Homeostatic and Hedonic Food Motivation Underlying Eating Disorder Trajectories

描述（由申请人提供）：进食障碍是一种异质性疾病，其特征是极端饮食限制、暴饮暴食和排泄的异常行为。该过程通常涉及青少年发病，并且在超过一半的个体中，从主要的限制性行为过渡到狂欢/清除行为。低体重进食障碍的病理生理学和限制与暴饮暴食/清除表型的基础机制几乎完全未知。一个关键的知识差距是神经生物学基础的发展轨迹，这些疾病（例如，从主要限制过渡到暴饮暴食或清洗）我们的初步数据认为，食物动机途径的关键作用，涉及改变调节（稳态）和积极的效价（奖励）系统在低体重饮食失调。与研究领域标准（RDoC）倡议一致，目前的研究利用了多PI的互补技能，来自儿科的Misra博士，来自神经内分泌科的Lawson博士和来自精神病学的Eddy博士通过检查我们假设这些关键饮食失调行为的纵向过程的稳态和享乐食物动机途径来解决这一知识差距。我们假设：（i）成功控制体重以维持低体重的青少年将具有较低的自我平衡和享乐食欲，fMRI食物动机通路的低激活，以及较高的餐后PYY，催产素和CCK分泌;（ii）最容易暴饮暴食行为的青少年将具有较高的享乐食欲，fMRI奖励区域的超激活，较高的餐后生长激素释放肽和较低的餐后瘦素和CCK分泌;和（iii）那些发展或坚持清除行为的人将表现出增加的餐后饱腹感、饱腹感区域的fMRI超活化和更高的餐后BDNF。我们将测试这个模型的特点青少年与低体重饮食失调跨多个单元的分析RDoC框架内使用功能磁共振成像范例，神经内分泌测定，行为范例，自我报告的措施。然后，我们将对这些人进行为期一年的跟踪调查，以评估谁会转为暴饮暴食/净化疾病，谁会保持限制。基于我们在患有低体重限制性饮食障碍的成年人中的试点数据，我们将使用我们团队开发和验证的新型食物动机范式。在低体重饮食失调青少年的纵向队列中，绘制标志性饮食失调行为（饮食限制，暴饮暴食，清除）和跨监管和正价系统总体领域的食物动机途径之间的关系，将使我们能够理解失调的稳态和享乐食物动机导致这些行为发展的机制。表征与进食障碍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的发病机制的深入了解，以及（ii）允许识别未来的治疗靶点， 在饮食行为不断发展的时候，以及在干预可能改变疾病进程的时候，影响行为。

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.