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

基本信息

批准号：
10756236
负责人：
Kamryn T Eddy
金额：
$ 4.99万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10756236
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 Estrogen deficiency 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 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 hypothalamic pituitary gonadal axis improved improved outcome neural novel pleasure preference response restraint reward processing therapy outcome young adult young woman

项目摘要

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 (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) 和高追求瘦身的动力与认知不灵活（认知灵活性）、对事物的反应能力降低有关。奖励（对奖励的初始响应）和改变的奖励评估（延迟），这有助于维持疾病和不良结果。低雌激素血症在 ED-R/E 中很常见 (~60%)，而在其他情况下，低雌激素血症也很常见。与认知不灵活以及奖励反应和评价改变有关。澄清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 ED 病理可能通过实验促进确定新的治疗目标以改善结果治疗方法。我们的初步数据表明：(i) RDoC 认知和认知领域异常与相比，低雌激素青少年/年轻人（与体重无关）的正价系统正常雌激素对照，以及 (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（对美味食物图像的神经反应），改变延迟（增加偏好较大的延迟超过立即较小的奖励），并增加 ED 病理。雌激素缺乏可能因此，通过作用于这些 RDoC 域，在维持 ED-R/E 方面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其他激素（例如骨）进行治疗结果以及我们团队和其他人的数据表明，雌激素替代疗法还可以改善认知能力灵活性、对奖励和延迟的初步反应。此外，我们的数据表明（i）长期雌激素替代疗法可改善 ED 病理学和食物摄入量，并且 (ii) 提高雌激素后的认知灵活性更换可预测 ED 病理改善。在其他性腺机能减退状态下已发表的研究表明，即使短期（8-12周）雌激素/雌激素激动剂给药可以改变认知灵活性和奖励加工。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 中的认知和正价 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 病理学。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 的机制探针。我们将随机抽取 120 名低雌激素女性使用 ED-R/E（16-26 岁）进行为期 12 周的生理雌激素或安慰剂挑战，以评估： RDoC 子结构（更新、表示和维护，即认知灵活性；对报酬;和延迟）8周； 12周时急诊科病理检查；并确定 RDoC 是否有 8 周变化亚结构介导 12 周 ED 病理学的改善。我们假设在 ED-R/E 中，纠正雌激素缺乏将改善认知灵活性、对奖励和延迟的初始反应以及 ED 病理； ED 病理学的改善将通过这些 RDoC 亚结构的变化来介导。