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

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: 10311480
• 负责人: Kamryn T Eddy
• 金额: $ 78.31万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311480
• 关键词: Adolescence; Adolescent; Age; Agonist; Anterior; Body Weight; Brain; Cognitive; Color; Data; Development; Diet Records; Eating; Eating Disorders; Energy Intake; Equipment and supply inventories; Estrogen Replacements; Estrogen Therapy; Estrogens; Female; Food; Functional Magnetic Resonance Imaging; Functional disorder; Gonadal Hormones; Hormonal Change; Hormones; Image; Impaired cognition; Investigational Therapies; Link; Maintenance; Measures; Mediating; Neurobiology; Neurocognitive; Outcome; Palate; Pathology; Performance; Physiological; Placebos; Play; Positive Valence; Prefrontal Cortex; Psychopathology; Publishing; Questionnaires; Randomized; Research Domain Criteria; Rewards; Role; Symptoms; System; Testing; Thinness; Time; Update; Ventral Striatum; Weight; Work; body dissatisfaction; bone; bone health; cingulate cortex; cognitive control; cognitive system; dietary; dietary restriction; discounting; estrogenic; excessive exercise; experience; flexibility; girls; health data; hypothalamic pituitary gonadal axis; improved; improved outcome; novel; pleasure; preference; relating to nervous system; response; restraint; reward processing; therapy outcome; young adult; young woman

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.

概括 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（认知灵活性）有关，降低了对 奖励（对奖励的最初回应）和更改奖励估值（延迟），这有助于维护 疾病和不良结果。低雌激素血症在ED-R/E（〜60％）中很常见，在其他情况下是 与认知能力的僵化和奖励反应能力和估值有关。澄清链接 雌激素状况，认知灵活性，对奖励和延迟的初步反应以及ED病理可能 促进通过实验的新型治疗靶标识别新的治疗目标 治疗方法。我们的初步数据表明：（i）认知和 低雌激素青少年/年轻人（与体重无关）的正价系统与 正常雌激素对照，（ii）低雌激素血症与认知灵活性降低有关 对奖励的初步反应（对可口食品图像的神经反应），延迟的改变（偏好增加 对于立即较小的奖励，较大的延迟）并增加了ED病理学。雌激素缺乏可能 因此，通过对这些RDOC域作用，在维持ED-R/E的维持中起关键的机理作用。重要的是， 肾小管青少年/年轻女性通常用其他雌激素替代（例如骨骼）治疗 结果，我们的团队和其他人的数据表明，雌激素替代也可以改善认知 灵活性，对奖励和延迟的初步响应。此外，我们的数据表明（i）长期雌激素 替代品改善了ED病理和食物摄入量，以及（ii）雌激素后的认知灵活性提高 替代预测的改善了ED病理。在其他性降低国家发表的工作表明，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 加工。现在检查雌激素缺乏是否导致功能障碍 ED-R/E中的认知和正价RDOC域，以及是否纠正雌激素缺乏症 通过对这些领域的影响来改善ED病理。要填补这一空白，我们建议使用生理学 雌激素替代作为ED-R/E中的机械探针。我们将随机化120个低雌激素女性 ED-R/E（16-26岁）面对生理雌激素或安慰剂的12周挑战：对 RDOC子构建（更新，表示和维护，即认知灵活性；对 报酬;和延迟）8周； 12周的ED病理学；并确定RDOC的8周变化 亚构造介导ED病理学的12周改善。我们假设在ed-r/e中，纠正 雌激素缺乏将提高认知灵活性，对奖励和延迟的初始反应以及ED病理学； ED病理学的改善将由这些RDOC亚构建体的变化介导。