Targeting Hypervigilance and Autonomic Arousal: the Psycho-physiologic Model of GERD

项目总结 GERD影响了大约20%的美国人口，GERD的直接和间接成本是巨大的， 每年总计近500亿美元。有证据支持这种成本的很大一部分是贫穷的 GERD的临床结果与医生和患者做出的糟糕的医疗决策有关。这个 GERD管理不当的问题源于三个主要问题。首先，这种疾病是异质性的。 并需要通过精确的模型进行治疗。其次，当前的范式在很大程度上忽略了 重要的大脑-肠道相互作用，推动症状和医疗保健利用。第三，井水稀少- 进行了比较有效性试验，重点评估了酸抑制以外的治疗方法。这个 该项目在前两个供资周期的总体目标主要集中在前两个问题和 我们已经取得了重大进展，开发出了新的预后生理预测指标和更有效的过程 表型患者的数量。在前两个周期中，我们还确定了心理痛苦的形式 过度警觉和自主神经唤醒是GERD患者预后的主要组成部分。我们能够 驳斥一种教条，即心理痛苦和器质性疾病之间存在相反的关系 疾病。相反，我们的数据证明，高度警惕与生理扰动一样重要 确定症状严重程度和生活质量以及这些因素在整个范围内都很重要 疾病表现。这项工作导致了GERD心理生理模型的创建，该模型专注于 针对导致疾病严重程度的主要生理异常和重要的脑-肠道相互作用。 当前的竞争更新将通过执行急需的随机化来关注第三个问题 评估功能性胃灼热患者行为干预效果的对照试验 难治性胃肠道反流病。我们将使用在前一个资助周期中定义的生理标记物来对患者进行表型分析 并使用认知行为干预来调节过度警惕，以检验心理-生理模型 格尔德。认知行为疗法(CBT)能够改善高度警觉和症状特定的自主神经 因此，我们将测试我们的理论，即CBT可以通过针对这两个目标来改善GERD的预后 重要的心理压力源。我们还将继续关注心理学和生理学的相互作用。 通过确定粘膜通透性增加是否与反流感觉有关，以及这是否 被高度警觉和自主神经干扰所修正。这项提议将对外地产生戏剧性的影响，因为 它将提供重要的临床数据来指导胃肠病学的行为治疗，并进一步定义 脑-肠道相互作用影响GERD的症状和生活质量。

PROJECT SUMMARY GERD affects roughly 20% of the U.S. population and the direct and indirect costs of GERD are substantial, totaling close to 50 billion dollars per year. Evidence supports that a large proportion of this cost and poor clinical outcomes in GERD are related to poor healthcare decisions by both the physician and the patient. The problem of inappropriate GERD management stems from three main issues. First, the disease is heterogeneous and requires treatment informed by a precision model. Second, the current paradigm largely ignores the important brain-gut interactions that drive symptoms and healthcare utilization. Third, there is a paucity of well- performed comparative effectiveness trials focused on assessing treatments beyond acid suppression. The overarching goal of this project over the first two funding cycles primarily focused on the first two problems and we have made major progress developing new physiological predictors of outcome and a more efficient process of phenotyping patients. During the first two cycles, we also determined that psychological distress, in the form of hypervigilance and autonomic arousal, is a major component of patient outcome in GERD. We were able to refute dogma suggesting that there is an inverse relationship between psychological distress and organic disease. Instead, our data proved that hypervigilance was as important as the physiologic perturbations in determining symptom severity and quality of life and these factors were important across the entire spectrum of disease presentation. This work led to the creation of the Psycho-Physiologic Model of GERD that focuses on targeting the primary physiologic abnormality and the important brain-gut interactions driving disease severity. The current competitive renewal will focus on the third problem by performing much needed randomized controlled trials evaluating the effectiveness of behavioral interventions in patients with functional heartburn and refractory GERD. We will use physiomarkers defined during the previous funding cycle to phenotype the patients and use cognitive behavioral interventions to modulate hypervigilance to test the Psycho-Physiologic Model of GERD. Cognitive Behavioral Therapy (CBT) is able to improve hypervigilance and symptom specific autonomic arousal and thus, we will test our theory that CBT can improve outcomes in GERD by targeting these two important psychologic stressors. We will also continue our focus on the interplay of psychology and physiology by determining whether increased mucosal permeability is associated with reflux perception and whether this is modified by hypervigilance and autonomic disruption. This proposal will have a dramatic impact on the field as it will provide important clinical data to guide behavioral treatments in gastroenterology and further define how brain-gut interactions influence symptoms and quality of life in GERD.