional connectivity of the default mode network, as shown via fMRI imaging. Again, the stimulation parameters used were not comprehensively reported, with density wave adjusted to 20 Hz, a wave width <1 ms, and intensity adjusted based on the tolerance of the patient (4–6 mA).

2.3. 일반적인 건강 상태를 위한 tVNS
2.3.1. 우울증
VNS와 tVNS의 치료적 항우울 효과에 대한 메커니즘은 아직 밝혀지지 않았습니다. 2007년에 크라우스 등은 기능적 자기공명영상(fMRI)을 통해 tVNS를 받은 건강한 피험자의 급성 뇌 활성화를 조사한 결과 편도체, 해마, 부해마, 중측 및 상측 측두엽의 저활성화와 섬, 전중격, 시상에서의 과활성화가 나타났습니다(Kraus 등, 2007). 이러한 피질 영역은 구심성 미주 입력을 가장 많이 받는 단독핵(NTS)과 직간접적으로 연결되어 있습니다. NTS는 자동 피드백 루프를 통해 들어오는 감각 정보를 뇌에 전달하고, 수질의 망상 형성으로 직접 투사하며, 편도체, 섬, 시상하부, 시상, 안와전두피질 및 불안과 기분 조절에 관여하는 기타 변연계 영역으로 상승 투사하여 시상하핵과 구상체(coeruleus)를 통해 전달합니다(Mohr et al., 2011). 편도체의 저활성화는 편도체에서 변연계의 편도체-해마-내측 피질로의 투사를 통해 우울증 환자(Mayberg, 1997)에서 볼 수 있는 것처럼 과활성 변연계 뇌 영역을 억제한다는 가설이 있습니다(Kraus et al., 2007).

이러한 결과는 VNS 동안 발견되는 변연계의 급성 활동 감소와 일치합니다(Henry et al., 1998; Chae et al., 2003; Mohr et al., 2011). 흥미롭게도 VNS에 의해 유발 된 국소 뇌 혈류의 변화는 편도체, 해마 또는 해마에서 선택적 세로토닌 재 흡수 억제제 (플루옥세틴)로 치료받은 우울증 환자에서 발견되는 것과 유사합니다 (Mayberg et al., 2000) (Nemeroff et al., 2006). 우울증 환자를 대상으로 한 1개월간 tVNS를 사용한 후의 fMRI 연구에 따르면 기본 모드 네트워크와 전전두피질, 복측 전대상피질, 내측 전전두피질 사이의 기능적 연결이 증가한 것으로 나타났습니다. 이는 우울증의 중증도 감소와도 관련이 있으며(Fang 등, 2016), 경두개 자기 자극의 치료 효과를 보여주는 결과와도 유사합니다(Fitzgerald 등, 2006).
말초 신경의 전기 자극을 통한 중추 신경계의 활성화는 미주 신경의 신경 생물학과 신경 활동에 미치는 영향에 근거한 가설인 "상향식" 메커니즘으로 알려져 있습니다. 이는 전기 경련 치료 및 경두개 자기 자극과 같이 자극이 중추 뇌 구조에 적용된 후 말초 부위로 전파되는 잘 알려진 '하향식' 메커니즘과는 대조적입니다(Shiozawa 외., 2014). 인간과 동물 연구 모두에서 VNS는 세로토닌, 노르에피네프린, GABA, 글루타메이트 등 우울증의 병태 생리와 관련된 신경전달물질의 변화를 유도하는 것으로 나타났습니다(Ben-Menachem 등, 1995; Krahl 등, 1998; Walker 등, 1999; Dorr and Debonnel, 2006; Manta et al., 2009).

Hein 등(2012)은 추가 연구 설계를 사용하여 2주간의 tVNS의 항우울 효과를 설명했으며, 그 결과 벡 우울증 인벤토리(BDI; 27.0~14.0점)에서 유의미한 개선이 나타났습니다. 그러나 해밀턴 우울증 평가 척도(HAMD)에서는 유의미한 변화가 관찰되지 않았습니다. 사용된 자극 매개변수에 대한 정보는 거의 제공되지 않았으며, 1.5Hz 단극 직사각형 파 및 전류는 고통스럽지 않은 최대 강도(0-600mA)로 개별적으로 조정되었습니다. 단독 치료로서 tVNS의 항우울 효과를 조사한 Fang 등(2016)이 실시한 단일 맹검 임상 시험에서 HAMD(28.5-15.0)뿐만 아니라 자기 평가 불안 척도(SAS; 56.56-42.83)와 자기 평가 우울 척도(SDS; 66.33-50.56)에서도 상당한 개선이 관찰되었습니다. 이러한 치료 효과는 fMRI 영상을 통해 볼 수 있듯이 기본 모드 네트워크의 휴식 상태 기능적 연결성의 조절에 기인하는 것으로 추정됩니다. 다시 말하지만, 사용된 자극 매개변수는 밀도파를 20Hz로 조정하고 파폭을 1ms 미만으로 조정하며 환자의 내성(4-6mA)에 따라 강도를 조정하는 등 종합적으로 보고되지 않았습니다.

2.3.2. Epilepsy 

In addition to depression, tVNS has also been investigated for its use as a treatment option for drug-resistant epilepsy, a neurological disorder characterized by recurring seizures that affects around 50 million people worldwide (Beghi, 2019). Drug resistance is diagnosed in up to 30% of epilepsy patients (Kwan and Brodie, 2000). Handforth et al. (1998) demonstrated that invasive stimulation of the vagus nerve could suppress the occurrence of seizures and offer a non-pharmacological treatment for epilepsy.

Due to the success of invasive vagus nerve stimulation as a valid treatment option for epilepsy, Stefan et al. (2012) devised a pilot study to investigate whether tVNS would elicit the same anti-convulsive effects. In the pilot study, 10 participants with drug-resistant epilepsy who experienced a minimum of four seizures a month were stimulated on the auricular branch of the vagus nerve transcutaneously through the tragus of the left ear. The stimulation parameters were set to a frequency of 10 Hz with a pulse width of 0.3 ms, and the stimulation intensity was set to the individual's tolerance threshold. The participants were trained to self-administer the tVNS for three 1-h sessions per day as part of their daily routine over a period of 9 months. The participants were encouraged to keep a seizure diary to report the frequency of their seizures both before and during tVNS treatment. In five out of the seven cases that completed the study, the seizure frequency was reduced, which suggested that tVNS could offer seizure-reduction effects.

He et al. (2013) also conducted a pilot study to investigate tVNS as a treatment option for pediatric epilepsy. The stimulation protocol differed to the study of Stefan et al. above, as the stimulation was delivered to the left concha with a frequency of 20 Hz for only 30 min at a time three times daily for 6 months. These parameters were found to also elicit seizure-reduction effects, with a 54% reduction in seizure frequency reported after the 6 months of tVNS treatment. More recently, Liu et al. (2018) found an average seizure reduction of 64.4% in 16 out of 17 of their patients after 6 months of treatment with tVNS. The participants were trained to administer 20 min of tVNS three times a day for 6 months to the left concha with a stimulation frequency of 10 Hz.

The exact mechanism by which tVNS prevents or inhibits seizures is not well-understood. It is thought that afferent projections from the ABVN to the nucleus tractus solitarius (NTS) may be responsible for the anti-convulsive effect, however, the neural networks projecting downstream are unclear (Henry, 2002).

2.3.3. Tinnitus 

Tinnitus is the perception of sound in the absence of actual external sound and it affects 10–15% of the general population (Han et al., 2009). Recent imaging studies have suggested that chronic tinnitus is linked to a dysfunction in the auditory system, which results in abnormal neuronal behavior. Pairing of invasive vagus nerve stimulation with sound therapy has been shown to reverse tinnitus in rat models (Engineer et al., 2011), and so Lehtimäki et al. (2013) devised a pilot study to investigate whether tVNS could provide any therapeutic benefits for patients with chronic tinnitus. In addition, they also investigated whether tVNS could affect neuronal activity in the auditory cortex by imaging the brain using magnetoencephalography (MEG).

During the study, 10 participants with chronic tinnitus were stimulated continuously on the left tragus at 25 Hz for 45–60 min over seven sessions. The stimulation was paired with tailored sound therapy, which was classical music with the dominant frequency of the individual's tinnitus removed. After the study, all participants reported improved mood and decreased severity of tinnitus. In addition, MEG scans demonstrated that tVNS modulated the auditory cortical response, which suggests that the auditory system can be accessed and modulated via stimulation of the vagus nerve.

2.3.4. Migraine 

A number of studies have looked at applying non-invasive VNS to the neck to treat migraines (Goadsby et al., 2014; Grazzi et al., 2014, 2016; Barbanti et al., 2015; Kinfe et al., 2015b). In all of these studies, the gammaCore device (ElectroCore, 2018) was held against the neck in the region of the cervical branch of the vagus nerve, where two stainless steel electrodes deliver 25 Hz of burst stimulation. Total stimulation time varies between studies, but most give 90 s doses of stimulation at a time. This approach has found success in not only reducing the frequency of migraine attacks in participants but also the severity and resultant disability of the attacks.

In addition to non-invasive VNS at the neck, Straube et al. (2015) also investigated whether tVNS at the tragus would have a similar therapeutic effect on migraine. They devised a study for 46 participants, testing the NEMOS tVNS device applying 25 Hz to the tragus for 4 h per day over 3 months, and they also used 1 Hz to the tragus as an active control. Interestingly, the 1 Hz stimulation elicited a more significant reduction in the number of headache days than the 25 Hz active stimulation. This was an unexpected result and demonstrates that a more robust investigation into different stimulation parameters is crucial.

Again, the mechanism of non-invasive VNS and its effect on migraine is not well-understood. One possibility for the therapeutic effects of non-invasive vagus nerve stimulation is thought to be due to activation of the thalamus, which is responsible for information processing and regulation of cortical activity. In patients with migraine, fMRI studies have shown that there is a decrease in thalamocortical activity, and so stimulation of the vagus may help to counteract this decline (Coppola et al., 2004). Alternatively, it is possible that stimulation of the vagus nerve inhibits nociceptive trigeminal neurons, which may have a pain-inhibitory effect (Randich and Gebhart, 1992).

2.3.5. Pain 

Johnson et al. first attempted to study the effect of transcutaneous electrical stimulation of the ear on pain threshold in 1991, with a pilot study of 18 participants receiving low frequency burst stimulation at 2.3 Hz for 15 min on three different auricular sites (Johnson et al., 1991). In this study, pain threshold was noted to increase in 10 out of the 18 participants. Three participants also experienced a prolonged analgesic effect even after the stimulation device was turned off.

This pain-inhibitory effect was also noted by Multon and Schoenen (2005) in a review of clinical data collected from patients with implanted VNS devices. The pain thresholds of the patients and any effect VNS had on headaches was measured and confirmed that implanted VNS offered an analgesic effect. Following on from this review of implanted VNS devices, Laqua et al. (2014) proposed a study to investigate whether non-invasive tVNS could offer the same analgesic effect. Electrical stimulation was delivered for 30 min transcutaneously at the cavum conchae in burst stimulation mode with a changing frequency between 2 and 100 Hz. The individual pain threshold was measured using a Neurometer device that measures the sensory nerve conduction threshold. Of the 21 participants, 15 responded with an increase in pain threshold during tVNS, while six noted a decrease in pain threshold during stimulation. These results, although contradictory, agree with the findings of Johnston et al. and support the view that the analgesic effects of VNS are very much dependent on individual sensitivity alongside stimulation parameters.

Busch et al. (2013) devised a study to investigate whether tVNS has the potential to alter pain processing by examining different submodalities of the somatosensory system. A total of 48 participants were stimulated at the left concha on the inner side of the tragus with a stimulation frequency of 25 Hz. Different tests were devised to measure different pain thresholds, such as heat, mechanical, and pressure-related pain thresholds. The results showed an inhibition of mechanical, heat and pressure pain sensitivity after 1 h of continuous tVNS. Detection thresholds for thermal or mechanical inputs were not altered. These results suggest that tVNS can influence pain processing and offer an inhibitory effect on different pain modalities. Analysis of these different submodalities also suggests that tVNS has an impact on the central pain processing centers rather than just peripheral nociceptor activity.

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3. Limitations of Current Study Protocols

While the use of tVNS has been shown to elicit therapeutic benefits through various studies (Hein et al., 2012; Lehtimäki et al., 2013; Mei et al., 2014; Straube et al., 2015; Liu et al., 2018), they mostly use different primary and secondary outcome measures and so the comparability between studies is limited. While this is partly due to the application of the technique to various ailments where primary efficacy endpoints differ between studies, there are also major issues with incomplete reporting and inconsistent use of terminology when reporting the results of incomparable and, in some cases, non-reproducible experiments. The stimulation parameters, devices, electrode types and the main findings of relevant studies are summarized in Table 2.

Table 2

Summary of previous tVNS clinical trials and studies.

ReferencesCondition/StudyParticipantstVNS deviceElectrode typeStimulation SideStimulationSiteSham controlPulse width (ms)Intensity (mA)Freq (Hz)Duty cycle/TimeBrain activation

Keute et al. (2019)

Visual bistable perception

34

Digitimer DS7

Ag/AgCl

L

Cymba Concha

Sham stimulation 25 Hz on ear lobe

0.2 ms

3 mA

25 Hz

30 s on, 30 s off for 40 min

Inferred—tVNS has null effect on dynamics of visual bistable perception; perhaps there is a slight effect of GABA transmission in motor but not in the visual cortex

Zhao et al. (2019)

Post-stroke insomnia

1

NS

NS

L, R

Concha

NS

<1 ms

4-6 mA

20 Hz

30 min twice a day for 4 weeks

Measured—Bold fMRI showed a decrease in functional connectivity between posterior cingulate cortex and other nodes of default mode network but a decrease in functional connectivity between posterior cingulate cortex, lingual gyrus, and cortex surrounding calcarine fissure due to tVNS

Badran et al. (2018b)

Improving oromotor function in newborns

5

Digitimer DS7AH

Custom ear electrode

L

Tragus

NS

0.5 ms

0.1 mA below perception threshold

25 Hz

Max 2 min or less per dose, paired with newborn feeding, stops when newborn stops sucking, up to 30 min a day over 10–22 days

NS

Badran et al. (2018a)

Neuro-physiologic effects of tVNS

17

Digitimer DS7

Ag/AgCl

L

Tragus

Sham stimulation 25 Hz on ear lobe

0.5 ms

200 % of perception threshold

25 Hz

3 × 60 s over 6 min

Measured—Bold fMRI showed active stimulation produced significantly greater increases in the right caudate, bilateral anterior cingulate, cerebellum, left prefrontal cortex, and mid-cingulate than in sham stimulation

Colzato et al. (2018)

Divergent thinking

80

NEMOS, Cerbomed

Titanium*

L

Concha

Sham stimulation 25 Hz on ear lobe

0.2–0.3 ms

0.5 mA

25 Hz

30 s on, 30 s off for 40 min

Inferred—tVNS enhances creativity in selective ways, increased divergent thinking which may be attributed to possible increase in GABA concentration

Fischer et al. (2018)

Conflict-triggered adjustment of cognitive control

21

CM02, Cerbomed

Two titan electrodes

L

Cymba Concha

Sham stimulation 25Hz on ear lobe

0.2–0.3 ms

Below pain threshold (average 1.3 mA)

25 Hz

Continuously for 36 min

Measured—EEG showed tVNS increasing behavioral and electrophysiological markers of conflict adaptation

Jongkees et al. (2018)

Response selection during sequential action

40

CM02, Cerbomed

Two titan electrodes

L

Tragus

Sham stimulation 25 Hz on ear lobe

0.2–0.3 ms

0.5 mA

25 Hz

30 s on, 30 s off for 45 min

Inferred—tVNS improves response selection, possibly due to tVNS increasing GABA concentration, which facilitates action control

Keute et al. (2018)

GABAergic modulation

16

Digitimer DS7

Ambu Neuroline

L

Concha

Sham stimulation 25 Hz on ear lobe

0.2 ms

8 mA (or below pain threshold if not tolerable)

25 Hz

30 s on, 30 s off for 25 min

Measured—EEG demonstrated direct GABAergic effects of tVNS, shows direct effect on electrophysiology after single session of tVNS and suggests non-linear relationship between tVNS and GABA transmission

Liu et al. (2018)

Epilepsy

17

TENS-sm device, Suzhou Medical Audio Supplies

Ear clip

L, R

Cymba Concha and outer ear canal

NS

200 s†

4 mA (increased by 2 mA each week until patient could not tolerate or seizures were completely controlled)

10 Hz

3 × 20 min daily for 6 months

Measured—tVNS reduced the number of epileptic seizures and reduced abnormal wave changes shown on electroencephalogram (EEG) monitoring. The EEG changes followed the reduction in the frequency of seizures

Yakunina et al. (2018)

Tinnitus

36

Custom-made

NS

L

Inner tragus and cymba concha

Sham stimulation 25 Hz on ear lobe

0.5 ms

0.1 mA lower than pain threshold

25 Hz

30 s on, 30 s off for 6 × 5 min runs

Measured—fMRI showed tVNS via both the tragus and concha successfully suppressed the auditory, limbic, and other brain areas implicated in the mechanisms involved in the generation/perception of tinnitus via auditory and vagal ascending pathways

Assenza et al. (2017)

Epilepsy

1

NEMOS, Cerbomed

Titanium*

L

External acoustic meatus

Sham stimulation on right ear lobe

NS

Sensitive threshold

NS

4 h

Inferred: tVNS engages same neural fibers as in invasive VNS

Fang et al. (2017)

Depression

38

Suzhou Medical Appliance Factory

Custom ear clip electrodes

Concha

Sham stimulation 20 Hz delivered to superior scapha

0.2 ms

Tolerance threshold (typically between 4 and 6 mA)

20 Hz

Continuously for 30 min twice a day, 5 days a week for 4 weeks

Measured—fMRI shows that tVNS targets left anterior insula, and activation of this region predicts the outcome of treatment for depression

Yu et al. (2017)

Disorders of consciousness

1

NS

NS

L, R

Concha

NS

<1 ms

4–6 mA

20 Hz

30 min twice a day for 4 weeks

Measured—fMRI shows that tVNS activated posterior cingulate/precuneus and thalamus and increased the functional connectivity between posterior cingulate/precuneus and hypothalamus, thalamus, ventral medial prefrontal cortex (vmPFC), superior temporal gyrus, yet decreased the functional connectivity between posterior cingulate/precuneus and the cerebellum

Bauer et al. (2016)

Epilepsy

76

NEMOS, Cerbomed

Titanium*

L

Cymba Concha

Active control 1 Hz stimulation

0.25 ms

Tingling without pain

25 or 1 Hz

30 s on 30 s off for 4 h

NS

Burger et al. (2016)

Fear extinction in health volunteers

38

NEMOS, Cerbomed

Titanium*

L

Cymba Concha

Sham stimulation 25 Hz on ear lobe

NS

0.5 mA

25 Hz

30 s on 30 s off

Inferred—tVNS improved extinction learning, increases in norepinephrine in the prefrontal cortex and limbic areas, such as the amygdala and hippocampus could be a possible working mechanism for the memory enhancing effects of VNS

Cha et al. (2016)

Sudden-onset vertigo

1

ES-420, Ito Company Ltd

Ball electrode

R

Cymba concha, cavum concha, and outer surface of tragus

NS

0.2 ms

Discomfort threshold

30 Hz

4 min each site

Inferred—tVNS may normalize autonomic imbalance due to increased sympathetic response causing vertigo

Frokaer et al. (2016)

Pain threshold

18

NEMOS, Cerbomed

Titanium*

L

Concha

Sham stimulation 30 Hz on ear lobe

0.25 ms

Tingling without pain

30 Hz

60 min

NS

Gaul et al. (2016)

Chronic cluster headache

45

NS

Stainless steel

R

Neck

NS

NS

60 mA

25 Hz

1 ms on, 40 ms off for three doses of 2 min of stimulation twice a day

NS

Grazzi et al. (2016)

Menstrual related migraine

51

gammaCore electroCore LLC

Stainless Steel

L, R

Neck

NS

0.2 ms

Up to 60 mA

25 Hz

Burst (1 ms on, 50 ms off) for 2 min three times a day

NS

Lerman et al. (2016)

Peripheral immune system modulation in healthy humans

20

gammaCore electroCore LLC

Stainless steel

L, R

Neck

Active control 1 Hz stimulation

0.2 ms

Tingling without pain

25 Hz

Burst (1 ms on, 40 ms off) for 2 min

NS

Rong et al. (2016)

Major depressive disorder

160

NS

Ear clips

NS

Concha

Sham stimulation 20 Hz at superior scapha

0.2 ms

Tolerance threshold (typically between 4 and 6 mA)

20 Hz

Continuously for 30 min twice a day

NS

Silberstein et al. (2016a)

Migraine

59

gammaCore electroCore LLC

Stainless steel

R

Neck

Sham device that did not deliver electrical stimulation

NS

Set by the user (up to 60 mA)

NS

2 × 2 min doses delivered 5–10 min apart three times a day

NS

Silberstein et al. (2016b)

Cluster headache

150

gammaCore electroCore LLC

Stainless steel

R

Neck

Sham device delivering 0.1 Hz biphasic pulse

0.2 ms

Set by the user (up to 60 mA)

25 Hz

Burst (1ms on, 40 ms off) for three consecutive 2 min stimulations 1 min apart

Inferred—stimulation of vagus nerve affects hypocretin and orexin pathway that affects pathophysiology of cluster headaches

Trevizol et al. (2016)

Depression

12

Ibramed Neurodyn II

Rubber electrodes

L, R

Mastoid process

NS

0.25 ms

12 mA

120 Hz

30 min a day 10 times over 2 weeks

NS

Fang et al. (2016)

Major depressive disorder

34

NS

Ear clip

L

Concha

Sham stimulation 20 Hz at superior scapha

<1 ms

Tolerance threshold (4–6 mA)

20 Hz

2 × 30 min daily, 5 days a week for 4 weeks

Measured—fMRI showed that after tVNS default mode network functional connectivity showed significant changes in brain regions involved in emotional modulation which is associated with depression severity

Frangos et al. (2015)

Bold fMRI effects of tVNS

12

NEMOS, Cerbomed

Titanium

L

Cymba Concha

Sham stimulation 25 Hz on ear lobe

0.25 ms

Tingling but not painful (0.3–0.8 mA)

25 HZ

Continuously for 14 min

Measured—fMRI shows tVNS significantly affects central projections of the vagus nerve.

Hyvärinen et al. (2015)

Tinnitus

15

Tinnoff Inc

Clip electrode

L

Tragus

Sham stimulation 25 Hz on ear lobe

0.5 ms

Above sensory threshold (~0.5 mA)

25 Hz

Continuously for 6 min

Measured—MEG showed tVNS modulates synchrony of tone-evoked brain activity, especially at the beta and gamma bands

Nesbitt et al. (2015)

Cluster headache

19

gammaCore electroCore LLC

Stainless steel*

L, R

Neck

NS

1 ms

Self-controlled

25 Hz

2 min per dose, up to three doses twice daily

NS

Sellaro et al. (2015b)

Post-error slowing

40

CM02, Cerbomed

Two titan electrodes

L

Outer auditory canal

Sham stimulation 25 Hz on ear lobe

0.2–0.3 ms

0.5 mA

25 Hz

30 s on and 30 s off for 75 min

NS

Sellaro et al. (2015a)

Pro-social behavior

24

CM02, Cerbomed

Two titan electrodes

L

Outer auditory canal

Sham stimulation 25 Hz on ear lobe

0.2–0.3 ms

0.5 mA

25 Hz

30 s on and 30 s off for 26 min

Inferred—tVNS expected to enhance prosocial helping behavior due to activation in the insula and prefrontal cortex but this was not observed

Altavilla et al. (2015)

Migraine

20

gammaCore electroCore LLC

Stainless steel*

NS

Neck

NS

NS

NS

NS

Continuously for 90 s

NS

Barbanti et al. (2015)

Chronic Migraine

50

gammaCore electroCore LLC

Stainless steel*

R

Neck

NS

NS

NS

NS

2 × 120 s doses 3 min apart per migraine

NS

Hasan et al. (2015)

Schizophrenia

20

CM02, Cerbomed

Two titan electrodes

L

Outer auditory canal

No electrical stimulation delivered

0.25 ms

Above perception threshold

25 Hz

30 s on, 180 s off for up to 3 ×3 h a day

NS

Jacobs et al. (2015)

Associative memory in older individuals

30

TENSTem dental, Schwa-medico BV

Circular ear clip

L

External acoustic meatus on inner side of tragus

No electrical stimulation delivered

0.2 ms

5 mA

8 Hz

Twice a day

Inferred—tVNS enhances memory performance by increasing locus coeruleus activity and noradrenalin levels to memory-relevant brain areas.

Kinfe et al. (2015a)

Cluster-Tic syndrome

1

gammaCore electroCore LLC

Stainless steel*

R

Neck

NS

1 ms

12–14 V

25 Hz

Burst for 2 × 90 s doses 15 min apart

NS

Kinfe et al. (2015b)

Migraine and sleep disturbance

20

gammaCore electroCore LLC

Stainless steel*

L, R

Neck

NS

1 ms

0–24 V

25 Hz

Burst for 2 × 2 min twice a day

Inferred—in patients with migraine, and tVNS may help to counteract the decline in thalamocortical activity

Stavrakis et al. (2015)

Atrial fibrillation

40

Grass S88, Natus Neurology Inc

Flat metal clip

R

Tragus

No electrical stimulation delivered

1 ms

Discomfort threshold

20 Hz

Continuously for 60 min following induction of atrial fibrillation

NS

Steenbergen et al. (2015)

Efficiency of action cascading processes in healthy humans

30

CM02, Cerbomed

Two titan electrodes

L

Outer auditory canal

Sham stimulation 25 Hz on ear lobe

0.2–0.3 ms

0.5 mA

25 Hz

30 s on, 30 s off for 45 min

Inferred—tVNS modulates efficiency of action cascading processes, likely via GABA and NE release

Straube et al. (2015)

Migraine

46

NEMOS, Cerbomed

Titanium*

L

Concha

Active control 1 Hz sham stimulation

0.25 ms

Tingling but not painful

1 or 25 Hz

30 s on, 30 s off for 4 h a day for 12 weeks

Inferred—headache decreased more significantly in 1 Hz active control group, possibly due to suppression of nociceptive signaling and pain perception in spinal trigeminal nucleus.tVNS may also alter cortical excitability

Weise et al. (2015)

Parkinson's disease

50

NS

Custom made fine silver wires

L, R

Tragus

NS

0.1 ms

8 mA

0.5 Hz

NS

Measured—scalp electrodes measured activation of brainstem after tVNS and observed somatosensory evoked potentials in the nerve which is believed to reflect neuronal activity

Mei et al. (2014)

Tinnitus

32

TENS-200, Suzhou Medical Supplies Co Ltd

NS

NS

Cavum Concha

NS

1 ms

1 mA

20 Hz

2 × 20 min daily for 8 weeks

NS

Aihua et al. (2014)

Epilepsy

60

TENS-200

NS

L, R

Outer auditory canal and conchal cavity

Sham stimulation 20 Hz on ear lobe

0.2 ms

Individual specific

20 Hz

Continuously for 20 min three times a day

NS

Capone et al. (2015)

Cortical excitability in healthy volunteers

10

Twister, EBM

Ag/AgCl

L

External acoustic meatus at inner side of tragus

Sham stimulation 20 Hz on ear lobe

0.3 ms

8 mA

20 Hz

30 s on, 270 s off for 1 h

Measured—measurement of motor evoked potentials showed a GABA modulation in the motor cortex contralateral to the tVNS stimulation side

Clancy et al. (2014)

Sympathetic nerve activity in healthy humans

48

V-TENS PLUS, Body Clock Health Care Ltd

Modified surface electrodes

NS

Tragus

Disconnected electrodes for sham

0.2 ms

Sensory threshold (10–50 mA)

30 Hz

Continuously for 15 min

NS

Goadsby et al. (2014)

Acute Migraine

30

gammaCore electroCore LLC

Stainless steel*

R

Neck

NS

NS

NS

NS

2 × 90 s doses 15 min apart after migraine onset

NS

Grazzi et al. (2014)

Migraine

30

gammaCore electroCore LLC

Stainless steel*

R

Neck

NS

NS

NS

NS

90 s

NS

Huang et al. (2014)

Impaired glucose tolerance

72

Huatuo TENS-200, Suzhou

NS

NS

Concha

Sham stimulation 20 Hz applied at superior scapha

=1 ms

1.0 (adjusted based on tolerance)

20 Hz

20 min twice daily for 12 weeks

NS

Kreuzer et al. (2014)

Tinnitus

50

Phase I: CM02, Cerbomed Phase II: NEMOS, Cerbomed

Two titan electrodes

NS

NS

NS

NS

0.1–10 mA

25 Hz

Phase I: 30 s on, 180 s off for 6 h per day Phase II: 30 s on, 30 s off for 4 h per day

NS

Laqua et al. (2014)

Pain threshold in healthy humans

22

TNS SM 2 MF, Schwamedico GmbH

Anode: Silver disc Cathode: PECG electrode

L, R

Cavum Concha and Mastoid area

No electrical stimulation delivered

0.2 ms

Perception threshold

2 and 100 Hz

Burst 30 min

Inferred—tVNS produces both anti- and pro-nociceptive effects

Busch et al. (2013)

Pain perception in healthy volunteers

48

STV02, Cerbomed

Bipolar electrode

L

Concha at inner side of tragus

No electrical stimulation delivered

0.25 ms

0.25–10 mA

25 Hz

Continuously for 1 h

Inferred—detailed analysis of different sub modalities of the somatosensory system suggest an impact of t-VNS on central pain processing rather than on peripheral nociceptor activity

He et al. (2013)

Pediatric epilepsy

14

TENS-200

Conductive rubber

L, R

Concha

NS

NS

0.4–1.0 mA depending on tolerance

20 Hz

3 × 30 min a day

Inferred—afferent projections from the ABVN to the nucleus tractus solitarius rather than to the spinal trigeminal nucleus may explain anti-seizure effect

Lehtimäki et al. (2013)

Tinnitus

10

Tinoff pulse generator

Clip electrode

L

Tragus

No electrical stimulation delivered

NS

Above sensory threshold (usually around 0.8 mA)

25 Hz

7 × 45/60 min sessions delivered over 10 days

Measured—MEG shows tVNS can modulate auditory cortical activation

Kraus et al. (2013)

Effects of sham-controlled transcutaneous electrical stimulation

16

Digitimer DS7A

Silver

L

Group I: Anterior wall of ear canal Group II: posterior side of ear canal

Sham stimulation 8 Hz on ear lobe

0.02 ms

Non-painful

8 Hz

4 × 30 s on, 60 s off

Measured—fMRI shows activations and deactivations of certain brain regions, especially frontal and limbic areas depending on area of stimulation, and showed more activation than in sham stimulation

Hein et al. (2012)

Depression

37

Study1: TENS-NET 2000, Auri-Stim Medical Inc Study 2: TENS-NET 1000, Auri-Stim Medical Inc

Headset (4 electrodes placed crosswise)

L, R

Outer auditory canal

No electrical stimulation delivered electrodes unplugged

NS

Study 1: Perception threshold Study 2: 130 μ A

1.5 Hz

Study 1: 1 × 15 min 5 days a week Study 2: 2 × 15 min 5 days a week

NS

Napadow et al. (2012)

Chronic pelvic pain

15

Cefar Acus II, Cefar Medical

Modified press-tack electrode

L

Cymba Concha and slope between antihelix and cavum concha

Sham stimulation 30 Hz on ear lobe

0.45 ms

Strong, non-painful

30 Hz

0.5 s on, matched to respiration for 30 min

NS

Stefan et al. (2012)

Epilepsy

10

NS

NS

L

Tragus

NS

0.3 ms

Tolerance threshold

10 Hz

3 × 1 h a day over 9 months

NS

Schulz-Stübner and Kehl (2011)

Hiccups

1

NMS 300, Xavant Technology

NS

L

Neck

NS

NS

6 mA

1 Hz

30 s

Inferred—Unclear whether hiccups were stopped due to interference with reflex arches at different neuronal levels

Dietrich et al. (2008)

Bold fMRI

4

Cerbomed

Silver

L

Tragus

NS

0.25 ms

4–8 mA

25 Hz

50 s on, 100 s off for 700 s

Measured—Bold fMRI showed tVNS elicited a robust activation in the left locus coeruleus, a brainstem nucleus related to clinical depression as well as bilateral activation of the thalamus

Kraus et al. (2007)

Bold fMRI

22

EMP2 Expert, Schwa-medico GmbH

Silver

L

Tragus

Sham stimulation 8 Hz on ear lobe

0.02 ms

Perception threshold

8 Hz

30 s on, 120 s off three times over 2 days

Measured—fMRI shows tVNS leads to prominent changes in cerebral activation patterns, with marked deactivation in limbic and temporal brain areas

Fallgatter et al. (2003)

Vagus sensory evoked potentials

6

NS

Bipolar electrode

NS

Tragus and acoustic meatus

NS

0.1 ms

8 mA

NS

2 s interstimulus interval

Measured—Evoked potential recordings are far field potentials of post-synaptic brainstem activity from vagus nerve nuclei that can be elicited on electrical stimulation

Johnson et al. (1991)

Pain threshold and autonomic function

24

Microtens 7757

Ag/AgCl and rubber

R

Concha

No electrical stimulation delivered

0.5 ms

Discomfort threshold

2.3 Hz

Burst for 15 min

NS

Open in a separate window

NS, not stated. An asterisk indicates that an electrode type was not stated in the study but was assumed by us from the type of the device. A dagger indicates parameters as stated in the original paper but that are outside the normal range (possible typing error).

3.1. Stimulation Devices

Research groups generally report the stimulation device used in the experiment, but many of the models used have now been discontinued, and access to their technical specifications is limited. The most commonly used devices are the gammaCore electroCore or Nemos Cerbomed (Figure 4), with a third of the studies included in Table 2 employing them for stimulation (e.g., Grazzi et al., 2014, 2016; Frangos et al., 2015; Straube et al., 2015; Frokaer et al., 2016; Lerman et al., 2016; Silberstein et al., 2016a,b). Almost always, the gammaCore electroCore device is used for stimulation at a neck site (e.g., Goadsby et al., 2014; Grazzi et al., 2014, 2016; Lerman et al., 2016; Silberstein et al., 2016a,b) whilst the NEMOS Cerbomed device is predominantly used for stimulation of the ABVN in the ear. The next most common stimulation device is CM02 Cerbomed, used in Sellaro et al. (2015a,b), Hasan et al. (2015), and Steenbergen et al. (2015) among others. The gammaCore or NEMOS devices are often selected for convenience as they provide an easy-to-use package that includes stimulation electrodes. On the other hand, devices, such as TENS-200 or Digitimer DS7A often require custom-made electrodes. The NMS 300 device from Xavant Technology has also been used (Schulz-Stübner and Kehl, 2011), while the device has not been specified in two studies (Gaul et al., 2016).

Figure 4

(A) Cerbomed NEMOS. Adapted from www.cerbomed.com. (B). Electrocore gammaCore. Adapted from www.gammacore.com.

3.1.1. ElectroCore Gammacore 

The gammaCore, marketed by electroCore, is a handheld tVNS device that stimulates the vagus nerve within the cervical carotid sheath. The device has been granted investigational FDA approval for the acute and/or prophylactic treatment of primary headache and medication overuse headache in adults. Conductive gel is applied to the stimulation surfaces, which are then placed over the sternocleidomastoid muscle. Stimulation intensity is user-controlled (up to 24 V and 60 mA), with individual treatment sessions lasting for 120 s. The treatment can be safely administered multiple times per day; having been applied up to 6–12 times per day in clinical studies (Yuan and Silberstein, 2016b). The remaining stimulation parameters are fixed, delivering 1 ms pulses of 5 kHz sine waves at 25 Hz. It delivers a proprietary pulse waveform that is designed to penetrate through various levels of tissue, including skin, muscle, and nerve sheaths, in order to stimulate the afferent vagus nerve fibers within the carotid sheath. Potential side effects can include tingling under the stimulation electrodes and mild facial twitching at high intensities. It is a limited-use device that is available in two models: 50 doses and 150 doses. Optimal device usage, in terms of the number of stimulations per day and/or total stimulation duration, is yet to be determined.

3.1.2. Cerbomed NEMOS 

The NEMOS device (distributed by tVNS Technologies, previously Cerbomed) is a portable transcutaneous electrical nerve stimulator that delivers stimulus to ABVN distributions located in the left cymba concha. NEMOS has been granted the CE mark for the treatment of resistant epilepsy. It is comprised of two main components: the stimulation unit, which houses the battery and pulse generator (and is roughly the size of a mobile phone), and a dedicated ear electrode, which is connected to the stimulator via a cable. Stimulation intensity is user-controlled (up to 25 V), with treatments lasting at least 1 h in three to four sessions per day for a total of 4–5 h. The stimulation current is adjusted until a slight tingling or pulsating sensation is perceived at the stimulation site, implying Aβ fiber activation. Prior to stimulation, the user must clean the site of stimulation, as well as the electrodes, to minimize impedance and ensure optimal conductivity. The remaining stimulation parameters are fixed, delivering continuous 0.25-ms-duration monophasic square wave pulses at 25 Hz. Adverse effects may include a slight pain, burning, tingling or itching feeling under the electrode, which dissipates upon electrode removal.

3.1.3. Other 

In addition to NEMOS and gammaCore, which are both manufactured specifically for tVNS, stimulation can also be performed by transcutaneous electrical nerve stimulator (TENS) devices, such as TENS-200, V-TENS PLUS, or TENS-NET 2000. Auri-Stim Medical have taken conventional TENS machines, which are typically used in pain management, and repurposed them for stimulating the ear by integrating the electrodes into a headset that can be worn by the user. These devices are portable battery powered control units that can administer tVNS in much the same way as the custom-built units, provided that the electrodes are placed in the correct location in the concha.

The TENS-NET 2000 was approved by the FDA in 2006 and labeled as a nerve stimulator for therapeutic use in depression, anxiety and depression (Hein et al., 2012). User-programmable stimulation parameters include frequency (0.5–100 Hz), intensity (0–6 mA), and mode of stimulation (normal, burst or modulated). However, the polarity of the pulses cannot be varied and are typically monophasic rectangular waves. The stimulation can also be delivered in combination with music or different sounds to enhance the therapeutic effects.

For trials in a clinical or research-based setting, mains-powered medical stimulators, such as Digitimer DS7A or DS5 can be used. These allow complete personalization of stimulation parameters but sacrifice portability. These stimulators are isolated from the mains and can be connected to a computer via BNC cable to allow custom stimulation protocols to be delivered. The Digitimer DS7 is a general-purpose nerve or muscle stimulator for human stimulation and can output up to 100 mA. The frequency and pulse widths of the waves, as well as the duty cycle, are typically programmed on a computer and delivered to the stimulator via BNC cable. There is also the option of alternating the polarity of the pulses, which allows both monophasic and biphasic stimulation pulses to be output.

3.2. Electrode Types

Several studies report using gammaCore or NEMOS devices but do not specify stimulation electrode types (e.g., Goadsby et al., 2014; Grazzi et al., 2014; Huang et al., 2014; Altavilla et al., 2015; Barbanti et al., 2015; Nesbitt et al., 2015; Straube et al., 2015). In these cases, we assume that stimulation electrodes provided with the device were not modified for the study, and we report manufacture specifications for the gammaCore/NEMOS electrodes in Table 2 (noted with an asterisk).

When reported, the most commonly used stimulation electrodes are made of titanium (for the ear) (Hasan et al., 2015; Sellaro et al., 2015a,b; Fischer et al., 2018; Jongkees et al., 2018) or stainless silver (for the neck) (Kinfe et al., 2015b; Gaul et al., 2016; Grazzi et al., 2016; Lerman et al., 2016; Silberstein et al., 2016a,b). Silver is also used as an electrode material for stimulation of ABVN (e.g., Laqua et al., 2014; Capone et al., 2015; Weise et al., 2015; Badran et al., 2018a; Keute et al., 2019). Information about stimulation electrodes is often somewhat insufficient: the material or size of the electrodes are often not specified (Stefan et al., 2012; Hyvärinen et al., 2015; Weise et al., 2015; Fang et al., 2016; Yakunina et al., 2018). This limits our collective understanding of the electrode-tissue interface and its interactions. However, the fact that the patient-specific pain threshold is often set as the stimulation current provides some control for variations in the electrode-tissue impedance.

3.3. Stimulation Site

Out of 61 studies included in Table 2, 13 use the neck as a stimulation location (Figure 5A) (see Gaul et al., 2016; Grazzi et al., 2016; Lerman et al., 2016; Silberstein et al., 2016a,b among others). Discrepancies exist between reported stimulation locations within the studies that stimulate ABVN (Figures 5B–F). This is true even when the same device is used; for example, Straube et al. (2015) and Frangos et al. (2015) both use the NEMOS device, yet report the concha and cymba concha as the location of stimulation, respectively. The stimulation location is often dictated by the geometry of an electrode, with clip electrodes typically attached to tragus or concha (Figures 5C,D) (Lehtimäki et al., 2013; Mei et al., 2014; Straube et al., 2015; Fang et al., 2016; Rong et al., 2016; Liu et al., 2018). Often the outer audio canal is reported as a site for stimulation, without further clarification for the location of an electrode (Hasan et al., 2015; Sellaro et al., 2015a,b; Steenbergen et al., 2015). Given that studies have been done in different participant groups with different clinical conditions and with different stimulation parameters, it is difficult to conclude an optimal stimulation site for any particular disorder.

Figure 5

Stimulation electrode positions. (A) Neck stimulation using a gammaCore device (Silberstein et al., 2016b). Image courtesy of electroCore Inc, electrocore.com. (B) Earlobe sham and cymba concha stimulation using NEMOS electrodes (Frangos et al., 2015). (C) External ear canal and concha stimulation using a TENS device from Suzhou (Liu et al., 2018). (D) Tragus stimulation (Lehtimäki et al., 2013). (E) External ear canal stimulation using a headset NET-1000 (Hein et al., 2012). Image courtesy of Auri-Stim Medical Inc, net1device.com. (F) Concha and cymba concha active stimulation (Rong et al., 2016). All figures reproduced with permission.

Initial investigations in this direction have been undertaken in Napadow et al. (2012) and Kraus et al. (2013). Napadow et al. concluded that the concha is the best site for stimulation, while Kraus et al. proposed that the anterior wall of the ear canal is the best for efficacy and participant's convenience. Studies, such as these are progressing in the right direction, but a more systematic approach is required to investigate the effect of the electrode placement on the ABVN recruitment and corresponding neural activations.

Although research groups acknowledge that the ABVN innervates the tragus, concha, and cymba concha as per Peuker and Filler's anatomical studies (Peuker and Filler, 2002), most do not mention antihelix innervation. Selection of the stimulation site appears to be arbitrary, either predetermined by the device employed in the experiment or based on other previous studies without providing any evidence or explanation for the designated stimulation site.

3.4. Stimulation Waveform

Most studies employ monophasic rectangular waveforms often set by the specifications of the device used (Hein et al., 2012; Busch et al., 2013; Stavrakis et al., 2015; Badran et al., 2018a; Yakunina et al., 2018), while some others report using biphasic waveform stimulation (Stefan et al., 2012; Hyvärinen et al., 2015; Liu et al., 2018). Lerman et al. (2016) and Silberstein et al. (2016b) reported using sinusoidal wave bursts; however, it is not clear from these studies whether this waveform is more optimal to activate neural fibers. The use of devices that employ “proprietary” or “modified” waveforms, such as electroCore's gammaCore, further hinders insights into the effect of stimulation waveforms on key research outcomes.

3.5. Stimulation Intensity

The justifications mentioned above are also employed to motivate the choice of stimulation parameters. Some studies have credited (Kraus et al., 2007; Polak et al., 2009) as having defined the optimal stimulation parameters for tVNS. However, further investigation suggests that these studies only elucidate the optimal stimulus intensity to induce the greatest vagus sensory evoked potential (VSEP) amplitudes (Polak et al., 2009), and that tVNS causes hypo- and hyperactivations of brain regions of interest relating to a decrease in depressive symptoms (Kraus et al., 2007). As Polak et al. (2009) have stated, “we chose a stimulation intensity of 8 mA allowing detection of sufficient VSEP amplitudes without perception of pain,” which reveals nothing about the effects observed post-synaptically in various structures of the brain.

They also acknowledge that VSEP amplitudes are directly correlated to stimulation intensity (i.e., stimulation intensities >8 mA would elicit even greater VSEP amplitudes). Similarly, the studies of Kraus et al. (2007) showed no systematic effects of stimulation parameters on brain activation, although they did illustrate that tVNS does indeed elicit acute changes in brain regions that are related to a decrease in depressive symptoms similar to those caused by VNS. Therefore, neither of these studies can claim to have identified the optimal stimulation parameters of tVNS for the greatest decrease in depressive symptoms or seizure occurrence.

Furthermore, despite electrical current values being reported, the amount, or amplitude, of energy delivered to tissues is largely unknown given the substantial effect of electrode and tissue impedance and need for precise placement (e.g., a stated current of 8 mA presupposes that there is no impact of tissue impedance variation, and therefore voltage, and also neglects waveform shape, rise/fall-time, or any resultant residual charge). The stimulation current is often set according to the subject's sensitivity or just below pain threshold (Napadow et al., 2012; Frangos et al., 2015; Cha et al., 2016; Lerman et al., 2016; Fischer et al., 2018; Yakunina et al., 2018). Given the different stimulation tolerance of different participants, stimulation amplitudes vary over a wide range (from 0.5 mA in Jongkees et al., 2018 to 12 mA in Trevizol et al., 2016). Undoubtedly, the stimulation electrode electrochemistry also contributes to the maximum current that is tolerated by a participant.

3.6. Stimulation Frequency

With regard to stimulation frequency, the currently used range of 20–30 Hz has never been validated for its therapeutic effects (Laqua et al., 2014). Following studies showing that stimulation frequencies of 50 Hz and above can cause major and irreversible damage to the vagus nerve during VNS (Agnew and McCreery, 1990), stimulation frequencies between 20 and 30 Hz were arbitrarily selected in order to limit adverse events associated with direct stimulation of the carotid sheath and were subsequently approved by the FDA (Groves and Brown, 2005). Lower frequencies of stimulation have also been explored. Liu et al. (2018) have found that 10 Hz tVNS for 20 min periods three times per day for 6 months reduced the number of seizures, while 8 Hz stimulation leads to activation in frontal and limbic brain areas as measured by fMRI (Kraus et al., 2007). Straube et al. (2015) have seen a stronger reduction in migraine episodes when stimulating at 1 Hz than when stimulating at 25 Hz. Thus, it should not be assumed that stimulation frequencies within the 20–30 Hz range are optimal for tVNS, and additional controlled studies are warranted to elucidate the effect of stimulation frequency rather than a selection based on past FDA approval of a related, yet different, technique.

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4. Brain Activation

Several studies have speculated about the brain areas that are activated as a result of tVNS (Schulz-Stübner and Kehl, 2011; Busch et al., 2013; Laqua et al., 2014; Colzato et al., 2018; Jongkees et al., 2018). For example, Burger and Verkuil (2018) proposed that tVNS leads to activation in limbic areas, such as the amygdala and hippocampus, whereas Cha et al. (2016) suggested that it normalizes autonomic imbalance due to an increase in sympathetic response in patients with vertigo. In contrast, Silberstein et al. (2016b) proposed that stimulation of the vagus nerve affects hypocretin and orexin pathways in people with cluster headache, while Kinfe et al. (2015b) hypothesized that tVNS may help counteract the decline in thalamocortical activity in people with migraine and sleep disturbances. Jacobs et al. (2015) suggested that tVNS enhances memory performance by increasing neural activity in the locus coeruleus. It is clear that researchers have proposed different effects of tVNS on neural activation depending on the focus of their study. Measuring neural activity using techniques, such as fMRI, EEG, or MEG is critically important to confirm‎ proposed hypotheses.

Brain activation in response to tVNS has been measured in Kraus et al. (2007), Kraus et al. (2013), Dietrich et al. (2008), Lehtimäki et al. (2013), Capone et al. (2015), Frangos et al. (2015), Hyvärinen et al. (2015), Weise et al. (2015), Fang et al. (2016), Yuan and Silberstein (2016b), Yu et al. (2017), Badran et al. (2018a), Fischer et al. (2018), Liu et al. (2018), Yakunina et al. (2018), Keute et al. (2019), Zhao et al. (2019), and Fallgatter et al. (2003). Most of these studies have been conducted in the last 5 years, with the exception of three that pioneered this field in the 2000s (Fallgatter et al., 2003; Kraus et al., 2007; Dietrich et al., 2008). Dietrich et al. (2008) showed that tVNS elicits activation in the left locus coeruleus, a brainstem nucleus that is implicated in clinical depression, as well as bilateral activation in the thalamus. Fallgatter et al. (2003) measured evoked potentials of post-synaptic brainstem activity from vagus nerve nuclei that can be elicited by electrical stimulation. Using fMRI, Kraus et al. (2007) demonstrated that tVNS leads to prominent changes in cerebral activation with marked deactivation in limbic and temporal brain areas.

Later fMRI studies have shown that active tVNS (i) produces a significantly larger increase in neural activity in the right caudate, bilateral anterior, left prefrontal cortex, cerebellum, and mid-cingulate than sham stimulation (Badran et al., 2018a); (ii) leads to a decrease in functional connectivity between posterior cingulate cortex and lingual gyrus (Zhao et al., 2019); and (iii) suppresses the auditory, limbic, and other brain areas implicated in the mechanisms involved in the generation of tinnitus (Yakunina et al., 2018).

EEG studies have shown a direct effect of tVNS on electrophysiological markers of conflict adaptation (Fischer et al., 2018) and on the number of seizures (Liu et al., 2018). MEG recordings have shown that tVNS modulates synchrony of tone-evoked brain activity, especially in the beta and gamma bands (Hyvärinen et al., 2015).

It is not clear why the areas of brain activation vary between these studies, but it may be due to the different conditions presented by the participants. Due to the variation in results, different studies have proposed different underlying mechanisms for tVNS, and, as such, there can be no clear conclusions made from the different imaging studies. Despite the breadth of research being undertaken, many questions remain regarding the most effective stimulation sites and parameters. As many of the described methods differ in the parameters and protocols applied, there is currently no firm evidence on the optimal parameters to provide the greatest benefit to subjects.

4.1. Side Effects

Although tVNS is on the whole well-tolerated as a treatment option, a number of different mild side effects have been noted, which Redgrave et al. (2018) summarized in their review. Common side effects include tingling or pain around the stimulation site, with some participants reporting itching or redness (Busch et al., 2013; He et al., 2013; Goadsby et al., 2014; Kreuzer et al., 2014; Rong et al., 2014; Barbanti et al., 2015; Hasan et al., 2015; Jacobs et al., 2015; Kinfe et al., 2015b; Stavrakis et al., 2015; Straube et al., 2015; Weise et al., 2015; Bauer et al., 2016; Cha et al., 2016; Grazzi et al., 2016; Lerman et al., 2016; Silberstein et al., 2016a,b; Trevizol et al., 2016). Other less common side effects that have been observed in <1% of the study population include gastrointestinal issues, such as nausea or vomiting (Schulz-Stübner and Kehl, 2011; Kreuzer et al., 2014; Jacobs et al., 2015; Bauer et al., 2016; Silberstein et al., 2016b; Trevizol et al., 2016), headache (Stefan et al., 2012; Kreuzer et al., 2014; Jacobs et al., 2015; Bauer et al., 2016; Gaul et al., 2016; Lerman et al., 2016; Silberstein et al., 2016a; Trevizol et al., 2016), heart palpitations (Bauer et al., 2016), facial drooping (Goadsby et al., 2014; Silberstein et al., 2016b), dizziness (Aihua et al., 2014; Goadsby et al., 2014; Huang et al., 2014; Kreuzer et al., 2014; Rong et al., 2014; Jacobs et al., 2015; Bauer et al., 2016; Gaul et al., 2016), vocal hoarseness (Stefan et al., 2012; Goadsby et al., 2014; Kreuzer et al., 2014), and nasopharyingitis (Bauer et al., 2016; Gaul et al., 2016). There is currently no study that links stimulation parameters or dose to the rate of side effects experienced, which should be a priority for future research in the field, and clear reporting of both side effects and stimulation parameters is important to be able to observe any trends.

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5. Discussion and Future Directions

This review has focused on a mechanistic understanding of transcutaneous vagus nerve stimulation (tVNS), with a detailed discussion of stimulation parameters, sites of stimulation, and devices used in current research. It should be noted that there is an ongoing discussion about the translation of non-invasive neural stimulation therapies into clinical practice. Transcranial magnetic stimulation (TMS) is another type of non-invasive neural stimulation therapy that is becoming more commonly used as a treatment option for different conditions, although use of the device is limited to clinical settings where it is operated by a healthcare professional. In contrast, transcranial direct stimulation (tDCS) (Wexler, 2015), much like tVNS, is a portable treatment option that does not require operation by a professional.

On the one hand, the affordability and easy availability of these devices, and an absence of severe adverse events, has led to a “do-it-yourself” movement that uses tDCS and tVNS at home for self-improvement purposes. Researchers are still trying to understand the risks and benefits of these techniques and fear that uncontrolled use may lead to unintended consequences (Bikson et al., 2013).

The situation is further complicated by the fact that, for regulatory purposes, the definition of a medical device focuses on the intended use of a device rather than the mechanism of action. This implies that manufacturers can skirt regulation by careful wording about the intended use. However, it is clear that a thorough risk analysis requires a sound understanding of the mechanism of action. Therefore, to promote the safe and efficacious use of tVNS in future, it is important to understand the mechanism of action of this promising technique.

The actual mechanisms of tVNS are still poorly understood. Many studies contradict the findings of similar studies and there is often very little homogeneity in results, making it difficult to draw conclusions from the findings. It has been proven by a number of studies that tVNS affects the same neural pathway as invasive VNS (He et al., 2009; Van Leusden et al., 2015); however, there is no conclusive evidence to explain why tVNS elicits therapeutic effects. It is therefore important for future studies to focus on the mechanism of action by following rigorous protocols that include objective measures of brain activation. It is also important that past assumptions about the effects of tVNS on brain neural activation and function do not restrict the direction of future investigations.

Given that stimulation parameters vary significantly between studies, a systematic approach is required to identify the optimal stimulation intensity, pulse width, waveform and frequency that provides the greatest clinical benefit. This may require participant-specific adjustment of parameters in a closed-loop setup, where stimulation parameters are set online, based on recorded neural activity. All current stimulation strategies for tVNS devices rely on open-loop control of the stimulation parameters, where the levels are set at the beginning of the stimulation protocol and do not change in response to any continuous measurement of the level of neuronal activation. It is reasonable to expect different outcomes in response to open-loop electrical stimulation between participants and between trials due to different ongoing brain activities at the time of stimulation. While many studies have been successful in using open-loop techniques (Barbanti et al., 2015; Trevizol et al., 2016; Liu et al., 2018), the outcomes differ from patient to patient. A customized closed-loop controller will allow the manipulation of specific patient-based neural responses. Pioneering steps in closed-loop VNS have been reported in Boon et al. (2015) and Fisher et al. (2016).

A closed-loop protocol will require continuous measurements of behavioral outcomes or brain activity. Since behavioral measures are often imprecise, it is preferable that imaging techniques, such as EEG or MEG, be used during the stimulation protocol to study neural activation and information transfer. The EEG signal has low spatial resolution that makes it difficult to interpret brain network connectivity. In contrast, MEG imaging has higher spatial resolution than EEG and higher temporal resolution than fMRI. The reconstruction of neuronal activity sources from MEG has less sensitivity to model approximations and smaller localization errors than EEG reconstruction. The MEG is sensitive to a wide range of frequencies in the oscillatory brain signals and has full brain coverage. There exist various techniques to reconstruct the anatomical origin of brain activity from MEG signal. When a structural MRI scan is available, it is possible to coregister MEG signals to anatomical locations. These advantages of MEG offer a powerful tool to study connectivity between brain areas and analyze brain networks and function (Baillet, 2017).

Such combined neuroimaging techniques can also help to resolve the origin of vagus connections in the brain. The “vagus” in the term tVNS is based on the assumption that the auricular branch of the vagus nerve has been activated. Some researchers believe that the auricular branch of the vagus is a misplaced branch of the trigeminal nerve and carries somatic-not visceral-afferent fibers. In this respect, this nerve is just like the trigeminal nerve branches to the rest of the face. If this hypothesis is true, then the auricular nerve would not connect to the NTS in the brain but rather to the trigeminal-or possibly paratrigeminal-nuclei. The latter nucleus receives cough receptor afferents from the airways, which may be why the auricular branch (“Arnold's nerve”) can stimulate coughing (Gupta et al., 1986). However, a recent investigation of central neuronal projections from nerves innervating the external auricle in rats, appears to challenge an opinion that stimulation of the tragal nerve is conducted by the auricular branch of the vagus (Mahadi et al., 2019). Similar studies need to be done in primates to confirm‎ whether the same conclusion may apply to humans.

Many studies have very few participants, with some having as few as one. This leads to difficulties in concluding whether the results or proposed mechanisms can be generalized to a larger population. To avoid the risk of accidentally having extreme or biased results, studies with a large number of participants are required. Due to heterogeneous populations with various health conditions and different medications and treatment responses often enlisted for a study, it is impossible to generalize to another condition or to a healthy group. Rigorous studies with a large number of healthy participants, where a wide range of stimulation parameters are tested within a participant and between a cohort, are needed to draw solid, evidence-based conclusions. Such studies may also reveal biomarkers for responders and non-responders to tVNS.

There has been very little investigation into how long the effects of tVNS last after the stimulation period has ended. Most clinical trials involve daily stimulation periods over the course of the trial, with the therapeutic results measured concurrently. Studies, such as that of Hein et al. (2012), have compared therapeutic results after the 2-weeks treatment period of daily stimulation to the baseline results recorded from before the stimulation period. Other studies (Huang et al., 2014; Mei et al., 2014; Rong et al., 2016) measured the therapeutic effects of daily stimulation continuously over set intervals during the trial period. Many studies found that participants who completed the entire treatment study had a better response to tVNS than those who dropped out, and longer treatment periods corresponded with better therapeutic outcomes (He et al., 2013; Bauer et al., 2016; Silberstein et al., 2016a; Liu et al., 2018). However, these studies did not offer a follow-up to see whether the effects of tVNS were long-lasting or remained after the cessation of the treatment period. In the case study by Zhao et al. (2019) on a single participant with insomnia, after 2 weeks of twice daily tVNS the treatment was stopped, but the participant still felt an improvement at the follow-up meeting, 3 months after the trial period. Similarly, Trevizol et al. (2016) had a stimulation period of 10 days, but found the clinical response remained stable 1 month after stimulation had stopped.

Some studies into the pain-relieving effects of tVNS have investigated whether the effects last for some time after the stimulation. Johnson et al. (1991) and Napadow et al. (2012) reported that an analgesic effect was present for up to 15 min after stimulation ceased. Other studies measured the therapeutic effects immediately after stimulation (Capone et al., 2015; Stavrakis et al., 2015; Keute et al., 2019) or at the same time as stimulation (Fallgatter et al., 2003; Kraus et al., 2007, 2013; Dietrich et al., 2008; Lehtimäki et al., 2013). This may offer interesting results for the measurement of brain activity as a result of tVNS but does not indicate whether these effects are long-lasting. Indeed, Frangos et al. (2015) noted that neural activation gradually returned to the baseline after tVNS was stopped. Immediate measurement of the therapeutic effects of tVNS do not therefore suggest whether these effects are merely a temporary result of stimulation or long-lasting.

When long periods of stimulation are required to achieve the maximum effect, it is unreasonable to expect participants to attend prolonged sessions several times per day. Therefore, portable stimulators are required, but gammaCore and NEMOS are currently the only tVNS devices available. It is difficult to track participants' compliance with these devices and record how stimulation parameters change over time. More research is required to produce miniaturized devices that are convenient and safe to use.

6. Conclusion

tVNS has proven to be an effective way to modulate the central nervous system in some cases. However, the mechanism of action is not clear, and the robustness of the results is yet to be proven. The technique is safe and convenient with only a few relatively minor side effects reported. More rigorous systematic studies are required to investigate the effects of stimulation parameters, sites of stimulation, and electrode types on brain activation and clinical outcomes. Current limitations in study protocols may lead to difficulties in obtaining regulatory approval and challenges in translating research studies into clinical practice.

Author Contributions

JY and PS conceived and designed the idea. JY, CK, TK, and PS wrote the manuscript. All authors aided in interpreting the results and commented on the manuscript.

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Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Handling Editor declared a past co-authorship with one of the authors TK.

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Footnotes

Funding. PS and JY acknowledge funding support from the Australian Research Council (IC140100023) and Grey Innovation Pty Ltd.

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