The Neural Substrates of Higher-Level Learning in Autism

描述（由申请人提供）：ASD患者在学习和记忆方面表现出独特的能力和残疾模式。他们对项目、事实、细节和惯例表现出完整的低层次学习。然而，他们在更高层次的学习中表现出障碍，包括抽象，解决问题，使用必须用自我生成的概念图式组织的信息，以及概括学习。这种不平衡和以情境为中心的学习概况对ASD患者的学术，社会和适应功能产生了深远的影响。此外，虽然与ASD的其他神经认知理论相一致，但基于学习的方法提供了与动物和计算模型系统的更清晰的联系，从而增强了其阐明病理生理机制的潜力。在这个应用程序中，我试图澄清神经机制的基础上更高层次的学习缺陷，并帮助确定其对青少年ASD的日常功能的确切影响。实验将包括行为和功能磁共振成像研究，对象为年龄在12-17岁，11个月的ASD青少年（n=40），以及年龄、智商和性别匹配的具有典型发育的对照参与者。（TYP; n=40）。第一个目标，研究了大脑中的神经回路，水平学习障碍的青少年与ASD使用功能磁共振成像和传递性推理范式，其中包括测试低级别的训练和高级别的抽象关系的刺激。这个目标采用了一个快速的事件相关的功能磁共振成像研究，这是解释在我们最近的行为研究的传递性推理学习在年轻人的背景下，和两个突出的机械学习模型。我们预测，ASD患者在更高级别的推理过程中会表现出额叶功能和功能连接的降低。在第二个目标中，我们研究了低水平和高水平学习的行为和神经指标如何与学习成绩，社会问题解决，以及限制和重复行为相关，使用回归分析来研究阅读，写作，数学和社会问题解决能力，以及限制的兴趣和重复行为，是如何通过抽象推理和概括的神经认知测量来预测的，和传递性推理的神经指标。这项工作提出了一个新的机制模型的ASD;试图联系神经认知的真实的生活问题;集中在研究不足的青少年人口在一个潜在的有效窗口进行干预;推进搜索心理药理学，心理社会和神经再训练的补救策略，为这些人谁是非常有能力的，但经验更高层次的学习问题，限制了他们的人类潜力;使用贝叶斯状态空间的定量方法，仔细研究学习的出现，并建立了一个概念基础，通过在小鼠ASD模型，可用于多巴胺能和其他药物治疗认知缺陷的临床前试验的平行任务的发展，在小鼠学习的泛化未来的调查。

DESCRIPTION (provided by applicant): Individuals with ASD display a unique pattern of abilities and disabilities in learning and memory. They exhibit intact lower-level learning of item, facts, details, and routines. However, they manifest impairments in higher- level learning involving abstraction, problem solving, using information that must be organized with self- generated conceptual schemas, and generalizing learning. This uneven and situation-focused learning profile has a profound impact on the academic, social, and adaptive functioning of those with ASD. Furthermore, while consistent with other neurocognitive theories of ASD, a learning-based approach offers clearer links to animal and computational model systems, thus enhancing its potential to illuminate pathophysiological mechanisms. In this application, I attempt to clarify the neural mechanisms underlying higher-level learning deficits, and help identify their precise effects on the day-to-day functioning of adolescents with ASD. Experiments will include behavioral and fMRI studies in a well-characterized group of adolescents aged 12-17 years, 11 months with ASD (n=40), and age, IQ, and gender-matched control participants with typical development (TYP; n=40).The first Aim, investigates the neural circuitry underlying higher-level learning deficits in adolescents with ASD using fMRI and a transitive inference paradigm which includes testing on lower-level trained and higher-level abstracted relationships between stimuli. This Aim employs a rapid event- related fMRI study which is interpreted in the context of our recent behavioral study of transitive inference learning in young adults, and two prominent mechanistic learning models. We predict that individuals with ASD will demonstrate reduced frontal functioning and functional connectivity during higher-level inferences. In the second Aim, we investigate how behavioral and neural indices of lower and higher-level learning relate to academic performance, social problem solving, and restricted and repetitive behaviors using regression analyses to examine how reading, writing, math, and social problem solving abilities, and restricted interests and repetitive behaviors, are predicted by neurocogntive measures of abstract reasoning and generalization, and neural indices of transitive inference. This work proposes a new mechanistic model of ASD; attempts to link neurocognition to real life problems; focuses on the understudied adolescent population during a potentially effective window for intervention; advances the search for psychopharmacological, psychosocial, and neural retraining remediation strategies for these individuals who are extremely able, but experience higher-level learning problems that limit their human potential; uses Bayesian state-space quantitative methods to closely examine the emergence of learning; and establishes a conceptual basis for future investigation of generalization of learning in mice through the development of parallel tasks in mouse models of ASD that can be used as preclinical assays for dopaminergic and other pharmacological treatments for cognitive deficits.