Neuromodulation of the Brain-Gut Axis by Transcutaneous Vagal Nerve Stimulation in Functional Dyspepsia

摘要 功能性消化不良（FD）是一种常见的功能性胃肠道疾病，影响数百万美国人 每年症状包括反复发作的上腹部不适，包括以下任何一种或多种 餐后饱胀，早饱，和/或上腹部疼痛或烧灼感，在缺乏明确的结构性 病因学一些FD患者特别受到餐后饱胀和过早饱食的困扰， 餐后窘迫综合征（PDS）亚型的标志。这些症状可能特别 使人衰弱，导致日常功能受损和生活质量下降。尽管负面影响 这些症状对患者的生活影响很大，PDS-FD的发病机制尚不清楚， 理解，尽管已经假设由异常的神经元驱动的脑肠轴的失调 脑干迷走神经回路可能是罪魁祸首目前治疗PDS-FD的主要方法是 药理学干预，这是最好的，适度有效。此外，在一些严重的情况下， 变得难治，药物引起不希望的副作用和/或患者变得耐治疗。 然而，鉴于FD症状和迷走神经功能受损之间的密切联系，我们提出了一个非- 通过经皮迷走神经靶向迷走神经的耳分支的侵入性方法 图4示出了递送到外耳的耳甲艇的电刺激（tVNS）的示例性实施例。因此，耳廓tVNS可以提供 新的治疗策略，以调节异常脑肠道信号在PDS为主的FD。在 目前的项目，我们使用胃/自主措施结合多模式神经成像技术， 询问伴随脑肠神经调节的外周和中枢神经系统变化 PDS-FD患者在餐时激发期间通过耳tVNS的轴信号传导。拟定的研究将 为PDS-FD的病理生理学提供新的见解， 非侵入性神经调节技术，如耳tVNS，以减轻FD症状。

ABSTRACT Functional Dyspepsia (FD) is a common functional gastrointestinal disorder that affects millions of Americans every year. Symptoms include recurrent epigastric discomfort consisting of any one or a combination of postprandial fullness, early satiation, and/or epigastric pain or burning, in the absence of a clear structural etiology. Some patients with FD are particularly bothered by postprandial fullness and early satiation, a hallmark of the Postprandial Distress Syndrome (PDS) subtype. These symptoms can be particularly debilitating, leading to impaired daily functioning and decreased quality of life. Despite the negative impact these symptoms have on patients' lives, the pathogenesis of PDS-predominant FD (PDS-FD) is not well understood, although it has been postulated that dysregulation of the brain-gut axis driven by abnormal brainstem vagal neurocircuitry is a possible culprit. The current mainstay of treatment for PDS-FD is pharmacological intervention which is, at best, modestly effective. Moreover, in some severe cases, symptoms become intractable, medication causes unwanted side effects and/or patient becomes treatment resistant. However, given the strong link between FD symptoms and compromised vagal function we propose a non- invasive approach that targets the auricular branch of the vagus nerve via transcutaneous vagal nerve stimulation (tVNS) delivered to the cymba conchae of the external ear. Thus, auricular tVNS may provide a novel therapeutic strategy to modulate aberrant brain-gut signaling in PDS-predominant FD. In the current project, we use gastric/autonomic measures combined with multimodal neuroimaging techniques to interrogate the peripheral and central nervous system changes that accompany neuromodulation of brain-gut axis signaling by auricular tVNS in PDS-FD patients during a prandial challenge. The proposed study will contribute new insights into the pathophysiology underlying PDS-FD as well as evaluate the fidelity of novel, non-invasive neuromodulatory techniques such as auricular tVNS to mitigate FD symptoms.