Elizabeth R. Sowell - US grants

The primary objectives of this proposal are to localized and stage structural maturational brain changes between childhood and adolescence using structural magnetic resonance imaging (sMRI), and to relate these brain changes to improving cognitive abilities assessed with cognitive psychological tests of learning and memory and functioning MRI (fMRI). Neurodevelopment in normal children and adolescents is not yet well understood, but the few studies in the literature that have focused on this topic have shown regionally specific age-related changes in brain morphology. These maturational changes are characterized by great variability between individuals, even within narrow chronological age ranges. Such variability is also found in normative studies of improving cognitive abilities, and correlations have been found between cognitive measures and some brain measures. Notably, these relationships do not tend to be mediated by age, suggesting that maturational factors that are not well indexed by chronological age are involved with the plasticity in brain structure and its neurobehavioral correlates. The increased understanding of normal brain development obtained through this proposed program of research will be useful in scientific endeavors to understand aberrant brain maturation and cognitive impairments in children with various neurodevelopmental disorders, understand aberrant brain maturation and cognitive impairments in children with various neurodevelopmental disorders. This proposal details a plan for didactic study, enabling the candidate to acquire new skills in acquisition and analysis of sMRI and fMRI data, with supervised research to address the following specific aims: (1) To analyze existing high resolution imaging data from 300 normal children and adolescents by adapting measurement tools that will provide localized information about structural change throughout development. (2) To categorize individuals based on sMRI data in such a way to enable reasonable comparisons across developmental stages. It is hypothesized that chronological age will only roughly correlate with groups of subjects that are categorized by patterns of changing brain structure. (3) To investigate neurobehavioral correlates of brain maturation in a small prospective study using sMRI, and modern cognitive psychological tests for detailed assessment of learning and memory abilities. (4) To assess neurobehavioral assessment. It is hypothesized that dissociative brain regions will be involved in distinct cognitive functions (e.g., verbal memory vs. spatial memory), and similar brain regions will be implicated in the fMRI studies of memory, and the sMRI/memory correlation studies.

DESCRIPTION (provided by applicant): The overarching goal of the proposed studies is to understand better the effects of severe prenatal alcohol exposure on the structure and function of the developing human brain by using advanced image analysis technology to combine functional and structural magnetic resonance imaging (MRI) data. While severe prenatal exposure to alcohol is known to cause mental retardation and generalized microcephaly, little is yet known about the subtler toxic effects of prenatal alcohol exposure on brain structure and function. Recent structural MRI studies have shown brain shape abnormalities in parietal and anterior frontal brain regions in alcohol-exposed individuals that exceed their generalized microcephaly. One might expect brain functional activity to be altered in regions of brain structural abnormality, but to date, no functional MRI studies have been reported in the fetal alcohol syndrome (FAS) literature. In these proposed studies, we will assess differences in brain activation between children and adolescents with FAS and those who were not exposed to alcohol prenatally. We expect that regional patterns of functional abnormality will parallel regional patterns of structural abnormality. Advanced image analysis technology is required to address this issue when the groups to be compared have different brain shapes. Traditional functional image analysis techniques require brain image data to be scaled into standard space, typically by using automated procedures. Unfortunately, brain anatomy is less likely to be well matched with the automated algorithms in regions where brain shape differs between groups, greatly reducing the likelihood that subtle differences in brain function can be measured in these regions. We will address this problem by refining existing and developing new high-dimensional continuum mechanical image warping algorithms to align functional images of FAS and control subjects based on gyral landmarks identified in each individual's structural image data. We will design functional MRI experimental paradigms which have been shown to recruit both structurally "normal" and structurally "abnormal" brain regions to assess the specificity of alteration in brain function, and we will compare results from the more traditional and the novel spatial normalization procedures. The results of these studies will help us in planning intervention strategies to optimize development in FAS children and provide more optimal image analysis techniques for other pediatric populations.

DESCRIPTION (provided by applicant): The overarching goal of this proposed Imaging Core is to understand better the effects of prenatal alcohol exposure on the structure and function of the developing brain by facilitating the use of advanced brain image processing tools by CIFASD members. One of the key limitations in understanding the role of severe prenatal alcohol exposure on the developing brain has been the limited number of subjects studied by any single research group. It is our intent to use this opportunity to pool structural brain imaging data across multiple research sites by standardizing the imaging protocols used to acquire image data, and standardizing image analysis tools used to compare individuals with fetal alcohol spectrum disorders (FASD) to controls. We will use our expertise to provide members of the Consortium with access to relatively simple automated image analysis tools that they can use in their laboratories to assess the shape and size of the corpus callosum (CC) and other regularly shaped brain structures. More specialized tools will be developed to assess differences in brain morphology in cortical and subcortical structures and to combine functional and structural MRI data for within-project functional-structural MRI studies. Specifically, our efforts will be directed towards: 1) the standardization of image acquisition protocols and validation of methods for controlling scanner specific geometric distortion through the use of human and mechanical phantom studies; 2) the adaptation of automated image analysis tools for distribution to CIFASD members; 3) adaptation and creation of more sophisticated tools for assessment of brain shape and tissue distribution abnormalities in cortical and subcortical regions, and the refinement of tools designed to facilitate the combination of functional and structural brain imaging data; and 4) the assessment of relationships between brain image data, and data collected by the other CIFASD projects and cores. Consortium members are proposing to collect either functional or structural (or both) brain imaging data from over 470 children and adolescents with FASD and 310 control subjects. The strategies and methods developed within the Imaging Core will for the first time allow the direct comparison of data collected at various sites, dramatically increasing our power to potentially outline diagnostic criteria from brain imaging data, and ultimately to help develop intervention and treatment approaches for FASD.

DESCRIPTION (provided by applicant): As outlined in the request for applications (RFA-DA-04-002) to which we respond here, research that uses rapidly advancing neuro imaging technology to address the effects of drug exposure during development is much needed. We have chosen to investigate this important topic by focusing our efforts on three populations of children, those with prenatal exposure to methamphetamine (MA), those with prenatal exposure to alcohol, and normally developing children without prenatal exposure to drugs of abuse. We will study these populations using structural and functional magnetic resonance imaging, neurocognitive testing, longitudinal data collection, and novel image analyses techniques to assess the following specific aims. 1) To examine brain structural abnormality as a function of prenatal exposure to MA or alcohol, both cross-sectional and longitudinally. 2) To examine differences in brain functional activation between children and adolescents who were exposed to large amounts of MA or alcohol prenatally and those who were not exposed. 3) To examine differences between groups in cognitive functioning using a broad battery of neuropsychological testing instruments. These studies are of critical importance given that very little is known about the effects of prenatal exposure to MA on the developing brain, and MA abuse is rapidly escalating in the United States. Pregnant women are likely among the increased population using this illicit drug, placing an increased sense of importance on our understanding of the consequences of its abuse during pregnancy. To date, there are no published studies describing detailed structural brain abnormalities, functional activation disturbances, or neurocognitive deficits in children with prenatal MA exposure. By comparison, relatively more is known about the teratogenic effects of alcohol on the developing brain, but its abuse during pregnancy is still a significant health problem. The proposal to study two populations with prenatal exposure is critical to our better understanding of the specific neural impact of each drug. This is because the alcohol-exposed individuals will be a better comparison group to assess the effects of prenatal MA exposure, given likely similarities between the groups in pre- and post-natal environments (i.e., nutrition, socioeconomic status, maternal smoking during pregnancy) relative to children without prenatal exposure who are typically studied as a comparison group.

DESCRIPTION (provided by applicant): As outlined in the request for applications (RFA-DA-04-002) to which we respond here, research that uses rapidly advancing neuro imaging technology to address the effects of drug exposure during development is much needed. We have chosen to investigate this important topic by focusing our efforts on three populations of children, those with prenatal exposure to methamphetamine (MA), those with prenatal exposure to alcohol, and normally developing children without prenatal exposure to drugs of abuse. We will study these populations using structural and functional magnetic resonance imaging, neurocognitive testing, longitudinal data collection, and novel image analyses techniques to assess the following specific aims. 1) To examine brain structural abnormality as a function of prenatal exposure to MA or alcohol, both cross-sectional and longitudinally. 2) To examine differences in brain functional activation between children and adolescents who were exposed to large amounts of MA or alcohol prenatally and those who were not exposed. 3) To examine differences between groups in cognitive functioning using a broad battery of neuropsychological testing instruments. These studies are of critical importance given that very little is known about the effects of prenatal exposure to MA on the developing brain, and MA abuse is rapidly escalating in the United States. Pregnant women are likely among the increased population using this illicit drug, placing an increased sense of importance on our understanding of the consequences of its abuse during pregnancy. To date, there are no published studies describing detailed structural brain abnormalities, functional activation disturbances, or neurocognitive deficits in children with prenatal MA exposure. By comparison, relatively more is known about the teratogenic effects of alcohol on the developing brain, but its abuse during pregnancy is still a significant health problem. The proposal to study two populations with prenatal exposure is critical to our better understanding of the specific neural impact of each drug. This is because the alcohol-exposed individuals will be a better comparison group to assess the effects of prenatal MA exposure, given likely similarities between the groups in pre- and post-natal environments (i.e., nutrition, socioeconomic status, maternal smoking during pregnancy) relative to children without prenatal exposure who are typically studied as a comparison group.

DESCRIPTION (provided by applicant): This new application is part of the competitive renewal for the "Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)". One of the overall goals of the entire CIFASD during this renewal period is to determine if innovative techniques can be used to identify brain alterations, neurobehavioral deficits and facial characteristics and relationships between these variables to help define prenatal alcohol spectrum disorders (FASD). To help address this overarching question, we will use quantitative brain mapping techniques with high-resolution structural and functional MRI collected both cross-sectionally and longitudinally from 80 FASD children evaluated across 3 multi-cultural data collection sites (San Diego, Los Angeles and Capetown, South Africa). While this brain imaging project can independently achieve some of the goals of the CIFASD by identifying brain structural and functional abnormalities across the broad spectrum of FASD, critically this funding opportunity will allow the assessment of relationships between the brain, neurocognitive deficits and facial dysmorphology through our active collaborations with the neurobehavioral project (Mattson PI), the facial imaging project (Foroud PI), and the dysmorphology core (Jones PI). Controlled animal studies are essential to determine timing and dosages of prenatal alcohol that result in FASD, but human imaging studies are essential to corroborate anatomical findings across species. Through our association with the UCLA Laboratory of Neuro Imaging, we have access to state-of-the-art brain mapping tools that allow the morphological evaluation of any brain structure that can be identified with MRI. Thus, we are in a unique position to allow findings in animal studies to drive hypothesis-based analyses in the human imaging data. The proposed longitudinal project will highlight how an integrated approach relating neurobehavioral, functional and structural brain imaging data, and measures of facial morphology might yield important new insights on the complex nature of brain-behavior interactions and how they are altered by prenatal alcohol exposure. To our knowledge, this will be the first study to undertake such challenges, and participation, in the CIFASD is essential to address our specific aims. Ultimately, as part of the CIFASD, this project will enhance the capability for definitive FASD diagnoses that, in turn, will help clinicians manage and treat neurobehavioral deficits and associated secondary disabilities.

The overarching goal of the proposed studies is to longitudinally investigate the functional and behavioral significance of structural change in the form of gray matter thickness increases recently observed in classical brain language regions during the process of normal development. We will also assess functional activation in non-language frontal lobe regions (where cortical thinning has been observed) to evaluate the cognitive/functional significance and regional specificity of dynamic changes observed in our earlier studies of structural brain maturation. By delineating the relationship among language developments, executive function development, brain function, and brain structure, this study will bridge the informational gap on the neural basis of language and frontal function in the normally developing brain. We will use functional and structural magnetic resonance imaging and detailed neurocognitive assessments to assess the following specific aims: 1) To quantify change in functional and structural signal within children studied longitudinally; 2) To investigate whether change in functional signal across time is related to change in the underlying brain structure; and 3) To relate behavioral language and frontal lobe functioning change to changes in brain structure and function. We propose to study children between the ages of 5 and 9 years (with 2 years between repeat evaluations) when so many language and frontal lobe functions are rapidly changing as are brain structures related to these cognitive domains. The proposed longitudinal project will highlight how an integrated approach relating behavioral, functional, and structural data might yield important new insights on the complex nature of brain- behavior interactions. To our knowledge, this will be the first study to undertake such challenges by using both functional and structural MRI to examine, longitudinally, the neural networks associated with language processing (i.e., reading), within the same individuals, and to relate the normal developmental changes in the neural networks subserving language processing (as observed with fMRI) to age-related changes in brain morphometry (as assessed by structural MRI). Similar evaluations will be made with tests of frontal lobe functioning allowing assessment of relationships between patterns of change in language and non-language brain regions. The data gathered from the proposed longitudinal research program should enable us to more fully elucidate the neural developments associated with the emergence of mature linguistic and frontal lobe competence in normally developing children. Furthermore, these developmental findings will provide normative data for evaluating the patterns of brain dysfunction associated with the linguistic, communicative, and frontal lobe impairments observed in a variety of developmental disorders (e.g., dyslexia, autism, ADHD).

DESCRIPTION (provided by applicant): Enormous progress has been made recently in understanding the age-related structural maturational changes that occur in the human brain during childhood and adolescence, but variability in brain structure is very large, even among individuals of the same chronological age. The literature suggests an offset in development of limbic structures which control affect, emotion, encoding information, which may develop prior to the executive centers (frontal cortices) that provide regulatory control over impulses and risk assessment. Almost nothing is yet known about neurodevelopmental, neuroendocrine, behavioral and environmental factors that likely relate to variability in brain structure and function, and cognitive abilities that change so dramatically during adolescence. In this project, we propose to longitudinally study 120 typically developing adolescents between 9 and 15 years of age with 2-year scan intervals, and to collect brain imaging (structural MRI, diffusion tensor imaging and functional MRI with tasks of response inhibition, reward processing, delayed discounting, facial affect processing), neurocognitive (with emphasis on executive functioning and cognitive control), physical sexual maturation (using Tanners staging), and hormonal (cortisol, testosterone, estrogen and Dehydroepiandrosterone (DHEA) using saliva samples) data as well as measures of daily stress. With these rich multimodal imaging, behavioral, cognitive and hormonal data, we will address the following specific aims: 1) to distinguish hormone-dependent from non-hormone dependent neurodevelopmental effects in adolescence, 2) to evaluate relationships between brain changes and behavioral indices of cognition (cognitive control, executive functions, daily stress) and motivation (e.g., reward sensitivity), and 3) to evaluate gender differences in relationships between brain changes and indices of pubertal progression. To our knowledge, this will be the first study to undertake such challenges by using cutting-edge integrative multimodal image analyses of functional and structural MRI to examine, longitudinally, brain development in adolescents and to distinguish hormonal from other age-related environmental and behavioral correlates.

DESCRIPTION (provided by applicant): This application is part of the competitive renewal for the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) in response to RFA-AA-12-004. Moving forward with the new theme for our project brain connectivity in FASDs, we propose to build on our work investigating the impact of prenatal alcohol exposure (AE) on the long-term development of the brain. Specifically, we will leverage advances in the field to implement two new imaging modalities to complement our existing work to address how structural and functional brain connectivity is affected, both cross-sectionally and longitudinally and how connectivity relates to cognitive function and facial dysmorphology in children with AE. The ultimate goal of this renewal application remains the same, to determine if innovative techniques can be used to identify brain alterations, neurobehavioral deficits and facial characteristics and relationships between these variables to help further define/diagnose prenatal alcohol spectrum disorders (FASD). This timely project will apply a cutting-edge multimodal Magnetic Resonance Imaging (MRI) protocols and sophisticated image analyses to study 240 children (120 with AE) longitudinally studied across 4 data collection sites. While this brain imaging project can independently achieve some of the goals of the CIFASD by identifying brain structural and functional connectivity abnormalities across the broad spectrum of FASDs, critically this funding opportunity will allow the assessment of relationships between the brain, neurocognitive deficits and facial dysmorphology leveraging our active collaborations with the neurobehavioral project (Mattson PI), the facial imaging project (Foroud PI), and the dysmorphology core (Jones PI). Controlled animal studies are essential to determine timing and dosages of prenatal alcohol that result in FASDs, but human imaging studies are essential to corroborate anatomical findings across species that will be facilitated by projects in the basic sciences (Sulik PI). Thus, by capitalizing on existing CIFASD infrastructure, this project will provide critical new knowledge concerning the effects of AE on brain structure, function, behavior assessed cross-sectionally; in addition, longitudinal examinations will determine if AE effects are static, or changing during childhood and adolescence. New knowledge gained through investigations during the renewal period could have strong implications for potential future interventions, given that the brain changes dramatically in even typically developing kids, and we know from animal studies that environment and experience (enriched environment vs. deprived, etc.) shape the way the brain develops. If trajectories of developmental change throughout childhood are impacted by damage resulting from teratogenic exposure to alcohol in utero, it could be possible to ultimately shift trajectories for the better in these children throuh interventions targeted towards brain regions and cognitive functions most affected by AE.

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/Abstract Prenatal alcohol exposure (PAE) can produce dramatic effects on brain, cognition, and facial morphology (BCF). Fetal alcohol spectrum disorder (FASD) is preventable, yet remains among the top 3 known causes of intellectual disability. The large variability in PAE-effects on BCF associations likely results, in part, from variability in maternal alcohol consumption patterns including quantity, frequency and timing (QFT) and early life experience. Both stigma and retrospective assessment of maternal alcohol consumption patterns during pregnancy have made it difficult to accurately understand what patterns of PAE are most harmful to development. Most children with FASD experience greater early life adversity than non-exposed children, but existing research on how PAE impacts brain development has not been able to disentangle the impact of early life adversity. Early intervention is believed to be key in attenuating PAE-effects, and may depend, in part, on understanding the impact of QFT and early life experience. In this proposal, we aim to better understand how QFT of PAE plus early life experience impact brain and cognitive development. Most prospective studies of PAE have recruited samples biased towards moderate-heavy PAE, limiting our understanding of the entire range of PAE patterns including minimal exposure. Here we capitalize on a unique prospective, community sample of approximately 6,000 South African children whose mothers reported on drinking behavior during pregnancy as part of the Prenatal Alcohol, SIDS and Stillbirth (PASS) Network. Thus, we are in an exceptional position to understand how QFT of PAE independently, or interactively, impacts associations between: 1) brain and cognition; 2) brain and early life environment; and 3) brain and facial morphology as function of environmental/maternal factors. 400 PASS participants (300 PAE/100 non-exposed Controls; 50% girls) aged 8-10 years at enrollment, will undergo multi-modal neuroimaging to assess A) structural MRI measures of brain volume, thickness and surface area; B) diffusion imaging of underlying white matter microstructure (i.e., structural connectivity); and C) resting state functional MRI (i.e., functional connectivity). Measures of cognition will utilize the NIH Toolbox Cognition Battery, and early life experience will be measured for maternal (i.e., age, nutrition, parity, mental health, co-substance use, parenting style, parent-child closeness) and environmental (i.e., multiple measures of SES, access to resources, stress) risk factors, measured both perinatally and during childhood. Quantitative measures from 3D facial imaging will be utilized in parallel with neuroimaging and cognitive assessments. Utilizing the entire range of PAE, we expect independent and interactive (e.g., quantity by timing, etc.) effects of QFT on BCF associations, with the largest effects driven by quantity, followed by frequency, and then timing of PAE. For example, we expect to see PAE-effects among children with very low exposure throughout pregnancy in more lateral brain regions (develop later in utero), whereas binge-like high exposure in early pregnancy will show more midline brain anomalies (develop earlier in utero).

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.

Children in the US are exposed to various neurotoxicants that can damage their developing brains. We have recently shown that the long-known negative impact of low SES on cognitive development is mediated by differences in brain structure. Specifically, the association between brain structure and SES is more pronounced in the poorest children, those who are often the most exposed to neurotoxic metals, such as lead (Pb). Here, we aim to better understand the impact of perinatal Pb exposure on brain, cognitive and behavioral development longitudinally using a novel tooth dentine assay. This novel measure allows quantification of prenatal and postnatal Pb exposure beginning with the 2nd trimester in utero and ultimately until the tooth is shed during later childhood; dentine develops over time, much like rings of a tree, trapping earlier exposures beneath the next ?ring? of dentine to form, allowing temporal measurements of Pb in consecutive rings of dentine. The effects of Pb exposure may be exacerbated in the context of low SES, but this important aspect of brain development in the environmental setting has received little research attention. In this proposal, we will leverage substantial existing funding by investigating Pb exposure among a subset of ~500 participants of the Adolescent Brain Cognitive Development (ABCD) study who have donated shed deciduous (baby) teeth. We will also leverage recent funding from the Children's Health Exposure Analysis Resource (CHEAR: Project #2017-1920; now HHEAR) to cover the costs of tooth analysis at three distinct developmental periods: the 2nd trimester and 3rd trimester of fetal development and the 1st year of life. Notably, the ABCD cohort of over 11,800 participants varies considerably on race and ethnicity, geographic location, family income, and parent education, and nearly 4,000 participants have donated teeth. This will allow a strategic selection of participants who are matched by Pb risk measures (based on publicly available risk maps of Pb exposure geocoded to each participant's home address) while controlling for SES and race factors that could be confounded by risk of Pb exposure. Pb risk may increase the likelihood of exposure, but it is clear that some at high risk could have low exposure whereas some at low risk may have high exposure. While our preliminary studies show that Pb risk status is associated with brain, cognition, and behavior as a function of SES in the ABCD cohort, only by measuring endogenous Pb levels within groups of individuals matched on SES by risk status can we determine how and where to focus future efforts to reduce remediable Pb risk factors and improve the health of children in the US. In this proposal, we will assess (1) associations between dentine Pb levels on structural brain development during childhood and determine if associations vary as a function of level of exposure at 3 developmental time points, (2) associations between dentine Pb levels and cognitive and behavioral development along with sex differences on these associations, and (3) the moderating or mediating effects of SES on brain-cognitive-behavioral development in the context of perinatal Pb exposure.