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（ED）通常发生在青春期，此时性腺激素变化和大脑快速发育。 发展以极端饮食限制和/或过度运动（ED-R/E）为特征的ED， 瘦的驱动力与认知能力有关，减少奖励反应，改变 奖励评估，这有助于疾病的维持和不良结果。低雌激素血症很常见 在ED-R/E（~60%）和其他条件下，与认知能力和奖励改变有关 响应性和评价。阐明雌激素状态、认知灵活性、初始 对奖励和延迟的反应以及艾德病理学可能有助于识别新的治疗方法 通过实验性治疗方法来改善结果。我们的初步数据表明：（一） 低雌激素青少年认知和正价系统RDoC域的异常 与正常雌激素对照组相比，年轻成人（与体重无关），以及（ii）低雌激素血症 与认知灵活性和对奖励的初始反应（对可口的神经反应）降低有关。 食物图像），改变延迟（增加对较大延迟的偏好，而不是立即较小的奖励），以及 增加的艾德病理。因此，雌激素缺乏可能在维持ED-R/E中发挥关键的机制作用 通过作用于这些RDoC域。重要的是，性腺功能减退的青少年/年轻女性通常接受 雌激素替代治疗其他（如骨）结果，我们团队和其他人的数据表明， 雌激素替代疗法也能改善认知灵活性，对奖励和延迟的初始反应。此外，本发明还 我们的数据显示：（i）长期雌激素替代治疗改善了艾德的病理学和食物摄入，以及（ii） 雌激素替代治疗后认知灵活性的改善预示着艾德病理学的改善。发表的作品 在其它性腺功能减退状态中显示即使短期（8-12周）雌激素/雌激素激动剂给药 可以改变认知灵活性和奖励处理。现在关键是要检查雌激素缺乏是否 导致ED-R/E中认知和正价RDoC域的功能障碍， 纠正雌激素缺乏是否通过对这些细胞的影响改善了艾德病理学 域.为了填补这一空白，我们建议使用生理性雌激素替代作为艾德的机制探针。 R/E。我们将120名患有ED-R/E的低雌激素血症女性（年龄16-26岁）随机分为12周的挑战组， 生理雌激素或安慰剂来评估：对RDoC结构的影响（更新，表示和 8周时的维持（即认知灵活性;对奖励的初始反应;和延迟）; 12周时的艾德病理学 并确定RDoC亚结构的8周变化是否介导了RDoC亚结构的12周改善。 艾德病理学。我们假设在ED-R/E中，纠正雌激素缺乏会改善认知灵活性， 对奖励和延迟的初始反应，以及艾德病理学;并且艾德病理学的改善将 通过这些RDoC亚结构的变化介导。

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.