Homeostatic and Hedonic Food Motivation Underlying Eating Disorder Trajectories

描述（由申请人提供）：饮食失调是一种异质性疾病，其特征是极端饮食限制、暴饮暴食和排便等异常行为。这个过程通常涉及青少年，在超过一半的个体中，从主要的限制性行为过渡到暴食/净化行为。低体重饮食失调的病理生理学和限制型与暴食型/排空型的机制几乎完全未知。一个关键的知识缺口是这些疾病的发展轨迹背后的神经生物学（例如，从最初的限制到暴饮暴食或排便的转变）。我们的初步数据表明，在低体重饮食失调中，涉及调节（稳态）和正效价（奖励）系统改变的食物动机途径发挥了关键作用。与研究领域标准（RDoC）倡议一致，目前的研究利用了多重pi的互补技能，儿科的Misra博士，神经内分泌科的Lawson博士和精神病学的Eddy博士通过检查稳态和享乐性食物动机途径来解决这一知识差距，我们假设这些关键饮食失调行为的纵向过程。我们假设(i)成功限制体重以维持低体重的青少年会有较低的内稳态和享乐性食欲，fMRI食物动机通路低激活，餐后PYY，催产素和CCK分泌较高；（ii）那些最容易出现暴食行为的人会有更大的享乐欲望，fMRI奖励区过度激活，餐后胃促生长素升高，餐后瘦素和CCK分泌降低；（iii）那些发展或坚持排便行为的人会表现出餐后饱腹感增加，饱腹感区域的fMRI过度激活，餐后BDNF更高。我们将通过在RDoC框架内使用功能磁共振成像范式、神经内分泌分析、行为范式和自我报告测量的多个分析单元来描述患有低体重饮食失调的青少年，从而测试该模型。然后，我们将对这些人进行为期一年的跟踪调查，以评估哪些人转为暴食/净化疾病，哪些人保持限制饮食。基于我们对患有低体重限制性饮食失调的成年人的试点数据，我们将使用我们团队开发并验证的一种新的食物动机范式。通过对低体重饮食失调青少年纵向队列的研究，绘制饮食失调行为（饮食限制、暴饮暴食、排便）和食物动机途径之间的关系，将使我们能够理解体内平衡失调和享乐性食物动机导致这些行为发展的机制。表征与饮食失调行为相关的神经回路、神经内分泌和行为特征将(i)提供对这些高死亡率疾病发病机制的深入了解，（ii）允许确定未来的治疗靶点

DESCRIPTION (provided by applicant): Eating disorders are heterogeneous illnesses characterized by aberrant behaviors of extreme dietary restriction, binge eating, and purging. The course often involves adolescent onset, and in more than half of individuals, transition from predominantly restrictive to binge/purge behaviors. The pathophysiology of low- weight eating disorders and mechanisms that underlie restricting vs. binge/purge phenotypes are almost entirely unknown. A critical knowledge gap is the neurobiology underlying the developmental trajectory of these illnesses (e.g. transition from primary restriction to binge eating or purging) Our preliminary data argue for a key role of food motivation pathways involving altered Regulatory (homeostatic) and Positive Valence (reward) systems in low-weight eating disorders. Consistent with the Research Domain Criteria (RDoC) initiative, the current study leverages the complementary skills of Multiple-PIs, Dr. Misra from Pediatrics, Dr. Lawson from the Neuroendocrine Unit and Dr. Eddy from Psychiatry to address this knowledge gap through examination of homeostatic and hedonic food motivation pathways that we hypothesize underlie the longitudinal course of these key eating disorder behaviors. We hypothesize that (i) adolescents who successfully restrict to maintain low weight will have lower homeostatic and hedonic appetite, fMRI hypoactivation of food motivation pathways, and higher postprandial PYY, oxytocin and CCK secretion; (ii) those most vulnerable to binge eating behavior will have greater hedonic appetite, fMRI hyperactivation of reward regions, higher postprandial ghrelin and lower postprandial leptin and CCK secretion; and (iii) those who develop or persist in purging behavior will exhibit increased postprandial fullness, fMRI hyperactivation of satiety regions, and higher postprandial BDNF. We will test this model by characterizing adolescents with low-weight eating disorders across multiple units of analysis within an RDoC framework using an fMRI paradigm, neuroendocrine assays, behavioral paradigms, and self-report measures. We will then follow these individuals for a year to assess who switches to a binge/purge illness and who maintains restriction. Building on our pilot data in adults with low-weight restrictive eating disorders, we will use a novel food motivation paradigm developed and validated by our team. Mapping the relationship between hallmark eating disorder behaviors (dietary restriction, binge eating, purging) and food motivation pathways across the overarching domains of the Regulatory and Positive Valence Systems in a longitudinal cohort of adolescents with low-weight eating disorders will enable us to understand mechanisms whereby dysregulated homeostatic and hedonic food motivation lead to development of these behaviors. Characterizing the neural circuitry, neuroendocrine, and behavioral features associated with eating disorder behaviors will (i) provide insight into mechanisms underlying the pathogenesis of these high-mortality illnesses and (ii) allow for identification of future therapeutic targets that impact behavior at a time when eating behaviors are evolving and when intervention may change disease course.