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 对苗条的驱使与认知缺乏灵活性(认知灵活性)、对 奖励(对奖励的初始反应)和改变的奖励估值(延迟)，这有助于维持 疾病和糟糕的结果。低雌激素血症在ED-R/E中很常见(约60%)，在其他情况下也是如此 与认知上的僵化以及奖赏反应和估值的改变有关。澄清两者之间的联系 雌激素状态、认知灵活性、对奖赏和延迟的初始反应以及ED病理可能 促进确定新的治疗目标，以通过试验性的 治疗方法。我们的初步数据表明：(1)RDoC认知和认知领域的异常 雌激素水平低下的青少年/年轻人的正价系统(与体重无关)与 正常雌激素对照，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(对美味食物图像的神经反应)，改变的延迟(增加的偏好 对于较大的延迟超过即时较小的奖励)，并增加ED病理。雌激素缺乏可能 因此，通过作用于这些RDoC结构域，在ED-R/E的维护中起到关键的机械作用。重要的是 性腺功能低下的青少年/年轻女性通常用雌激素替代其他部位(如骨骼)。 结果，来自我们团队和其他人的数据表明，雌激素替代也可以改善认知能力 灵活性，对奖励和延迟的初步反应。此外，我们的数据显示：(I)长期雌激素 替代疗法改善了ED的病理和食物摄入，以及(Ii)提高了雌激素后的认知灵活性 替代治疗预示着ED病理的改善。在其他性腺功能低下状态发表的研究表明，即使是 短期(8-12周)服用雌激素/雌激素激动剂可以改变认知灵活性和奖赏 正在处理。现在，关键是要检查雌激素缺乏是否会导致全身功能障碍 ED-R/E中认知和正价RDoC结构域以及是否纠正雌激素缺乏 通过对这些领域的影响来改善ED的病理。为了填补这一空白，我们建议使用生理学 雌激素替代作为ED-R/E中的机械性探针我们将随机选择120名低雌激素血症女性 用ED-R/E(16-26岁)对生理性雌激素或安慰剂12周的挑战进行评估：对 RDoC子结构(更新、表示和维护，即认知灵活性；对 奖励；和延迟)在8周；在12周时进行ED病理检查；并确定RDoC在8周内是否发生变化 亚结构在12周的ED病理改善中起中介作用。我们在ED-R/E中假设，更正 雌激素缺乏会改善认知灵活性、对奖赏和延迟的初始反应以及ED病理； 而ED病理的改善将通过这些RDoC亚结构的变化来调节。

Summary 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 (Cognitive Flexibility), reduced responsiveness to reward (Initial Response to Reward), and altered reward valuation (Delay), which contribute to maintenance of illness 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 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 subconstructs (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.