经皮颈迷走神经刺激的数字化心血管生物标志物反应：状态空间建模、预测和模拟。

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) is a promising alternative to implantable stimulation of the vagus nerve. With demonstrated potential in myriad applications, ranging from systemic inflammation reduction to traumatic stress attenuation, closed-loop tcVNS during periods of risk could improve treatment efficacy and reduce ineffective delivery. However, achieving this requires a deeper understanding of biomarker changes over time. OBJECTIVE: The aim of the present study was to reveal the dynamics of relevant cardiovascular biomarkers, extracted from wearable sensing modalities, in response to tcVNS. METHODS: Twenty-four human subjects were recruited for a randomized double-blind clinical trial, for whom electrocardiography and photoplethysmography were used to measure heart rate and photoplethysmogram amplitude responses to tcVNS, respectively. Modeling these responses in state-space, we (1) compared the biomarkers in terms of their predictability and active vs sham differentiation, (2) studied the latency between stimulation onset and measurable effects, and (3) visualized the true and model-simulated biomarker responses to tcVNS. RESULTS: The models accurately predicted future heart rate and photoplethysmogram amplitude values with root mean square errors of approximately one-fifth the standard deviations of the data. Moreover, (1) the photoplethysmogram amplitude showed superior predictability (P=.03) and active vs sham separation compared to heart rate; (2) a consistent delay of greater than 5 seconds was found between tcVNS onset and cardiovascular effects; and (3) dynamic characteristics differentiated responses to tcVNS from the sham stimulation. CONCLUSIONS: This work furthers the state of the art by modeling pertinent biomarker responses to tcVNS. Through subsequent analysis, we discovered three key findings with implications related to (1) wearable sensing devices for bioelectronic medicine, (2) the dominant mechanism of action for tcVNS-induced effects on cardiovascular physiology, and (3) the existence of dynamic biomarker signatures that can be leveraged when titrating therapy in closed loop. TRIAL REGISTRATION: ClinicalTrials.gov NCT02992899; https://clinicaltrials.gov/ct2/show/NCT02992899. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1016/j.brs.2019.08.002.

背景：经皮颈部迷走神经刺激（tcVNS）是一种有前途的植入式迷走神经刺激替代方法。由于在从减轻全身炎症到减轻创伤应激等众多应用中具有潜力，因此在风险期间进行闭环 tcVNS 可以提高治疗效果并减少无效输送。但是，要实现这一点，需要更深入地了解随时间变化的生物标志物变化。

目的：本研究旨在揭示从可穿戴感测模式中提取的相关心血管生物标志物对 tcVNS 的反应动态。

方法：招募了 24 名人类受试者参加随机双盲临床试验，分别使用心电图和光体积描记法来测量 tcVNS 对心率和光体积描记图幅度的响应。我们在状态空间中对这些响应进行建模，（1）根据可预测性和主动与假刺激的区分能力来比较生物标志物，（2）研究刺激开始与可测量效果之间的潜伏期，以及（3）可视化 tcVNS 对真实和模型模拟生物标志物的响应。

结果：模型可以准确地预测未来的心率和光体积描记图幅度值，其均方根误差约为数据标准差的五分之一。此外，（1）光体积描记图幅度显示出更高的可预测性（P=.03）和主动与假刺激的区分能力，与心率相比；（2）发现 tcVNS 起始与心血管效应之间存在大于 5 秒的一致延迟；（3）动态特征可区分 tcVNS 与假刺激的反应。

结论：这项工作通过对 tcVNS 相关生物标志物响应进行建模，进一步推进了该领域的研究。通过后续分析，我们发现了三个关键发现，这与（1）用于生物电子医学的可穿戴感测设备有关，（2）tcVNS 对心血管生理学影响的主要作用机制有关，以及（3）在闭环中调整治疗时可以利用的动态生物标志物特征有关。

试验注册：ClinicalTrials.gov NCT02992899；https://clinicaltrials.gov/ct2/show/NCT02992899。

国际注册报告标识符（IRRID）：RR2-10.1016/j.brs.2019.08.002。