Adam T. Eggebrecht, Ph.D. - US grants

? DESCRIPTION (provided by applicant): The candidate is a committed scientist in optical radiology, who aspires to become an independent investigator focused on developing novel imaging strategies to elucidate underlying mechanisms, inform clinical interventions, and improve outcome of Autism Spectrum Disorder (ASD). Recent advances in functional brain imaging show promise that neural signatures may provide useful markers of ASD severity and may be sensitive to interventional therapy. However, current neuroimaging methods (e.g. functional magnetic resonance imaging, fMRI) are limited in ASD due to the constrained imaging environment. The candidate has been developing diffuse optical tomography (DOT) methods that overcome ergonomic limitations of fMRI and image brain function with a wearable cap. In Aim 1, task-based DOT methods will be established in children with ASD and age/sex/IQ- matched typically developing children (TDC) using a biological motion processing task shown to be sensitive to ASD diagnosis and social ability. In Aim 2, the proposal will employ task-free DOT methods to investigate functional brain organization of in the same subjects as Aim 1. Additionally, Aim 3 of this proposal will extend neuroimaging to three non-overlapping sub-groups of patients with ASD who have been especially challenging to study with fMRI: school-aged children that are minimally verbal, have a low full-scale IQ, or score in the severe range of social ability assessments. These studies will be innovative and significant because the comfortable scanning environment of DOT will enable brain imaging of ASD throughout an extended spectrum of patients, and will lay the groundwork for DOT neuroimaging studies on infants and toddlers at high risk for ASD. The candidate has assembled and has fully engaged a superb interdisciplinary Scholarship Advisory Committee composed of primary mentor Dr. John Constantino, and co-mentors Drs. John Pruett, Bradley Schlaggar, Lori Markson, and Joseph Culver, who are internationally-recognized funded scientists with a diverse range of expertise in ASD research and clinical care, child psychology, neurology, developmental and experimental psychology and functional brain imaging. A well-developed, formal Career Development Program builds on the candidate's extensive experience in physics, systems neuroscience, and technology development by augmenting his current skill set with detailed training in phenotypic assessment and developmental and experimental psychology as they pertain to ASD. This Career Development Award complements the training with world-class coursework in Advanced Cognitive Psychology, Neurobiology of Disease, and Advanced Functional Imaging Methods. The Institution, Washington University School of Medicine, has committed to supporting the candidate by providing the necessary laboratory space and financial resources needed to carry out the proposed research. This training grant will provide the candidate with both the basic science and clinical aspects of autism research, and the critical training period necessary to lead his own independent research effort using optical imaging to address specific questions in ASD.

Project Summary/Abstract The long-term goals of these studies are to establish and apply emerging optical neuroimaging methods, namely diffuse optical tomography (DOT), to map brain function in school-aged children with Autism Spectrum Disorder (ASD) during direct within-room social communication. DOT has the potential to elucidate underlying mechanisms, inform clinical interventions, and improve outcome of ASD, thus these aims are in direct correspondence 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. ASD, defined by deficits in social communication and restricted interests/repetitive behaviors, is a serious psychiatric disorder of childhood, is treatable but currently incurable, and affects an estimated 1 in 68 children in the United States at an estimated annual cost of $268B. Early behavioral and educational interventions, starting at 18-24 months of age, improve outcomes in a subset of patients. Recent advances in functional brain imaging show promise that signatures of brain function may provide reliable markers of ASD severity and may be sensitive to interventional therapy. However, current neuroimaging methods (e.g. functional magnetic resonance imaging, fMRI) are not ideal in research on cognitive-behavioral domains affected in ASD; the loud and constraining MRI environment limits studies on direct within-room social communication involving auditory processing and language generation and presents an excessively challenging setting for sensitive participants, such as school-aged and in particular young children or those severely affected with ASD. DOT provides a compelling alternative that overcomes the significant ergonomic limitations of fMRI and silently images brain function with a wearable cap. However, DOT has yet to be established in studies involving direct within-room social communication. To progress DOT towards this goal, simple language paradigms, validated in healthy adults against subject-matched fMRI, will be adapted for within-room dyadic studies. This project will follow a systematic progression away from the computer interface, standard in neuroimaging, towards a direct natural socio-communicative paradigm, and will lay the foundation for follow-up studies of early childhood development. Aim 1 will use established paradigms of hierarchical language processing for within-subject validation of DOT-based neuroimaging in school-aged children with ASD and sex-, age-, and IQ- matched typically developing controls against fMRI. In Aim 2, a within- room participant will present language and social-communication paradigms. These studies are innovative and significant because the comfortable scanning environment of DOT will enable brain imaging of ASD throughout an extended spectrum of patients, and will lay the groundwork for DOT neuroimaging studies on infants and toddlers at high risk for ASD. This will facilitate longitudinal studies that will map the developmental trajectory of ASD, using paradigms that may combine neuroimaging with behavioral assessment, from infancy to adulthood, and track the effects of interventions with neurophysiological metrics and behavior.

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 infants and toddlers at risk for developing autism spectrum disorder (ASD) while they are awake and engaged within a naturalistic setting. This application is being submitted in response to FOA: RFA-MH-18-200, NIMH Biobehavioral Research Awards for Innovative New Scientists (BRAINS R01), because the PI is an early stage investigator who is building a program of research that 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. ASD, defined by deficits in social communication and restricted interests/repetitive behaviors, is a serious psychiatric disorder of childhood, is treatable but currently incurable, and affects an estimated 1 in 59 children in the United States at an estimated annual cost of $268B. Early behavioral and educational interventions, starting at 18-24 months of age, improve outcomes in a subset of patients. Neuroimaging methods, including both task-based functional magnetic resonance imaging (fMRI) and task-free functional connectivity MRI, have demonstrated sensitivity to neural signatures of ASD that may inform diagnosis and track responses to interventions. However, the MRI environment can prove intolerable for many children due to noise, claustrophobia, and the need to lie supine and still. 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 awake and engaged infants and toddlers. However, studies in young children over multiple imaging sessions present significant challenges in optical data registration and fidelity that motivate a new set of software tools to enable accurate and reliable mapping of brain function. Here we address these needs by developing novel algorithms for photometric head modeling and data fidelity management. With these advancements, we will conduct a prospective longitudinal study of brain function and behavior in toddlers at risk for developing ASD. Specifically, we will measure neural signatures derived from naturalistic movie viewing, determine the relationship between these signatures and behavioral assays across development, and investigate how these signatures are affected in toddlers at risk for ASD in a case-control sample. 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 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 infants and toddlers at risk for developing autism spectrum disorder (ASD) while they are awake and engaged within a naturalistic setting. This application is being submitted in response to FOA: RFA-MH-18-200, NIMH Biobehavioral Research Awards for Innovative New Scientists (BRAINS R01), because the PI is an early stage investigator who is building a program of research that 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. ASD, defined by deficits in social communication and restricted interests/repetitive behaviors, is a serious psychiatric disorder of childhood, is treatable but currently incurable, and affects an estimated 1 in 59 children in the United States at an estimated annual cost of $268B. Early behavioral and educational interventions, starting at 18-24 months of age, improve outcomes in a subset of patients. Neuroimaging methods, including both task-based functional magnetic resonance imaging (fMRI) and task-free functional connectivity MRI, have demonstrated sensitivity to neural signatures of ASD that may inform diagnosis and track responses to interventions. However, the MRI environment can prove intolerable for many children due to noise, claustrophobia, and the need to lie supine and still. 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 awake and engaged infants and toddlers. However, studies in young children over multiple imaging sessions present significant challenges in optical data registration and fidelity that motivate a new set of software tools to enable accurate and reliable mapping of brain function. Here we address these needs by developing novel algorithms for photometric head modeling and data fidelity management. With these advancements, we will conduct a prospective longitudinal study of brain function and behavior in toddlers at risk for developing ASD. Specifically, we will measure neural signatures derived from naturalistic movie viewing, determine the relationship between these signatures and behavioral assays across development, and investigate how these signatures are affected in toddlers at risk for ASD in a case-control sample. 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.