Charles A. Nelson - US grants

The studies described in the present proposal are designed to explore the conceptual basis of the infant's perception of facial expression. The need for such work is critical if we are to understand the important role the face plays in the communication of affect prior to the onset of language. Two experiments are described herein that speak to the issue of whether infants are able to categorize the expressions happy and fear when these expressions vary along two dimensions: a) person posing the expression, and b) the intensity of the expression (e.g., mild or very happy). Using a paired-comparison procedure, 4-, 7-, and 8-month-old infants in the first experiment will be tested on their ability to discriminate and generalize their discrimination of a within-category change of either a happy or fear facial expression (i.e., can they discriminate a female face posing a mild-happy expression from the same face posing a very-happy expression, and can they generalize such discrimination across four different female faces?) Using the same procedure, a second experiment will explore the 4-, 7-, and 8-month-old infant's ability to discriminate and generalize their discrimination of a happy vs. fear facial expression (i.e., a between-category discrimination), when these expressions range in intensity (mild vs. very) and model (4 females). It is hoped that from such work our knowledge of the infant's perception of facial expressions will be greatly improved. In future work these findings will be extended to : a) infants born to parents who provide misleading or erroneous affective information (e.g., those suffering from affective disorders), and b) infants viewing faces of chimpanzees posing a variety of facial expressions. While different in conception, both studies are designed to explore the infant's ability to perceive affect.

Investigators of cognitive development have historically relied nearly exclusively on studying how the infant behaves. This has limited our knowledge of this area in several important respects. For example, the link between cognition and behavior is not always clear, both because the infant is a motorically immature organism and because what the infant knows may not always be reflected in how the infant behaves. More importantly, we know from behavioral studies that infants attain certain milestones in their cognitive growth over the first year of life (e.g., object permanence). Although it is often assumed that these behavioral changes are brought about by corresponding changes in the brain, behavioral measures alone are unable to elucidate this relationship. For these and other reasons it seems imperative to move beyond the study of behavior to include, as well, the study of underlying physiological activity. Because of the critical role the brain plays in mediating cognitive processes, it seems reasonable to propose that the brain be the subject of this study. It is to this end that the current proposal is directed. Specifically, long-latency Event-Related Potentials (ERPs) will be recorded from the scalp in 4- to 12-month-old infants as a means of studying infant memory. In order to relate changes in the brain to changes in infants' behavior in several of the proposed studies behavioral measures will be recorded as well. The first two experiments are designed to extend previous research by the P. I. (Nelson & Salapatek, 1986), by examining infants' cortical and behavioral responses to stimulus noveity (Experiment 1), and infants' cortical responses to a stimulus omission (Experiment 2). The third experiment examines the relationship between infants' ERP response to novelty, and subsequent recognition memory as assessed behaviorally. Experiment 4 has as its focus infants' memory for changes in stimulus duration, and in the final experiment the electrophysiological correlates of cross-modal transfer are examined. Collectively the goal of this proposal is to study infant memory through the examination of both cortical and behavioral response systems.

Over the past several years remarkable progress has been made in addressing the development of a number of cognitive abilities in infants (e.g., memory, categorization) using a variety of behavioral techniques. In contrast, the study of sensory development (e.g., acuity, contrast sensitivity) has profited by the use of both behavioral and electrophysiological techniques. The latter has been particularly useful in not only providing corroborating evidence for many of the behavioral findings, but more inportantly, has begun to shed light on the neurological correlates of many of these behaviors. Accordingly, it would seem useful to extend electrophysiological procedures to the study of infant cognition. That is the goal of the present proposal. Specifically, research is outlined that will attempt to use long-latency event-related potentials (ERPs) to study memory in 4- and 6-month-old infants. In addition, a procedure is outlined whereby behavioral recordings will be obtained from these same infants in this paradigm. The Experiment described in this application extends the work of the Principal investigator (Nelson & Salapatek, in press), and is designed to lay the groundwork for a series of studies examining brain/behavior relations in infants' cognitive abilities. Because of the suitability of the described paradigms for studying atypical populations, it is anticipated that special populations of infants and children (e.g., those suffering from anoxia, focal brain damage, etc.) will be tested in this future work.

The research outlined in the current Revised proposal is designed to elucidate the relation between Medial Temporal Lobe (MTL) structures and memory in epileptic individuals before and after undergoing a temporal lobectomy. A secondary goal is to determine whether the non-invasive recording of event-related potentials (ERPs) can provide an index of the integrity of the MTL structures that subserve memory. Such work has implications for the neurological and neurosurgical treatment of epilepsy. Individuals suffering from medically intractable complex partial seizures will be studied immediately before and 6 months after undergoing a unilateral temporal lobectomy. Non-surgical epileptic and neurologically normal control subjects will also be tested. Two research protocols employing scalp-recorded event-related potentials (ERPs) will be used to examine memory. In one protocol subjects will be asked to attend to a target stimulus presented in one or the other visual field, and to keep a running count of the total number of targets presented. In a second protocol, subjects will be presented with words flashed on a screen, some of which will repeat at different lags (i.e., a word might repeat 1, 6, or 16 times after it was first presented). Subjects will be told to push a button whenever they see a word a second time.

Neonatal prediction of subsequent neurologic and cognitive outcome following subtle early, chronic or repetitive fetal brain injury remains problematic because of the poor predictive value of current assessment tools (e.g., newborn neurological exam, CT/MRI, cranial ultrasound). This is particularly true in infants who are neurologically asymptomatic in the newborn period, and in whom gross anatomic insults rarely occur. The current proposal is designed to redress this problem by testing the hypotheses that direct assessment of developing cognitive-neural pathways can be accomplished by 1) using neurophysiological tasks that have been experimentally developed in a developmental cognitive neuroscience context, and 2) applying such tools to infants in whom pathophysiology is well defined. Specifically, in this proposal neurophysiological (event-related potentials) and behavioral (looking time) measures will be used to evaluate a number of cognitive abilities in three groups of infants; infants following intrauterine growth retardation secondary to uteroplacental insufficiency, infants born to diabetic mothers, and healthy control infants. At birth all infants will be tested with two auditory tasks using event-related potentials. In one task infants will be asked to discriminate a speech from a non-speech stimulus; in the other they will be asked to discriminate their mother's voice from the voice of a stranger. These same infants will be tested again at 4 months. Here the same two auditory tasks will be presented. In addition, two tests of visual recognition memory will be performed, one while recording event-related potentials, and the other while recording looking behavior,. At 8 months event-related potentials will be recorded during a test of cross-modal recognition memory. Visual recognition memory will also be avaluated by an assessment of looking behavior. Finally, at 12 months all infants will receive a Bayley exam. The multiple measures adopted in this project will be used to develop profiles of performance on groups of infants (e.g., IUGR vs. IDM) as well as individual infants.

Research in cognitive neuroscience utilizing infant monkeys and human adults suffering from temporal lobe damage has suggested that visual recognition memory is mediated by the same limbic structures that support other forms of explicit or declarative memory. Unfortunately, the behavioral procedures typically used to study recognition memory in the human infant do not lend themselves to an explication of the neural processes or structures that underlie such memory. In addition, the anatomical/lesion method used with non-human primates and neurologically compromised human adults does not permit an examination of the neural transactions that transpire during recognition memory; this method also does not lend itself to the study of the normal young of our species. In order to examine the neurophysiological processes that underlie the development of recognition memory, and to relate these processes to overt behavior, approaches other than those used thus far must be employed. To this end a series of studies is being proposed with human infants that will involved recording event-related potentials from the scalp. An overt behavioral measure (looking time) will also be recorded, permitting us to relate our electrophysiological data to the overt (behavioral) expression of memory. The specific issues to be addressed in this proposal concern a) the neural processes that underlie visual recognition memory, b) the link between the behavioral and physiological expression of recognition memory, c) changes in the physiological and behavioral expression of visual recognition memory over the first year of life, and d) to a very limited degree, the anatomical locus of visual recognition memory as inferred from its electrophysiological expression. Finally, to assist in interpreting the functional significance of the obtained results, a series of parallel studies will also be conducted with adults.

[unreadable] DESCRIPTION (provided by applicant): The primary goal of this grant proposal is to promote interdisciplinary research in neurobehavioral development at the postdoctoral level. We will target trainees who have received a Ph.D. in Child Psychology, Neuroscience or Developmental Neuroscience-related disciplines (e.g., molecular or developmental biology), as well as M.D.'s in various Pediatric disciplines, such as Neonatology, Pediatric Neurology and Child Psychiatry. The motivation behind this proposal is to foster the development of junior investigators who can integrate research and theory in human behavioral development with explication of underlying neural circuitry and neurodevelopmental processes. A long-range goal is to create a discipline we have come to call "neurobehavioral development." Clearly, knowledge of the neurobiological mechanisms underlying behavioral development would benefit those interested in a range of behavioral phenomena, and vice versa. To date there are relatively few developmental researchers who work at this interdisciplinary boundary in either basic or clinical domains. Consequently, there is a tremendous need to foster this integration among principal investigators and to support the interdisciplinary training of students. This is the mission of the Center for Neurobehavioral Development (CNBD) at the University of Minnesota, which will be home to this training grant. The CNBD accomplishes this mission by providing research space, educational colloquia and classes co-listed in multiple relevant departments, and by having a core faculty consisting of developmental, cognitive, behavioral, and basic neuroscientists working at multiple tiers of investigation in the human and in animal models. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): In this competing renewal (2R01 NS034458-08A1), we hypothesize that the adverse fetal events common in the diabetic pregnancy (i.e. iron deficiency, hypoxemia, and hypoglycemia) will have a deleterious and specific effect on the hippocampus. This should result in selective impairments in explicit memory due to the established vulnerability of this structure to these metabolic disturbances. Our results thus far have established a consistent pattern of deficits in recognition memory, from birth through 2 years of age, as inferred from electrophysiological data (event-related potentials) and behavioral data (Elicited Imitation). The goal of the current proposal is to continue to study our cohort of children as they enter the elementary school years. We are focusing our efforts specifically on 3 areas. First, we intend to document more specifically the nature of the functional and structural deficits observed to date: thus, what types of memory are impaired, and how extensive is the damage to the hippocampus? Second, we seek to determine whether deficits in other cognitive functions emerge as our study populations makes the transition to school age;specifically, do we observe deficits in striatal or prefrontal functions? And, is there an association between such deficits and school performance? Finally, we wish to characterize further what neural circuits have been compromised by the adverse fetal environment that is common among IDMs;specifically, confirm our prediction of hippocampal damage (as inferred from reduced hippocampal volume and/or metabolism) and/or whether we observe damage to striatum, and/or whether we observe reductions in white matter due to prenatal iron deficiency. We will address these questions conducting detailed electrophysiological (ERPs), metabolic (fMRI), anatomic (MRI), and behavioral (neuropsychologic) studies on our current samples of IDMs and comparison children. Given that approximately 10% of all pregnancies are complicated by maternal diabetes, the current project has important implications for public health.

[unreadable] DESCRIPTION (provided by applicant): The aim of the current competing renewal proposal is to extend previous work conducted under the auspices of NS32976. The conceptual framework of the proposal is that the neural circuitry involved in processing faces becomes specialized as a result of experience viewing faces. A series of studies is proposed that examines how the timing, dose, and duration of different types of experience influence the development and neural bases of face processing. Particular attention will be directed toward the infant's and child's ability to recognize faces from unfamiliar species ("other-species effect"), unfamiliar races ("other race effect"), unfamiliar gender (e.g., infants reared disproportionately by mothers or by fathers), and unfamiliar ages (i.e., the ability to recognize faces of infants, children or elderly adults, co-varied against experience viewing such faces). The premise underlying these studies is that the perceptual window through which faces are viewed is broadly tuned at birth, and narrows with experience. To examine the developmental function of this perceptual narrowing, a training study will also be performed to ascertain whether the perceptual window can be kept open (or the sensitive period prevented from closing) by enriched experience. The specific questions to be addressed are: a) What is the developmental course of perceptual narrowing? b) Can the perceptual window be kept open with training? And c) How broadly tuned is the perceptual window? Across all studies, the primary means by which brain function will be inferred will be the recording of event-related potentials; various behavioral probes, appropriate to each age group, will also be employed. With regard to ERPs, particular attention will be paid to face-specific components and the spatial distribution of these components, from which inferences will be drawn about underlying neural sources. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Specific language impairment (SLI) and autism spectrum disorders (ASD) are complex, highly heritable disorders that involve primary impairments in language and communication. Both disorders are heterogeneous, longer-term outcomes vary considerably, and in families that have a diagnosed child, other relatives may share some behavioral features without meeting diagnostic criteria. At around 12 months, delays in major language and communication milestones are first reported for children later diagnosed with SLI or ASD, but thus far, relatively little is known about signs that may be detected during the first year of life. This research program is designed to address this important clinical and theoretical issue by investigating the early development of infants at risk for these disorders (with risk defined on the basis of an older sibling with a confirmed diagnosis). Building on earlier work by others and our own preliminary data, we propose that neurobehavioral markers of risk in fundamental processing systems (e.g., auditory/speech;visual/social) can be detected in the latter half of the first year of life. This is a highly significant stage because during this time development of both language and social perception depend on critical socially-embedded learning experiences. We hypothesize that infants at risk for SLI and ASD have risk markers that signal problems in speech/communication processing mechanisms;infants at risk for ASD have additional (non-shared) risk markers that signal problems in development that are grounded in socially-embedded experiences. These markers may result in altered developmental trajectories. The specific aims of the research are (1) to identify markers that distinguish between infants at risk for SLI or ASD and low risk controls;(2) to identify the predictors of later SLI and ASD diagnoses (at 36 months of age) from measures collected between 6 and 12 months of age;and (3) to compare developmental trajectories of key language and related social/cognitive measures between 6 and 36 months in infants with and without clinical outcomes. These aims will be pursued in a longitudinal prospective design following infants from 6 to 36 months of age. Data will be collected on language and social perception using behavioral, eye-tracking and neurophysiological measures as well as general measures of cognitive and brain development (head circumference;EEG). The findings from this research will have a significant impact on developing novel clinically useful methods for identifying infants at high risk for SLI and ASD;in turn this will improve their prognosis because it will open the doors for early entry into interventions that are known to lead to better outcomes. PUBLIC HEALTH RELEVANCE: This project is designed to detect the earliest risk markers in the first year of life for the two most prevalent developmental disorders of language. The findings from this research will have a major influence in developing novel approaches to early screening and diagnosis for specific language impairment and autism spectrum disorders. In turn, children identified as showing significant risk signs at much younger ages will be able to take advantage of early interventions that may prevent the onset of symptoms or reduce the severity of the disorder.

DESCRIPTION (provided by applicant): Sensitive periods are defined as a time in development during which the brain is particularly responsive to experiences in the form of patterns of activity (Daw, 1997).This time point may be termed a "critical" period if the presence or absence of an experience results in irreversible change (Newport, Hindle, &Jackson, 2001;Trachtenberg &Stryker, 2001). Those factors that allow a circuit underlying development to be plastic - or render it unchangeable - are becoming increasingly well understood in a small number of domains (i.e., visual and perceptual development). However, there is a paucity of data on sensitive periods for normative social and emotional development in human infants and children and little is known about the effects of aberrant experiences during early development on the emergence of psychopathology. The case of infants abandoned since birth into institutions provides an opportunity to examine the effects of severe psychosocial deprivation and sensitive periods in typical neural, social-emotional and cognitive development, as well as in trajectories that lead to psychopathology. Over the past 10 years we have conducted just such a study in which infants, abandoned since birth and raised in institutions in Bucharest, Romania, were randomly assigned either to be removed from the institution and placed into a family/foster care intervention or to be left in the institutions to care as usual. These children have been followed through 8 years of age and thus far, the data through 54 months of age indicate that a) early institutionalization leads to perturbations in brain electrical activity, profound deficits and delays in cognitive and socio- emotional behaviors, and a greatly elevated incidence of psychiatric disorders and impairment, b) our intervention was broadly effective in enhancing children's development, but c) for specific domains of neural activity, language, cognition and social-emotional functioning there appear to be sensitive periods regulating recovery. In the current proposal, we will extend these analyses with the aim to predict mental health outcomes in two groups of children: those originally assigned to our Foster Care intervention [FCG] and those originally randomized to remain in the institution (Care as Usual Group [CAUG] when they are 12 years of age, and we will compare their functioning to typically developing age-matched Romanian children (Never Institutionalized Group [NIG]). Using both brain (EEG/ERP) and behavioral measures, we propose to 1) reexamine, at age 12, the long term impact of early institutionalization on mental health outcomes and the efficacy of our intervention in ameliorating the burden of mental health outcomes using an intent-to-treat design;2) examine how the dose of institutionalization (percent time spent in an institution) influences long term outcomes;and 3) examine sensitive periods in recovery from early institutionalization. PUBLIC HEALTH RELEVANCE: There are currently more than 70 million orphaned or abandoned children throughout the world. A common societal response to caring for such children is to house them in institutions. Children with histories of early institutionalization are at risk for developing a variety of mental health problems that have their origin in abnormal social behavior. The current application will examine the long term effects of early institutionalization on mental health outcomes in two groups of children with a history of institutionalization, as well as explore sensitive periods in recovery from institutionalization.

DESCRIPTION (provided by applicant): An important function of the brain is to scan incoming sensory information for the presence of biologically relevant features and process and act on this information. For humans, the most salient signals of emotion are often social in nature, such as expressions of fear or anger. The goal of the current competing renewal is to study the nature and neural architecture of emotion processing across the first three years of life. Five-, seven-, and twelve-month-old infants, as well as three-year-old typically developing children will serve as participants across 5 specific aims. Aim 1 seeks to examine the neural and cardiac correlates of the infant's ability to process emotion in both faces and non-face stimuli. Aim 2 examines a similar question, except that autonomic activity (skin conductance and pupil diameter) will be recorded in conjunction with functional Near Infrared Spectroscopy (fNIRS). Aim 3 seeks to elucidate the neural networks involved in emotion processing, and will do so by using state-of-the-art signal processing software to extract theta activity from the ongoing EEG. Aim 4 will focus on individual differences in emotion processing viewed through the lens of genetics; specifically, all infants serving as participants in Aims 1 and 2 will be genotyped, with most attention focused on 5 SNPs, with an additional 5 SNPs serving as a secondary aim. All SNPS have been shown to be relevant to emotion processing in both humans and non-human species. Finally, in Aim 5 we examine whether early biases in emotion processing (i.e., whether infants show greater visual or neural activity to one emotion vs. another; e.g., fear) predict (or are associated with) behavioral inhibition and anxiety. Although the current project focuses on typically developing children, this work has enormous implications for children and adults who suffer from deficits in social-emotional communication. First, this work seeks to explicate the ontogeny of facial emotion processing; an ability that likely provides a foundation upon which higher-level social communication builds. As a result, it may well be the case that errors in this ability that occur early in development can develop into more insidious deficits that occur later i development. Second, the approach adopted in this project is highly innovative, and can easily be extended to various clinical populations, such as toddlers with autism or children diagnosed with depression or bipolar illness.

For the past 12 years we have conducted the first-ever randomized controlled trial (RCT) of foster care as an intervention for young abandoned children placed in institutions. Beginning with a sample of 136 Romanian infants abandoned to institutions early in life, we compared two groups. Half of this sample was randomly assigned to be removed from the institution and placed into a family/foster care intervention. The other half remained in the institutions receiving care as usual. We did not interfere with any placements deemed in the children?s best interest by child protection authorities in Bucharest. Over time, some children from both groups were adopted within Romania or reintegrated with their biological parents. Throughout we followed intent-to-treat analyses so that original group assignment defined group membership despite the fact that few of the ?care as usual? children remained in the institutions over the long run. A comparison sample of 72 never institutionalized children provided normative data. The original sample of institutionalized children has been followed through 12 years of age. We assessed the children's cognitive, social, psychiatric and brain outcomes at multiple assessment points across these 12 years. To date, the results indicate that a) early institutionalization leads to perturbations in the brain?s electrical (EEG) and structural (MRI) development, with profound deficits and delays in cognitive and socio-emotional behaviors, and an elevated incidence of psychiatric disorders and impairment, b) our intervention was broadly effective in enhancing children?s development, but c) for specific domains of neural activity, language, cognition and social-emotional functioning there appear to be sensitive periods mediating recovery. In the current proposal, we assess the children when they are 16 years of age and extend these analyses with the aim to predict mental health outcomes in two groups of children: those originally assigned to our Foster Care intervention [FCG] and those originally randomized to remain in the institution (Care as Usual Group [CAUG]) and we will compare their functioning to typically developing age-matched Romanian children (Never Institutionalized Group [NIG]). Using a variety of both brain and behavioral measures, we will 1) examine, at age 16, the long term impact of early institutionalization on mental health outcomes and the efficacy of our intervention in ameliorating the burden of mental health outcomes using an intent-to-treat design; 2) examine how the dose of institutionalization (percent time spent in an institution) influences long term outcomes; 3) examine sensitive periods in recovery from early institutionalization; and 4) focus particularly on risk taking behavior, substance use, and mental health outcomes.

Project Summary/Abstract The ongoing goal of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is to establish electroencephalography (EEG) and eye-tracking (ET) biomarkers that can be used for stratification and/or as sensitive and reliable objective assays related to social function in autism spectrum disorder (ASD) clinical trials. This renewal application seeks to further validate promising measures through three studies designed to enhance and extend the original ABC-CT study: (1) a confirmation study of the original findings in a new cohort using similar design (T1: Baseline, T2: 6 weeks post baseline, T3: 24 weeks post baseline) and sample size/characteristics (200 with ASD, 200 with typical development (TD)); (2) a follow-up study of the original cohort (N=399) to re-administer the biomarker and clinical batteries 2.5-4 years after original ABC-CT enrollment; (3) a feasibility study of parallel EEG and ET biomarkers in preschool-aged (3-5-year-old) children (25 with ASD, 25 with TD). The biomarker and clinical batteries measure key facets of social-communication in ASD using well- validated paradigms appropriate for the intended developmental and cognitive range. The study will rely on the same leadership and five Collaborating Implementation Sites (?Sites?) from the first phase, all highly experienced in multi-site collaborative clinical research using the proposed clinical, EEG, and ET methodologies. The Data Coordinating Core (DCC) will provide a secure informatics infrastructure for communication and data integration across the consortium to ensure organized data management, quality control, and reliable upload to the National Database for Autism Research (NDAR) and NIH Data Repositories. The Data Acquisition and Analysis Core (DAAC) will oversee consistent use of scientific standards and methodological rigor for data acquisition, processing, and analytics. The Administrative Core, in coordination with federal partners in this cooperative agreement, will oversee the operations of the sites, DCC, and DAAC to ensure methodologically and ethically rigorous, efficient completion of study aims: 1) In the confirmation study with a new cohort, evaluate whether EEG and ET measures, individually or in combination, have utility as stratification biomarkers and/or sensitive, reliable measures of change in clinical trials; 2) In the follow-up study of the original ABC-CT cohort, assess long-term stability, sensitivity to change, and longitudinal predictive value of the markers; 3) In the feasibility study, determine the viability of parallel EEG and ET measures as potential biomarkers in 3-5-year-old children with ASD and TD. Blood (DNA) samples will be collected from participants with ASD and biological parents for future genomic analyses, and raw, processed, and analyzed data will be shared to create a community resource accessible for use by all qualified investigators. These objectives are designed to further develop promising biomarkers to advance qualification with the FDA Biomarker Qualification Program.

? DESCRIPTION (provided by applicant): Searching for biomarkers and behavioral signs of early risk for neurodevelopmental disorders has emerged as an important line of clinical research in an effort to improve diagnosis and develop the most effective treatments and preventive interventions. In our current award period we identified several significant differences between infants at high familial risk for ASD (defined as having an older sibling with the disorder) and low risk control infants, including alterations in EEG, atypical lateralization for speech and faces, and reduced cortical connectivity all of which might serve as early risk markers. These differences were not only identified during the first year of life, their developmental trajectories were also atypical; a finding that appears to be a hallmark of risk for ASD. Our findings open up important questions about whether these risk markers extend to other infants later diagnosed with ASD, particularly infants from the general population, and whether they might also serve as risk markers for other related disorders, particularly language and social communication delay. In the next award period we address these questions by adding a new group of infants who fail a developmental screener (the CSBS) at 12 months. This group will be drawn from general pediatric practices, and will be compared to high-risk infant siblings and low risk controls on a battery of electrophysiological and behavioral measures that will be administered at 12-14 months, and again at 18, 24 and 36 months, at which time diagnostic outcomes will be evaluated. The project will address two specific aims. First, Do neural and behavioral risk markers (and their developmental trajectories) that distinguish infants at familial risk for ASD from low risk controls extend to infants at risk based on early behavioral differences detected on a 12-month screening instrument? We hypothesize that some risk markers will be shared across both high-risk groups, though for the screened group this may only hold for infants with clinical outcomes and show different developmental trajectories. Other risk markers may be unique to infants at familial risk. Our second aim addresses the question: Do the developmental profiles of neural and behavioral risk markers we identify predict only to later diagnoses of ASD or do they extend to other non-ASD neurodevelopmental outcomes at 36 months, including language or social communication delay? We hypothesize that some of our risk markers will be shared across these non-ASD related (and overlapping) clinical outcomes, while others will be unique to ASD outcomes. As research progresses on identifying behavioral and neural markers in infants that are at risk for neurodevelopment disorders, it is critical that we extend our research beyond familial risk to the general population and to evaluate risk markers across several diagnostic outcomes. In this way our goal is to advance knowledge of the shared and unique mechanisms that can ultimately be the focus of more targeted interventions at a time when there is greatest plasticity and opportunity for preventing adverse outcomes.

PROJECT SUMMARY/ABSTRACT Anxiety disorders are the most common psychiatric illnesses of childhood, affecting 10-20% of youth. Childhood anxiety often has a chronic course, negatively affecting academic, social, and adaptive functioning, and increases the risk for mental illness throughout life. Research has highlighted a number of risk factors that likely contribute to the development and maintenance of anxiety. However, there is limited understanding of the earliest precursors of anxiety or how multiple risk factors interact within and across development to influence anxiety risk. Prospective studies beginning in infancy are needed to explicate the origins of anxiety so that (a) biomarkers can be discovered that identify at-risk children prior to the emergence of symptoms and (b) preventive strategies can be developed and implemented with at-risk children. The overall goal of the current project is to test the combined effects of neural, physiological, behavioral, and environmental risk factors in early life on vulnerability to childhood anxiety. The study aims will be accomplished by following an established longitudinal cohort (R01 MH078829; N=807). The current study will build on an extensive database that includes repeated assessments of neurophysiology (EEG, ERP), neural metabolic functioning (fNIRS), physiological stress reactivity, behavioral indicators of reactivity to threat, and family environmental risk (maternal psychopathology, stress exposures) between infancy and age 3 years. In the current proposal, we seek funds to support a follow up study at ages 5 and 7 years. At these ages, we will phenotype our cohort for anxiety symptomatology, as well as implement a battery of brain-based measures similar to what was used at age 3 years. Analyses will test whether early patterns of neural processing (in infancy and again at age 3 years) predict risk for later anxiety; examine how measures of neural, physiological, behavioral, and family environment factors jointly contribute to the development of anxiety; and explore whether different patterns of risk factors and trajectories of development predict different anxiety phenotypes. We expect that the findings will (a) elucidate the neurodevelopmental bases of anxiety, (b) contribute to the discovery of non-invasive biomarkers that can identify at-risk children and (c) inform the design of innovative strategies to prevent the development of anxiety.

Project Summary/Abstract: The Translational Post-doctoral Training in Neurodevelopment (TPND) Program at Boston Children's Hospital is designed to provide promising post-doctoral neuroscience investigators (MD, PhD or MD/PhD) with advanced training in essential translational topics ranging from preclinical considerations through implementation of clinical trials for individuals with a range neurodevelopmental disorders. Large numbers of children, adolescents, and adults are affected by neurodevelopmental disorders that begin early in life, are rooted in aberrant brain circuitry, and have profound short- and long-term consequences on critical domains of development, cognition, social interaction, and behavioral regulation; yet most available medical and psychological treatments have had limited impact on the course of neurodevelopmental disorders. We propose to build on the significant strengths of the Translational Neuroscience Center (TNC) and the Laboratories of Cognitive Neuroscience at Boston Children's Hospital and Harvard Medical School to provide trainees with research experiences ranging from pre-clinical and cognitive neuroscience labs through clinical trial involvement in neurodevelopmental disorders. In addition, a key premise of this program is that effective research training in the field of translational neuroscience requires both mentors with expertise in areas across the continuum of translational research with neurodevelopmental disorders and ongoing programs to support the trainees to conduct innovative, high impact translational research. The 17 faculty mentors will involve trainees over a 2 year period (2 new entrants per year) with a range of state of the art methods in translational neurodevelopmental science that reflect core areas of the TNC program including basic science and translational methods as well as application to clinical populations in therapeutic trials for neurodevelopmental disorders. This research experience will be supplemented with both didactic and clinical immersion experiences designed to provide trainees with the skills needed to be successful independent investigators in this critical and emerging field. Ultimately this research experience will yield treatments that have an impact on the field by reducing the burdens and costs of care and costs to society that is now associated with neurodevelopmental disorders. In addition, the TPND will develop models of interdisciplinary research training for promising young scientists that will have a transformative impact on the field.

Project Summary/Abstract Beyond the grave health threats posed by COVID-19, this world-wide pandemic has also dramatically increased psychological distress among much of the population. For those particularly vulnerable to stress-related disorders, COVID-19 represents an unprecedented challenge. Individuals both directly and indirectly affected by the virus are forced to navigate through a range of hardships, including social isolation, financial insecurity, and uncertainty about the health and safety of self and loved ones. High on the list of psychologically vulnerable groups are pregnant women. Psychological distress may be compounded both by the uncertainty surrounding COVID-19's vertical transmission and by the potential effects of maternal distress on fetal brain development. Numerous studies have reported strong associations between maternal stress during pregnancy and disruptions in child development. The effects of maternal psychological stressors on fetal and infant development have been demonstrated across multiple levels, including disrupted fetal brain maturation, alterations in miRNA expression and DNA methylation, and increased risks for altered developmental outcomes and neuropsychiatric disorders (Babenko, 2015; Bick & Nelson, 2016; Hackman et al., 2010; Nelson, 2020; Lupien et al., 2019; McEwen, 2012, 2017; Vanderberg et al., 2017; Laplante et al., 2015; Wu et al., 2020). Previous work supports that mothers who experienced either a bacterial or viral infection and elevated stress during pregnancy were more likely to have an adolescent child diagnosed with depression (Murphy et al., 2017). Similarly, children exposed to a prenatal infection of the 2001 H1N1 virus displayed slightly delayed development (Borren et al, 2018).With these findings in mind, it is critical to determine the extent to which a COVID-19 exposure and related prenatal stress affects infant development in order to provide appropriate treatment and interventions. At Boston Children's Hospital, we are in the unique position to build on our current funding (R34 DA050289) to study infants born to COVID-19-positive women. Among our Boston-based collaborative group, we estimate that over the next 6 months we should be able to enroll 75 pregnant women, limiting ourselves to just one Harvard-affiliated hospital, Brigham and Women's Hospital (BWH). Our plan is to administer a number of questionnaires to these women prior to giving birth. At birth, we will work with the OB team to decide which mothers to approach about seeking consent to perform an MRI on their newborns, as well as 2 follow up visits to the PI's lab at Boston Children's Hospital.

PROJECT SUMMARY Neurodevelopmental processes are shaped by dynamic interactions between genes and environments. Maladaptive experiences early in life can alter developmental trajectories, leading to harmful and enduring developmental sequelae. Pre- and postnatal hazards include maternal substance exposure, toxicant exposures in pregnancy and early life, maternal health conditions, parental psychopathology, maltreatment, structural racism, and excessive stress. To elucidate how various environmental hazards impact child development, it is imperative that a normative template of developmental trajectories over the first 10 years of life be established based on a sufficiently large and demographically diverse sample of the US population. To accomplish this, the Healthy Brain and Child Development National Consortium study (HBCD) under the leadership and management of the HBCD National Consortium Administrative Core (HCAC) will deploy a harmonized, optimized, and innovative set of neuroimaging (MRI, EEG) measures complemented by an extensive battery of behavioral, physiological, and psychological tools, and biospecimens to understand neurodevelopmental trajectories in a sample of 7,500 mothers and infants enrolled at sites across the US. The overarching goal of the HBCD is to create a comprehensive, harmonized, and high-dimensional dataset that will characterize typical neurodevelopmental trajectories in US children and that will assess how biological and environmental exposures affect those trajectories. A special emphasis will be placed on understanding the impact of pre- and postnatal exposure to opioids, marijuana, alcohol, tobacco and/or other substances. To address these broad objectives, the HCAC will oversee study design, development of the common protocol, and monitor recruitment and retention to ensure that the sample of women enrolled includes: 1) a racially, ethnically, and socioeconomically diverse cohort that is representative of the US population; 2) pregnant woman with use of targeted substances (opioids, marijuana, alcohol, tobacco); and 3) demographically and behaviorally similar women without substance use in pregnancy to enable valid causal inferences. The HCAC will ensure study objectives are met, monitor performance, provide for training, establish and carry out decision-making and ethical policies, manage all study communications, and oversee processes for considering study modifications. In collaboration with the HBCD National Consortium Data Coordinating Center (HDCC), the HCAC will ensure that approximately annual study datasets are released to the broader scientific community. The HBCD National Consortium study will inform public policy to improve the health and development of children across the nation.

Project Summary/Abstract Over a year into the global pandemic, COVID-19 poses serious threats to physical health and emotional well-being. Pregnant women are at risk for serious morbidity due to COVID-19 and may be particularly vulnerable to psychological distress, compounded by continued social isolation, financial insecurity, and uncertainty about their own health, as well as that of their unborn child. To date, 73,617 pregnant women in the U.S. have tested positive for COVID-19. Understanding how prenatal exposure to COVID-19 and associated stress impact the developing fetus is of critical relevance to public health. Prenatal exposure to maternal infection and related stress has been strongly associated with disrupted child neurodevelopment. Although risk for vertical transmission of COVID-19 is low (Golden & Simmons, 2020), maternal immune activation is a potential mechanism by which prenatal exposure to infection can impact neurodevelopment. Epidemiological studies have revealed that maternal infections during pregnancy are linked to higher incidence of autism, schizophrenia, and central nervous system disorders (e.g., cerebral palsy) among offspring (Solek et al., 2018; Knuesel et al., 2014; Bauman & Van de Water, 2020). Animal models suggest that maternal immune activation can alter fetal brain development, increasing neurodevelopmental risk (Bergdolt & Dunaevsky, 2019). Effects of maternal stressors are observed at multiple levels, including disrupted brain maturation, epigenetic alterations, and poor developmental outcomes among offspring (Bick & Nelson, 2016; Nelson, 2020; Lupien et al., 2019; McEwen, 2012, 2017; Vanderberg et al., 2017; Wu et al., 2020). Cumulative effects of prenatal infection and stress may exacerbate neuropsychiatric risk: for example, mothers who experienced an infection and elevated stress during pregnancy are more likely to have adolescent offspring with depression (Murphy et al., 2017). To inform effective interventions, it is critical to examine whether?? and how?? maternal COVID-19 exposure and related stress affect infant neurodevelopment. At Boston Children's Hospital (BCH), we are ideally positioned to build on current funding (R34 DA050289) and an approved IRB protocol (IRB-P00035929) to perform neurodevelopmental follow-up of infants born to COVID-19-positive women, enrolled in the Massachusetts General Hospital (MGH) COVID-19 Pregnancy Biorepository (PI: Edlow). In the next 6 months, we will enroll 60 mother-infant dyads from this large cohort to participate in two visits at the PI's BCH lab (ages 9 and 12 months). At each visit, we will conduct study procedures assessing maternal stress, neurophysiology (EEG, eyetracking), and developmental outcomes. A subset of participants will complete an MRI at 9 months.