Intervention-induced plasticity of flexibility and learning mechanisms in ASD

干预引起的自闭症谱系障碍灵活性和学习机制的可塑性

• 批准号: 10237686
• 负责人: LAUREN KENWORTHY
• 金额: $ 22.76万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-21 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10237686
• 关键词: 18 year old; Adaptive Behaviors; Address; Adolescence; Attention; Behavior; Behavioral; Biological Markers; Brain; Canis familiaris; Categories; Child; Clinical; Cognitive; Cognitive Therapy; Computer Models; Coupled; Development; District of Columbia; Effectiveness of Interventions; Enrollment; Environment; Executive Dysfunction; Exhibits; Feedback; Functional Magnetic Resonance Imaging; Gap Junctions; Generations; Heterogeneity; Impairment; Individual; Individual Differences; Infrastructure; Intellectual and Developmental Disabilities Research Centers; Intelligence; Intervention; Investigation; Knowledge; Learning; Light; Link; Medial; Memory; Mental Health; Methodology; Modeling; Outcome; Outcome Measure; Performance; Prediction of Response to Therapy; Prefrontal Cortex; Psychological Transfer; Recording of previous events; Research Personnel; Resources; Rest; Roter; Specificity; Temporal Lobe; Testing; Time; Treatment outcome; Universities; Youth; adolescent with autism spectrum disorder; autism spectrum disorder; autistic children; base; behavior measurement; behavioral response; bench to bedside; comorbidity; design; executive function; experience; flexibility; improved; individual variation; intervention effect; neural correlate; neurobehavioral; neuroimaging; neuromechanism; novel; personalized medicine; prototype; relating to nervous system; response; skills; social; social skills; success; treatment response

PROJECT SUMMARY This exploratory project between CNH and Georgetown University leverages the DC-IDDRC infrastructure and its Neuroimaging, Neurobehavioral and Clinical Translational Cores to test mechanistic hypotheses about individual differences in the ability to transfer learned knowledge to novel settings in Autism Spectrum Disorders (ASD). The history of ASD intervention is rife with poor real-world outcomes and high heterogeneity in generalization success (1). One known contributing factor is executive dysfunction, particularly behavioral inflexibility (2, 3). Understanding this nexus of learning and executive function (4) likely holds the key to resolving the generalization challenge in ASD, but it has received little attention. The proposed project aims to elucidate the association between learning and flexibility by testing whether intervening to promote flexible behavior in ASD changes learning and associated neural mechanisms. The scientific premise of the proposed study is that flexible use of learned concepts depends on generating prototypes, whereas learning tuned to individual exemplars promotes specificity (5, 6). Current models of concept learning (7) have used computational modeling of individual generalization performance and model-based functional magnetic resonance imaging (m-fMRI) to attribute prototype-generation to ventral medial prefrontal cortex (vmPFC) and exemplar-biased learning to the medial temporal lobes (MTL) (8). We propose that variability in prototype/exemplar learning mechanisms is associated with behavioral flexibility and explains differences in adaptive and treatment outcomes. We employ a longitudinal case-controlled design in 54 14-18 year old youth with ASD at 3 time-points 8 months apart, each including m-fMRI during category learning and behavioral measurement of executive and adaptive function. Aim 1 tests the hypothesis that individual variation in learning biases (prototype/exemplar) and their neural correlates predicts behavioral flexibility (Time1) and is stable over time (Time2). Aim 2 tests plasticity of learning mechanisms induced by a cognitive-behavioral intervention for flexibility (Unstuck-and-On-Target) that targets development of prototypical knowledge (9). Intervention will strengthen prototype learning, and associated vmPFC involvement will be associated with better behavioral response to intervention. Aim 3 tests hypothesis about intervention-induced plasticity of intrinsic functional connectivity. Stronger resting- state functional connectivity between MTL and vmPFC specifically and network connectivity of the MTL subsystem of the default mode network (10) will be associated with prototype learning and intervention response. Our approach is novel, methodologically in the use of individualized characterization of learning mechanisms, and theoretically in unifying learning and executive function to explain mechanisms of treatment response and heterogeneity in treatment outcome in ASD. Findings will inform larger investigations of personalized treatments for promoting adaptive behavior in ASD.

项目概要 CNH 和乔治城大学之间的这一探索性项目利用了 DC-IDDRC 基础设施及其神经影像、神经行为和临床转化核心进行测试 关于将学到的知识转移到小说中的能力的个体差异的机制假设 自闭症谱系障碍 (ASD) 中的设置。 ASD 干预的历史充满了糟糕的现实世界 结果和泛化成功的高度异质性 (1)。一个已知的影响因素是执行力 功能障碍，特别是行为僵化 (2, 3)。了解学习和执行功能的这种联系 (4) 可能是解决自闭症谱系障碍泛化挑战的关键，但它很少受到关注。这 拟议项目旨在通过测试是否可以阐明学习与灵活性之间的关联 促进自闭症谱系障碍患者灵活行为的干预会改变学习和相关的神经机制。 本研究的科学前提是，所学概念的灵活使用取决于生成 原型，而根据个体范例进行学习可以提高特异性 (5, 6)。当前的概念模型 学习（7）已经使用了个体泛化性能的计算建模和基于模型的 功能磁共振成像（m-fMRI）将原型生成归因于腹侧内侧前额叶 皮质 (vmPFC) 和内侧颞叶 (MTL) 的范例偏向学习 (8)。我们建议 原型/范例学习机制的可变性与行为灵活性和 解释了适应性和治疗结果的差异。我们采用纵向病例对照设计 在 54 名患有 ASD 的 14-18 岁青少年中，在相隔 8 个月的 3 个时间点进行研究，每个时间点均包括类别期间的 m-fMRI 执行和适应功能的学习和行为测量。目标 1 检验假设 学习偏差（原型/范例）的个体差异及其神经相关预测 行为灵活性（时间 1）并且随着时间的推移保持稳定（时间 2）。目标 2 测试学习的可塑性 由认知行为干预引起的灵活性机制（Unstuck-and-On-Target） 目标是开发原型知识 (9)。干预将加强原型学习，并且 相关的 vmPFC 参与将与对干预的更好的行为反应相关。目标 3 测试 关于干预引起的内在功能连接可塑性的假设。更强的休息- 状态 MTL 和 vmPFC 之间的功能连接以及 MTL 的网络连接 默认模式网络（10）的子系统将与原型学习和干预响应相关联。 我们的方法是新颖的，在方法论上使用学习机制的个性化特征， 并从理论上统一学习和执行功能来解释治疗反应和 ASD 治疗结果的异质性。研究结果将为更大规模的个性化治疗研究提供信息 促进自闭症谱系障碍 (ASD) 的适应性行为。