Neural and behavioral predictors of cognitive development and internalizing problems in adolescents with autism spectrum disorder

摘要： 青春期是一个大脑皮层可塑性强的时期，伴随着认知、社会、 和适应性功能。尽管这一时期的特点是充满希望，但它也是一个社会 关系和情绪处理可能会加剧，抑郁症和其他形式的精神病理学首先 出现。缺乏对青少年自闭症谱系障碍（ASD）的纵向研究，再加上 混乱的异质性，在这个复杂的时期，我们对发展的理解模糊了， 治疗发展。因此，我们建议扩大我们的纵向调查儿童从加州大学戴维斯分校 MIND研究所自闭症表型组项目队列进入青春期。在具体目标#1中，我们预测了 基于资助期研究的ASD青少年认知发展。我们假设ASD会 继续表现出至少三种智力功能（IQ）轨迹-一组持续低于 从幼儿期到青春期的平均智商（< 75）（Persistent Low或P-Low），智商< 75在幼儿期，到青春期增加至少1个标准差（积极改变者或 +CHG），以及具有持续平均或更好的IQ（>75）的组（持续高或P-高）。我们也 预测预备认知控制将继续与TYP相当，但将与 行为能力;所有组在情景记忆方面表现出可比的表现;以及 P-低会表现出更少的负面情绪错误记忆。在具体目标#2中，我们研究了社会 意识，动机和适应性功能之间的童年中期和青春期的ASD。我们 预测+CHG与P-低和P-高相比将显示出改善的社会意识和功能， 而所有组都显示出社会动机下降，静息状态下的功能性磁共振成像 执行/认知控制（ECN）、默认模式（DMN）和显著性之间的功能连接（FC） (SN)网络将预测青少年的社会意识和社会功能，而社会动机 是通过纹状体的同时参与来预测的。具体目标#3调查了 ASD患者在童年中期和青春期之间的抑郁症。我们测试了一个著名的模型预测， 童年中期和青春期之间抑郁增加在P-高和+CHG中更常见， 并将与增加的社会意识，更大的负面情绪记忆的保留， 认知控制的灵活性较低。此外，我们预测，在一个有效的基于任务的功能磁共振成像悲伤， 内省范式，ECN、DMN、SN、杏仁核和海马之间的功能连接 在P-High和+CHG中，悲伤内省与青少年抑郁相关。我们也 与金标准的临床医生访谈相比，预测父母问卷将低估抑郁症 在P低。本研究对患有抑郁症的青少年的认知、社会功能和抑郁进行了纵向研究， ASD有可能识别抑郁症的早期标志物和更有针对性的精准医疗解决方案。

ABSTRACT: Adolescence is a period of strong cortical plasticity accompanied by significant changes in cognitive, social, and adaptive functioning. Despite the promise characteristic of this period, it is also a time when social relationships and emotion processing may intensify, and depression and other forms of psychopathology first emerge. The lack of longitudinal studies of adolescents with autism spectrum disorder (ASD), coupled with the disorder's heterogeneity, clouds our understanding of development during this complex period, and hinders treatment development. We thus propose to extend our longitudinal investigation of children from the UC Davis MIND Institute Autism Phenome Project cohort into adolescence. In Specific Aim #1, we predict aspects of cognitive development in adolescents with ASD based on grant period studies. We hypothesize that ASD will continue to exhibit at least three trajectories of intellectual functioning (IQ) -- a group with persistently below average IQs (< 75) from early childhood through adolescence (Persistently Low or P-Low), a group with IQs < 75 in early childhood that increase by at least 1 standard deviation by adolescence (Positive Changers or +CHG), and a group with persistently average or better IQs (>75) (Persistently High or P-High). We also predict that preparatory cognitive control will continue to be comparable to TYP, but will be associated with behavioral inflexibility; that all groups will exhibit comparable performance on aspects of episodic memory; and that P-Low will show fewer negative emotional false memories. In Specific Aim #2, we examine social awareness, motivation, and adaptive functioning in between middle childhood and adolescence in ASD. We predict that +CHG will show improved social awareness and functioning compared to P-Low and P-High, while all groups show declining social motivation, and that resting state functional magnetic resonance imaging functional connectivity (FC) between the executive/cognitive control (ECN), default mode (DMN), and salience (SN) networks will be predictive of adolescent social awareness and social functioning while social motivation is predicted by concurrent engagement of the striatum. Specific Aim #3 investigates the emergence of depression in ASD between middle childhood and adolescence. We test a prominent model predicting that increased depression between middle childhood and adolescence will be more common in P-High and +CHG, and will be associated with increased social awareness, greater retention of negative emotional memories, and less flexible cognitive control. Additionally, we predict that during a well-validated task-based fMRI Sadness Introspection Paradigm, functional connectivity between the ECN, DMN, SN, amygdala, and hippocampus during sadness introspection will be associated with adolescent depression in P-High and +CHG. We also predict that parent questionnaires, compared to gold standard clinician interviews, will under-report depression in P-Low. This longitudinal examination of cognition, social functioning, and depression in adolescents with ASD holds the potential to identify early markers of depression and more tailored precision medicine solutions.