Neuroimaging signatures of autism: Linking brain function to genes and behavior

自闭症的特征是巨大的表型异质性，可能是由于其复杂的遗传和神经基础。我们自己的实验室和其他实验室的研究提供了越来越多的证据，表明自闭症谱系障碍(ASD)患者对社会刺激的反应性降低，大脑连接模式发生变化。此外，我们最近发现，功能和结构上的异常连接与遗传性疾病的易感性显著相关。尽管取得了这些重大进展，但关键问题 关于(I)可能导致对社会刺激的反射和奖赏相关反应减少的潜在机制，(Ii)这些回路的功能与异常连接之间的关系，(Iii)后者在多大程度上反映了自闭症发展轨迹改变的原因或影响，以及更广泛地说，(Iv)已知的自闭症遗传风险因素如何影响从属于复杂社会行为的大脑回路，仍然没有答案。建议数 研究旨在解决这些问题，同时寻求在ASD的相互竞争的神经生物学账户之间建立协同效应。利用我们NIH资助的ASD儿童研究的历史，以及因此研究先前特征队列的机会，我们处于独特的地位，可以系统地绘制患有和不患有ASD的儿童大脑活动和连接的纵向变化，并将观察到的发育轨迹与行为表型和自闭症风险基因联系起来。 更具体地说，采用交叉滞后纵向设计，我们将在两个先前表征的年龄队列(首次评估的年龄分别为6-9岁和12-14岁)的两个时间点(相隔3年)进行功能磁共振成像(FMRI)、静息功能磁共振成像(rS-fMRI)和扩散张量成像(DTI)，并将这些数据与行为表型和ASD风险多态联系起来。这种综合研究方法将 利用每种研究方法的长处以及它们之间的协同作用，确定与典型发育最早的背离，并描绘驱动和约束社会性脑ASD非典型发育的基因、大脑和行为之间的复杂相互作用。

Autism is characterized by tremendous phenotypic heterogeneity likely due to its complex genetic and neural underpinnings. Research from our own lab and others' have provided mounting evidence of decreased responsivity to social stimuli and altered patterns of brain connectivity in individuals with autism specrum disorders (ASD). Moreover, we have recently shown that aberrant functional and structural connectivity is significantly related to genetic vulnerability to the disorder. Despite these significant strides, critical questions remain unanswered with regard to (i) the underlying mechanisms that may give rise to the reduced mirroring and reward-related responses to social stimuli we have previously characterized, (ii) the relationship between the functioning of these circuits and aberrant connectivity, (iii) the extent to which the latter reflects the cause or the effect of altered developmental trajectories in ASD and, more broadly, (iv) how known genetic risk factors for ASD impact brain circuitry subserving complex social behaviors. The proposed studies are designed to address these issues, while seeking to build synergy amongst competing neurobiological accounts of ASD. Capitalizing on our history of NIH funded research in children with ASD, and thus the opportunity to study previously characterized cohorts, we are uniquely positioned to systematically chart longitudinal changes in brain activity and connectivity in children with and without ASD, and to relate the observed developmental trajectories to both behavioral phenotypes and autism risk genes. More specifically, using a cross-lagged longitudinal design, we will perform functional magnetic resonance imaging (fMRI), resting-state fMRI (rs-fMRI) and diffusion tensor imaging (DTI) at two timepoints (3 years apart) in two previously characterized age cohorts (6-9 & 12-14 years of age at first assessment) and relate these data to behavioral phenotypes and ASD risk polymorphisms. This integrated research approach will exploit the strengths of each investigative method, as well as the synergy amongst them, to identify the earliest departures from typical development and delineate the complex interactions among genes, brain,and behavior that drive and constrain the atypical development of the social brain ASD.