NOSI to The Role of Estrogen in the Neurobiology of Eating Disorders: A Study of Cognitive Flexibility and Reward in Eating Disorders

摘要 进食障碍(EDS)通常发生在青春期，此时性腺激素变化和大脑快速 发展。以极端饮食限制和/或过度运动为特征的ED(ED-R/E)和高 瘦身的驱动力与认知的僵化、奖赏反应的降低和改变有关 奖励评估，这会导致疾病维持和糟糕的结果。低雌激素血症很常见 在ED-R/E(~60%)中，以及在其他情况下，与认知缺乏灵活性和奖赏改变有关 响应性和估值。阐明雌激素状态、认知灵活性、初始 对奖赏和延迟的反应和ED病理可能有助于识别新的治疗方法 目标是通过实验性治疗方法改善结果。我们的初步数据显示：(I) 雌激素水平低下的青少年认知和正价系统RDoC领域的异常 年轻成年人(与体重无关)与正常雌激素对照组的比较，以及(Ii)低雌激素血症 与认知灵活性降低和对奖励的初始反应(对可口的神经反应)有关 食物图像)、改变的延迟(更倾向于更大的延迟而不是立即的更小的奖励)，以及 增加ED的病理改变。雌激素缺乏可能在ED-R/E的维持中起关键的机制作用 通过对这些RDoC域采取行动。重要的是，性腺功能低下的青少年/年轻女性通常得到治疗。 雌激素替代用于其他(如骨骼)结果，来自我们团队和其他人的数据表明 雌激素替代也提高了认知的灵活性，对奖励和延迟的初始反应。此外， 我们的数据显示：(I)长期雌激素替代改善了勃起功能障碍的病理和食物摄入，以及(Ii) 雌激素替代治疗后认知灵活性的提高预示着ED病理的改善。已出版作品 在其他性腺功能低下的状态下，即使是短期(8-12周)雌激素/雌激素激动剂的服用 可以改变认知灵活性和奖励处理。现在至关重要的是检查雌激素缺乏 导致ED-R/E中认知和正价RDoC领域的功能障碍，以及 纠正雌激素缺乏是否通过影响这些细胞来改善ED病理 域名。为了填补这一空白，我们建议使用生理性雌激素替代作为ED-ED的机械性探针。 R/E我们将120名患有ED-R/E的低雌激素女性(年龄16-26岁)随机分为12周的挑战 评估生理性雌激素或安慰剂：对RDoC结构的影响(更新、表示和 维持，即认知灵活性；对奖励的初始反应；和延迟)8周；12周时ED病理学 ；并确定RDoC亚结构8周的变化是否中介了12周的 ED病理学。我们假设，在ED-R/E中，纠正雌激素缺乏将提高认知灵活性， 对奖励和延迟的初步反应，以及ED病理学；ED病理学的改进将是 由这些RDoC子结构中的变化调节。

Abstract Eating disorders (EDs) typically onset in adolescence at a time of gonadal hormone changes and rapid brain development. EDs characterized by extreme dietary restriction and/or excessive exercise (ED-R/E) and high drive for thinness are associated with cognitive inflexibility, reduced reward responsiveness, and altered reward valuation, which contribute to illness maintenance and poor outcomes. Hypoestrogenemia is common in ED-R/E (~60%), and in other conditions has been linked to cognitive inflexibility and altered reward responsiveness and valuation. Clarifying the link between estrogen status, Cognitive Flexibility, Initial Response to Reward and Delay, and ED pathology may facilitate identification of novel treatment targets to improve outcomes via an experimental therapeutics approach. Our preliminary data indicate: (i) abnormalities in RDoC domains of Cognitive and Positive Valence systems in hypoestrogenic adolescents/ young adults (independent of weight) compared to normo-estrogenic controls, and (ii) that hypoestrogenemia is associated with reduced Cognitive Flexibility and Initial Response to Reward (neural response to palatable food images), altered Delay (increased preference for larger delayed over immediate smaller rewards), and increased ED pathology. Estrogen deficiency may thus play a key mechanistic role in maintenance of ED-R/E by acting on these RDoC domains. Importantly, hypogonadal adolescents/young women are commonly treated with estrogen replacement for other (e.g. bone) outcomes, and data from our team and others demonstrate that estrogen replacement also improves Cognitive Flexibility, Initial Response to Reward and Delay. Further, our data show that (i) long-term estrogen replacement improves ED pathology and food intake, and (ii) improved Cognitive Flexibility following estrogen replacement predicts improved ED pathology. Published work in other hypogonadal states shows that even short-term (8-12 weeks) estrogen/estrogen agonist administration can alter cognitive flexibility and reward processing. It is now critical to examine whether estrogen deficiency contributes to dysfunction across Cognitive and Positive Valence RDoC domains in ED-R/E, and whether correcting estrogen deficiency improves improves ED pathology via its impact on these domains. To fill this gap, we propose using physiologic estrogen replacement as a mechanistic probe in ED- R/E. We will randomize 120 hypoestrogenemic females with ED-R/E (ages 16-26) to a 12-week challenge of physiologic estrogen or placebo to evaluate: effects on RDoC constructs (Updating, Representation and Maintenance i.e. Cognitive Flexibility; Initial Response to Reward; and Delay) at 8 weeks; ED pathology at 12 weeks; and determine whether 8-week changes in RDoC subconstructs mediate the 12-week improvement in ED pathology. We hypothesize that in ED-R/E, correcting estrogen deficiency will improve Cognitive Flexibility, Initial Response to Reward and Delay, and ED pathology; and that improvement in ED pathology will be mediated by changes in these RDoC subconstructs.