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.

总结 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， 瘦的驱动器与认知灵活性（认知灵活性）有关，减少对 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 疾病和不良后果。低雌激素血症在ED-R/E中很常见（约60%），在其他情况下， 与认知能力和改变的奖励反应和评价有关。澄清以下方面之间的联系 雌激素状态、认知灵活性、对奖励和延迟的初始反应以及艾德病理可能 促进识别新的治疗靶点，以通过实验性 治疗方法。我们的初步数据表明：（i）认知和认知功能的RDoC域异常， 低雌激素性青少年/年轻成人（与体重无关）中的阳性效价系统与 正常雌激素对照，和（ii）低雌激素血症与认知灵活性降低有关， 对奖励的初始反应（对可口食物图像的神经反应），改变的延迟（增加偏好） 对于较大的延迟超过立即较小的奖励）和增加的艾德病理学。雌激素缺乏可能 因此，通过作用于这些RDoC结构域，在维持ED-R/E中发挥关键的机制作用。重要的是， 性腺功能减退的青少年/年轻女性通常用雌激素替代治疗其他（例如骨） 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功能， 灵活性，对奖励和延迟的初始反应。此外，我们的数据表明，（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）雌激素治疗后改善了认知灵活性 置换可预测改善的艾德病理学。在其他性腺功能减退状态下发表的研究表明，即使 短期（8-12周）雌激素/雌激素激动剂给药可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 通过其对这些领域的影响改善艾德病理学。为了填补这一空白，我们建议使用生理 雌激素替代治疗作为ED-R/E的机制探针。我们将随机抽取120名低雌激素血症女性 ED-R/E（年龄16-26岁）对生理雌激素或安慰剂的12周挑战，以评估： RDoC子结构（更新，表示和维护，即认知灵活性;对 奖励;和延迟）; 12周时的艾德病理学;并确定RDoC的8周变化是否 亚构建体介导艾德病理学的12周改善。我们假设在ED-R/E中， 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; 并且艾德病理学的改善将由这些RDoC亚结构的变化介导。