Project Summary / Abstract The long-term goal of these studies is to advance high-density diffuse optical tomography (HD-DOT) methods for evaluating brain-behavior relationships in school-aged children with autism spectrum disorder (ASD) and toddlers at risk for developing ASD while they imitate novel gross motor movements within a naturalistic setting. We are submitting this application in response to FOA: PA-21-200, Research on Autism Spectrum Disorders. In typical development, imitation is associated with the emergence of several behaviors crucial to normal social interaction and communication, including joint attention, play initiation, social affiliation, and prosocial behaviors. Indeed, patterns of impaired imitation, and visual-motor integration (VMI) more generally, have been observed across a wide range of children with ASD, with imitation ability being associated with social-communicative skills in ASD. A challenge in developing imitation as a phenotypic biomarker is the lack of understanding of the neural mechanisms contributing to imitation deficits in ASD, and the variable results in the neuroimaging literature. The mixed findings may be due to the significant limitations in assessing motor imitation in the functional magnetic resonance imaging (fMRI) scanning environment where there are severe restrictions on motion. This disconnect between consistent behavioral differences in children with ASD and the variable neuroimaging literature motivated the current proposal to use instead HD-DOT during motor imitation. HD-DOT provides a compelling alternative that overcomes the significant ergonomic limitations of fMRI and silently images brain function with a wearable cap in a naturalistic setting ideal for studies on gross motor movement and imitation in both school- aged children and toddlers. The proposed program of research is highly innovative, transformative, and has the potential to elucidate underlying mechanisms, inform clinical interventions, and improve outcome of ASD. As such, this research is harmonious with the mission of NIMH: to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. Early behavioral and educational interventions, starting at 18-48 months of age, improve outcomes in a subset of patients. Neuroimaging methods have demonstrated sensitivity to neural signatures of ASD that may inform diagnosis and track responses to interventions. Here we propose to forge new paths with a dual-armed study of brain function directly underlying motor movement in school- and pre-school-aged children with ASD. Specifically, we will measure neural signatures while participants perform naturalistic motor imitation and movement observation. These data may provide markers to the specific aspects of impaired behavior observed in ASD, namely affected social communication, receptive and expressive language, motor coordination disruption, and even restricted and repetitive behaviors. Further, this strategy provides a diversified approach to assessment that will be applicable across development, and may facilitate identification of common mechanisms by which disparate genetic pathways to autism result in the broad autistic phenotype.

Project Narrative It is estimated that ~1/54 children are affected with Autism Spectrum Disorder (ASD), one of the most serious psychiatric disorders of childhood, defined by deficits in social communication and restricted interests/repetitive behaviors. Recent advances in functional brain imaging show promise that pre-diagnostic neural signatures for ASD may provide useful risk markers and may even be sensitive to responses to interventional therapies that have been shown to improve quality of life. In this R01 proposal, we will extend high-density diffuse optical tomography methods, which can silently image brain function in a naturalistic setting and have the potential to be useful for pre-symptomatic risk monitoring, for an innovative study of brain function underlying overt motor imitation in preschool- and school-aged children with ASD.