Brain Reward Circuits and Computational Modeling in Adolescent Anorexia Nervosa

青少年神经性厌食症的大脑奖励回路和计算模型

• 批准号: 8517204
• 负责人: Guido KW Frank
• 金额: $ 29.58万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-26 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517204
• 关键词: 17 year old; Accounting; Adolescent; Adult; Affect; Age; American Psychiatric Association; Animal Model; Anorexia Nervosa; Anxiety; Basic Science; Biological Markers; Biology; Body Image; Body Weight decreased; Brain; Brain imaging; Cause of Death; Chronic Disease; Cognition; Computer Simulation; Data; Death Rate; Disease; Dopamine; Eating; Eating Disorders; Education; Emotions; Failure; Female; Female Adolescents; Food; Food Processing; Fright; Functional Magnetic Resonance Imaging; Goals; Hormones; Hydrocortisone; Inorganic Sulfates; Intervention; Learning; Link; Magnetic Resonance; Malnutrition; Methods; Modeling; Motivation; Neurotransmitter Receptor; Neurotransmitters; Outcome; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Public Health; Recovery; Research; Rewards; Role; Saliva; Scanning; Shapes; Simulate; Staging; Steroids; Stimulus; Stress; System; Taste Perception; Testing; Time; Underweight; Unspecified or Sulfate Ion Sulfates; Weight; Weight Gain; age group; base; conditioning; critical period; dehydroepiandrosterone; expectation; feeding; food restriction; improved; insight; mathematical model; mortality; neurosteroids; novel; response; restoration; reward circuitry; reward processing

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) is the third most common chronic illness among adolescents, and its mortality rate is 12 times higher than the death rate associated with all causes of death for females 15-24 years old. AN is characterized by severe weight loss and refusal to eat, suggesting altered brain processing of food rewards. In this application we will study in adolescents with AN brain reward pathways, and how those circuits are affected by malnutrition and re-feeding, as well as stress hormones that are frequently altered in AN. Our long term goal is to characterize pathologic brain circuits in AN that are biomarkers for the disorder, link those alterations to specific neurotransmitter mechanisms, and identify potential treatment targets for adolescent AN. In Aim 1. we test the hypothesis that adolescent AN is characterized by an increased response of dopamine related brain reward pathways. The proposed results will suggest that malnutrition in adolescent AN is associated with heightened brain reward sensitivity. In Aim 2. We test the hypothesis that weight recovered adolescent AN will have improved brain reward sensitivity compared to AN who did not restore weight, but will still show an exaggerated brain response compared to control adolescents. This will indicate long lasting alterations in brain reward function in adolescent AN beyond weight recovery. In Aim 3. We will test the hypothesis that the stress, feeding and reward related hormones cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), will be associated with increased reward sensitivity in adolescent AN. This will indicate potential mechanisms that contribute to altered reward processing in adolescent AN. We will study adolescents with restricting type AN, ages 12-17 years old, when underweight at the begin of treatment, as well as after either successful weight restoration or failure to restore weight. Results will be compared to age and education matched healthy adolescents. We will use taste and monetary reward stimuli and tasks that are related to brain dopamine function, together with functional magnetic resonance brain imaging (fMRI). We will examine adolescent AN brain response to reward stimulus expectation, as well as unexpected and expected receipt of reward stimuli. Those brain processes have important implications on reward learning and conditioning. We will further apply on the brain imaging results computational models that simulate brain dopamine action, and this will help getting insight into dopamine related brain function in adolescent AN. Those models will also help identify the larger brain reward circuitry that involves the effects of cognition and emotion on brain reward function in adolescent AN and healthy controls. The stress hormones cortisol, DHEA and DHEA-S have implications on feeding and brain dopamine function and show alterations in AN. We will analyze those neurosteroid hormones in saliva and test their affect on brain reward function in adolescent AN.

描述（由申请人提供）：神经性厌食症（AN）是青少年中第三大最常见的慢性疾病，其死亡率是15-24岁女性所有死因死亡率的12倍。AN的特点是严重的体重减轻和拒绝进食，这表明大脑对食物奖励的处理发生了改变。在这个应用程序中，我们将研究患有AN的青少年大脑奖励通路，以及这些回路如何受到营养不良和重新喂食的影响，以及AN中经常改变的应激激素。我们的长期目标是表征AN的病理脑回路，这些神经回路是该疾病的生物标志物，将这些改变与特定的神经递质机制联系起来，并确定青少年AN的潜在治疗靶点。在目标1中。我们测试了青少年AN的特征是多巴胺相关大脑奖励通路的反应增加的假设。提出的结果将表明青少年AN营养不良与大脑奖励敏感性升高有关。在目标2中。我们检验了体重恢复的青少年AN与未恢复体重的AN相比，大脑奖励敏感性有所提高的假设，但与对照组相比，大脑反应仍然会被夸大。这表明除了体重恢复之外，青少年AN的大脑奖励功能还会发生长期的改变。在目标3。我们将验证应激、喂养和奖励相关激素皮质醇、脱氢表雄酮（DHEA）及其硫酸盐（DHEA- s）与青少年AN奖励敏感性增加有关的假设。这将揭示导致青少年AN奖赏加工改变的潜在机制。我们将研究患有限制性AN型的青少年，年龄在12-17岁，在治疗开始时体重不足，以及在体重恢复成功或恢复失败后。结果将与年龄和受教育程度相匹配的健康青少年进行比较。我们将使用与大脑多巴胺功能相关的味觉和金钱奖励刺激和任务，以及功能磁共振脑成像（fMRI）。我们将研究青少年AN大脑对奖励刺激预期的反应，以及意外和预期收到的奖励刺激。这些大脑过程对奖励学习和条件反射有重要的影响。我们将进一步在脑成像结果上应用模拟脑多巴胺作用的计算模型，这将有助于深入了解青少年AN中多巴胺相关的脑功能。这些模型还将有助于确定更大的大脑奖励回路，该回路涉及青少年AN和健康对照组中认知和情感对大脑奖励功能的影响。应激激素皮质醇、DHEA和DHEA- s对摄食和脑多巴胺功能有影响，并在AN中表现出改变。我们将分析唾液中的这些神经类固醇激素，并测试它们对青少年AN脑奖励功能的影响。