Clinical perspectives on vagus nerve stimulation: present and future
迷走神经刺激的临床前景:现在和未来

The word vagus is Latin for ‘wandering’, a name this exceptional nerve fully deserves. The vagus nerve (VN), the tenth cranial nerve, is the longest of the cranial nerves and has the most complex and diverse functions. One can envision the vagus wandering throughout the body, affecting numerous processes in its tracts. The VN is involved in regulation of the autonomic, immune, cardiovascular, gastrointestinal, respiratory and endocrine systems.
迷走神经这个词在拉丁语中是“徘徊”的意思，这个特殊的神经完全配得上这个名字。迷走神经(VN)是脑神经中长度最长、功能最复杂多样的第十脑神经。我们可以想象迷走神经在全身游走，影响其束内的许多过程。VN参与调节自主神经系统、免疫系统、心血管系统、胃肠系统、呼吸系统和内分泌系统。

The VN is a mixed nerve composed of 20% efferent fibers and 80% afferent fibers and it serves as a bidirectional communicator between the brain and body [1]. Efferent functions include sending parasympathetic cholinergic signals, originating from the nucleus ambiguus and dorsal motor nucleus (DMN), to target organs including the lungs, digestive tract, and heart [2–5]. There are three afferent VN types including general somatic afferent (GSA), general visceral afferent (GVA), and special visceral afferent (SVA). These afferents transmit ascending sensory information and terminate in four vagal nuclei located within the medulla including nucleus of the solitary tract (NTS), the nucleus ambiguus, the trigeminal spinal nucleus and DMN [6].
VN是一种由20%的传出纤维和80%的传入纤维组成的混合神经，是大脑和身体之间的双向通讯器[1]。传出功能包括将副交感神经胆碱能信号从模棱两可核和背运动核(DMN)发送到目标器官，包括肺、消化道和心脏[2-5]。传入神经有一般躯体传入神经(GSA)、一般内脏传入神经(GVA)和特殊内脏传入神经(SVA)三种类型。这些传入神经传递上行感觉信息，并终止于位于髓质内的四个迷走神经核，包括孤束核(NTS)、歧义核、三叉神经脊髓核和DMN[6]。

The use of vagus nerve stimulation (VNS) can be first credited to American neurologist James Corning who attempted the technique in the 1880s for treatment of epilepsy [7]. His idea, which was based on evidence suggesting increased blood flow to the brain caused seizures, was largely abandoned for many years due to inconsistent results but resurfaced again in the 1900s [7]. While Corning focused on the indirect physiological effects of VNS, Bailey and Bremer, in the 1930s, investigated the direct effects of VNS on the central nervous system (CNS) [8]. These investigations led to the observation that VNS causes electroencephalogram (EEG) changes. Throughout the rest of the century, various animal studies utilizing VNS were conducted, but it was not until the 1990s that these transitioned into clinical studies. In 1988, the first implanted VNS device in a human was reported [9]. In 1997, the Food and Drug Administration (FDA) approved the first implantable VNS device for treating refractory epilepsy. Since this time, the FDA has approved the use of VNS for depression, migraines and cluster headaches, and in the abdomen for obesity. In this review, we focus on the current uses of VNS, potential applications and recent advancements in the field of VNS including auricular VNS (aVNS).
迷走神经刺激(VNS)的使用最早可以归功于美国神经学家James Corning，他在19世纪80年代尝试使用该技术治疗癫痫[7]。他的想法是基于有证据表明流向大脑的血流量增加会导致癫痫发作，由于结果不一致，这个想法在很大程度上被放弃了很多年，但在20世纪又重新浮出水面[7]。Corning关注的是VNS的间接生理作用，而Bailey和Bremer在20世纪30年代研究了VNS对中枢神经系统(CNS)的直接作用[8]。这些研究导致观察到VNS引起脑电图(EEG)的变化。在这个世纪剩下的时间里，利用迷走神经刺激进行了各种动物研究，但直到20世纪90年代，这些研究才过渡到临床研究。1988年，首次报道了人类植入式VNS装置[9]。1997年，美国食品和药物管理局(FDA)批准了第一个用于治疗难治性癫痫的植入式VNS设备。从那时起，FDA批准了VNS用于抑郁症、偏头痛和丛集性头痛，以及腹部肥胖。本文主要介绍了耳廓声神经系统的应用现状、潜在的应用前景以及耳廓声神经系统的研究进展。

VNS is a general term that describes any technique that stimulates the VN (Figure 1). Different indications require different approaches to target the VN, as will be discussed subsequently. Most commonly, VNS involves stimulating the left cervical VN by surgically implanting a pulse generator device. The left as opposed to the right cervical VN is targeted to minimize cardiac effects including bradycardia. Right cervical VNS has been used mainly in the context of heart failure [10,11]. In early trials, a programmable device was implanted into the right chest and connected to the right cervical VN. This device was designed to affect cardiac function by preferentially activating vagal efferent fibers. The subdiaphragmatic VN can also be targeted by implantation of electrodes on the ventral and/or dorsal vagal trunks below the diaphragm. This approach has been investigated for its effects on food intake and in the treatment of obesity [12–16]. Transcutaneous VNS is a non-invasive alternative to the invasive implantable VNS devices. Most commonly, surface electrodes are placed on the external ear to target the auricular branch of the VN (described in depth in later sections). Another form of transcutaneous VNS targets the cervical VN in the neck and has been investigated in various disorders including headaches [17–19].
VNS是一个通用术语，描述了任何刺激VN的技术(图1)。不同的适应症需要不同的方法来靶向VN，这将在后面讨论。最常见的是，VNS包括通过手术植入脉冲发生器装置刺激左侧颈部VN。与右颈VN相反，左颈VN的目标是尽量减少包括心动过缓在内的心脏影响。右颈VNS主要用于心力衰竭[10,11]。在早期的试验中，一个可编程装置被植入右胸部并连接到右颈VN。该装置通过优先激活迷走神经传出纤维来影响心功能。通过在膈下的迷走神经腹侧和/或背侧干上植入电极，亦可定位膈下VN。已经研究了这种方法对食物摄入和肥胖治疗的影响[12-16]。经皮VNS是一种非侵入性的替代侵入性植入式VNS装置。最常见的是，将表面电极放置在外耳上，以瞄准耳廓分支(在后面的章节中深入描述)。另一种经皮VNS以颈部的颈VNS为靶点，已经在包括头痛在内的各种疾病中进行了研究[17-19]。

In 1997, the first VNS device was approved by the FDA for patients, aged 12 and older, with medically refractory partial onset seizures. After preclinical studies demonstrating encouraging results in dogs [20] and monkeys [21], two pilot, single-blind trials of an implantable VNS device were initiated [22]. Following this, two multicenter, prospectively randomized, double-blind trials began [23,24]. Sixty-seven patients were randomized to receive high or low VNS treatment for 14 weeks. At the end of the study period, 38.7% of patients receiving high VNS achieved at least 50% reduction in seizure frequency compared with 19.4% of patients receiving low VNS, and the device was well-tolerated [23]. These trials prompted the initial approval of VNS by the FDA and since this time, the approval has been expanded to include children as young as 4 and to include additional stimulation devices. Additionally, while initially used for focal seizures, it is now also being used to treat generalized seizures [25].
1997年，第一个VNS设备被FDA批准用于12岁及以上的难治性部分发作性癫痫患者。在狗[20]和猴子[21]的临床前研究显示出令人鼓舞的结果后，两项植入式VNS装置的先导单盲试验开始了[22]。随后，两项多中心、前瞻性随机、双盲试验开始[23,24]。67例患者随机接受高或低VNS治疗，疗程14周。在研究期结束时，38.7%的高VNS组患者癫痫发作频率至少降低了50%，而低VNS组患者的这一比例为19.4%，该装置耐受性良好[23]。这些试验促使VNS获得了FDA的初步批准，从那时起，批准范围已经扩大到4岁的儿童，并包括额外的刺激装置。此外，虽然最初用于局灶性癫痫发作，但现在也被用于治疗全身性癫痫发作[25]。

Implantable VNS devices are now widely used in the treatment of drug-resistant epilepsy for patients who are not eligible for epilepsy surgery. The device consists of implantable elements including the pulse generator and lead wire and external remote controls that allow the patient to stop the stimulation or trigger a pulse [26]. These devices generally last 6–10 years depending upon the amount of use and settings. Although efficacious, VNS is not first-line therapy, and side effects, including cough, dysphonia, surgical site infection and hoarseness, are not uncommon. Other surgical complications have been reported including postoperative hematoma, infection, and vocal cord palsy, in addition to hardware-related complications such as lead fracture [27].
植入式VNS装置现在广泛用于治疗不适合癫痫手术的耐药癫痫患者。该装置由可植入的元件组成，包括脉冲发生器和引线，以及允许患者停止刺激或触发脉冲的外部遥控器[26]。这些设备通常可以使用6-10年，具体取决于使用量和设置。虽然有效，但VNS不是一线治疗，副作用，包括咳嗽，发音困难，手术部位感染和声音嘶哑，并不罕见。其他手术并发症有报道，包括术后血肿、感染、声带麻痹，以及与硬件相关的并发症，如铅骨折[27]。

A review encompassing 30 years of data suggests that VNS achieves optimal efficacy at 6 months of treatment with a 50–100% reduction in seizure frequency [26]. A large retrospective study using patient outcome registry data from over 4000 patients examined the effects of VNS for the treatment of epilepsy based on patient age, epilepsy duration, and seizure type [28]. After 3 months, a 46% reduction in seizure frequency was achieved with 44% of patients having at least a 50% reduction. These positive outcomes were increased at the 1- and 2-year follow-ups. Patients less than 18 years old and those with a history of epilepsy of less than 10 years achieved a more favorable response to VNS therapy compared with older adults and those with a longer disease history. Additionally, the largest benefit was achieved in those with predominantly simple-partial seizures [28].
一项包含30年数据的综述表明，VNS在治疗6个月时达到最佳疗效，癫痫发作频率降低50-100%[26]。一项大型回顾性研究使用了来自4000多名患者的患者结局登记数据，根据患者年龄、癫痫持续时间和发作类型，研究了VNS治疗癫痫的效果[28]。3个月后，癫痫发作频率降低了46%，44%的患者至少减少了50%。这些积极的结果在1年和2年的随访中有所增加。年龄小于18岁和癫痫史小于10年的患者对VNS治疗的反应优于年龄较大和癫痫史较长的患者。此外，单纯性部分性癫痫患者获益最大[28]。

Despite many years of its use and numerous preclinical and clinical studies demonstrating its clear therapeutic effect, the exact mechanism by which VNS controls epilepsy has not been elucidated [29]. Multiple mechanisms have been proposed and have mostly focused on the ability of VNS to reduce excitability in various brain regions, its neuroelectrophysical role, and its effects on the release of neurotransmitters [30,31]. For example, studies have suggested that the mechanism of benefit is due to the increased norepinephrine release from the locus coeruleus [32,33]. More recent evidence has demonstrated the role of inflammation in epilepsy. This has led to the speculation that the protection by VNS in epilepsy is in part mediated by its anti-inflammatory effect [31]. Despite the proven benefit of VNS in epilepsy, more work is needed to understand its mechanism of protection. Identifying the precise mechanism of action of VNS in epilepsy may help identify responders vs. non-responders and tailor the treatment to those who will be most likely to benefit. Interestingly, a recent study used a statistical model based on preoperative heart rate variability (HRV) to predict which patients would be suitable for VNS [34]. Vagal efferents innervate the sinoatrial node and the atrioventricular node to control heart rate [35]. HRV is an indirect reflection of the heart’s autonomic function and VNS has been shown to induce acute increases in HRV [36]. The investigators found that perioperative HRV indices, recorded during sleep, could better predict response to VNS therapy, compared with measurements recorded during the awake state [34].
尽管VNS使用多年，大量临床前和临床研究表明其具有明确的治疗效果，但VNS控制癫痫的确切机制尚未阐明[29]。已经提出了多种机制，主要集中在VNS降低大脑各区域兴奋性的能力、其神经电物理作用及其对神经递质释放的影响[30,31]。例如，研究表明，益处的机制是由于蓝斑释放的去甲肾上腺素增加[32,33]。最近的证据证明了炎症在癫痫中的作用。这导致人们猜测VNS对癫痫的保护部分是由其抗炎作用介导的[31]。尽管VNS在治疗癫痫方面的益处已得到证实，但还需要更多的工作来了解其保护机制。确定VNS在癫痫中的确切作用机制可能有助于识别有反应者和无反应者，并为最有可能受益的人量身定制治疗方案。有趣的是，最近的一项研究使用了基于术前心率变异性(HRV)的统计模型来预测哪些患者适合进行VNS[34]。迷走神经传出神经支配窦房结和房室结控制心率[35]。HRV是心脏自主神经功能的间接反映，VNS已被证明可诱导HRV急性升高[36]。研究人员发现，与清醒状态下记录的HRV指数相比，睡眠期间记录的围手术期HRV指数可以更好地预测对VNS治疗的反应[34]。

Patients with epilepsy treated with VNS were noted to have improvement in mood [37]. In 2000, Rush et al. conducted the first study investigating the effects of VNS on patients with depression and without epilepsy [38]. In 2005, the FDA approved a VNS device, made by Cyberonics, for treatment-resistant depression based on the results from a 12-week randomized controlled acute phase trial, a 12-month prospective naturalistic study, and a prospective 1-year comparison of VNS with treatment as usual for treatment-resistant depression [39–41]. Since this time, more studies have been conducted supporting the efficacy of VNS in depression. A study by Bajbouj et al. demonstrated that 53.1% of patients with chronic treatment refractory depression met the response criteria of a 50% reduction in the Hamilton Rating Scale for Depression (HRSD28) score after treatment with VNS [42]. A recent meta-analysis found that adjunctive VNS in treatment-resistant depression appears to be effective, relatively safe, and well-tolerated [43]. However, in order to gain more widespread acceptance among clinicians, larger trials are needed. A large 5-year randomized controlled trial is currently underway and the results obtained from this will likely help in clarifying the role of VNS in depression [44].
经VNS治疗的癫痫患者情绪有所改善[37]。2000年，Rush等人首次研究了VNS对抑郁症和非癫痫患者的影响[38]。2005年，基于一项为期12周的随机对照急性期试验、一项为期12个月的前瞻性自然研究和一项为期1年的前瞻性比较，FDA批准了Cyberonics公司生产的用于治疗难治性抑郁症的VNS设备[39-41]。从那时起，越来越多的研究支持VNS治疗抑郁症的功效。Bajbouj等人的研究表明，53.1%的慢性难治性抑郁症患者在接受VNS治疗后，达到汉密尔顿抑郁评定量表(HRSD28)评分降低50%的应答标准[42]。最近的一项荟萃分析发现，辅助VNS治疗难治性抑郁症似乎是有效的，相对安全，并且耐受性良好[43]。然而，为了在临床医生中获得更广泛的接受，需要进行更大规模的试验。目前正在进行一项为期5年的大型随机对照试验，从中获得的结果可能有助于阐明VNS在抑郁症中的作用[44]。

Multiple techniques including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) have been employed to elucidate the mechanism of action of VNS in depression [45]. These mechanisms can be divided into acute and chronic effects. Conway et al., using oxygen 15-labeled water PET, demonstrated that acute VNS produced changes in mean cerebral blood flow in multiple regions implicated in depression [46]. Increases in blood flow were seen in the bilateral orbitofrontal cortex, bilateral anterior cingulate cortex, and right superior and medial frontal cortex while decreases were seen in the bilateral temporal cortex and right parietal area. Additionally, Nahas et al. used blood oxygenation level-dependent (BOLD) fMRI to study the sustained effects of VNS [47]. In the acute setting, VNS led to activation in both the right medial prefrontal cortex and the right anterior insular cortex. However, at approximately 30 weeks, this activation switched to deactivation which correlated with a decrease in depressive symptoms [45,47].
包括功能磁共振成像(fMRI)、正电子发射断层扫描(PET)和单光子发射计算机断层扫描(SPECT)在内的多种技术已被用于阐明VNS在抑郁症中的作用机制[45]。这些机制可分为急性和慢性效应。Conway等人使用氧15标记水PET证实，急性迷走神经综合征导致与抑郁相关的多个区域的平均脑血流量发生变化[46]。双侧眶额皮层、双侧前扣带皮层、右侧额上皮层和内侧皮层血流量增加，双侧颞叶皮层和右侧顶叶区血流量减少。此外，Nahas等人使用血氧水平依赖(BOLD) fMRI研究了VNS的持续效应[47]。在急性情况下，VNS导致右侧内侧前额叶皮层和右侧前岛皮层的激活。然而，在大约30周时，这种激活转变为失活，这与抑郁症状的减少相关[45,47]。

The effect of VNS on noradrenergic and serotonergic neurons has also been proposed to be part of its beneficial effect. In multiple studies, VNS has been shown to increase noradrenaline concentrations and improve noradrenaline and serotonergic neurotransmission in brain regions important in depression [48–50]. Furthermore, Grimonprez et al. evaluated the anti-depressant effects of VNS after lesioning of noradrenergic neurons from the locus coeruleus in rats during the forced swim test (to assess depression-like behavior) or open field test (to assess locomotor activity) [51]. While VNS reduced the immobility time during the forced swim test, this effect was not seen with lesioning of the locus coeruleus, suggesting that noradrenergic neurons from the locus coeruleus contribute to the anti-depressant effect of VNS. While anti-depressants can increase neurotransmitter release and affect the sensitivity of inhibitory receptors, VNS appears to alter the baseline firing rate of noradrenergic and serotonergic neurons and thus has a distinct mechanism. Additionally, an effect of VNS on the dopaminergic system has been suggested. For example, VNS treatment of patients with treatment-resistant depression increased cerebrospinal fluid levels of homovanillic acid, a dopamine metabolite [52]. Clearly much work has been done to decipher the anti-depressant effects of VNS, however, there are still many unknowns and more studies are needed to gain a more precise understanding.
VNS对去甲肾上腺素能和血清素能神经元的作用也被认为是其有益作用的一部分。多项研究表明，VNS可增加去甲肾上腺素浓度，改善抑郁症重要脑区去甲肾上腺素和血清素能神经传递[48-50]。此外，Grimonprez等人在强迫游泳试验(评估抑郁样行为)或开阔场地试验(评估运动活动)中，对大鼠蓝斑去肾上腺素能神经元损伤后VNS的抗抑郁作用进行了评估[51]。虽然VNS在强迫游泳试验中减少了静止时间，但这种作用在蓝斑损伤中没有观察到，这表明来自蓝斑的去肾上腺素能神经元参与了VNS的抗抑郁作用。虽然抗抑郁药可以增加神经递质释放并影响抑制受体的敏感性，但VNS似乎改变了去甲肾上腺素能和血清素能神经元的基线放电率，因此具有独特的机制。此外，VNS对多巴胺能系统也有影响。例如，对难治性抑郁症患者进行VNS治疗可增加脑脊液中多巴胺代谢物同质香草酸的水平[52]。显然，人们已经做了很多工作来解读VNS的抗抑郁作用，然而，仍有许多未知因素，需要更多的研究来获得更精确的理解。

Inspired by the finding that patients being treated with VNS for epilepsy experienced weight loss, VNS was investigated for its effects on body weight and food intake and in the treatment of obesity [12,13,53,54]. Furthermore, in a study of patients with depression treated with cervical VNS for 2 years, participants were observed to have a decrease in weight unassociated with mood changes [55]. Additionally, altered vagal activity had been demonstrated in rodent models of obesity [56,57].
受VNS治疗癫痫患者体重减轻这一发现的启发，研究了VNS对体重和食物摄入以及肥胖治疗的影响[12,13,53,54]。此外，在一项用颈椎VNS治疗抑郁症患者2年的研究中，观察到参与者的体重下降与情绪变化无关[55]。此外，迷走神经活动的改变已经在肥胖的啮齿动物模型中得到证实[56,57]。

A study investigating the mechanism of VNS in treating obesity in rats demonstrated that VNS delayed gastric emptying by releasing anorexigenic hormones and enhancing vagal activity [58]. These hormones included glucagon-like peptide-1, polypeptide YY, and pancreatic polypeptide. In this study, electrode wires were implanted in the subdiaphragmatic vagal nerves on both the left and right and externally at the back of the neck. The mechanism for the increase in these hormones with VNS was not determined. In another preclinical study, PET was employed to determine the effect of VNS on eating behavior in pigs [59]. After 5 weeks of VNS, food intake decreased and PET demonstrated activation of central dopaminergic reward areas with VNS. Because gastric compliance and emptying were unaltered, the authors suggest that this effect was not due to vagus efferents [59,60].
一项探讨VNS治疗大鼠肥胖机制的研究表明，VNS通过释放厌氧性激素和增强迷走神经活动来延迟胃排空[58]。这些激素包括胰高血糖素样肽-1、多肽YY和胰多肽。在本研究中，电极丝在左右两侧的膈下迷走神经和颈部后部的外部植入。这些激素在VNS中增加的机制尚未确定。在另一项临床前研究中，PET被用于确定VNS对猪进食行为的影响[59]。VNS 5周后，食物摄取量减少，PET显示VNS激活中枢多巴胺能奖励区。由于胃顺应性和排空没有改变，作者认为这种影响不是由于迷走神经传出[59,60]。

These data suggested that modulating the VN could represent a possible therapy for obesity. Most of these preclinical and clinical studies used low frequency (<30 Hz) VNS. While low-frequency VNS elicits action potentials in vagal fibers, high frequency reversibly blocks action potentials [61,62]. The use of high-frequency (kilohertz) stimulations that reversibly block conduction to the subdiaphragmatic VN has been investigated in the treatment of obesity. In 2011, the ReCharge trial, a multicenter randomized double-blind clinical trial evaluating the effectiveness of the Maestro Rechargeable System, began (NCT01327976). This device delivers intermittent, electrical blocking signals to the anterior and posterior trunks of the intra-abdominal VN. A total of 162 and 77 obese individuals were randomized to the vagal nerve block (5 kHz) or sham device group, respectively. After 12 months, participants in the vagal nerve block group had a statistically significant greater weight loss (24.4%) compared with those in the sham group (15.9%) [15]. However, this did not reach the primary efficacy endpoint of at least a 10% greater weight loss reduction. Still, based on these results and the sustained results after 18 months, in 2015, the FDA approved the use of this device in the treatment of obesity [16]. It is important to note that, while these data suggest efficacy, vagal blockade does not play a main role in the treatment of obesity and more trials and long-term follow-up studies will be needed before devices such as the Maestro Rechargeable System are incorporated into clinical practice.
这些数据表明，调节VN可能是治疗肥胖的一种可能的方法。这些临床前和临床研究大多使用低频(<30 Hz) VNS。低频VNS激发迷走神经纤维的动作电位，而高频则可逆地阻断动作电位[61,62]。使用高频(千赫兹)刺激，可逆地阻断膈下VN的传导，已被研究用于治疗肥胖。2011年，一项评估Maestro可充电系统有效性的多中心随机双盲临床试验(NCT01327976)启动。该装置向腹内静脉网络的前后主干传递间歇性的电阻断信号。共有162名和77名肥胖者被随机分为迷走神经阻滞组(5 kHz)和假装置组。12个月后，迷走神经阻滞组的体重减轻(24.4%)明显高于假手术组(15.9%)[15]。然而，这并没有达到至少10%的体重减轻的主要疗效终点。尽管如此，基于这些结果和18个月后的持续效果，2015年，FDA批准使用该设备治疗肥胖[16]。值得注意的是，虽然这些数据表明了疗效，但迷走神经阻断在治疗肥胖方面并不起主要作用，在将Maestro可充电系统等设备纳入临床实践之前，还需要进行更多的试验和长期随访研究。

Additionally, the effect of transcutaneous auricular VNS (TENS) in the treatment of obesity is currently under exploration in human trials (NCT05230628, NCT04926415). In a randomized triple-blind trial, 150 obese participants will receive either active TENS, at 25 Hz, three to four times a day for 10 min, 30 min before the main meals, or sham stimulation, for 6 months (NCT05230628). Primary outcome measures include changes in percentage of body fat, BMI, and waist circumference.
此外，经皮耳穴VNS (TENS)治疗肥胖症的效果目前正在人体试验中探索(NCT05230628, NCT04926415)。在一项随机三盲试验中，150名肥胖参与者将接受25赫兹的主动TENS，每天三到四次，每次10分钟，主餐前30分钟，或假刺激，为期6个月(NCT05230628)。主要结果测量包括体脂百分比、BMI和腰围的变化。

Several case reports demonstrated improvement in migraine in patients with refractory epilepsy treated with VNS. Additionally, it had been shown that VNS could modulate pain. Together, these findings suggested the possible utility of VNS in the treatment of migraine. However, the invasive nature of surgically implanted devices limited VNS’s widespread adoption despite demonstrated benefit. GammaCore is a patient-controlled handheld non-invasive transcutaneous device designed to deliver electrical stimulation to the cervical VN during acute migraine attacks. In 2012, a pilot study was initiated which demonstrated the potential tolerability and efficacy of the non-invasive VNS (nVNS) device in the treatment of migraine [17]. Following this, in a multicenter study, patients with high-frequency episodic migraine or chronic migraine were treated with nVNS during acute migraine attacks [18]. Over the course of 2 weeks, patients self-delivered two 120-s doses of electrical stimulation, 3 min apart, at the onset of a migraine attack. In this population, 56.3% reported pain relief at 1 h post-stimulation and 64.6% at 2 h post-stimulation. In the PREVA trial, patients with chronic cluster headache were randomly assigned to receive adjunctive prophylactic nVNS or standard of care (SOC) alone [19]. In this trial, patients prophylactically administered stimulations 10 h apart with the option of administering additional stimulations during acute headache attacks. Patients treated with nVNS and SOC, over the course of 4 weeks, reported a greater reduction in the number of attacks during the study period compared with those treated with SOC alone. In 2018, nVNS was approved by the FDA for migraines and then in 2019 for cluster headaches. More recently, the FDA approved the use of an nVNS device for children aged 12–17 with migraine. The mechanism of VNS’s beneficial effect in headaches is not well understood. In a review, Silberstein et al. suggest that VNS has effects on four main areas: the autonomic system, neurotransmitters, cortical spreading depression, and nociception [63]. Recently, Hu et al. investigated whether the anti-nociceptive effect of VNS involved opioidergic mechanisms. In this preclinical model, the authors provide evidence that VNS engages the δ opioid receptor (DOR) [64]. Together, these data suggest that VNS may provide an efficacious non-pharmacological approach to treating migraines and cluster headaches.
几个病例报告表明，用VNS治疗难治性癫痫患者的偏头痛得到改善。此外，研究表明VNS可以调节疼痛。总之，这些发现提示了迷走神经刺激在偏头痛治疗中的可能效用。然而，手术植入装置的侵入性限制了VNS的广泛采用，尽管证明了其益处。GammaCore是一种患者控制的手持式非侵入性经皮装置，设计用于在急性偏头痛发作时向颈部VN提供电刺激。2012年，一项初步研究证实了无创VNS (nVNS)装置治疗偏头痛的潜在耐受性和有效性[17]。随后，在一项多中心研究中，在急性偏头痛发作期间使用nVNS治疗高频发作性偏头痛或慢性偏头痛患者[18]。在两周的时间里，患者在偏头痛发作时自行进行两次120秒剂量的电刺激，每次间隔3分钟。在这个人群中，56.3%的人在刺激后1小时疼痛缓解，64.6%的人在刺激后2小时疼痛缓解。在PREVA试验中，慢性丛集性头痛患者被随机分配接受辅助预防性nVNS或单独标准治疗(SOC)[19]。在这项试验中，患者预防性地间隔10小时给予刺激，并在急性头痛发作时选择给予额外的刺激。在4周的研究过程中，与单独接受SOC治疗的患者相比，接受nVNS和SOC治疗的患者在研究期间发作次数的减少幅度更大。2018年，nVNS被FDA批准用于偏头痛，然后在2019年被批准用于丛集性头痛。 最近，FDA批准了一种nVNS设备用于12-17岁患有偏头痛的儿童。VNS对头痛的有益作用机制尚不清楚。在一篇综述中，Silberstein等人认为VNS对四个主要领域有影响:自主神经系统、神经递质、皮质扩张性抑制和伤害感觉[63]。最近，Hu等人研究了VNS的抗伤害作用是否涉及阿片能机制。在这个临床前模型中，作者提供了VNS参与δ阿片受体(DOR)的证据[64]。综上所述，这些数据表明VNS可能为治疗偏头痛和丛集性头痛提供了一种有效的非药物方法。

Much excitement has focused on using VNS as an anti-inflammatory therapy in treating diseases including diabetes, Alzheimer’s disease, cardiovascular disease, and arthritis. VNS can attenuate the inflammatory response by activating a neuroimmune circuit known as the cholinergic anti-inflammatory pathway (CAP). The CAP, first described by Kevin Tracey, is the efferent limb of the inflammatory reflex [65,66]. Two immune cell types, β₂ adrenergic receptor positive CD4+ T cells and α7 nicotinic acetylcholine receptor (α7nAChR) expressing macrophages, play an important role in the CAP. Firing of the efferent VN initiates the CAP. This signal is then transmitted to the splenic nerve which releases norepinephrine which binds to β₂ adrenergic receptors on choline acetyltransferase-positive T cells in the spleen. Acetylcholine is released from these cells and binds to α7nAChRs on macrophages. This ultimately results in the suppression of inflammation by reducing cytokine production in the spleen. The initial finding that activation of cholinergic neurons can decrease inflammation instigated the exploration of the use of VNS in inflammation-mediated diseases. Recent evidence suggests that VNS can also activate other neuroimmune circuits to decrease inflammation, which has been reviewed elsewhere [67,68]. Preliminary evidence suggests that VNS may be applied as an anti-inflammatory treatment for a broad range of diseases, a few of which will be reviewed here.
许多令人兴奋的研究都集中在使用VNS作为一种抗炎疗法来治疗包括糖尿病、阿尔茨海默病、心血管疾病和关节炎在内的疾病。VNS可以通过激活被称为胆碱能抗炎途径(CAP)的神经免疫回路来减弱炎症反应。CAP是炎症反射的传出肢，最早由Kevin Tracey描述[65,66]。两种免疫细胞类型，β ₂ 肾上腺素能受体阳性CD4+ T细胞和α7烟碱胆碱受体(α7nAChR)表达巨噬细胞，在CAP中发挥重要作用。输出VN的放电启动CAP，该信号随后传递到脾神经，释放去甲肾上腺素，与脾脏胆碱乙酰转移酶阳性T细胞上的β ₂ 肾上腺素能受体结合。乙酰胆碱从这些细胞中释放出来，并与巨噬细胞上的α 7nachr结合。这最终导致通过减少脾脏细胞因子的产生来抑制炎症。激活胆碱能神经元可以减少炎症的初步发现激发了VNS在炎症介导疾病中的应用探索。最近的证据表明，VNS还可以激活其他神经免疫回路来减少炎症，这在其他地方也有报道[67,68]。初步证据表明，VNS可作为一种抗炎治疗广泛的疾病，其中一些将在这里进行综述。

The VN connects the CNS to the digestive system through the brain–gut axis. Vagal afferents contain chemoreceptors, mechanoreceptors, thermoreceptors, and osmoreceptors. They can detect the status of the gastrointestinal tract and communicate this information to the CNS. Vagal efferent fibers, originating in the brain, synapse with second order post-ganglionic neurons located in the digestive wall [69].
VN通过脑肠轴连接中枢神经系统和消化系统。迷走神经传入神经包括化学感受器、机械感受器、热感受器和渗透感受器。它们可以检测胃肠道的状态，并将此信息传递给中枢神经系统。迷走神经传出纤维起源于大脑，与位于消化壁的神经节后二级神经元发生突触[69]。

Inflammatory bowel disease (IBD) is a group of inflammatory conditions that involve the colon and small intestine. It is generally divided into ulcerative colitis (UC) and Crohn’s disease (CD). Currently, there is no cure for IBD. Treatment often involves pharmacologically targeting pro-inflammatory cytokines or surgery. Most commonly, IBD is treated with anti-TNF agents, however, these face numerous issues including side effects, loss of response, low patient compliance, and high cost [69]. Thus, additional anti-inflammatory therapies are of great interest [69].
炎症性肠病(IBD)是一组涉及结肠和小肠的炎症性疾病。一般分为溃疡性结肠炎(UC)和克罗恩病(CD)。目前，还没有治愈IBD的方法。治疗通常包括药物靶向促炎细胞因子或手术。最常见的是，IBD使用抗tnf药物治疗，然而，这些药物面临许多问题，包括副作用、反应丧失、患者依从性低和高成本[69]。因此，额外的抗炎疗法引起了极大的兴趣[69]。

In 2003, Miceli and Jacobson, showed that administration of anticholinesterase drugs improved colitis in a CD model [70]. It was later shown, in a mouse model, that vagotomy exacerbated colitis [71]. Low vagal tone was shown to be associated with high plasma TNF-α levels [72]. In a cohort study, vagotomy was associated with an increased risk of developing IBD, enforcing a beneficial role of vagal tone in IBD [73]. Kevin Tracey’s group demonstrated that VNS during endotoxemia decreased TNF-α production by splenic macrophages [74]. Additionally, dysbiosis is a common feature in IBD and, through the CAP, the VN could affect the intestinal microbiota [75].
2003年，Miceli和Jacobson发现，在CD模型中使用抗胆碱酯酶药物可改善结肠炎[70]。后来在小鼠模型中显示，迷走神经切开术加重了结肠炎[71]。低迷走神经张力与高血浆TNF-α水平相关[72]。在一项队列研究中，迷走神经切断术与IBD发生风险增加相关，这加强了迷走神经张力在IBD中的有益作用[73]。Kevin Tracey等研究小组证实，内毒素血症时VNS可降低脾巨噬细胞产生TNF-α[74]。此外，生态失调是IBD的共同特征，VN可通过CAP影响肠道微生物群[75]。

These data suggested an anti-inflammatory role of the VN during digestive inflammation and laid down the groundwork for the potential use of VNS in TNF-mediated chronic inflammatory diseases. In multiple studies, it was shown that chronic VNS improved colitis in rats [76–78]. The first clinical trial involving treatment of patients with IBD with VNS began in 2012 [69,79,80]. Nine patients were recruited to receive VNS continuously for 12 months. Clinical, biological, and autonomic markers were measured over the course of the study period. Five of the seven patients who completed the study achieved remission and five were shown to have a decrease in the CD endoscopic score of severity. Additionally, VNS was shown to restore vagal tone in these patients. These findings were supported by a study conducted by d’Haens et al. (NCT02311660) who found that VNS monotherapy or as adjunctive therapy improved clinical and endoscopic markers in half of IBD patients [81]. For 2 weeks, daily VNS for 60 s was initiated. From 4 to 6 weeks, stimulation was increased to 5 min daily along with an increase in output current. If the Crohn’s Disease Activity Score (CDAI) did not improve by week 8, stimulations increased to four times daily for the remainder of the 16-week study period. Response to therapy was assessed based on CDAI, fecal calprotectin levels, and Simple Endoscopic Score for CD. While these data are promising, more trials are needed to assess the clinical efficacy of VNS in IBD. Recently, in 2021, a pilot study was initiated investigating the effects of transcutaneous VNS in CD. In this open-label, single-arm trial, patients will self administer VNS to the cervical VN three times per day for 16 weeks, using a handheld device (NCT05165108). Changes in CDAI, fecal calprotectin levels, cytokines, and HRV will be assessed at the end of the study period.
这些数据提示VNS在消化道炎症中具有抗炎作用，并为VNS在tnf介导的慢性炎症性疾病中的潜在应用奠定了基础。多项研究表明，慢性VNS可改善大鼠结肠炎[76-78]。首个IBD患者联合VNS治疗的临床试验开始于2012年[69,79,80]。9例患者连续接受VNS治疗12个月。在整个研究过程中测量了临床、生物学和自主神经标志物。完成研究的7名患者中有5名获得缓解，5名CD内窥镜严重程度评分下降。此外，VNS显示恢复这些患者的迷走神经张力。d 'Haens等人(NCT02311660)的一项研究支持了这些发现，该研究发现VNS单一治疗或作为辅助治疗可改善一半IBD患者的临床和内镜标记物[81]。连续2周，开始每日VNS 60 s。从4到6周，随着输出电流的增加，刺激时间增加到每天5分钟。如果克罗恩病活动评分(CDAI)在第8周没有改善，在16周研究期间的剩余时间内，刺激增加到每天4次。根据CDAI、粪便钙保护蛋白水平和CD的简单内镜评分来评估对治疗的反应。虽然这些数据很有希望，但需要更多的试验来评估VNS在IBD中的临床疗效。最近，在2021年，一项试点研究开始调查经皮VNS对CD的影响。在这项开放标签的单臂试验中，患者将使用手持设备(NCT05165108)，每天三次自我给颈椎VNS，持续16周。 在研究期结束时，将评估CDAI、粪便钙保护蛋白水平、细胞因子和HRV的变化。

In 2010, Hoeger et al. investigated the effects of VNS on brain death-induced inflammation. Specifically, the authors performed VNS on brain-dead kidney transplant donor rats and assessed its impact on graft outcome [82]. VNS resulted in improved renal function in the transplant recipient. This was followed by a study demonstrating that VNS on brain-dead donor rats also decreased chronic allograft nephropathy in recipients [83]. Thus, these studies suggested a role for VNS in kidney pathology.
2010年，Hoeger等人研究了VNS对脑死亡诱导炎症的影响。具体而言，作者对脑死亡肾移植供体大鼠进行了VNS，并评估了其对移植结果的影响[82]。VNS可改善移植受者的肾功能。随后的一项研究表明，脑死亡供体大鼠的VNS也减少了受体的慢性同种异体移植肾病[83]。因此，这些研究提示VNS在肾脏病理中的作用。

In 2016, another study was conducted to gain a more mechanistic insight into the effects of VNS on acute kidney injury (AKI) [84]. Prior preclinical studies had demonstrated that pulsed ultrasound administered before renal ischemia–reperfusion injury (IRI) could attenuate injury [85] leading to the hypothesis that VNS could protect against renal IRI similar to ultrasound treatment. Indeed, Inoue et al. demonstrated that VNS ameliorates kidney IRI and showed that this effect was dependent upon the CAP [84]. Of note, VNS was effective when delivered 24 h but not 10 min before IRI. From a clinical perspective, this study suggested that VNS could be employed prophylactically in situations in which the patient is at high risk of developing AKI. This was followed by a study demonstrating that VNS administered 24 h after cisplatin treatment was protective against kidney injury which was dependent upon the CAP [86]. Preclinical studies have clearly demonstrated a protective role of VNS in kidney injury and clinical trials are now warranted to determine its therapeutic benefit in patients.
2016年，另一项研究对VNS对急性肾损伤(AKI)的影响进行了更深入的机制研究[84]。先前的临床前研究表明，在肾缺血再灌注损伤(IRI)之前给予脉冲超声可以减轻损伤[85]，这导致了VNS可以像超声治疗一样保护肾脏IRI的假设。事实上，Inoue等人证明了VNS改善肾脏IRI，并表明这种效果依赖于CAP[84]。值得注意的是，VNS在IRI前24小时有效，而不是10分钟。从临床角度来看，本研究提示在患者发生AKI的高风险情况下，可以预防性地使用VNS。随后的一项研究表明，顺铂治疗后24小时给予VNS对依赖于CAP的肾损伤具有保护作用[86]。临床前研究已经清楚地证明了VNS在肾损伤中的保护作用，现在有必要进行临床试验以确定其对患者的治疗益处。

Recently, Hilderman and Bruchfeld conducted a pilot clinical trial involving VNS treatment in hemodialysis patients [87]. The authors hypothesized that VNS would suppress inflammation and alter HRV in hemodialysis patients. Twelve hemodialysis patients were treated with a minimally invasive oscillating device before dialysis three times a week for 4 weeks. In the present study population, VNS did not significantly change cytokine levels, nor did it alter HRV. However, there were many limitations to the present study. Firstly, VNS was not administered daily due to practical limitations. Additionally, the minimally invasive device used may not have been optimal in this context. Finally, the small sample size and lack of control group hinders interpretation of the results. Clearly more research will be needed to assess the efficacy of VNS in hemodialysis patients and in other kidney pathologies.
最近，Hilderman和Bruchfeld进行了一项关于VNS治疗血液透析患者的临床试验[87]。作者假设VNS可以抑制血透患者的炎症并改变HRV。12例血液透析患者在透析前采用微创振荡装置治疗，每周3次，连续4周。在目前的研究人群中，VNS没有显著改变细胞因子水平，也没有改变HRV。然而，本研究存在许多局限性。首先，由于实际限制，VNS不是每天使用。此外，在这种情况下，使用的微创设备可能不是最佳的。最后，小样本量和缺乏对照组阻碍了对结果的解释。显然，需要更多的研究来评估VNS在血液透析患者和其他肾脏疾病中的疗效。

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive erosions of bone and cartilage. Inflammation plays a critical role in the pathogenesis. Pro-inflammatory cytokines are released and thus pharmaceutical agents that suppress this response, including glucocorticoids, methotrexate, and monoclonal antibodies, have been the focus of treatment [88]. Specifically, anti-TNF drugs are widely used. Despite advances in therapeutic agents, there is no mainstay of treatment and many patients do not respond adequately.
类风湿性关节炎(RA)是一种慢性自身免疫性疾病，其特征是滑膜炎症和骨骼和软骨的进行性侵蚀。炎症在其发病机制中起关键作用。促炎细胞因子被释放，因此抑制这种反应的药物，包括糖皮质激素、甲氨蝶呤和单克隆抗体，一直是治疗的重点[88]。具体来说，抗tnf药物被广泛使用。尽管在治疗药物方面取得了进展，但没有主要的治疗方法，许多患者没有充分的反应。

Koopman et al. demonstrated that stimulating the inflammatory reflex with an implantable VNS device can modulate TNF and other cytokines [88]. As part of the study, 18 patients with RA were enrolled to receive VNS for 60 s up to four times daily. Peripheral blood was collected on day 42 which showed a decrease in TNF levels with VNS. Stimulation was stopped for 14 days during which time TNF levels increased. Restarting VNS on day 56 led to another decrease in TNF by day 84. This suggested that active stimulation is needed to decrease TNF levels and withdrawal of treatment may worsen disease. RA clinical disease severity also significantly improved with active VNS. The present study was followed by a pilot study evaluating the safety and efficacy of a novel miniaturized VNS device in patients with multidrug refractory RA [89]. This was a two-stage study; stage 1 was open label and three participants received active stimulation for 1 min daily. In stage 2, 11 patients were randomly assigned to receive active stimulation (1 min) once daily, active stimulation (1 min) four times daily, or sham stimulation for 12 weeks. Investigators and participants were blinded during stage 2. The device was safe and well-tolerated and, similar to earlier findings, reduced biomarkers and clinical signs of RA. Furthermore, in a recent open-label single-center pilot study, transcutaneous non-invasive cervical VNS was delivered to 36 patients with RA of either high- or low-disease activity [90]. Outcome measures included changes in Disease Activity Score based on 28-joint count–C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines. In the 16 patients with high disease activity, VNS reduced the levels of DAS28-CRP, CRP, and interferon-γ after 4 days of treatment. These data suggest a role for VNS as a safe and efficacious anti-inflammatory treatment for RA and support the undertaking of larger clinical trials.
Koopman等研究表明，通过植入式VNS装置刺激炎症反射可以调节TNF等细胞因子[88]。作为研究的一部分，18名RA患者接受了60秒的VNS治疗，每天最多4次。第42天采集外周血显示VNS组TNF水平降低。停止刺激14天，在此期间TNF水平升高。在第56天重新启动VNS导致第84天TNF再次下降。这表明需要主动刺激来降低TNF水平，而停止治疗可能会使疾病恶化。VNS活动组RA临床疾病严重程度明显改善。在本研究之后，又进行了一项初步研究，评估一种新型小型化VNS装置在多药难治性RA患者中的安全性和有效性[89]。这是一个两阶段的研究;第一阶段为开放标签，3名参与者每天接受1分钟的主动刺激。在第二阶段，11名患者被随机分配接受每日1次主动刺激(1分钟)，每日4次主动刺激(1分钟)或假刺激，持续12周。研究人员和参与者在第二阶段采用盲法。该装置安全且耐受性良好，并且与早期发现相似，减少了RA的生物标志物和临床体征。此外，在最近的一项开放标签单中心试点研究中，经皮无创颈椎VNS治疗了36例疾病活动性高或低的RA患者[90]。结果测量包括基于28关节计数- c反应蛋白(DAS28-CRP)的疾病活动评分的变化，心脏迷走神经张力和促炎细胞因子。在16例疾病活动度高的患者中，VNS在治疗4天后降低了DAS28-CRP、CRP和干扰素-γ的水平。 这些数据表明，VNS作为一种安全有效的抗炎治疗类风湿性关节炎的作用，并支持进行更大规模的临床试验。

The RESET-RA study is an ongoing multicenter, randomized, sham-controlled blinded trial in which 250 participants will be recruited to receive either active VNS or sham stimulation (NCT04539964). Participants with moderate-to-severe RA who have failed to respond to biologic agents or DMARDs are eligible. All participants will receive an implantable VNS device on the left cervical VN. Stimulations will be delivered for 1 min daily for 12 weeks. At week 12, after endpoint assessments, participants in the control group will receive active stimulations. All patients will be monitored in an open label 180-week follow-up. The primary endpoint is an American College of Rheumatology (ACR) 20 response at 12 weeks.
RESET-RA研究是一项正在进行的多中心、随机、假对照盲法试验，将招募250名参与者接受主动VNS或假刺激(NCT04539964)。对生物制剂或dmard无效的中重度RA患者符合条件。所有参与者将在左侧颈椎VNS上接受植入式VNS装置。每天刺激1分钟，持续12周。在第12周，终点评估后，对照组的参与者将接受主动刺激。所有患者将在180周的开放标签随访中进行监测。主要终点是12周时美国风湿病学会(ACR) 20反应。

Motor function is often significantly impaired following ischemic stroke, a leading cause of disability worldwide [91]. Although multiple motor rehabilitation methods, which can promote major neural plasticity, have been developed, significant deficits often persist following stroke. Pharmacological agents acting on neurotransmitters have been shown to generate neural plasticity and potentiate motor rehabilitation treatments [92]. Similarly, VNS can modulate the release of neurotransmitters and enhance neural plasticity. For example, VNS, through muscarinic receptors, influences cortical synchrony and excitability [93]. Additionally, repeatedly pairing VNS with a specific movement reorganizes the primary motor cortex and increases the cortical representation of that movement [94].
缺血性中风是世界范围内致残的主要原因之一，运动功能常显著受损[91]。尽管多种运动康复方法可以促进主要神经可塑性，但卒中后仍存在明显的功能缺陷。作用于神经递质的药物已被证明可产生神经可塑性并增强运动康复治疗[92]。同样，VNS可以调节神经递质的释放，增强神经的可塑性。例如，VNS通过毒蕈碱受体影响皮质同步性和兴奋性[93]。此外，反复将VNS与特定运动配对会重组初级运动皮层，并增加该运动的皮层表征[94]。

In 2014, VNS was delivered during motor rehabilitation in a rat model of stroke to test the hypothesis that this could improve recovery of motor function [95]. Indeed, the authors found that VNS repeatedly paired with successful upper forelimb movements improved recovery after stroke compared with rehab alone. VNS delivered after rehab did not have an effect compared with rehab alone. The present study provided initial indication that VNS could represent a novel method to improve stroke rehabilitation and has since been followed-up with trials in humans. In 2016, Dawson et al., in a pilot clinical study, demonstrated the safety and feasibility of VNS paired with upper-limb rehabilitation after ischemic stroke [96]. Participants were implanted with a VNS device on the left cervical VN. While the patients performed a task involving the upper limb, a therapist manually delivered a stimulation using a push button on a wireless external device. In the recent VNS-REHAB trial, 108 patients with moderate­-to-­severe loss of arm function after ischemic stroke were enrolled and were randomly assigned to receive active VNS or sham stimulation paired with intensive motor rehabilitation for 6 weeks [97]. The primary outcome was the change in Fugl­Meyer Assessment Upper Extremity (FMA­UE) score. After 6 weeks, the mean FMA­UE increased by 5.0 points (SD 4.4) in the VNS group and 2.4 points (3.8) in the control group. After 90 days, a clinically meaningful response was seen in 47% of patients in the VNS group compared with 24% of patients in the sham group. Interestingly, the improvement with VNS was observed even in patients who suffered from stroke many years prior (mean time since stroke was 3.1 years). This well executed trial provides strong support for the efficacy of VNS in patients with stroke, however, many questions still remain. Neuroplasticity may vary by individual, particularly by age and sex, and thus larger studies with subgroup analyses should be conducted to investigate the effect this may have. Additionally, longer follow-up studies will be needed to assess whether long-term synaptic changes occur with stimulation. The excitement for the potential of VNS to improve motor recovery following stroke is growing and is now supported by both preclinical and clinical data.
2014年，在脑卒中大鼠模型的运动康复过程中给予VNS，以验证其可以促进运动功能恢复的假设[95]。事实上，作者发现，与单独康复相比，VNS反复与成功的上肢运动相结合可以改善中风后的恢复。康复后给予VNS与单独康复相比没有效果。目前的研究初步表明，VNS可能是一种改善中风康复的新方法，并已在人体中进行了后续试验。2016年，Dawson等在一项临床先导研究中证实了VNS配合缺血性脑卒中后上肢康复的安全性和可行性[96]。参与者在左侧颈椎VN上植入一个VNS装置。当患者执行涉及上肢的任务时，治疗师通过无线外部设备上的按钮手动传递刺激。在最近的VNS- rehab试验中，108例缺血性卒中后出现中度至重度手臂功能丧失的患者被纳入研究，并被随机分配接受主动VNS或假性刺激，同时进行6周的强化运动康复[97]。主要结果为Fugl-Meyer上肢评估(FMA-UE)评分的变化。6周后，VNS组平均FMA-UE增加5.0分(SD 4.4)，对照组增加2.4分(3.8)。90天后，VNS组47%的患者出现有临床意义的反应，而假手术组为24%。有趣的是，VNS的改善甚至在多年前患有中风的患者中也能观察到(中风后的平均时间为3.1年)。 这项执行良好的试验为VNS在脑卒中患者中的疗效提供了强有力的支持，然而，许多问题仍然存在。神经可塑性可能因个体而异，特别是因年龄和性别而异，因此应该进行更大规模的亚组分析研究，以调查其可能产生的影响。此外，还需要更长的随访研究来评估刺激是否会引起长期的突触变化。VNS在改善中风后运动恢复方面的潜力越来越令人兴奋，现在得到了临床前和临床数据的支持。

NECTAR-HF was a randomized sham-controlled trial designed to evaluate whether right cervical VNS would attenuate cardiac remodeling, improve cardiac function, and increase exercise capacity in symptomatic heart failure patients with severe left ventricular systolic dysfunction [98,99]. All patients (n=96) were implanted with a VNS system and randomized in a 2:1 ratio to receive therapy (VNS) or control (sham stimulation) for a 6-month period. The primary endpoint was the change in left ventricular-end systolic diameter. Secondary endpoints included other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter-derived indices of autonomic nerve modulation, and circulating biomarkers. There were statistically significant improvements in quality of life, New York Heart Association (NYHA) class, and the SF-36 Physical Component in the VNS group although the other endpoints were not different between the groups. INOVATE-HF was a multinational, randomized trial involving 85 centers including patients with chronic heart failure, NYHA functional class III symptoms, and ejection fraction ≤ 40% [100]. Patients (n=707) were assigned to device implantation to provide VNS or continued medical therapy in a 3:2 ratio and were followed-up for a mean of 16 months. A nerve stimulation cuff was implanted on the right cervical VN in addition to a transvenous lead in the right ventricle to detect ventricular activation. There was no difference in the primary efficacy outcome (composite of death from any cause or first event for worsening heart failure). Quality of life, NYHA functional class, and 6-min walking distance were better in the VNS group, but left ventricular end-systolic volume index was not different. Thus, these clinical trials failed to show beneficial effects of VNS on death, heart failure events, or cardiac remodeling/function in chronic heart failure patients although quality-of-life measures were significantly improved by VNS.
NECTAR-HF是一项随机假对照试验，旨在评估右颈VNS是否能减轻伴有严重左室收缩功能不全的症状性心力衰竭患者的心脏重构、改善心功能和增加运动能力[98,99]。所有患者(n=96)植入VNS系统，并按2:1的比例随机分为治疗组(VNS)和对照组(假刺激组)，为期6个月。主要终点是左心室收缩末端直径的变化。次要终点包括其他超声心动图测量、运动能力、生活质量评估、24小时霍尔特衍生的自主神经调节指数和循环生物标志物。VNS组在生活质量、纽约心脏协会(NYHA)评分和SF-36 Physical Component评分方面均有统计学上的显著改善，尽管其他终点在两组之间没有差异。innovate - hf是一项多国随机试验，涉及85个中心，包括慢性心力衰竭、NYHA功能III类症状和射血分数≤40%的患者[100]。707例患者按3:2的比例被分配到植入装置以提供VNS或继续药物治疗，平均随访16个月。在右颈VN上植入一个神经刺激袖带，并在右心室植入经静脉导联以检测心室激活。主要疗效结局(任何原因导致的死亡或心力衰竭加重的首次事件的综合)没有差异。VNS组患者的生活质量、NYHA功能分级、6 min步行距离均优于VNS组，但左室收缩末期容积指数差异无统计学意义。 因此，这些临床试验未能显示VNS对慢性心力衰竭患者的死亡、心力衰竭事件或心脏重构/功能的有益影响，尽管VNS显著改善了生活质量。

While cervical VNS has demonstrated to be a feasible and efficacious treatment in various diseases, it is invasive and thus poses a risk to individuals. Therefore, the development of a non-invasive approach with similar efficacy has been of great interest.
虽然颈椎VNS已被证明是一种可行和有效的治疗多种疾病的方法，但它是侵入性的，因此对个人构成风险。因此，开发一种具有相似疗效的非侵入性入路一直备受关注。

The external ear is the only location where the vagus sends its peripheral branch, the auricular nerve (aVN). The antihelix, cavity of concha, tragus, crus of helix, and crura of antihelix of the ear are partly innervated by the aVN, while the cymba concha is innervated exclusively by the aVN [101]. As with the VN, the aVN is composed of myelinated A and B fibers as well as unmyelinated C fibers [102]. The ear also contains endings of other nerves including the great auricular nerve, the auriculotemporal nerve, and the lesser occipital nerve.
外耳是迷走神经的外周分支——耳神经(aVN)的唯一位置。耳廓的反耳廓、耳廓腔、耳屏、耳廓脚和反耳廓脚部分受中耳廓神经支配，而钹的耳廓只受中耳廓神经支配[101]。与VN一样，aVN由有髓鞘的A和B纤维以及无髓鞘的C纤维组成[102]。耳还包括其他神经的末梢，包括耳大神经、耳颞神经和枕小神经。

Although auricular acupuncture has been used in eastern medicine going back 2500 years [103], the potential to electrically stimulate the auricular nerve was first demonstrated in healthy subjects in 2003 [104]. Stimulation of the aVN sends signals directly to the brainstem and thus, the aVN provides an external gateway to brain. Both transcutaneous and percutaneous aVNS techniques exist and are approved for treatment of select diseases [102]. In transcutaneous aVNS, the afferent VN endings are stimulated with electrodes placed on the skin of the external ear. Strong currents are needed to pass through the skin and a relatively large surface area is stimulated. Percutaneous aVNS, on the other hand, is a minimally invasive technique in which electrodes penetrate the skin of the ear in the regions of the aVN. The needles can be focused to the target region, circumventing the large surface area required in transcutaneous aVNS.
虽然耳穴针灸在东方医学中的应用可以追溯到2500年前[103]，但电刺激耳神经的潜力在2003年首次在健康受试者中得到证实[104]。对aVN的刺激直接向脑干发送信号，因此，aVN提供了通往大脑的外部通道。经皮和经皮aVNS技术都存在，并被批准用于治疗某些疾病[102]。在经皮aVNS中，通过放置在外耳皮肤上的电极刺激传入的VN末梢。需要强大的电流通过皮肤，并刺激相对较大的表面积。另一方面，经皮aVNS是一种微创技术，电极穿透耳内aVNS区域的皮肤。针可以聚焦到目标区域，绕过经皮aVNS所需的大表面积。

The NSS-2 BRIDGE Device is a percutaneous neurostimulator that recently received FDA clearance for the treatment of symptoms resulting from opioid withdrawal. The device, which is placed behind the patient’s ear, stimulates cranial nerves V, VII, IX and X and the occipital nerves. A recent study assessed the role of the NSS-2 BRIDGE Device in managing Post-Operative Pain in Total Knee and Hip Arthroplasties, Bariatric, and Kidney Transplant Surgeries (NCT03834142). For each surgery, ten patients were recruited to receive the device and were compared with ten historical controls who had received SOC. The primary endpoint was a reduction in opioid requirement 24 h after surgery. The NSS-2 BRIDGE Device reduced the oral morphine equivalent (OME) by 75.4% and reduced pain by 41.5% 24 h after surgery in kidney donor patients [105]. In bariatric patients, the NSS-2 BRIDGE Device reduced the OME by 60.2% and pain by 28% at 24 h following laparoscopic Roux-en-Y gastric bypass surgery [106]. A recent study evaluated the use of a transcutaneous aVNS device in pediatric patients with relapsing nephrotic syndrome (FRNS) and steroid-resistant nephrotic syndrome (SRNS) [107]. The device used was the transcutaneous electrical nerve stimulation (TENS) unit that was attached to the patients’ ears via an ear clip to left cymba concha. Guardians performed transcutaneous aVNS on their child 5 min daily for 26 weeks. All patients with FRNS remained relapse free during the study period. In three of the four patients with SRNS, TENS reduced the urine protein:creatinine below the nephrotic range. Additionally, there was a significant decrease in serum TNF levels compared with baseline. The results of the present study warrant larger trials studying the efficacy of transcutaneous aVNS in the treatment of nephrotic syndrome.
NSS-2 BRIDGE装置是一种经皮神经刺激器，最近获得FDA批准用于治疗阿片类药物戒断引起的症状。该装置放置在患者耳后，刺激V、VII、IX、X颅神经和枕神经。最近的一项研究评估了NSS-2 BRIDGE装置在全膝关节和髋关节置换术、减肥和肾脏移植手术中治疗术后疼痛的作用(NCT03834142)。对于每次手术，招募10名患者接受该装置，并与10名接受SOC的历史对照进行比较。主要终点是术后24小时阿片类药物需求减少。NSS-2 BRIDGE装置使供肾患者术后24小时口服吗啡当量(OME)减少75.4%，疼痛减少41.5%[105]。在肥胖患者中，NSS-2 BRIDGE装置在腹腔镜Roux-en-Y胃旁路手术后24小时使OME减少60.2%，疼痛减少28%[106]。最近的一项研究评估了经皮aVNS装置在小儿复发性肾病综合征(FRNS)和类固醇抵抗性肾病综合征(SRNS)患者中的应用[107]。所使用的装置是经皮神经电刺激装置(TENS)，通过耳夹连接到患者的耳朵上。监护人对其孩子进行经皮aVNS，每天5分钟，持续26周。所有FRNS患者在研究期间均无复发。在4例SRNS患者中的3例中，TENS将尿蛋白:肌酐降低到肾病范围以下。此外，与基线相比，血清TNF水平显著下降。 目前的研究结果支持更大规模的试验，研究经皮aVNS治疗肾病综合征的疗效。

The ability of aVNS to modulate multiple central brain structures has been evaluated using various techniques including fMRI, extracellular recordings, EEGs, and transcranial magnetic stimulation [101]. In general, the neurophysiological effects of aVNS are considered to be similar to that of VNS [101]. The aVN directly projects to the NTS and thus affects both the central and autonomic nervous systems, resulting in widespread and systemic effects [108]. As discussed above, VNS has an anti-inflammatory effect. Similarly, aVNS reduced pro-inflammatory cytokine levels in humans [109] and increased norepinephrine levels in rats [110]. Additionally, aVNS may exert its actions through the CAP, as shown in endotoxemic rats [111]. Thus, like VNS, aVNS shows promise in the treatment of inflammatory conditions. The anti-nociceptive effects of cervical VNS have also been similarly demonstrated in both preclinical and clinical studies of aVNS (as reviewed [101]). In addition, transcutaneous electrical auricular stimulation was reported to reduce cardiac remodeling after myocardial infarction in dogs, an effect similar to that of cervical VNS [112]. Although the authors did not investigate the mechanism behind this effect, they state that the stimulation produced the same effects as cervical VNS on vagal efferent fibers. For a deeper review of the evidence for the effects of aVNS, the reader is referred to the comprehensive review by Kaniusas et al. [101].
aVNS调节多个中央脑结构的能力已经通过各种技术进行了评估，包括功能磁共振成像、细胞外记录、脑电图和经颅磁刺激[101]。一般认为，aVNS的神经生理作用与VNS相似[101]。aVN直接投射到NTS，从而影响中枢和自主神经系统，导致广泛和全身的影响[108]。如上所述，VNS具有抗炎作用。同样，aVNS降低了人体内的促炎细胞因子水平[109]，增加了大鼠体内的去甲肾上腺素水平[110]。此外，aVNS可能通过CAP发挥作用，如内毒素大鼠[111]所示。因此，像VNS一样，aVNS在治疗炎症方面显示出希望。在aVNS的临床前和临床研究中，颈椎VNS的抗伤害性作用也得到了类似的证实(如综述[101])。此外，经皮耳电刺激被报道可以减少狗心肌梗死后的心脏重构，其效果与颈型VNS相似[112]。虽然作者没有研究这种效应背后的机制，但他们指出，刺激产生的效果与颈VNS对迷走神经传出纤维的效果相同。为了更深入地回顾aVNS效应的证据，读者可以参考Kaniusas等人[101]的综合综述。

Currently, aVNS is being explored in many of the diseases that VNS has been used to treat. Importantly, many of these studies and clinical trials have shown similar efficacy of aVNS compared with invasive VNS. For example, aVNS and VNS both decreased epileptic seizure activity in rat models [113]. The anti-seizure effect of aVNS was shown to have a similar duration of effect compared with that of invasive cervical VNS. There are also numerous ongoing clinical trials investigating the use of aVNS in a broad range of applications. For example, it is being examined in the treatment of fibromyalgia (NCT04260906), alcohol withdrawal (NCT04159909), and for kidney transplant recipients (NCT04256837). It is even being used paired with bottle feeding to improve feeding in newborn infants [114–116] and in a trial to determine whether it can influence consciousness (NCT04065386).
目前，aVNS正在探索在许多疾病，VNS已被用于治疗。重要的是，许多研究和临床试验表明，与有创性VNS相比，aVNS的疗效相似。例如，aVNS和VNS在大鼠模型中均能降低癫痫发作活动[113]。aVNS抗癫痫作用的持续时间与侵入性颈椎VNS相似。还有许多正在进行的临床试验调查aVNS在广泛应用中的使用。例如，它正在纤维肌痛(NCT04260906)、戒酒(NCT04159909)和肾移植接受者(NCT04256837)的治疗中进行试验。它甚至被与奶瓶喂养配合使用，以改善新生儿的喂养[114-116]，并在一项试验中确定它是否能影响意识(NCT04065386)。

Although aVNS, compared with cervical VNS, offers the clear advantage of being less invasive, it still has its own shortcomings. For example, the stimulation may cover a large area of the auricle, particularly with transcutaneous aVNS, and thus additional auricular nerves may be stimulated. This is complicated by the controversy surrounding the precise innervation of the auricle, as only few studies have been conducted in this area. The concha is generally used as the ear target for aVNS; however, some suggest that stimulation of the tragus may be more advantageous [117]. Stimulation of different regions of the ear can produce different effects which may impact a study’s results and reproducibility [108,118]. Additionally, multiple reflexes can be triggered during aVNS, particularly the Arnold’s ear cough reflex, but also the ear-gag, ear-syncope, and ear-lacrimation reflexes [101]. Finally, aVNS can cause many of the same side effects of VNS such as dizziness, headache, and stimulation site skin irritation [119].
尽管与颈椎VNS相比，aVNS具有侵入性小的明显优势，但它仍有自己的缺点。例如，刺激可能覆盖耳廓的大片区域，特别是经皮aVNS，因此可能会刺激额外的耳廓神经。由于在这一领域进行的研究很少，围绕耳廓精确神经支配的争议使这一问题变得复杂。aVNS通常使用耳廓作为耳靶;然而，一些人认为刺激耳屏可能更有利[117]。刺激耳朵的不同区域会产生不同的效果，这可能会影响研究的结果和可重复性[108,118]。此外，在aVNS期间可触发多重反射，特别是阿诺德耳咳嗽反射，以及耳呕吐、耳晕厥和耳流泪反射[101]。最后，aVNS可引起许多与VNS相同的副作用，如头晕、头痛和刺激部位皮肤刺激[119]。

The enthusiasm for the potential applications of aVNS are clear. Whether this therapy can live up to these high expectations across a multitude of disciplines remains to be determined.
对aVNS潜在应用的热情是显而易见的。这种疗法是否能在众多学科中达到这些高期望仍有待确定。

VNS simultaneously excites all neurons surrounding the electrode tip and thus it is nonspecific and lacks spatial resolution. Optogenetics is a neuromodulatory technique that uses light to manipulate cells, typically neurons, which have been genetically manipulated to express light-sensitive opsins [120]. Optogenetics is a powerful tool and the use of optogenetics in combination with VNS has been under investigation in a few select diseases thus far. For example, with the use of optogenetics, we recently performed selective VNS (efferent vs. afferent fibers) and found that stimulation of either vagal efferent or afferent fibers was sufficient to protect mice from renal IRI [121]. Additionally, it has been unclear whether the benefit of VNS in HF in clinical trials is due to the recruitment of efferent or afferent fibers or both. In a few preclinical studies, selective stimulation of specific vagal fibers by optogenetics demonstrated that vagal efferent fiber stimulation may be crucial in the beneficial effect of VNS in HF and can reduce afferent fiber-related side effects [122–124]. The authors suggest that it will be necessary to develop a VNS device with selective stimulation of a subset of vagal fibers if VNS is to be applied in the treatment of HF.
VNS同时刺激电极尖端周围的所有神经元，因此它是非特异性的，缺乏空间分辨率。光遗传学是一种神经调节技术，它利用光来操纵细胞，通常是神经元，这些细胞已经被基因操纵以表达光敏视蛋白[120]。光遗传学是一种强大的工具，迄今为止，光遗传学与VNS的结合已经在一些选定的疾病中进行了研究。例如，利用光遗传学，我们最近进行了选择性VNS(传出纤维与传入纤维)，发现刺激迷走神经传出纤维或传入纤维足以保护小鼠免受肾IRI[121]。此外，尚不清楚VNS在临床试验中对HF的益处是由于输出或传入纤维的募集，还是两者兼而有之。在一些临床前研究中，通过光遗传学对特定迷走神经纤维的选择性刺激表明，迷走神经传出纤维刺激可能对VNS在HF患者中的有益作用至关重要，并且可以减少传入纤维相关的副作用[122-124]。作者认为，如果要将迷走神经刺激应用于心衰治疗，有必要开发一种选择性刺激迷走神经纤维亚群的迷走神经刺激装置。

Although therapeutic application of optogenetics is not yet a reality, preclinical studies utilizing optogenetics have the potential to identify a specific neural circuit important in mediating the protective effect of VNS and greatly enhance our understanding of the mechanisms of VNS.
尽管光遗传学的治疗应用尚未成为现实，但利用光遗传学的临床前研究有可能确定在介导VNS保护作用中起重要作用的特定神经回路，并大大增强我们对VNS机制的理解。

VNS is an effective therapy that has already received FDA approval in the treatment of epilepsy, depression, migraines and cluster headaches, and in the abdomen for obesity. Preclinical studies and clinical trials have suggested a potential benefit in an even broader range of diseases. FDA approval for the use of VNS in the treatment of some of these diseases may be on the horizon. Before then, however, larger clinical trials and continued investigations into the mechanism of VNS’s benefit in each disease will be needed. The non-invasive nature of aVNS may help to expand and accelerate the application of VNS in the treatment of more diseases, although this will require further studies. Finally, optogenetics shows great promise in aiding mechanistic investigations of VNS.
VNS是一种有效的治疗方法，已经获得FDA批准，用于治疗癫痫、抑郁症、偏头痛和丛集性头痛，以及腹部肥胖。临床前研究和临床试验表明，它对更广泛的疾病有潜在的益处。FDA可能很快就会批准使用VNS治疗这些疾病。然而，在此之前，还需要进行更大规模的临床试验，并继续研究VNS对每种疾病的益处机制。aVNS的非侵入性可能有助于扩大和加速VNS在治疗更多疾病中的应用，尽管这需要进一步的研究。最后，光遗传学在辅助VNS机制研究方面显示出巨大的前景。

Data are not present in this review article.
这篇综述文章中没有数据。

The authors declare that there are no competing interests associated with the manuscript.
作者声明，没有与稿件相关的竞争利益。

This work was supported by the MSTP Training [grant number 5T32GM007267 (to Eibhlin Goggins)]; the Grant-in-Aid for Research Activity Start-up (JSPS KAKENHI) [grant number JP21K20894 (to Shinji Tanaka)]; the Grant-in-Aid for Early-Career Scientists (JSPS KAKENHI) [grant number JP22K16232 (to Shinji Tanaka)]; the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Shinji Tanaka); the MSD Life Science Foundation (to Shinji Tanaka); the Ichiro Kanehara Foundation (to Shinji Tanaka); the Daiwa Securities Health Foundation (to Shinji Tanaka); the Japan Diabetes Foundation (to Shinji Tanaka); the Life Science Foundation of Japan (to Shinji Tanaka); the Manpei Suzuki Diabetes Foundation (to Shinji Tanaka); and the Salt Science Research Foundation [grant number 2225 (to Shinji Tanaka)].
这项工作得到了MSTP培训的支持[授权号5T32GM007267(给Eibhlin Goggins)];研究活动启动资助计划(JSPS KAKENHI)[资助编号JP21K20894(给田中真司)];早期职业科学家资助计划(JSPS KAKENHI)[资助号JP22K16232(给田中真司)];望田医药研究纪念财团(田中真司);MSD生命科学基金(Shinji Tanaka);金原一郎财团(对田中真司);大和证券健康财团(田中真司);日本糖尿病基金会(对田中真司);日本生命科学基金会(田中真司);铃木万平糖尿病基金会(田中真司);盐科学研究基金会[拨款号2225(给Shinji Tanaka)]。

Open access for this article was enabled by the participation of University of Tokyo in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society.
东京大学与波特兰出版社和生化学会签署了一项全面的阅读与出版协议，使本文的开放获取成为可能。

AKI 阿基

acute kidney injury 急性肾损伤

aVNS avn

auricular vagus nerve stimulation
耳迷走神经刺激

BMI 身体质量指数

body mass index 身体质量指数

CAP 帽

cholinergic anti-inflammatory pathway
胆碱能抗炎途径

CDAI

Crohn’s disease activity score
克罗恩病活动度评分

CD

Crohn’s disease 克罗恩氏病

CNS 中枢神经系统

central nervous system 中枢神经系统

DAS28-CRP

disease activity score based on 28-joint count–C-reactive protein
基于28关节计数- c反应蛋白的疾病活动性评分

DMARD

disease-modifying antirheumatic drug
改善疾病的抗风湿药

DMN 静息状态

dorsal motor nucleus 背运动核

EEG 脑电图描记器

electroencephalogram 脑电图

FDA 食品及药物管理局

Food and Drug Administration
美国食品药品监督管理局

HF 高频

heart failure 心脏衰竭

FMAUE

Fugl­-Meyer assessment upper extremity
Fugl -Meyer评估上肢

fMRI 功能磁共振成像

functional magnetic resonance imaging
功能磁共振成像

FRNS 根据

frequently relapsing nephrotic syndrome
反复发作的肾病综合征

HRV

heart rate variability 心率变异性

IBD 炎症性肠病

inflammatory bowel disease
炎症性肠病

IRI

ischemia–reperfusion injury
缺血再灌注损伤

nVNS

non-invasive VNS 非侵入性迷走神经刺激法

NYHA

New York Heart Association
纽约心脏协会

OME 渗出性中耳炎

oral morphine equivalent 口服吗啡当量

PET 宠物

positron emission tomography
正电子发射断层扫描

RA 类风湿性关节炎

rheumatoid arthritis 类风湿性关节炎

SOC

standard of care 注意标准

SRNS

steroid-resistant nephrotic syndrome
类固醇抵抗性肾病综合征

TENS 数以千万计

transcutaneous electrical nerve stimulation
经皮神经电刺激

TNF 肿瘤坏死因子

tumor necrosis factor 肿瘤坏死因子

UC 加州大学

ulcerative colitis 溃疡性结肠炎

VNS 迷走神经刺激法

vagus nerve stimulation 迷走神经刺激

α7nAChR α7乙酰胆

α7 nicotinic acetylcholine receptor
α7烟碱乙酰胆碱受体