Neurodevelopment of cognitive control in autism: adolescence to young adulthood

 描述(由申请者提供)：患有自闭症的青少年已经开始向成年期过渡。尽管社会支出巨大，但他们中的许多人在成年初期继续经历着极差的社会和角色功能以及生活满意度。非常需要进行更深入的研究，以调查导致这一严重问题的因素，并为干预措施的发展提供信息。认知控制是NIMH的RDoC项目确定的认知的关键和组成部分。与反应抑制相关的认知控制障碍是自闭症患者中最常见的缺陷之一，并与较差的社会和适应功能以及增加的重复行为症状有关。虽然认知控制的神经基础在青春期典型发育(TYP)期间基本成熟，但我们的实验室已经证明，在这一时期，患有ASD的人在认知控制方面经历了持续的延迟。与TYP相比，他们显示减少了对成熟的“主动”控制的使用，这种控制依赖于外侧前额叶皮质(LPFC)的参与和额顶连接的增加，以准备目标导向行为。相反，他们变得越来越依赖于通过LPFC和前扣带皮质(ACC)的晚期参与的“反应性”控制进行晚期纠错。我们的发现表明，持续过度依赖不成熟的认知控制机制可能与ASD的不良成人结局有关。这意味着认知控制的不成熟及其相关的神经回路构成了成人功能低下的潜在生物标记物，也是治疗的目标/终点。我们在拟议的行为和功能磁共振成像(FMRI)加速纵向设计(ALD)研究中测试了这一论点，研究对象为206名12-22岁的青少年(n=88名ASD；n=88名匹配的TYP)。在具体目标1中，我们比较了青春期和自闭症儿童从青春期到成年期认知控制行为测量的发展轨迹。与我们的横断面研究一致，我们预测，三分之二的自闭症患者在青壮年期间在认知控制任务上的表现将持续滞后，尽管其余三分之一的人将表现出与TYP相当的表现。在具体目标#2中，我们考察了从青春期到成年的认知控制神经机制的发展。我们假设，像TYP一样，没有滞后的1/3将表现出主动认知控制，而表现滞后的2/3将表现出更持续的反应控制发展。在具体目标#3中，我们调查了自闭症患者青年期认知控制的两种模式与成人功能之间的关系。我们预测，主动控制的使用将与社会和角色功能、复杂的关系信息处理和生活满意度正相关；而反应性控制的使用将与内化和重复行为相关。认知控制除了是结果标记物和治疗目标外，还有可能在实验治疗学试验中作为一种机制。

 DESCRIPTION (provided by applicant): A "tsunami" of adolescents with ASD has begun to transition to adulthood. Despite enormous societal expenditures, many of them continue to experience extremely poor social and role functioning and life satisfaction in early adulthood. There is a great need for more in-depth research to investigate factors contributing to this serious problem and inform the development of interventions. Cognitive control is a critical and component of cognition identified by the RDoC project of the NIMH. Cognitive control impairments related to response inhibition are among the most frequently reported deficits in individuals with ASD, and have been associated with poorer social and adaptive functioning as well as increased repetitive behavior symptoms. While the neural substrates of cognitive control mature substantially during adolescence in typical development (TYP), our Lab has demonstrated that those with ASD experience persistent delays in cognitive control during this period. Relative to TYP, they show reduced use of mature "proactive" control that relies on increased engagement of the lateral prefrontal cortex (LPFC) and fronto-parietal connectivity in preparation for goal- directed behavior. Instead, they become increasingly reliant on late error correction through "reactive" control involving late engagement of the LPFC and the anterior cingulate cortex (ACC). Our findings suggest that persistent over-reliance on immature mechanisms of cognitive control may be associated with poor adult outcomes in ASD. This would imply that the immaturity of cognitive control and its associated neural circuitry constitute potential biomarkers of risk for poor adult functioning, as well as a therapeutic target/endpoint. We test this contention in the proposed behavioral and functional magnetic resonance imaging (fMRI) accelerated longitudinal design (ALD) study of 206 adolescents recruited at ages 12-22 (n = 88 ASD; n = 88 matched TYP). In Specific Aim #1, we compare the developmental trajectory of behavioral measures of cognitive control from adolescence into young adulthood in TYP and ASD. Consistent with our cross-sectional studies, we predict that 2/3 of those with ASD will show a persistent lag in performance on cognitive control tasks through young adulthood, although the remaining 1/3 will show performance comparable to TYP. In Specific Aim #2, we examine the development of the neural mechanisms of cognitive control from adolescence into young adulthood. We hypothesize that, like TYP, the 1/3 showing no lag will exhibit proactive cognitive control, whereas the 2/3 exhibiting a lag will exhibit more persistent development of reactive control. In Specific Aim #3, we investigate relationships between the two modes of cognitive control and adult functioning in young adulthood in ASD. We predict that the use of proactive control will be positively associated with social and role functioning, complex relational information processing, and life satisfaction; whereas reactive control will be associated with internalizing and repetitive behaviors. In addition to being an outcome marker and treatment target, cognitive control holds the potential to serve as a mechanism in experimental therapeutics trials.