Neural Correlates of Reinforcement Learning Specific to Hyperactivityin Adolescent Anorexia Nervosa

项目摘要/摘要 神经性厌食症(AN)是一种常见的慢性饮食障碍，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。迫切需要确定基于大脑的因素， 使症状持续存在，这可能成为现有和新疗法的机械性靶点。多数 AN的神经生物学研究主要集中在与食物相关的行为上，并特别将这些行为与 症状表现为额叶纹状体激活的广泛缺陷。然而，到目前为止，生物行为研究未能 解释了可能保持动力运动的基于大脑的机制，这是一种令人震惊的症状，由 大多数青少年患有老年痴呆症(59%-80%)。K23的目标是指导以患者为导向的研究生涯 开发奖是为了更好地理解强化学习的神经计算基础 患有运动障碍的青少年(ANDEX)。具体地说，拟议的研究利用 检查患有ANDEX的青少年是否表现出强化方面的差异的决策任务 与食物或运动相关的学习奖励刺激。这项研究将比较50名青少年的任务反应 对于50名患有AN的患者和100名年龄和活动匹配的对照组，使用An-Dex。作为二次探索者 目的：本研究将使用功能磁共振成像(FMRI)来表征神经活动。 证明每组一部分人的任务表现(每组25人，总计75人)。这项研究设计将测试 以下假设：目标1：H1a：与对照组相比，An+an-Dex将显示模型- 以应对食物和运动刺激为基础的策略(前瞻性计划)。H1B：与An相比，An-Dex将 证明基于模型的策略对运动刺激的反应存在缺陷；目标2：H2A：与 对照组，An+An-Dex将显示OFC-NAcc功能连接性增加(额叶-边缘通路， 与抑制控制有关的关键脑区)。H_2B：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。来自该项目的数据将证实 Dex的解释模型，精确指出强化学习的哪些组成部分在Dex中发生了变化，以及 确定以行为控制为重点的干预可能最有效的方法。这条调查路线将 最终告知可以更有效地中断Dex和其他强迫症的有针对性的干预措施 症状。目前的研究还将成为指导和培训以下概念和技能的工具 对候选人当前的项目和下一步行动至关重要。具体而言，拟议的培训将使 在以下方面获得新知识的候选人：(I)认知神经科学和特定于饮食的神经底物 (2)神经计算任务和建模，以及(3)功能磁共振初步培训。这个项目和 培训目标的实现将开启候选人在翻译神经科学领域的独立职业生涯 并为未来的高影响研究奠定基础，这些研究结合了复杂的分析方法和 神经成像，以改善进食障碍的治疗。

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.