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

NOSI 对雌激素在饮食失调神经生物学中的作用：饮食失调认知灵活性和奖励的研究

• 批准号: 10766612
• 负责人: Kamryn T Eddy
• 金额: $ 46.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10766612
• 关键词: Adolescence; Adolescent; Age; Agonist; Brain; Cognitive; Data; Development; Eating; Eating Disorders; Estrogen Replacements; Estrogen Therapy; Estrogen deficiency; Estrogens; Female; Food; Functional disorder; Gonadal Hormones; Hormones; Image; Impaired cognition; Investigational Therapies; Link; Maintenance; Mediating; Neurobiology; Neurocognitive; Outcome; Pathology; Physiological; Placebos; Play; Positive Valence; Psychopathology; Publishing; Randomized; Research Domain Criteria; Rewards; Role; System; Thinness; Time; Update; Weight; Work; bone; dietary restriction; estrogenic; excessive exercise; flexibility; improved; improved outcome; neural; novel; preference; response; reward processing; young adult; young woman

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.

抽象的 饮食失调（EDS）通常在性腺激素变化和大脑快速的时候开始青春期发作 发展。 EDS以极端饮食限制和/或过度运动（ED-R/E）和高度为特征 瘦弱的动力与认知的僵化性，降低奖励反应能力和改变有关 奖励估值，有助于疾病维持和不良后果。低雌激素血症很常见 在ED-R/E（〜60％）中，在其他情况下，与认知的僵化和奖励改变了 响应能力和估值。澄清雌激素状态，认知灵活性，初始之间的联系 对奖励和延迟以及ED病理的反应可能有助于鉴定新的治疗方法 通过实验治疗方法改善结果的目标。我们的初步数据表示：（i） 低雌激素青少年的认知和正价系统的RDOC领域异常 与正常雌激素对照相比，年轻人（独立于体重），以及（ii）低雌激素血症 与降低的认知灵活性和对奖励的初步反应有关（对可口的神经反应 食物图像），延迟的改变（对较大的延迟比立即较小的奖励的偏好增加），并且 增加了ED病理。因此，雌激素缺乏症可能在维持ED-R/E中起关键机械作用 通过对这些RDOC域作用。重要的是，通常对性交青少年/年轻女性进行治疗 替代其他（例如骨骼）结果的雌激素，我们团队和其他结果的数据证明了 雌激素替代也提高了认知灵活性，对奖励和延迟的初始反应。更远， 我们的数据表明，（i）长期雌激素替代可改善ED病理学和食物摄入量，以及（ii） 雌激素替代后改善的认知灵活性预测了ED病理的改善。出版的作品 在其他性降压状态下，即使是短期（8-12周）的雌激素/雌激素激动剂给药 可以改变认知灵活性和奖励处理。现在检查是否缺乏雌激素 导致ED-R/E中认知和正价RDOC域的功能障碍，以及 是否纠正雌激素缺乏症可以通过对这些影响来改善ED病理的影响 域。为了填补这一空白，我们建议将生理雌激素替代作为ED-的机械探针 关于。我们将以ED-R/E（16-26岁）的120个低雌激素女性随机，为12周的挑战 评估生理雌激素或安慰剂：对RDOC构建体的影响（更新，表示和 维护，即认知灵活性；对奖励的初步回应；和延迟）8周； ED病理12 几周；并确定RDOC子构造的8周变化是否介导了12周的改善 ED病理学。我们假设在ED-R/E中，校正雌激素缺乏将提高认知灵活性， 对奖励和延迟以及ED病理学的初步反应； ED病理学的改善将是 由这些RDOC子构造的变化介导。