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

摘要： 青春期是一个皮质可塑性很强的时期，伴随着认知、社交、 和适应性功能。尽管这一时期充满希望，但这也是一个社会 人际关系和情绪处理可能会加剧，首先是抑郁症和其他形式的精神病理 浮出水面。缺乏对患有自闭症谱系障碍(ASD)的青少年的纵向研究，加上 无序的异质性，模糊了我们对这一复杂时期发展的理解，并阻碍了 治疗的发展。因此，我们建议扩大我们对加州大学戴维斯分校儿童的纵向调查 心灵研究所自闭症现象组项目进入青春期队列。在具体目标#1中，我们预测以下方面 基于授权期研究的青少年自闭症患者的认知发展。我们假设ASD会 继续表现出至少三种智力功能(IQ)轨迹--一组持续以下的 从儿童早期到青春期(持续低智商或低智商)的平均智商(75)，智商和智商低的一组； 75在儿童早期，青春期至少增加1个标准差(积极的改变者或 +CHG)，以及智商持续平均或更好的一组(&gt；75)(持续高或P-高)。我们也 预测预备性认知控制将继续与TYP相当，但将与 行为不灵活；所有群体在情节记忆方面的表现都相当；以及 这种P-LOW会显示出较少的负面情绪错误记忆。在第二个具体目标中，我们考察了社交 自闭症儿童中期和青春期之间的意识、动机和适应功能。我们 预计与P-Low和P-High相比，+CHG将显示出更好的社会意识和功能， 虽然所有的组都表现出社会动机的下降，而且休息状态下的功能磁共振成像 执行/认知控制(ECN)、默认模式(DMN)和显著之间的功能连接(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 可以通过纹状体的同时参与来预测。具体目标#3调查了 儿童期中期至青春期自闭症患者的抑郁状态。我们测试了一个重要的模型，预测 儿童中期和青春期之间的抑郁加重在P-High和+CHG患者中更为常见， 这将与提高社会意识、更好地保留负面情绪记忆有关，以及 不太灵活的认知控制。此外，我们预测，在经过充分验证的基于任务的功能磁共振成像中，悲伤 自省范式、ECN、DMN、SN、杏仁核和海马区之间的功能连接 在悲伤期间，内省会与P-High和+CHG的青少年抑郁有关。我们也 预测，与黄金标准的临床医生访谈相比，父母问卷将低估抑郁症的报告 在P-LOW中。这项关于青少年认知、社会功能和抑郁的纵向检查 ASD有可能识别抑郁症的早期标志和更多量身定制的精确药物解决方案。

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.