Neural Correlates of Reinforcement Learning Specific to Hyperactivityin Adolescent Anorexia Nervosa

项目总结/摘要 神经性厌食症（AN）是一种慢性进食障碍，在所有精神疾病中死亡率最高， 巨大的成本和全球疾病负担。有一个关键的需要，以确定基于大脑的因素， 使AN症状永久化，并且可以作为现有和新治疗的机制靶点。最 AN的神经生物学研究主要集中在与食物相关的行为上，并将这些行为具体地联系起来。 症状到额纹状体激活的广泛缺陷。然而，迄今为止的生物行为研究未能 解释了大脑机制，可能维持驱动运动，一个令人震惊的症状，经历了 大多数青少年患有AN（59 - 80%）。K23的目标是指导以患者为导向的研究生涯 发展奖是为了更好地理解强化学习的神经计算基础， 青少年与AN谁从事驱动运动（AN-DEx）。具体而言，拟议的研究利用了 决策任务，以检查是否有AN-Dex青少年表现出不同的强化 与食物或运动奖励刺激有关的学习。本研究将比较50名青少年的任务反应 与AN-DEX组相比，50例AN组和100例年龄和活动匹配的对照组。作为二次探索 目的：本研究将利用功能磁共振成像（fMRI）来表征神经活动 证实每组一部分人的任务表现（每组25人，总共75人）。本研究设计将测试 以下假设：目标1：H1a：与对照组相比，AN + AN-Dex将在模型中表现出缺陷- 基于策略（前瞻性计划）对食物和运动刺激的反应。H1b：与AN相比，AN-Dex将 在对运动刺激的反应中表现出基于模型的策略的缺陷;目标2：H2a：与 对照，AN + AN-DEx将显示增加的OFC-NAcc功能连接（额叶-边缘通路， 抑制性控制中涉及的关键脑区）。H2b：与AN相比，AN-Dex将表现出增加 OFC-NAcc功能连接对运动刺激的反应。该项目的数据将证实 DEx的解释模型，查明强化学习的哪些组件在AN-DEx中被改变，以及 确定以行为控制为重点的干预措施可能最有效的方法。这条调查路线将 最终告知有针对性的干预措施，可以更有效地中断DEX和其他强迫性AN 症状目前的研究还将作为概念和技能方面的指导和培训工具， 对候选人当前的项目和下一步至关重要。具体而言，拟议的培训将使 候选人获得新的知识：（一）认知神经科学和神经基板具体到吃 障碍，（ii）神经计算任务和建模，以及（iii）功能磁共振成像的初步培训。这个项目和 实现培训目标将启动候选人在转化神经科学领域的独立职业生涯 并为未来结合联合收割机复杂分析方法和 神经成像来改善饮食失调的治疗。

PROJECT SUMMARY/ABSTRACT Anorexia nervosa (AN) is an often-chronic eating disorder with the highest mortality rate of any mental illness, significant costs, and global disease burden. There is a critical need to identify brain-based factors that perpetuate AN symptoms and that may serve as mechanistic targets for existing and novel treatments. Most neurobiological studies in AN have focused on food-related behavior, and have specifically linked these symptoms to broad deficits in frontostriatal activation. However, biobehavioral research to date has failed to account for brain-based mechanisms that may maintain driven exercise, an alarming symptom experienced by a majority of adolescents with AN (59-80%). The goal of this K23 mentored patient-oriented research career development award is to better understand the neurocomputational underpinnings of reinforcement learning in adolescents with AN who engage in driven exercise (AN-DEx). Specifically, the proposed study leverages decision tasks to examine whether adolescents with AN-DEx demonstrate differences in reinforcement learning related to food or exercise reward stimuli. This study will compare task responses in 50 adolescents with AN-DEx, to those of 50 with AN, and 100 age-and activity-matched controls. As a secondary exploratory aim, this study will use functional magnetic resonance imaging (fMRI) to characterize neural activity substantiating task performance for a portion of each group (25 from each, 75 total). This study design will test the following hypotheses: Aim 1: H1a: Compared to controls, AN + AN-DEx will demonstrate deficits in model- based strategy (forward planning) in response to food and exercise stimuli. H1b: Compared to AN, AN-DEx will demonstrate deficits in model-based strategy in response to exercise stimuli; Aim 2: H2a: Compared to controls, AN + AN-DEx will demonstrate increased OFC - NAcc functional connectivity (frontal-limbic pathway, key brain regions implicated in inhibitory control). H2b: Compared to AN, AN-DEx will demonstrate increased OFC-NAcc functional connectivity in response to exercise stimuli. Data from this project will substantiate an explanatory model of DEx, pinpoint which components of reinforcement learning are altered in AN-DEx, and identify ways in which behavioral control-focused interventions may be most effective. This line of inquiry will ultimately inform targeted interventions that can more effectively interrupt DEx, and other compulsive AN symptoms. The current study will also serve as a vehicle for mentorship and training in concepts and skills that are critical to the candidate’s current project, and next steps. Specifically, the proposed training will allow the candidate to gain new knowledge in: (i) cognitive neuroscience and neural substrates specific to eating disorders, (ii) neurocomputational tasks and modeling, and (iii) preliminary training in fMRI. This project and fulfillment of the training goals will launch the candidate’s independent career in the translational neuroscience of AN and lay groundwork for future high-impact studies that combine sophisticated analytic approaches and neuroimaging to improve eating disorder treatment.