Project Grant R21MH133239

MULTIFACTORIAL DYNAMIC MODELING OF BRAIN ASYMMETRY IN NEURODEVELOPMENTAL DISORDERS - PROJECT SUMMARY/ABSTRACT NEURODEVELOPMENTAL DISORDERS (NDDS) COMPRISE OF A GROUP OF DISORDERS ASSOCIATED WITH ABNORMAL BRAIN DEVELOPMENT, LEADING TO ABNORMAL BRAIN FUNCTION OF LANGUAGE, MOTOR, BEHAVIOR, MEMORY AND LEARNING. NDDS, E.G., ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD), AUTISM SPECTRUM DISORDER (ASD) AND INTELLECTUAL DISABILITY, AFFECT APPROXIMATELY 15% OF CHILDREN IN THE UNITED STATES AND POSE A SIGNIFICANT PUBLIC HEALTH BURDEN ON SOCIETY. THE CAUSES OF NDDS ARE STILL LARGELY UNKNOWN. A GROWING BODY OF EVIDENCE SUPPORT THAT MOST NDDS ARE RESULT FROM A COMBINATION OF GENETIC, BIOLOGICAL, PSYCHOSOCIAL AND ENVIRONMENTAL RISK FACTORS RATHER THAN ANY SINGLE ORIGIN. FURTHERMORE, THERE ARE HIGH RATES OF CO-OCCURRENCE BETWEEN DIFFERENT NDDS, AS WELL AS SIMILARITIES IN FUNCTIONAL IMPAIRMENT AND CLINICAL FEATURES, WHICH MAKE THE DIAGNOSIS AND TREATMENT OF NDDS DIFFICULT. HEMISPHERIC ASYMMETRY IS A CORE ELEMENT OF THE BRAIN'S USUAL ORGANIZATION REQUIRED FOR OPTIMAL FUNCTIONING AND A KEY LANDMARK OF BRAIN DEVELOPMENT. WE HAVE RECENTLY REVEALED THAT BRAIN ASYMMETRY IS CLOSELY ASSOCIATED WITH NDDS AND THEIR GENETIC/ENVIRONMENTAL RISK FACTORS AND CLINICAL FEATURES, THOUGH THE CAUSAL INTERACTING RELATIONSHIPS ARE UNCLEAR. HERE WE HYPOTHESIZE THAT THE BIOLOGICAL PROCESS OF BRAIN ASYMMETRY DEVELOPMENT IS INFLUENCED BY COMPLEX GENETIC AND ENVIRONMENTAL CONTRIBUTORS FOR NDDS, AND DIFFERENT DYSREGULATIONS OF THIS MULTIFACTORIAL DYNAMIC SYSTEM MAY MEDIATE THE EMERGENCE OF DIFFERENT CLINICAL SYMPTOMS/BEHAVIORS IN NDDS. PREVIOUS STUDIES OF BRAIN ASYMMETRY IN NDDS ARE LIMITED BY THE CASE-CONTROL AND CROSS-SECTIONAL STUDY DESIGNS, AND THE FACTORS CONTRIBUTING TO NDDS HAVE YET TO BE STUDIED USING AN INTEGRATIVE METHOD. THIS PROPOSAL SEEKS TO OVERCOME THE LIMITATIONS OF PREVIOUS STUDIES BY APPLYING OUR NOVEL INTEGRATIVE ANALYTIC ALGORITHMS AND A TRANSDIAGNOSTIC APPROACH TO SEVERAL EXISTING PUBLIC AND INTERNAL LONGITUDINAL (AND CROSS-SECTIONAL) DATASETS (TOTAL N~16,000), WHICH ARE DESIGNED FOR STUDYING BRAIN DEVELOPMENT AND RELATED HEALTH ISSUES AND COMPRISE EXTENSIVE DATA OF DEMOGRAPHICS, MEDICAL RECORDS, BEHAVIORAL/CLINICAL ASSESSMENTS, COGNITIVE TESTS, GENETICS, AND MULTIMODAL BRAIN IMAGING. THE PROPOSED ANALYSES SEEK TO ADDRESS THE FOLLOWING AIMS: 1) MODEL THE DEVELOPMENTAL MECHANISMS OF BRAIN ASYMMETRY INVOLVING SPATIOTEMPORAL INTERACTIONS BETWEEN MULTIMODAL BRAIN ASYMMETRY COMPONENTS, GENETIC AND ENVIRONMENTAL INFLUENCES AND THIS SYSTEM'S IMPACT ON CHILDREN BEHAVIOR/COGNITION IN TYPICALLY AND ATYPICALLY DEVELOPING CHILDREN AND ADOLESCENTS OVER TIME, AND 2) CHARACTERIZE WITHIN-DIAGNOSES TRAJECTORIES AND CLUSTER BIOLOGICALLY SIMILAR PARTICIPANTS CUTTING ACROSS CONVENTIONAL DIAGNOSTIC BOUNDARIES TO UNDERSTAND BOTH SHARED AND DISTINCT DEVELOPMENTAL TRAJECTORIES OF BRAIN ASYMMETRY AND BEHAVIOR/COGNITION IN NDDS. OUR STUDY HAS THE POTENTIAL TO PROVIDE DEFINITIVE NEUROBIOLOGICAL MODELS OF NDDS, WITH PRACTICAL IMPLICATIONS FOR HELPING IN REFORMULATING CURRENT DIAGNOSTIC CATEGORIES OF NDDS WITH NOVEL DISORDER DEFINITIONS ROOTED IN THE BIOLOGY OF NEURODEVELOPMENT PROCESSES, AND IN IDENTIFYING PREDICTIVE BIOMARKERS FOR DIAGNOSIS AND THE RIGHT TIME WINDOW FOR PROPER INTERVENTION/TREATMENT.