Clinical Core

临床核心摘要 这个揭示项目(研究评估迷走神经兴奋和解剖联系)的总体目标是区分多个外周器官的传出和传入VNS调制的贡献作用，以及它们对刺激参数的依赖，如频率、电流输出和占空比。我们提出了一个共同的研究协议(CSP)，该协议战略性地设计用于揭示特定的VNS参数设置，这些参数设置调节三个生理系统(心血管、免疫和代谢)的自主神经系统控制。CSP还配有三个辅助项目：1)活体人体电刺激和迷走神经记录；2)胃排空和调节的测量；3)通过IDE调节的微爆发(LivaNova)对这四个不同系统上的高频刺激设置进行独特评估，这是CSP中使用的标准LivaNova VNS设备无法实现的。我们将对144名主要是新植入的VNS患者(新植入=96名，以前植入=48名；平均分布在癫痫或抑郁症患者中)进行评估，使用标准的LivaNova临床设备(Sentiva用于癫痫，对称性用于抑郁症)或新型LivaNova微爆发设备。我们将通过测量以下各项来检验不同的VNS刺激参数的急性和慢性影响：1)自主神经：MSNA、压力反射敏感性、心脏交感迷走神经张力、自主神经反射、自主神经应激源； 2)心血管：心率(时频分析)、血压(时频分析)、心电(时间、频率、特征、非线性分析)、心电负荷、心脏力学(超声心动图)、呼吸性窦性心律失常；3)免疫：细胞因子、C反应蛋白、细胞计数、细胞周期； 4)代谢：常规临床生物标志物(如葡萄糖、血脂、糖化血红蛋白)、激素(肠道和脂肪来源，如胰岛素、胰升糖素)、血清LC-MS/MS代谢组学、PBMC LC-MS/MS代谢组学。通过对新植入和以前植入的VNS患者进行严格而复杂的研究设计，一系列全面的标准和尖端结果衡量标准，以及最高水平的质量控制和监管监督，我们将产生首个此类数据集，以便迅速和广泛地分享给神经科学和自主临床和研究社区。这些数据将提供人类迷走神经功能连接的多系统视图，填补一个关键的知识空白，并导致新的治疗和研究。

CLINICAL CORE Abstract The overarching goal of this REVEAL Project (Research Evaluating Vagal Excitation and Anatomical Linkages) is to distinguish the contributing roles of efferent versus afferent VNS modulation of multiple peripheral organs and their dependence on stimulation parameters such as frequency, current output, and duty cycle. We propose a Common Study Protocol (CSP) that is strategically designed to reveal specific VNS parameter settings that modulate the autonomic nervous system control of three physiological systems (cardiovascular, immune, and metabolic). The CSP is complemented with three ancillary projects: 1) in vivo human electrical stimulation and recordings of the vagus nerve; 2) measurements of gastric emptying and accommodation; and 3) unique assessment of high frequency stimulation settings on these four different systems with the IDE-regulated Microburst (LivaNova) that is not possible with the standard LivaNova VNS devices used in the CSP. We will conduct assessments on 144 mostly newly implanted VNS patients (newly implanted=96, previously implanted=48; evenly distributed across epilepsy or depression patients) with either a standard LivaNova clinical device (Sentiva for epilepsy and Symmetry for depression) or a novel LivaNova Microburst device. We will examine the acute and chronic effects of various VNS stimulus parameters by measuring the following: 1) Autonomic: MSNA, baroreflex sensitivity, cardiac sympathovagal tone, autonomic reflexes, autonomic stressors; 2) Cardiovascular: heart rate (time & amp; frequency analyses), blood pressure (time & amp; frequency analyses), ECG (time, frequency, features, nonlinear analyses), ECG electrical burden, cardiac mechanics (Echocardiography), respiratory sinus arrythmia; 3) Immune: cytokines, C reactive protein, cell counts, CyTOF; 4) Metabolic: routine clinical biomarkers (e.g., glucose, lipids, HbA1c), hormones (gut and adipose derived, e.g., insulin, glucagon), serum LC-MS/MS metabolomics, PBMC LC-MS/MS metabolomics. Through a rigorous and sophisticated study design with both newly and previously implanted VNS patients, a comprehensive battery of standard and leading-edge outcome measures, and the highest caliber of quality control and regulatory oversight, we will produce a first-of-its-kind data set to share rapidly and broadly to the neuroscience and autonomic clinical and research communities. These data will provide a multi-system view of the vagus nerve’s functional connectivity in humans, filling a critical knowledge gap and leading to new therapies and research.