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 (ED) 通常在青春期发病，此时性腺激素发生变化，大脑快速变化 发展。 ED 的特点是极度饮食限制和/或过度运动 (ED-R/E) 和高 对瘦身的渴望与认知僵化、奖励反应能力降低以及改变有关。 奖励评估，这有助于疾病维持和不良结果。低雌激素血症很常见 在 ED-R/E (~60%) 和其他情况下，与认知不灵活和奖励改变有关 响应能力和估值。阐明雌激素状态、认知灵活性、初始能力之间的联系 对奖励和延迟的反应以及 ED 病理学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。我们的初步数据表明：（i） 低雌激素青少年认知和正价系统 RDoC 域异常/ 与正常雌激素对照相比，年轻人（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（对美味的神经反应）的降低有关 食物图像），改变延迟（与立即较小的奖励相比，更倾向于较大的延迟），以及 ED 病理增加。因此，雌激素缺乏可能在 ED-R/E 维持中发挥关键机制作用 通过作用于这些 RDoC 域。重要的是，性腺功能减退的青少年/年轻女性通常接受治疗 用雌激素替代其他（例如骨骼）结果，我们团队和其他人的数据表明 雌激素替代还可以改善认知灵活性、对奖励和延迟的初始反应。更远， 我们的数据表明 (i) 长期雌激素替代可以改善 ED 病理学和食物摄入量，以及 (ii) 雌激素替代后认知灵活性的改善预示着 ED 病理学的改善。发表作品 在其他性腺功能减退状态中，即使是短期（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。现在至关重要的是检查雌激素是否缺乏 导致 ED-R/E 中认知和​​正价 RDoC 域功能障碍，以及 纠正雌激素缺乏是否可以通过对这些因素的影响来改善 ED 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 ED 的机制探针 关于。我们将随机抽取 120 名患有 ED-R/E 的低雌激素女性（16-26 岁）接受为期 12 周的挑战： 生理雌激素或安慰剂来评估：对 RDoC 结构的影响（更新、表示和 维护，即认知灵活性；对奖励的初步反应；和延迟）8周； 12岁时ED病理 几周；并确定 RDoC 子结构的 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，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 病理学的改善将是 由这些 RDoC 子结构的变化介导。