Defining Adolescent Nausea through Brain-Gut Physiology and Neurostimulation Response

通过脑肠生理学和神经刺激反应定义青少年恶心

• 批准号: 10671285
• 负责人: Katja Kristina Karrento
• 金额: $ 8.49万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671285
• 关键词: Abdominal Pain; Adolescent; Affect; Amygdaloid structure; Animals; Anxiety; Area; Arousal; Autonomic nervous system; Brain; Brain Stem; Brain region; Child; Childhood; Clinical; Complex; Cranial Nerves; Development; Devices; Diagnostic; Diagnostic tests; Disease; Dizziness; Down-Regulation; Electric Stimulation; Emotional; Equilibrium; Esthesia; External Ear; Feeling suicidal; Functional Gastrointestinal Disorders; Functional Magnetic Resonance Imaging; Functional disorder; Gastric Emptying; Gastroenterologist; Gastroenterology; Gastroparesis; Heat Exhaustion; High Prevalence; Human; Hyperalgesia; Hypothalamic structure; Impairment; Irritable Bowel Syndrome; Knowledge; Label; Learning; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Modality; Morbidity - disease rate; Motor; Nausea; Nerve; Nervous System Physiology; Neurologist; Neurons; Outcome; Output; Pain; Pain Disorder; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Physiology; Placebos; Play; Prefrontal Cortex; Psychologist; Psychophysiologic Disorders; Public Health; Quality of life; Questionnaires; Randomized; Rest; Safety; Satiation; Schools; Signal Transduction; Stomach; Subcategory; Subgroup; Symptoms; Techniques; Testing; Time; Training; Visceral; affective disturbance; base; brain pathway; cell motility; common symptom; comorbidity; disability; effective therapy; efficacy testing; falls; functional disability; heart rate variability; improved; indexing; motility disorder; motor disorder; neural circuit; neuroimaging; novel; novel therapeutics; patient population; pediatrician; prospective; psychologic; reduce symptoms; response; side effect; social; treatment response

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.

项目摘要 高患病率、生活质量下降和对功能性胃肠道疾病的认识不足 要求开发更好的诊断模式和新的治疗方法。功能性恶心（FN）是一种 特别具有挑战性的亚类，因为没有指导治疗的机制的知识。较近 症状重叠，FN患者介于几个亚专业和其他更好定义的裂缝之间 紊乱胃运动功能障碍，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复合体， 儿童可用的测试。焦虑的共同出现导致许多人被贴上了未定义的标签。 伴有心身疾病的恶心。我们先前的描述性研究指向自主神经系统（ANS） 不平衡和高唤醒的青少年“功能性恶心”。大脑中枢通路和觉醒 神经回路与ANS信号紧密结合。本研究的主要目的是探讨脑- 肠道机制在FN青少年中发挥作用，以及一种新型神经刺激装置对恶心的疗效。 在K23奖项中提出了两个目标。第一个目的是试图将恶心分为定义的亚型 基于临床和生理参数（胃运动异常和自主神经失衡）。没有事先 一项前瞻性研究描述了儿童FN。我们将根据自主神经失衡/低 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来分类 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，以进一步定义FN。 第二个目标集中在对神经刺激治疗的反应和假设的功能脑 FN患者的连接变化。我们的团队最近证明了调节中枢神经系统的能力， 脑通路在动物与外围，非侵入性神经刺激装置。这本小说FDA批准了 神经刺激装置将低于感觉阈值的经皮电刺激递送到神经系统的分支。 包括迷走神经在内的几条颅神经，位于外耳中。在动物身上，这种疗法抑制杏仁核的输出 并改善内脏痛觉过敏。在人类中，我们已经证明了相对于安慰剂的安全性和有效性， 功能性腹痛障碍的青少年。并发恶心改善的一个亚组， 治疗后迷走神经张力显著增加。我们假设，神经刺激通过调节FN， ANS功能和边缘脑区（杏仁核，下丘脑）。我们将研究迷走神经张力和功能 与基线和健康对照相比，这种疗法诱导的脑连接变化。通过这个 我们希望收集更多关于功能性恶心的脑肠道通路的知识， 研究一种具有强大生理基础的新疗法来治疗这种使人衰弱的疾病。