Brain Reward Circuits and Computational Modeling in Adolescent Anorexia Nervosa

描述（由申请人提供）：神经性厌食症（AN）是青少年中第三常见的慢性疾病，其死亡率是15-24岁女性所有死亡原因相关死亡率的12倍。AN的特征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，我们将研究青少年的大脑奖励途径，以及这些回路如何受到营养不良和再喂养的影响，以及在AN中经常改变的应激激素。我们的长期目标是表征AN中的病理性脑回路，这些脑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。我们检验了这样一个假设，即青少年AN的特征是多巴胺相关的大脑奖赏通路的反应增加。拟议的结果表明，青少年AN的营养不良与大脑奖赏敏感性的提高有关。在目标2中。我们测试的假设，体重恢复的青少年AN将有改善的大脑奖励敏感性相比，AN谁没有恢复体重，但仍然会显示出夸张的大脑反应相比，控制青少年。这将表明，在青少年AN的大脑奖励功能的长期持久的改变超出了体重恢复。目标3.我们将测试的假设，即压力，喂养和奖励相关的激素皮质醇，脱氢表雄酮（DHEA）及其硫酸盐（DHEA-S），将与青少年AN奖励敏感性增加。这将表明潜在的机制，有助于改变奖励处理青少年AN。我们将研究12-17岁的限制型AN青少年，在治疗开始时体重不足，以及体重恢复成功或未能恢复体重后。将结果与年龄和教育程度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，以及功能性磁共振脑成像（fMRI）。我们将研究青少年的大脑反应奖励刺激的期望，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影响。我们将进一步应用于脑成像结果的计算模型，模拟大脑多巴胺的行动，这将有助于了解多巴胺相关的大脑功能在青少年AN。这些模型还将有助于识别更大的大脑奖励回路，该回路涉及认知和情绪对青少年AN和健康对照组大脑奖励功能的影响。应激激素皮质醇、DHEA和DHEA-S对摄食和大脑多巴胺功能有影响，并显示AN的改变。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大脑奖赏功能的影响。

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.