The high and rapidly increasing prevalence of autism spectrum disorder (ASD) presents a major public health challenge, as costs of care and the need for more effective interventions are growing. While classified as a brain development disorder, its diagnostic criteria remain entirely behavioral because reliable biomarkers have yet to be established. Despite a growing number of findings converging on network dysfunction and abnormal brain connectivity as potential biomarkers of the disorder, the precise patterns of the network abnormalities in ASD are still a matter of debate. Furthermore, given the positive impact that early interventions can have on both behavior and the developing brain, identification of specific patterns of brain disturbances characteristic of ASD early in life, when ASD symptoms first emerge and manifest, is needed to enhance early detection and opportunities for early interventions. The present application aims to implement a multimodal approach, in a longitudinal design, combining cutting-edge techniques from anatomical, functional and diffusion MRI to examine functional and structural network changes and their links to well documented early anatomical overgrowth in young children with ASD. Specifically, we propose to fully characterize the macro- and micro- structure, and function of cortical networks in 18-24 month old toddlers who exhibit first behavioral signs of ASD as compared to age-matched typically developing (TD) peers, and to examine changes in brain network organization from the age of the first symptom onset through the full symptom manifestation at age 4-5 years, using a longitudinal design. The multimodal MRI approach, including anatomical and functional connectivity MRI (aMRI, fcMRI) and advanced diffusion-weighted imaging (DWI), implementing advanced acquisition and analytic methods, will yield a range of measures indexing brain network maturation across different scales, including volumetric growth, functional and structural connectivity, and cortical organization. Thus, the proposed design will allow characterization of changes in brain network organization coinciding with the accelerated brain growth in ASD, the timing of ASD's deviation from typical network development, and the links between these neurobiological changes and the progressive expression of behavioral symptoms. More specifically, in line with PI's research focus on social neural circuits, the project will examine whether atypical organization and connectivity of sensorimotor networks (considered to be potential 'building blocks' for higher- order social cognition) early in life will predict behaviorl and brain impairments in the social domain at later time points, consistent with the NIMH strategic objective to determine how brain development maps onto observable behavior. The unique contributions of the proposed research are expected to be an understanding of primary causative brain anomalies underlying ASD symptomatology (which cannot be isolated in older children) and identification of early biomarkers that may inform targeted interventions.
As a disorder of brain development, autism spectrum disorder (ASD) affects how the brain grows and works; yet, brain development trajectories accompanying the emergence of first symptoms of ASD, at age 18-24 months, are almost completely unknown. This is because brain imaging studies have been conducted almost exclusively with high functioning adolescents and adults with autism. The proposed longitudinal multimodal imaging study of functional and structural brain network organization during the most critical developmental window when first ASD symptoms emerge promises to identify neural markers of risk that can guide diagnostic and intervention strategies for this increasingly prevalent life-long disorder.
