Mirella Dapretto - US grants

The proposed study will use both functional and structural magnetic resonance imaging (fMRI and MRI) to begin to delineate the neural systems associated with the emergency of high-level linguistic functions in normally developing children, aged 7 to 14. More specifically, this pilot project has two main goals. First, we will use fMRI to qualify and quantify developmental changes in the pattern or cortical activity (in terms of localization, magnitude, spatial extent, and inter-regional connectivity) associated with language processing at the level of closed formal linguistic systems (i.e., phonology, semantics, syntax), as well as with language processing in its broader communicative context (i.e., prosody, discourse, pragmatics). Second, we will relate the developmental changes in the neural networks subserving language processing observed with fMRI, to age-related changes in brain morphometry (in terms of regional volume, gray and white matter concentrations, shape, and asymmetry) as assessed by structural MRI. The findings of the proposed cross-sectional study will form the cornerstone of a longitudinal research program aimed at fully elucidating the neural developments associated with the emergence of mature linguistic competence in normally developing children. Furthermore, these developmental findings will provide normative data for evaluating the patterns of brain dysfunction associated with the linguistic and communicative impairments observed in a variety of developmental disorders (e.g., dyslexia, autism, early-onset schizophrenia). By delineating the relationship among language processing, brain function, and brain structure, this study will begin to bridge the informational gap on the neural basis of language in the normally developing brain. Moreover, the proposed project will highlight how an integrated nature of brain-behavior interactions. At a theoretical level, a deeper understanding of the neural basis of language processing, particularly of how it changes and develops as a function of learning, will enlighten our thinking about the origin and modularity of language.

neuroimaging; autism; neuroanatomy; brain; biomedical resource; language; clinical research;

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.

DESCRIPTION (provided by applicant): While social communication deficits are considered the hallmark of Autism Spectrum Disorders (ASD), there is increasing evidence that sensorimotor deficits are also common in individuals with ASD diagnoses. A large body of research suggests that brain systems for execution and observation of actions are involved in higher social cognitive processes, including intention understanding and empathy, yet research has not yet clarified the extent to which motor deficits, such as imitation ability and motor planning, are central to ASD nor whether social and motor deficits are related neurobiologically in ASD. Understanding the neurobiological basis for ASD is crucial for developing effective therapies. However, researching the neurobiology of ASD is complicated by the heterogeneity of ASD; patients vary in symptomology- e.g., some individuals may show extensive impairment in motor functioning while others may not. Our study is designed to accommodate and understand the relationship between symptomalogical variation in ASD along the dimensions of both social and motor impairments. We aim to show how variations in social and motor symptoms in ASD relate to functioning in social and motor brain networks and functional connectivity between them. We propose to conduct functional MRI studies that compare 120 children on two continua of symptomology: (1) degree of social impairment (as measured by the SRS-2 and NEPSY-II), and (2) degree of motor impairment (as measured by the MABC-2 and Praxis Test). To ensure a range of impairment along these continua, children with ASD and children with Developmental Coordination Disorder (DCD, sometimes called dyspraxia) as well as typically developing (TD) children will participate in the study. The ASD group will range in motor impairment but should show high social impairment, while the DCD group will range in social impairment (generally lower than ASD) but high in motor impairment. Our fMRI tasks are likewise selected to range on a continuum from purely motor tasks to social processing tasks, beginning with motor (hand) execution and imitation tasks and progressing to tasks that incorporate increasing dimensions of social processing (e.g., non-emotional face imitation, emotional face imitation, intention understanding). By testing individuals who represent a continuum of social and motor deficits along a continuum of social and motor tasks we will be able to isolate and understand, in ASD, interactions between: (1) social and sensorimotor symptomologies; (2) activity in social and motor brain networks; and (3) functional connectivity between social and motor brain networks. This understanding will be crucial for developing individualized treatments for ASD. To our knowledge, no fMRI study has examined children with ASD across these multiple continua, nor directly compared them to children with DCD. In addition to contributing to our understanding of ASD, this study will better elucidate the neural mechanisms underlying DCD, which affects 6-13% of school-aged children.

? DESCRIPTION (provided by applicant): The major technological and analytical advances in human brain imaging achieved as part of the Human Connectome Projects (HCP) enable examination of structural and functional brain connectivity at unprecedented levels of spatial and temporal resolution. This information is proving crucial to our understanding of normative variation in adult brain connectivity. It is now timely to use the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain develops. Using state-of-the art HCP imaging approaches will allow investigators to push our currently limited understanding of normative brain development to new levels. This knowledge will critically inform prevention and intervention efforts targeting well known public health concerns (e.g., neurological and psychiatric disorders, poverty). The majority of developmental connectivity studies to date have used fairly coarse resolution, have not been multi-modal in nature, and few studies have used comparable methods to assess individuals across a sufficiently wide age range to truly capture developmental processes (e.g., early childhood through adolescence). Here we propose a consortium of five sites (Harvard, Oxford, UCLA, University of Minnesota, Washington University), with extensive complimentary expertise in brain imaging and neural development, including many of the investigators from the adult and pilot lifespan HCP efforts. Our synergistic integration of advances from the HARVARD-MGH and WU-MINN-OXFORD HCPs with cutting edge expertise in child and adolescent brain development will enable major advances in our understanding of the normative development of human brain connectivity. The resultant unique resource will provide rich, multimodal data on several biological and cognitive constructs that are of critical importance to health and well-being across this age range and allow a wide range of investigators in the community to gain new insights about brain development and connectivity. Aim 1 will be to optimize existing HCP Lifespan Pilot project protocols on the widely available Prisma platform to respect practical constraints in studying healthy children and adolescents over a wide age range and will also collect a matched set of data on the original Skyra and proposed Prisma HCP protocols to serve as a linchpin between the past and present efforts. Aim 2 will be to collect 1500 high quality neuroimaging and associated behavioral datasets on healthy children and adolescents in the age range of 5-21, using matched protocols across sites, enabling robust characterization of age-related changes in network properties including connectivity, network integrity, response properties during tasks, and behavior. Aim 3 will be to collect and analyze longitudinal subsamples, task, and phenotypic measures that constitute intensive sub-studies of inflection points of health-relevant behavioral changes within specific developmental phases. Aim 4 will capitalize on our success in sharing data in the HCP, and use established tools, platforms and procedures to make all data publically available through the Connectome Coordinating Facility (CCF).

PROJECT DESCRIPTION Despite the tremendous variability observed across individuals diagnosed with Autism Spectrum Disorder (ASD), most research to date has treated ASD as a unitary condition, comparing individuals with ASD to neurotypical controls. This approach has hindered our progress in unraveling the neurobiological mechanisms that give rise to ASD symptomatology and it also undermines the potential of translational research to contribute to `precision medicine' in ASD. In this project, we take a critical step toward dissecting the significant heterogeneity observed in ASD by combining state-of-the-art imaging methods, novel approaches to account for genetic susceptibility, and a deep phenotypic characterization of a large and unique sample of males and females with ASD that we curated as part of our recently renewed ACE Network (MH100028). Capitalizing on the comprehensive assays already collected in this cohort (i.e., phenotyping, genotyping, MRI, EEG) and our involvement in the Human Connectome Project - Development (MH109589), here we will collect and analyze a rich dataset of brain-based measures of unparalleled resolution and quality in order to characterize individual differences in brain network properties and examine how these relate to a vast phenotypic battery of measures tapping into key domains of interest. Using resting-state fMRI and innovative fMRI activation tasks as neural assays of social and sensory responsivity, we will examine how functional connectivity and brain responses in associated neural circuits co-vary within and between individuals in order to determine how atypical reactivity to sensory stimuli impacts neural processing of socially relevant stimuli, and assess how distinct neural endophenotypes of social and sensory responsivity relate to altered functional connectivity and behavioral phenotypes. Building upon our prior imaging-genetics work, we will also examine how polygenic risk, and risk genetic variants on ASD-associated polymorphisms, influence brain function, connectivity, as well as core ASD symptoms. Our overarching hypothesis is that both distinct and shared neuroendophenotypes will be identified across our sample based on different brain function and connectivity metrics and that these will map onto varying dimensions of social and sensory atypicalities manifested at the neural and behavioral level. We further expect that higher polygenic risk will predict increasingly aberrant patterns of brain activity, connectivity, and overall symptom severity, whereas genetic variance on ASD-associated polymorphisms will selectively modulate brain function and connectivity in brain circuits where these ASD risk genes are expressed. By employing (a) cutting-edge imaging methods to examine brain function and connectivity, (b) innovative paradigms to relate social attention and motivation to sensory processing atypicalities, (c) novel approaches to integrate genetic risk with neural and behavioral phenotypes, and (d) sophisticated data-analytic strategies to sensibly stratify our ASD sample, this research will further our understanding of the neural mechanisms underlying heterogeneity in ASD and ultimately inform more personalized and efficacious interventions.

DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use (SU). Identifying the pathways to SU and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain function and behavioral, health, and psychological outcomes. This Research Project Site application from the University of Southern California/Children's Hospital Los Angeles and UCLA is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (8/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of SU on children and adolescents. A representative community sample of 850 9-10 year olds enriched for high-risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD-USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of SU, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of SU patterns on the adolescent brain; 2) the effects of SU on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and SU patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and SU outcomes; and 5) the gateway interactions between use of different substances. Elements Unique to This Site: Our Research Project focuses on the mediating or moderating effects of 1) pubertal hormones and sex differences, 2) socioeconomic (SES) factors, and 3) prenatal exposure (PE) to drugs of abuse on SU and other psychopathologies. These three factors are known to influence timing and trajectories of neurodevelopment, and have been linked to SU, but are seldom studied in tandem in neurodevelopmental studies of typically developing children. In this proposal, in conjunction with the larger ABCD-USA consortium, we are in a unique position to investigate the extent that SES and PE individually or interactively perturb the timing or outcomes of maturation of frontolimbic circuits important in reward processing and decision making, and, how pubertal changes (independent of age) may correspond with the onset of SU and co-occurring psychopathology within the context of the developmental environment. In Y03, we will focus on studying cross-sectional relationships between brain structure and function and puberty, SES and PE prior to onset of SU, and in subsequent years, we will focus on longitudinal studies from onset of SU and SU disorder progression, and precursors or consequences of SU on brain structure and function in Y6-Y10.

PROJECT SUMMARY Developmental cognitive and affective neuroscience has been a major force in the renewed focus upon adolescence as a critical period in development with life-long consequences for health and well-being. Scientific advances have highlighted the significance of brain development during this period, with a profound effect on public policy for children and youth, from Supreme Court rulings on culpability and juvenile justice to public health campaigns on smoking, concussion risk, and sexual health. The foundational contributions of research on adolescent brain and behavioral development up to this point offer promise for even broader contributions to the country's public health in the future. In order to best enhance healthy and productive adolescent development, the field will need to expand by developing research and training the next generation of scientists in four primary areas: (1) an integrative approach that incorporates both typical and atypical brain development; (2) the interaction between brain development and the social environment; (3) sophisticated approaches to examining longitudinal change over time; and (4) attention to population diversity according to ethnicity and socioeconomic resources. To our knowledge, however, there is no integrated predoctoral training program on adolescent brain and behavioral development in the U.S. Existing doctoral programs, including those at UCLA, alone cannot systematically and sustainably provide students with the training necessary to advance the future of research in the field. Key limitations include curricular and lab rotation barriers, financial constraints, and the lack of integrated professional socialization in both brain and behavioral development. At UCLA, we possess unique strengths that with the support of an Institutional Research Training Grant from NICHD, can be brought together to create a cutting-edge training program for the next generation of scholars who can advance science in the four areas describe above, and ultimately enhance the health and well-being of adolescents. We propose a predoctoral training program that supports five trainees per year for a two-year period in which students from our existing Psychology and Neuroscience Ph.D. programs enroll in new courses on substantive and methodological issues in adolescent brain and behavioral development, participate in new colloquia and scientific events, receive guidance on professional development and ethical practices, and actively engage in cutting-edge research mentored by top scientists in brain and behavioral development. Trainees will be able to take advantage of UCLA's many institutional resources and commitments to neuroscience and the training of next generation of skilled scientists from diverse backgrounds, including those traditionally underrepresented in the field. Our goal is for the proposed program to help NICHD achieve the scientific vision of ?basic and translational research that combines neuropsychological, behavioral, and social science perspectives, as well as new tools? to improve our understanding of typical and atypical development. .

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA- DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child?s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.