作者感谢研究团队（玛丽亚·费尔南达·安德拉德、艾莉森·金、罗宾·希梅尔斯）。

所有研究程序均在斯波尔丁神经调控中心/斯波尔丁剑桥医院进行。该协议的伦理批准已获得麻省总伯翰 IRB（编号协议 #：2022P003200）。使用加密的研究电子数据捕获 （REDCap） 平台获得所有受试者的知情同意（见 材料表）。试验注册号：NCT05801809。
1. 课题筛选
<ol><li>通过多个来源确定潜在主题。 注：在本研究中，人类受试者是从 （1） 波士顿地区公共区域的传单中识别出来的，（2） 互联网和报纸广告，（3） 张贴在公共交通工具上的广告 （The T），（4） 通过 麻省总会布里格姆研究的 Rally 平台（见 材料表）。本研究选择了 44 名健康受试者。</li>
	<li>联系符合条件的受试者或以电子方式请求许可以与他们联系以提供有关研究的更多信息。</li>
	<li>在第一次接触时（通常是电话或 Zoom Enterprise 电话），研究合作研究员会管理一份在线 PR 筛选问卷。在线预筛选过程完成后，将共同研究者收集的信息提交给研究的 PI 进行进一步审查以确认资格。然后，将从预筛选中获得的数据存储在基于网络的加密平台（REDCap，见 材料表）中。<ol><li>包括 18 岁以上且未接受过刺激的受试者 （taVNS）。</li>
		<li>排除孕妇、存在医疗状况以及存在任何经耳迷走神经刺激的禁忌证。</li>
	</ol></li>
</ol>二、设备详情
<ol><li>使用经皮耳迷走神经刺激 （taVNS） 装置（图 1），该装置由一个耳筒（图 2）组成，导电耳塞放置在耳朵的耳廓上（图 3）。</li>
	<li>将电极连接到刺激器，在主动刺激期间，以 30 Hz、200-250 μs 刺激耳廓的两个钹，持续 60 分钟。 注意： 有关设备及相关配件的商业详细信息，请参阅 材料表。</li>
</ol>3. taVNS 程序
注意：该协议包括两次访问：访问 1（同意、筛选和收集人口统计信息）和访问 2（评估和干预）。研究流程如图 4 所示。
<ol><li>在第 2 次就诊时，随机分配受试者接受干预。 注意：活动组接收活动 taVNS，假组接收假 taVNS。</li>
	<li>在试验期间对受试者、干预团队（执行 taVNS 干预的共同研究者/CO-I）和结果评估者（执行评估或分析数据的 CO-I）进行盲法。确保一名未参与的工作人员生成分配顺序，密封信封，并使用外部和视觉显示相同的设备将个人随机分配到干预措施组，这些设备在他们是否处于活动状态（活动电流）或是否（假）方面有所不同，由另一名未参与数据收集或分析的工作人员提供。</li>
	<li>使用电子格式捕获系统 （REDCap） 从受试者那里收集本研究的数据。 表 1 中显示了以下执行的评估。</li>
	<li>当受试者到达时，提供有关该过程的信息。首先，按照 Granot17 和 Nirl18 建议的适应方案，使用右前臂的热刺激作为疼痛阈值，并使用冷水进行条件性疼痛调节 （CPM），评估疼痛程度和疼痛调节。<ol><li>首先，通过在受试者的右前臂上应用帕尔帖热化剂（参见 材料表）并进行短暂的热刺激 （41-48 °C），确定疼痛 60 测试温度（在 60-60 NPS 上引发疼痛体验的温度），每个温度持续 7 秒从刺激强度达到目标温度开始。</li>
		<li>要求受试者使用数字疼痛量表 （NPS） 对疼痛强度水平进行评分，范围从 0 = “没有疼痛”到 100 = “可以想象到的最严重的疼痛”。</li>
		<li>一旦确定了疼痛 60 温度，通过在该温度下应用相同的刺激来给予测试刺激 30 秒，并要求受试者对他们的疼痛强度水平进行 3 次评分：在 10 秒、20 秒和 30 秒后热度达到 pain-60 温度（将计算三个疼痛等级的平均分数）。</li>
		<li>在提供测试刺激后 5 分钟， 将受试者的左手浸入设置为 10 °C 至 12 °C 的水浴中 30 秒，以进行条件刺激。然后，在受试者的右前臂（左手仍将浸入水中）施加相同的 pain-60 温度 30 秒，并再次要求受试者在热疗达到 pain-60 温度后对他们的疼痛强度水平进行 3 次评分：10 秒、20 秒和 30 秒。 注意：CPM（条件性疼痛调节）反应将计算为测试刺激的疼痛评级平均值减去条件刺激期间疼痛评级平均值之间的差值。</li>
	</ol></li>
	<li>要求受试者放置 HRV 监测器（ 如图 5 和 图 6 所示）。</li>
	<li>接下来，使用通过蓝牙连接到平板电脑的监视器进行 5 分钟的基线 HRV（分析频率 HF、LF、LF/HF 和时域指标）记录。</li>
	<li>设置连接到计算机系统的脑电图，并开始评估（休息和任务相关），持续约 30 分钟。</li>
	<li>接下来，设置 taVNS 设备。<ol><li>检查，用 70% 的酒精垫清洁，并准备受试者的耳皮以放置电极。</li>
		<li>接下来，将生理盐水溶液涂在eatips上，将电极放在耳朵上，并开始刺激，持续60分钟。</li>
	</ol></li>
	<li>当 taVNS 达到 30 分钟时，仅再次记录 HRV 和 EEG 5 分钟。</li>
	<li>刺激 60 分钟后，评估受试者的脑电图、HRV 和疼痛，并重复审前程序（如下所述）：<ol><li>进行脑电图和 HRV 评估，持续约 30 分钟。</li>
		<li>按照步骤 3.4 执行 CPM 评估。</li>
	</ol></li>
	<li>进行有关副作用、疲劳和情绪的评估。</li>
	<li>完成会话。</li>
</ol>4. 后续程序
<ol><li>随机分配受试者并完成数据收集后，进行数据分析3.</li>
</ol>

经皮耳迷走神经刺激的神经调控测量

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<span style="font-size: 11pt; font-family: Arial, sans-serif; color: rgb(34, 34, 34); font-variant-numeric: normal; font-variant-east-asian: normal; font-variant-alternates: normal; font-variant-position: normal; vertical-align: baseline; white-space-collapse: preserve;">H.C.和J.S.与Neurive Co直接相关，Neurive Co是一家开发神经调控技术的公司，如taVNS，用于治疗常见的脑部疾病。F.F.得到了美国国立卫生研究院（NIH）的资助，并得到了Neurive的咨询。斯波尔丁康复医院收到了该研究的赞助商 Neurive， Co.， Ltd. 的一份重要礼物。财务利益是根据SRH的所有者Mass General Brigham的利益冲突政策进行审查和管理的。

经耳迷走神经刺激 （taVNS） 正在成为解决多种神经精神疾病的有前途的治疗途径。抑郁症和焦虑症等情绪障碍构成了巨大的全球健康负担，尤其是在 COVID-19 大流行之后19.最近探索 taVNS 的研究表明，它有可能缓解与这些疾病相关的症状。 
迷走神经在脑-肠轴和情绪反应的调节中起着关键作用20.通过 taVNS 刺激迷走神经被认为可以调节神经递?...

经耳迷走神经刺激 （taVNS） 是一种最新的神经调控技术，不需要手术，并利用放置在耳廓或耳屏上的非侵入性刺激装置。因此，它对患者来说更容易获得和安全1.近年来，taVNS领域迅速扩展，主要集中在临床试验上，这些试验展示了对各种病理状况的潜在治疗优势，包括癫痫、抑郁症、耳鸣、帕金森病、葡萄糖耐量受损、精神分裂症和心房颤动2。关于taVNS及其对中央和外围系统中枢和外围系统中生物过程的影响，有很多值得讨论的地方。理想情况下，生物标志物可能证明迷走神经的耳支受到刺激，影响颅内结构，并允许研究人员分析taVNS如何影响生理功能。然而，如果没有可靠的生物标志物，就不容易理解taVNS数据的含义以及如何有效地解释它们。
脑电图 （EEG） 是一种令人鼓舞的成像工具，可为 taVNS 提供生物标志物。它是一种非侵入性、可靠、廉价的方法来测量和量化皮质活动 3,4。在此过程之后，我们小组进行了系统评价，展示了 taVNS 可能影响皮层活动的基本细节，主要是增加较低频率（delta 和 theta）的 EEG 功率谱活动。然而，还检测到了较高频率 （alpha） 和与抑制任务相关的早期 ERP 组件变化的不同结果。发现研究之间的异质性很高;因此，更均匀、更重要和计划周密的研究对于就 taVNS 对 EEG3 测量的大脑活动的影响得出更可靠的结论至关重要。在 taVNS 期间评估脑电图可以推进未来关于将这两种技术整合为移动、闭环、监测和非侵入性刺激工具以影响大脑振荡活动的研究4.
Alpha 不对称性评估大脑半球之间的相对 α 带活动，尤其是额电极处的相对 α 带活动，是一种经常研究的 EEG 生物标志物。以前的文献已经使用这种生物标志物来分析进近-退出假说 5,6，该假设认为大脑的右额叶与退出行为有关。相比之下，左前侧与进近行为有关。由于 alpha 与低大脑活动有关，因此大脑左侧 alpha 的增加表明活动较低，并且可能表现出缺乏接近行为。这个概念有助于解释抑郁症患者左半球 α 带的一些结果7.此外，脑电图电极记录神经元群的活动，检查功能连接 （FC） 或大规模大脑网络的变化，例如默认模式网络 （DMN）7,8。
在此基础上，定量脑电图可用于评估 taVNS 对大脑活动的影响;然而，需要更多的研究来系统地证明具体的指标和效果，这些指标和效果将突出通过迷走神经耳支的非侵入性刺激。
在外周，迷走神经和交感神经系统介导心脏的收缩和电功能9。这种调节促进了心脏的起搏器能力，并通过身体的生理表现（称为窦去极化）来控制心脏起搏器的能力。心率变异性 （HRV） 记录窦去极化每次心跳的变化，从而非侵入性地描述迷走神经对窦房结的影响10。鉴于此功能，HRV 已被视为和研究与个体健康状况以及发病率、死亡率和压力可能性相关的突出神经心脏功能生物标志物11,12。
在 taVNS 的背景下，许多试验都记录了 HRV，并且被认为刺激可以调节 HRV 9,11,12。考虑到 HRV 的降低通过交感神经系统的过度活动、炎症反应和氧化应激等机制与不同疾病的发病率和死亡率有关，taVNS 的迷走神经调节被认为直接影响 HRV 及其鼻窦调节13,14。事实上，一些试验已经表明，taVNS 可以增加健康受试者的 HRV，从而支持这一假设15,16。然而，仍然需要更好地理解不同的taVNS参数是否会对HRV产生不同的影响。
目前，还没有机理研究将该技术的taVNS神经网络和自主神经系统效应结合起来。因此，该协议旨在评估 taVNS 如何影响 EEG 指标和 HRV 并评估其安全性。此外，这还旨在确定可以影响对 taVNS 反应的预测因子。了解与taVNS反应相关的变量可以帮助设计未来的临床试验，以最大限度地提高这种干预措施的效果。

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			<td>Articulated arm</td>
			<td>Electrical Geodesics, Inc.</td>
			<td>20090645</td>
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			<td>Baby shampoo</td>
			<td>Dynarex</td>
			<td>1396</td>
			<td></td>
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			<td>NEURIVE Co.</td>
			<td>HV12303003</td>
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			<td>Computer</td>
			<td>Apple</td>
			<td>YM92704U4PC</td>
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			<td>Condutive eartip</td>
			<td>NEURIVE Co.</td>
			<td>HV12303003</td>
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			<td>Earset</td>
			<td>NEURIVE Co.</td>
			<td>HV12303003</td>
			<td></td>
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			<td>EEG 64-channel cap&#160;</td>
			<td>Electrical Geodesics, Inc.</td>
			<td>H11333</td>
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			<td>Heart rate sensor</td>
			<td>Polar</td>
			<td>M311370175396</td>
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			<td>Monitor</td>
			<td>Dell</td>
			<td>REVA01</td>
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			<td>Electrical Geodesics, Inc.</td>
			<td>A09370244</td>
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			<td>Peltier thermode</td>
			<td>Advanced Medical Systems, Ramat Yishai, Isreal</td>
			<td></td>
			<td></td>
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			<td>Potassium Chloride (dry)</td>
			<td>Electrical Geodesics, Inc.</td>
			<td>820127755</td>
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			<td>Rally</td>
			<td>Mass General Brigham Research</td>
			<td></td>
			<td>online platform</td>
		</tr>
		<tr>
			<td>Research Electronic Data Capture (REDCap)</td>
			<td>Vanderbilt</td>
			<td></td>
			<td>web-based software platform</td>
		</tr>
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			<td>Thermosensory Stimulator</td>
			<td>Medoc Ltd</td>
			<td>1241</td>
			<td></td>
		</tr>
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			<td>Transauricular vagus nerve stimulator</td>
			<td>NEURIVE Co.</td>
			<td>HV12303003</td>
			<td></td>
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understanding the effects of non&#45;invasive transauricular vagus nerve stimulation on eeg and hrv

几项研究表明，经皮耳迷走神经刺激 （taVNS） 在治疗各种疾病方面取得了有希望的结果;然而，没有机制研究研究过这种技术的神经网络和自主神经系统效应。本研究旨在描述 taVNS 如何影响 EEG 指标、HRV 和疼痛水平。健康受试者被随机分为两组：活性taVNS组和假taVNS组。在基线、30 分钟和 30 Hz、200-250 μs taVNS 或假刺激后 60 分钟记录脑电图 （EEG） 和心率变异性 （HRV），并计算指标之间的差异。关于迷走神经投射，一些研究已经证明了迷走神经在调节大脑活动、自主神经系统和疼痛通路方面的作用。然而，仍然需要更多的数据来理解taVNS在这些系统上的机制。在此背景下，本研究提出了一些方法，为更深入地讨论该技术的生理影响提供数据，这可以帮助未来在各种条件下的治疗研究。

Transauricular vagus nerve stimulation (taVNS) is a recent neuromodulation technique that does not require surgery and utilizes a non-invasive stimulation device placed at the concha or tragus of the ear. Consequently, it is more accessible and safer for patients1. In recent years, the taVNS field has rapidly expanded, primarily focusing on clinical trials demonstrating potential therapeutic advantages for various pathological conditions, including epilepsy, depression, tinnitus, Parkinson's disease, impaired glucose tolerance, schizophrenia, and atrial fibrillation2. There is much to discuss about taVNS and its effects on biological processes in the central and peripheral systems. Ideally, a biological marker might demonstrate that the auricular branch of the vagus was stimulated, affecting intracranial structures and allowing researchers to analyze how taVNS affects physiological function. Nevertheless, without a trustworthy biomarker, it is not easy to understand what the taVNS data mean and how to interpret them effectively.
Electroencephalography (EEG) is an encouraging imaging tool to provide biomarkers for taVNS. It is a non-invasive, reliable, inexpensive approach to measure and quantify cortical activity3,4. Following this process, our group performed a systematic review, demonstrating elementary details that taVNS could influence cortical activity, mainly increasing EEG power spectrum activity in lower frequencies (delta and theta). However, diverse results in higher frequencies (alpha) and changes in early ERP components related to inhibitory tasks were also detected. High heterogeneity between the studies was found; therefore, more homogeneous, more significant, and well-planned studies are essential to make more robust conclusions about the effects of taVNS on brain activity measured by EEG3. Assessing EEG during taVNS could advance future research on integrating the two techniques for a mobile, closed-loop, monitoring, and non-invasive stimulation tool to affect brain oscillatory activity4.
Alpha asymmetry, which assesses the relative alpha band activity between the brain hemispheres, particularly at frontal electrodes, is a frequently researched EEG biomarker. Previous literature has used this biomarker to analyze the approach-withdraw hypothesis5,6, which holds that the right frontal side of the brain is associated with withdrawal behaviors. In contrast, the left frontal side is associated with approach behaviors. Since alpha is associated with low brain activity, an increase in alpha on the left side of the brain suggests lower activity and may show a lack of approach behavior. This concept helps to explain some results in the alpha band at the left side hemisphere in depressed patients7. Additionally, EEG electrodes record the activity of neuronal populations, examining Functional Connectivity (FC) or changes in large-scale brain networks, such as the default mode network (DMN)7,8.
Based on that, quantitative electroencephalography can be employed to assess the effects of taVNS on brain activity; however, more studies are required to systematically demonstrate the specific metrics and effects that would highlight the non-invasive stimulation through the auricular branch of the vagus nerve.
Peripherally, the vagus nerve and sympathetic nervous system mediate the heart's contractile and electrical function9. This regulation promotes the heart's pacemaker ability and controls it through physiological manifestations of the body, known as sinus depolarizations. Heart rate variability (HRV) records the changes per beat of sinus depolarization, thus non-invasively describing vagal influences on the sinus node10. Given this function, HRV has been seen and studied as a prominent neurocardiac function biomarker associated with an individual's well-being and the likelihood of morbidity, mortality, and stress11,12.
In the context of taVNS, HRV has been recorded in many trials, and stimulation has been thought to modulate HRV9,11,12. Considering that decreased HRV has been related to the morbidity and mortality of different diseases through mechanisms such as over-activity of the sympathetic nervous system, inflammatory response, and oxidative stress, the vagal nerve modulation of taVNS is thought to directly impact HRV and its sinus regulation13,14. In fact, some trials have already indicated that taVNS can increase HRV in healthy subjects, thus supporting this hypothesis15,16. However, there is still a need to understand better whether different taVNS parameters can affect HRV differently.
Currently, no mechanistic studies have investigated the taVNS neural network and autonomic nervous system effects of this technique together. Therefore, this protocol aims to assess how taVNS can affect EEG metrics and HRV and evaluate its safety. Additionally, this also aims to identify predictors that can influence the response to taVNS. Understanding the variables associated with the response to taVNS can help design future clinical trials to maximize the effects of this intervention.

作者聚焦：探索经耳迷走神经刺激的效果

了解非侵入性耳迷走神经刺激对脑电图和 HRV 的影响

Transauricular Vagus Nerve Stimulation, taVNS for short, is a safe, noninvasive stimulation technique that targets the auricular branch of the vagus nerve. Placing the electrodes at the concha of the ear as an alternative to invasive stimulation, taVNS can affect several brain functions by stimulating the vagal afferent fibers. Several studies have demonstrated promising results of taVNS.However, there is a lack of mechanistic studies to investigate its effect on neural network and autonomic nervous system. So in this clinical trial, we are assessing taVNS in health subjects, looking for potential biomarkers such as EEG metrics and heart rate variability. With this protocol, we are proposing a bilateral stimulation that does not significantly increase the likelihood of cardiovascular events, but enhances the effect of vagus stimulation.taVNS holds significant promise for addressing mood disorders and chronic pain conditions, among others. This study will provide insights into the safety, feasibility and general effects of taVNS on psychological processes, therefore establishing a baseline understanding of how taVNS influences neurophysiological mechanisms, fostering confidence in the techniques potential therapeutic value. Understanding the variables associated with response to taVNS can help design future clinical trials to maximize the effects of this intervention.Based on that, our studies will be focused on how taVNS can be optimized to target specific neural pathways and treat different conditions.

我们对第一个随机分组的受试者进行了初步的描述性分析，但没有揭开研究的盲法。出于这个原因，这个主题被分配给哪些武器是未知的。第一个受试者是一名 69 岁的女性，非西班牙裔，白种人，拥有大学学位，在刺激期间或之后没有报告任何不良事件。临床数据如 表2所示。
此外，在静息态脑电图中，在三个时间段内（基线、术中和术后）为 theta、alpha 和 beta ...

Read this Scientific Article Protocol about Author Spotlight: Exploring the Effects of Transauricular Vagus Nerve Stimulation at JoVE.com

该协议提供了有关如何在临床试验中应用经皮耳迷走神经刺激 （taVNS） 的信息，包括潜在的生物标志物，例如 EEG 指标和心率变异性 （HRV） 以衡量这种治疗对自主神经系统的影响。

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no ...

经耳迷走神经刺激，简称taVNS，是一种针对迷走神经耳支的安全、无创的刺激技术。将电极放置在耳朵的耳廓上作为侵入性刺激的替代方法，taVNS 可以通过刺激迷走神经传入纤维来影响多种大脑功能。几项研究表明，taVNS 的结果是有希望的。然而，目前缺乏机理研究来研究其对神经网络和自主神经系统的影响。因此，在这项临床试验中，我们正在评估健康受试者的 taVNS，寻找潜在的生物标志物，例如 EEG 指标和心率变异性。通过该协议，我们提出了一种双侧刺激，该刺激不会显着增加心血管事件的可能性，但会增强迷走神经刺激的效果。taVNS在解决情绪障碍和慢性疼痛疾病等方面具有巨大的前景。本研究将深入了解 taVNS 对心理过程的安全性、可行性和一般影响，从而建立对 taVNS 如何影响神经生理机制的基线理解，增强对技术潜在治疗价值的信心。了解与taVNS反应相关的变量可以帮助设计未来的临床试验，以最大限度地提高这种干预措施的效果。基于此，我们的研究将集中在如何优化taVNS以靶向特定的神经通路并治疗不同的疾病。

understanding-effects-non-invasive-transauricular-vagus-nerve

Research

JoVE Journal

Neuroscience

Understanding the Effects of Non&#45;Invasive Transauricular Vagus Nerve Stimulation on EEG and HRV

1.4K 次观看.  Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School. 经耳迷走神经刺激，简称taVNS，是一种针对迷走神经耳支的安全、无创的刺激技术。将电极放置在耳朵的耳廓上作为侵入性刺激的替代方法，taVNS 可以通过刺激迷走神经传入纤维来影响多种大脑功能。几项研究表明，taVNS 的结果是有希望的。然而，目前缺乏机理研究来研究其对神经网络和自主神经系统的影响。因此，在这项临床试验中，我们正在评估健康受试者的 taVNS?...