Defining Adolescent Nausea through Brain-Gut Physiology and Neurostimulation Response

项目总结 患病率高，生活质量下降，对功能性胃肠道疾病认识不足 呼吁开发更好的诊断模式和新的治疗方法。功能性恶心是一种 尤其具有挑战性的子类，因为没有关于指导治疗的机制的知识。由于要关门 症状重叠，FN患者介于几个亚专科和其他更明确的 精神错乱。胃运动功能障碍，如胃排空延迟(胃轻瘫)和受损 胃顺应性具有非常相似的症状组合，很难与FN区分 儿童中的可用测试。焦虑的常见并存导致许多人被贴上未定义的标签 伴有心身疾病的恶心。我们先前的描述性研究指出自主神经系统(Ans)。 患有“功能性恶心”的青少年的不平衡和高唤醒。中枢脑通路与觉醒 神经回路与ANS信号紧密结合。这项研究的主要目的是研究大脑-- FN青少年的肠道机制和一种新型神经刺激设备对恶心的疗效。 在这个K23奖项中提出了两个目标。第一个目标是尝试将恶心分为不同的亚型 根据临床和生理参数(胃运动异常和自主神经失衡)。没有之前的 这项研究前瞻性地描述了儿科FN。我们将根据自主神经失衡/低将FN分类 迷走神经张力和缺乏胃运动功能障碍。我们将使用非侵入性胃功能测试对 患者和心率变异性测量作为自主神经平衡/迷走神经张力的指标，以进一步确定FN。 第二个目标集中在对神经刺激治疗的反应和假想的功能脑 FN患者的连接性改变。我们的团队最近展示了调节中枢神经系统的能力 使用外周、非侵入性神经刺激设备的动物的大脑通路。这部小说获得了FDA的批准 神经刺激装置将低于感觉阈值的经皮电刺激传递到 外耳有几条脑神经，包括迷走神经。在动物身上，这种疗法抑制杏仁核的输出 改善内脏痛觉过敏。在人类身上，我们已经显示出比安慰剂更安全和有效的治疗 患有功能性腹痛障碍的青少年。同时恶心症状有所改善的一组患者有 治疗后迷走神经张力显著增加。我们假设神经刺激通过调制来改善FN ANS功能和边缘脑区(杏仁核、下丘脑)。我们将调查迷走神经张力和功能性 与基线和健康对照组相比，这种疗法引起的大脑连通性改变。通过这件事 我们希望收集更多关于功能性恶心和功能性恶心的大脑-肠道通路的知识。 研究一种具有强大生理学基础的新疗法来治疗这种虚弱的情况。

PROJECT SUMMARY The high prevalence, reduced quality of life and poor understanding of functional gastrointestinal disorders calls for development of better diagnostic modalities and novel therapies. Functional nausea (FN) is a particularly challenging subcategory as there is no knowledge of mechanisms to direct therapy. Due to close symptom overlap, patients with FN fall between the cracks of several subspecialties and other better defined disorders. Disorders of gastric motor function such as delayed stomach emptying (gastroparesis) and impaired gastric compliance share very similar symptom complex and are difficult to distinguish from FN based on available tests in children. The common co-occurrence of anxiety results in labeling many with undefined nausea with psychosomatic disease. Our prior descriptive studies point to autonomic nervous system (ANS) imbalance and high arousal in adolescents with “functional nausea.” Central brain pathways and the arousal neurocircuitry are closely integrated with ANS signals. The main purpose of this study is to investigate brain- gut mechanisms at play in adolescents with FN and the efficacy of a novel neurostimulation device for nausea. Two aims are proposed in this K23 award. The first aim attempts to classify nausea into defined subtypes based on clinical and physiologic parameters (gastric motor abnormalities and autonomic imbalance). No prior study has prospectively described pediatric FN. We will classify FN based on autonomic imbalance/low vagal tone and lack of gastric motor dysfunction. We will use non-invasive gastric function tests to categorize patients and heart rate variability measures as an index of autonomic balance/vagal tone to further define FN. The second aim focuses on response to neurostimulation therapy and hypothesized functional brain connectivity changes in patients with FN. Our group has recently demonstrated the ability to modulate central brain pathways in animals with a peripheral, non-invasive neurostimulation device. This novel, FDA-cleared neurostimulation device delivers percutaneous, electrical stimulation below sensation threshold to branches of several cranial nerves including the vagus, in the external ear. In animals, this therapy inhibits amygdala output and improves visceral hyperalgesia. In humans, we have shown safety and efficacy over placebo for adolescents with functional abdominal pain disorders. A subset with improvement in concurrent nausea had a notable increase in vagal tone with therapy. We hypothesize that neurostimulation improves FN by modulating ANS function and limbic brain areas (amygdala, hypothalamus). We will investigate vagal tone and functional brain connectivity changes induced by this therapy compared to baseline and healthy controls. Through this proposal, we hope to gather more knowledge on the brain-gut pathways underlying functional nausea and study a novel therapy with strong physiologic basis for this debilitating condition.