Nathan A. Fox - US grants

A number of primary discrete emotions emerge over the first year of life. Little is known about the relation between facial signs of these affects and concomitant central nervous system processes. The research proposed in this application is designed to provide the first fundamental knowledge on this question. It is novel methodologically in combining the precision of detailed coding procedures for the measurement of facial affect with sophisticated techniques for the analysis of noninvasively recorded brain activity. Infants at 6 months and 12 months of age will be studied. The same affect eliciting conditions will be presented at each age. These include presentation of a sweet and sour taste, placement on the visual cliff and the mother smiling or frowning at her infant. Brain electrical activity from left and right sided leads in the frontal and parietal regions will be recorded. The research will focus on hemispheric asymmetry associated with the presence of different facial signs of discrete emotion. These findings will provide important new information on the relation between maturational changes in brain function and the emergence of different emotion systems over the first year of life.

A number of primary discrete emotions emerge over the first year of life. Little is known about the relation between facial signs of these affects and concomitant central nervous system processes. The research proposed in this application is designed to provide the first fundamental knowledge on this question. It is novel methodologically in combining the precision of detailed coding procedures for the measurement of facial affect with sophisticated techniques for the analysis of noninvasively recorded brain activity. Infants at 6 months and 12 months of age will be studied. The same affect eliciting conditions will be presented at each age. These include presentation of a sweet and sour taste, placement on the visual cliff and the mother smiling or frowning at her infant. Brain electrical activity from left and right sided leads in the frontal and parietal regions will be recorded. The research will focus on hemispheric asymmetry associated with the presence of different facial signs of discrete emotion. These findings will provide important new information on the relation between maturational changes in brain function and the emergence of different emotion systems over the first year of life.

The purpose of this project is to examine the stress response of preterm infants to certain routine nursing procedures in the Neonatal Intensive Care Unit (NICU). The underlying premise is that given the same medical condition, there are individual differences among preterm infants in their response to the routine procedures of neonatal intensive care. These individual differences are reflected in infant baseline behavioral and physiological patterning. Individual differences will affect response to stressful and beneficial nursing procedures and subsequent behavioral organization at term age as reflected by performance on the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). The baseline differences in patterning can potentially discriminate those infants most likely to be negatively affected by the stressful environment of the NICU, thus allowing clinicians to intervene to reduce stress. This project will examine the preterm infant's immediate response on physiological and behavioral levels to four routine nursing procedures, heelprick, turning, nonnutritive sucking, and stroking. Examining the relationship between the immediate response and behavioral and physiological organization at discharge can provide further information not only about the effect of stressors in the NICU environment but also about individual differences in preterm infants' response patterns. This project will study 100 preterm infants of similar post- conceptional age and medical status residing in a level three NICU. Each infant will be studied for baseline values and during four nursing care procedures. All procedures will be those routinely carried out in the NICU. Detailed behavioral and physiological data will be collected prior to, during, and after the procedure by assessing activity, state organization, oxygen saturation, salivary cortisol, and autonomic patterning. At the time of discharge, behavioral organization will be assessed using the BNBAS and a final physiological and behavioral baseline recording.

Recent advances in behavioral neuroscience research have permitted investigation of the relations between developing areas of the neocortex and emerging behavioral skills. There is evidence which suggests that while the frontal cortex is among the last areas of the brain to mature, it may subserve important functions during the period of infancy. One potential method for exploring brain/behavior relations is the measurement of scalp recorded brain electrical activity (EEG). Recent conceptual and computational advances have led to the use of the EEG as a measure of both regional development and of the emerging cortico-cortical connections. The purpose of the present study is to extend, into the second year of life, basic research on the maturation of the EEG and its relation to specific cognitive and language behaviors. It is our intention to chart developmental changes in a subset of cognitive and language competencies and to relate these changes to specific parameters of the EEG. We will complete a longitudinal study of 48 infants, beginning at age 14 months, and will see them every two months (14, 16, 18, 20, 22, and 24 months of age). At each age we will assess infant performance on tasks designed to tap frontally and non-frontally mediated competencies. In addition, we will assess the emergence of infant self-regulatory skills and have parents of the infants complete a standardized language assessment questionnaire. We will also record multi-lead EEG. Our aims include documenting changes in brain electrical activity-across the second year of life and investigating the associations between EEG changes and cognitive, language, and self-regulatory development. Enhanced understanding of these processes and their interrelationships will provide an important window into understanding cognitive-neuro development in the second year of life. It may also be of importance in understanding the cognitive, language, and self-regulatory development of atypical populations.

Recent data suggest that peer interaction is an important force in the development of normal social relationships and social skills. Over the past number of years our research has focussed on the relations between dimensions of infant behavior and preschool social behavior with an understanding of the mediating role of EEG asymmetry. We have also studied, within the general population, the developmental continuities and dis-continuities associated with behavioral inhibition and social withdrawal. We have reported that social withdrawal is a behavioral 'marker' of social anxiety in early childhood and that socially withdrawn children are less confident and competent in their interactions with peers. Over the past five years we have also performed a number of studies which suggest that the affective behavior displayed by young children in novel social situations is, in part, associated with specific patterns of frontal EEG asymmetry. And, we have documented that specific patterns of infant temperament are associated with withdrawn and inhibited behavior during the preschool period. Specifically, we have found that individual differences in the pattern of frontal EEG asymmetry are associated with the valence of affective response and the child's disposition to respond in a pro-social or withdrawn manner to peers. The research proposed in this application is designed to extend our findings on the relations between dimensions of infant behavior and preschool social behavior with an under-standing of the mediating role of EEG asymmetry. The current grant will focus on two independent samples of children who were each selected at four months of age for specific behavioral characteristics thought to be associated with behavioral inhibition. Subjects in two cohorts (N=72) and (N=120) have been seen at ages 9, 14, and 24 months of age. At each age, measures of behavioral response to novel events were recorded. At each age, brain electrical activity (EEG) was recorded from each subject. We propose to see these two cohorts when children are four years of age. At that time each child will be seen twice. Once with three others in a same sex quartet play session and once individually when EEG will be recorded. Based upon our previous work with an unselected sample of children at age four, we believe that infant temperament and frontal EEG asymmetry will predict social withdrawal and social competence at four years of age.

The goal of this project is to examine the social skills, self-perceptions, and social relationships of 11-year-old children who, at earlier ages, had been identified as extremely wary and socially inhibited. In our longitudinal program of research we have found that the pattern of brain electrical activity (EEG), recorded over the anterior frontal lobes, represents a marker of individual differences in the tendency to express and modulate positive and negative emotions. Thus, infants and toddlers who exhibit wariness and behavioral inhibition during the first two years of life, and who display greater negative right frontal EEG activation are more likely to be socially reticent during preschool peer interaction. Furthermore, 4 year social reticence predicts social withdrawal in the peer group at age 7 years. We posit that socially withdrawn 7-year-old children, especially those who display greater relative right frontal asymmetry, will be rejected by peers in later childhood. Moreover, we hypothesize that the friendships of these children, at age 11 years, will be qualitatively inferior and more fragile than those of their non-withdrawn counterparts. And finally, we postulate that physiologically assessed wariness, in combination with impoverished social skills and peer relationships, will predict negative self perceptions of social competence and peer relationships, as well as internalizing problems in early adolescence (11 years). These hypotheses will be examined by bringing the participants in our longitudinal project to the laboratory for three visits at 11 years of age. Session 1 will consist of same-sex quartets, much like the ones in which the children participated at ages 4 and 7 years. Session 2 will consist of a friendship dyad interaction in which the target child will be observed interacting with his/her best friend. Also in Session 2, both the focal child and his/her best friend will participate in a same-sex quartet with two additional unfamiliar children. Session 3 will allow collection of psychophysiological data. As a result of these three sessions, we will be able to describe the friendship and social interactive patterns of both reticent and non-reticent children. We will also be able to characterize the processes through which competent peer interaction develops. %%% The goal of this project is to examine the social skills, social relationships, and self-perceptions of 11-year-old children who, at earlier ages, had been identified as extremely wary and socially inhibited. Earlier research has suggested that adolescent and adult depression, anxiety, and other problems of an `internalizing` nature may be predicted from negative self appraisals and withdrawal from the peer group during childhood. The developmental precursors of negative self appraisals and social withdrawal, however, are by-and-large unknown. In our longitudinal program of research we have found that infants and toddlers who display greater negative right frontal EEG activation tend to be wary and behaviorally inhibited during the first two years of life. This constellation of psychophysiology and behavior predicts extremely wary, socially reticent behavior during preschool peer interaction. And, 4 year social reticence, combined with negative right frontal EEG activation, predicts social withdrawal from the peer group at age 7 years. In the present study, we are predicting that socially withdrawn 7-year-old children, especially those who display greater relative right frontal asymmetry, will, at 11 years, be rejected when they attempt to initiate interactions with their peers. We hypothesize also that the friendships of these children, at age 11 years, will be qualitatively inferior and more fragile than those of their non-withdrawn counterparts. And finally, we posit that physiologically assessed wariness, in combination with impoverished social skills and peer relationships, will predict negative self perceptions of social competence and peer relationships, as well as internalizing problems in early adolescence (11 years). These hypotheses will be examined by bringing the participants in our longitudinal project to the laboratory for three visits at 11 years of age. In these sessions, we will assess the quality of the children's peer relationships, with a special emphasis on the quality and strength/fragility of their relationships with their best friends. We will also assess the children's self-expressed perceptions of their social skills and social relationships, as well as their feelings of anxiety, social wariness, and depression. Finally, we will continue to collect EEG data, given the purported significance of right frontal asymmetries in the prediction of internalizing disorders in childhood and adolescence. As a result of this study, we will be able to document some of the early origins, and some of the early adolescent concomitants of negative thoughts and feelings about the self, social wariness, and other problems of an internalizing nature.

SUBPROJECT ABSTRACT NOT PROVIDED

DESCRIPTION: Over the first four years of life children develop the skills to interact with both familiar and unfamiliar peers and adults in a socially appropriate manner. They learn to modulate their behavioral and emotional responses across multiple contexts and they develop skills to overcome initial hesitations to engage others. There are, however, instances, in which children are less successful in the development of regulated social behavior. Some children display social withdrawal and miss out opportunities to interact with peers and develop friendships. The lack of such experiences is often associated with low self-esteem and signs of depression in withdrawn children during the school years. Other children display impulsivity and low frustration tolerance and often find themselves engaged in conflict and struggles with peers and adults. The processes by which infants and young children develop the skills for regulated social interaction involve the interaction of their inborn temperamental styles with supportive, guiding, care giving behaviors across a variety of contexts, and the development of certain information processing skills that facilitate the transition from the use of external supports in the modulation of behavior to internal self-reliant responses. In order to fully understand these processes, we will study each of these components and their interactions over time. The current proposal draws upon the research literature in four domains: temperament, frontal EEG asymmetry, mother-child interaction and socialization and the role of cognitive processes in the development of regulated and unregulated social behavior. We propose a longitudinal study in which will select two temperament groups, infants who are temperamentally fearful and infants who are temperamentally exuberant. We will follow these children over the first four years of life assessing the expression of their temperament, the pattern of maternal caregiving, and the development of executive function skills. We will assess frontal EEG asymmetry in these infants and over time. This measure has been found to be a significant correlate of temperament and our repeated assessment of frontal EEG asymmetry and child temperament will provide an important model for understanding the plasticity of neural development and the coordination of brain behavior relations in early childhood. Our proposed study will attempt an innovative analytical approach, growth modeling with latent cluster analysis so that we might identify, clusters of children who show particular patterns of change or continuity in the expression of temperament over time. To accomplish this we will repeatedly assess the child's social behavior with an unfamiliar peer across the grant period. This program of research will identify the significant components that mediate a child's inborn temperament to produce either socially appropriate and regulated social behavior or socially inappropriate and maladaptive unregulated social behavior.

[unreadable] DESCRIPTION (provided by applicant): Over the first four years of life children make tremendous strides in acquiring the social skills that are essential for the lifelong development of healthy relationships. They learn how to engage with other children and adults, and develop skills in negotiation, the co-regulation of play, and sustaining friendships. The current investigation, to which the proposed supplemental project is linked, is following two temperament groups - infants who are temperamentally fearful and those who are temperamentally exuberant - for whom prior evidence suggests these early social tasks are particularly challenging. The study is focusing on the contribution of maternal caregiving behaviors and the development of information processing skills as they influence the trajectories of these children towards regulated or unregulated social behavior between infancy and age four years. During this same period, most children in the U.S. enter child care environments with other children which, as a result, provide a critical arena for social development. Early social development has figured prominently in the child care literature and is now a focal point of research in light of evidence that, of the range of developmental outcomes examined, social behavior may be particularly susceptible to variation in the amount and quality of child care the children experience. The supplemental project would add to the current investigation an examination of the critically important mediating influence of child care environments. By examining the children's exposure to child care with peers from early infancy through preschool, as well as their experiences in child care when they are 24, 36 and 48 months of age, this project would significantly expand our understanding of the kinds of experiences that either increase or decrease the odds of compromised social development among temperamentally vulnerable infants during a crucial period when their trajectories begin to diverge towards adaptive or maladaptive outcomes. On-site child care assessments will focus on the quality of caregiving the children receive, the extent to which their caregivers support positive peer interactions in child care, and the children's actual peer experiences in child care. These data will supplement the growth models being employed in the current study to include child care among the processes that affect the development of adaptive or maladaptive social behavior among temperamentally vulnerable infants. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Previous research suggests that early temperamental biases shape the manner in which individuals perceive and process emotional information. These processes in turn create the conditions around which individuals view their own self-efficacy as well as the responses of others and hence contribute to the formation of adult personality. The interplay of early temperament and styles of cognitive processing is critical if researchers are to examine the complex trajectories of the development of social behavior into adolescence. With these considerations in mind, the current proposal will initiate an assessment in adolescence of a longitudinal sample that has been followed since early infancy. 150 infants were selected at 4-months of age from a larger normative sample based upon their motor and affective reactions to novel auditory and visual stimuli. These children were re-assessed at 9, 14, and 24 months of age and at 4 and 7 years of age. Previous assessments of this sample included measures of physiology, behavior, and maternal perception of temperament. The currently proposed study will provide assessments of these same subjects in adolescence when they are 14-16 years of age. 6 broad areas are to be assessed: Cognitive processing of emotional and social stimuli; resting physiological activity and reactivity to threat, self-concept and behavioral adaptation, observed social behavior in response to an unfamiliar peer, the presence of anxiety disorders, and the social contextual demands of adolescence. With data from these tasks, we will examine the confluence of early temperament and the demands of the social context in adolescence on styles of cognitive processing of social and emotional stimuli, the influence of early temperament on physiological reactivity to threat, and the mediating role of styles of cognitive processing and physiological reactivity on social and anxious behaviors.

Over the first four years of life children develop the skills to interact with both familiar and unfamiliar peers and adults in a socially appropriate manner. They leam to modulate their behavioral and emotional responses across multiple contexts and they develop skills to overcome initial hesitations to engage others. There are, however, instances, in which children are less successful in the development of regulated social behavior. Some childrendisplay social withdrawal and miss out opportunities to interact with peers and develop friendships. The lack of such experiences is often associated with low self-esteem and signs of depression in withdrawn children during the school years. Other children display impulsivityand low frustration tolerance and often find themselves engaged in conflict and struggles with peers and adults. The processes by which infants and young children develop the skills for regulated social interaction involve the interaction of their inborn temperamental styles with supportive, guiding, caregivtngbehaviors across a variety of contexts, and the development of certain information processing skills that facilitate the transition from the use of external supports in the modulation of behavior to internal self-reliant responses. In order to fully understand these processes, we will study each of these components and their interactions over time. The current proposal draws upon the research literature in four domains: temperament, frontal EEC asymmetry, mother-child interaction and socialization and the role of cognitive processes in the development of regulated and unregulated social behavior. We propose a longitudinal study in which will select two temperament groups, infants who are temperamentally fearful and infants who are temperamentally exuberant. We will follow these children over the first four years of life assessing the expression of their temperament, the pattern of maternal caregiving, and the development of executive function skills. We will assess frontal EEG asymmetry in these infants and over time. This measure has been found to be a significant correlate of temperament and our repeated assessment of frontal EEG asymmetry and child temperament will provide an important model for understanding the plasticity of neural development and the coordination of brain behavior relations in early childhood. Our proposed study will attempt an innovativeanalytical approach, growth modeling with latent cluster analysis so that we might identify clusters of children who show particularpatterns of change or continuity in the expression of temperament over time. To accomplish this we will repeatedly assess the child's social behavior with an unfamiliar peer across ths grant period. This program of research will identify the significant components that mediate a child's inborn temperament to produce either socially appropriate and regulated social behavior or socially inappropriate and maladaptive unregulated social behavior.

This project, Core C of the Center proposal, involves data integrity for neuropsychological and electrophysiological data as well as training of Center personnel and graduate students in neuropsychological and electrophysiological methods with young children. The Center proposes two projects that involve the acquisition of neuropsychological and electrophysiological data with young children. Core C will insure the quality and integrity and comparability of the data, both behavioral and electrophysiological across both these projects. As well, we have identified tasks that activate similar neural structures in both human children and non-human primates. Core C will insure that these tasks are administered similarly across projects and will assist in the analysis of their comparability across human and non-human primate populations. Finally, Core C is involved in training and dissemination of methods for acquisition, processing and analysis of electrophysiological data to human child populations as well as training and dissemination of neuropsychological tasks to researchers with both human children and non-human primates. This will be accomplished by holding training workshops and training directly graduate students who will work at the different Center sites and projects. RELEVANCE (See instructions): A Center dedicated to translational research in the neuroscience of early life stress must maintain high standards of quality control for the behavioral and electrophysiological measures to brain functioning collected across sites and species. The main goal of Core C is to insure these standards. As well, Core C will be involved in training and dissemination of neurocognitive and electrophysiological methods.

DESCRIPTION (provided by applicant): Early childhood temperament, particularly behavioral inhibition, is seen as an expression of a child's biologically based negative reactivity to novelty and threat. Behavioral inhibited children have difficulty with peer interactions and exhibit withdrawal in novel social situations. Although expressed behavior may change with development, the underlying tendencies and general thresholds for attending to and reacting to novel or threatening stimuli in the environment may remain stable. These differences in reactivity may influence patterns of social competence particularly as individuals enter into periods of change and transition in their social contexts. . The period of young adulthood may be of particular importance in the lives of behaviorally inhibited individuals since it is marked by structural and cultural changes in the individual's social environment. This period also marks the peak for the emergence of anxiety disorders and substance use. Insofar as behavioral inhibition selectively influences the direction of attention to threat (i.e., anxiety) and the likelihood of engaging in substance use these individuals may be most at-risk for the development of maladaptive outcomes in young adulthood. We propose to study the mechanisms involving attention bias to threat and anticipation of reward and their role in the formation of personality and the emergence of psychopathology and substance use within a sample of 20-year-olds who were initially selected for differences in temperamental reactivity including behavioral inhibition. These subjects have been followed in a longitudinal study since they were four months of age. At multiple age points, measures of temperament, social behavior, physiological reactivity, and cognitive processing were obtained. The subjects in the current study will be seen for a two-day visit where they will be assessed for psychiatric status, and then presented with two different tasks during functional neuroimaging. The two tasks include assessment of their attention bias to threat and assessment of their reactivity to reward anticipation. We will also collect questionnaire data, via internet methods, on each subject and a peer nominated by the target subject. The goal is to identify developmental trajectories from early childhood temperament to psychiatric outcomes and substance use and examine the mediating effects of social competence and the moderating roles of attention to threat and reward processing. PUBLIC HEALTH RELEVANCE: The goal of this is to examine how the trajectories of childhood temperament predict the behavioral and neural correlates of attention bias to threat and incentive for reward in young adults with a history of behavioral inhibition, focusing specifically on the manner in which these processes moderate the association between temperament and anxiety disorders and substance use. Results from these studies will inform both prevention and intervention of anxiety disorders and associated substance use.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

Studying activity of the human brain non-invasively is a major scientific challenge, yet it is essential for enhancing our understanding of the neural bases of action, emotion, and thought. A major technological advancement in studying the neural basis of behavior has been the development of functional magnetic resonance imaging (fMRI), a hemodynamic technique based on the tight coupling between neuronal activity and oxygenated blood flow. fMRI is a powerful tool for non-invasively measuring local changes in the brain with high spatial resolution (~1 mm) in the blood oxygen level dependent (BOLD) signal. Additionally, structural imaging using MRI can characterize volumetric differences in brain tissue and specify major pathways of neural processing and transmission. These approaches can be combined with other neuroimaging data examining the temporal dynamics of brain activity, to establish a more complete understanding of the human brain and the neural processes underlying human cognition, action, and emotion.

A state-of-the-art 3-Tesla Magnetic Resonance Imaging (MRI) scanner will provide access to this powerful technology to the University of Maryland College Park community for studying human brain activity. The MRI scanner will serve as the centerpiece of the Brain Imaging Center at Maryland (BICAM) and will transform the research and educational environment at the University of Maryland. The scanner will provide the foundation for research in cognitive and affective neuroscience, with specific foci on human development, attention and memory, decision making and risk, motor-control, and language and communication. The center will also create opportunities for innovations in signal processing and magnetic resonance physics. The center and its shared instrumentation will foster an intensive learning environment through the integration of research and education within the University of Maryland and through its partnerships in the local community. The MRI scanner will enhance graduate and undergraduate education through directed research projects, courses with a hands-on focus in functional neuroimaging, and accessibility to students from underrepresented groups. The center will also sponsor a summer institute in developmental cognitive neuroscience which will bring experts in the study of brain development and neuroimaging to the University of Maryland.

BICAM is part of the Neuroscience and Cognitive Science (NACS) program at the University of Maryland. This program consists of faculty from traditional behavioral and neuroscience departments such as Psychology, Human Development, Linguistics, Hearing and Speech, and Kinesiology, as well as faculty from Computer Science, Physics, Applied Mathematics, and Electrical and Computer Engineering with expertise in imaging, signal processing, and the physical basis of magnetic resonance technology. Acquisition of the new scanner will lead to broad interdisciplinary collaboration in areas of the basic physical and behavioral sciences with the goal of understanding the neural bases of behavior.

PROJECT SUMMARY (See Instructions): A fundamental issue in cognitive neuroscience is how the brain is able to encode others' actions and intentions. In this perspective one of the most important advances of our knowledge on how these processes can take place in the cortex is the discovery of mirror neurons. The main conceptual breakthrough open by their discovery is that perceptual and motor processes share a common code. The proposed research will investigate, with non-invasive electroencephalography methods, the emergence of the MN system in infancy and young children. It will compare the EEG activity depicted by specific frequency bands in infants with that of children and adults in which the MNs has been widely studied. Acquisition of EEG will be combined with a careful behavioral assessment of subjects in order to test the hypothesis that MNs are at the basis of specific matching behaviors that are important landmarks in the development of perception action relations. We will as well, carry out experiments in non-human primates to identify these EEG rhythms in infant Rhesus Macaque and to link, for the first time, single cell recordings of mirror neurons to the ongoing EEG.

DESCRIPTION (provided by applicant): As children transition from elementary to middle school, there are changes to their social context that include exposure to unfamiliar age mates and reorganization of existing peer groups which generate a number of challenges to be met. Some children negotiate these changes and new challenges easily, while others have greater difficulty. A child's temperament may influence their success or failure in this process. Behavioral Inhibited children may be particularly vulnerable to problems in social adaptation across the middle school years and into adolescence. Behavioral Inhibition is a temperament, identified early in childhood that involves heightened sensitivity to novelty, withdrawal from mildly stressful and unfamiliar events, and social reticence. We have recruited a large cohort (n=315) of infants and have carefully characterized their temperamental disposition to behavioral inhibition over the period of infancy and early childhood. We now wish to see these children before they enter middle school (10-11 years of age) and then soon after they transition to early adolescence (12-13 years of age). We will observe their social competence with familiar and unfamiliar peers and assess their attention bias to threat, as well as cognitive self-monitoring, in order to gain a detailed understanding of the social and cognitive mechanisms that influence the pathways from temperament to adaptive or maladaptive outcomes during this important period of development. Our unique and innovative approach involves behavioral observation of dyadic social interaction with familiar and unfamiliar peers when children are 10-11 years of age, assessment of cognitive factors at that age, as well as questionnaire measures of biological factors and school context. We will use these data to predict social competence in a peer group as well as incidence of psychopathology at age 12-13. This approach will allow us to identify how specific social and cognitive mechanisms moderate initial child temperament of behavioral inhibition to increase or diminish the risk for poor social adaptation and heightened incidence of psychopathology. PUBLIC HEALTH RELEVANCE: Child temperament is a critical factor shaping the social skills and competencies that are important for negotiating the challenges of key developmental transitions, including the early adolescent period. Behavioral Inhibition, a well characterized temperament identified in early childhood, is one important marker for risk for the incidence of anxiety in adolescence. This project will examine behaviorally inhibited children as they transition into early adolescence in order to identify the social and cognitive factors associated with psychopathology in this population of children.

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 Childhood temperament broadly shapes psychological adjustment across the lifespan, having particular influence during critical and complex periods of development such as adolescence. While risk for psychopathology rises sharply during adolescence, temperamental differences further enhance risk. Behavioral Inhibition (BI) is a temperament identified early in life, marked by strong physiological, behavioral, and emotional reactions to unfamiliar contexts, and associated with a four-fold increased risk for anxiety disorders in mid-adolescence, as well as mood disorders and substance abuse in late adolescence. Despite the dramatic increase in risk, we have found that not all children with a childhood history of BI go on to display psychopathology. Given this heterogeneity in risk outcomes, it is critical to identify the mechanisms that differentiate adolescents who struggle from those who adapt despite early risk factors. For adolescents with a history of BI, the increasing demands of their rapidly evolving social context may be particularly challenging. Unsuccessful attempts to negotiate the complex social challenges of adolescence are linked to increases in psychopathology, making mid-adolescence a critical period for isolating mechanisms that might influence variability in outcomes. We are proposing to examine two such mechanisms, cognitive control and supportive relationships with friends and parents, and their impact on adolescents? reactions to, and regulation following, social challenges assessed in the laboratory and using daily diary reports. We will examine: (1) two types of cognitive control (reactive versus proactive) with the expectation that reactive control will be positively associated, and proactive control will be negatively associated with heightened reactions to social challenge and greater psychopathology, and (2) the effects of supportive relationships with friends and parents with the expectation that such relationships will buffer the effects of stressful social challenges and increased incidence of psychopathology. Finally, we will examine whether adolescents? responses to social challenge mediate the association between childhood history of BI and psychopathology in late adolescence.

Project I Project Summary A fundamental issue in cognitive neuroscience is how the brain encodes others? actions and intentions. In recent years, an important advance in our knowledge on how these processes may take place is the discovery of mirror neurons (MNs). The main conceptual breakthrough spurred on by their discovery is that perceptual and motor processes may share a common code. Over the past five years, as part of a Program Project, we have made a number of discoveries regarding the mirror neuron system (MNS) in human infants, children and adults. First, data from functional MRI studies suggest that there are differences in the extent of overlap in mirror areas between 8-year olds and adults, reflecting continued development of the MNS during childhood. Second, we find age differences in the magnitude of EEG mu Event Related Desynchronization (ERD) during observation of actions over central-parietal sites and as well as the emergence of a second MNS signal in the EEG, ERD in the beta frequency during middle childhood. Third, analysis of EEG coherence patterns across age suggest development of organized brain networks that continue to develop across childhood underlying an extended MNS. Fourth, individual differences in motor skills are associated with the magnitude of mu ERD during observation in infants, 4- and 8-year-old children and adults. Together, these data suggest that the MNS early in life supports the emergence of basic motor skills and learning to attend to actions, but that development continues through childhood. The specific aims for the next grant period are first, to examine the effects of experience on the MNS and its links to social-communicative gestures in infancy. Second, to use fMRI and EEG to chart the developmental trajectory and functional significance of the MNS in childhood. Through these aims we will provide an expanded and broader view of the role that the MNS plays in development of social cognition and the links between the MNS and motor competence.

The ability to understand other people's goals and intentions is critical for social competence. A key component of this is interpreting the reasons for others' actions. Infants appear to be able to determine others' goals based on observing others' actions early in life, and this sensitivity to others' goals is associated with developments in infants' own ability to perform goal-based actions. The purpose of this project is to investigate the neural and cognitive systems that support infants' emerging sensitivity to goal-based actions in themselves and others. This work will shed new light on how neurocognitive development supports early social cognition.

The proposed studies will record electroencephalogram (EEG), a technique for recording the brain's electrical activity, while 8- to 10-month-old infants perform actions on objects, when they perform joint actions with others, and when they observe others' actions. A first goal of the research is to characterize the neural processes that are involved when infants learn to engage in new actions and social collaborations. A second goal is to test the prediction that these neural processes also support infants' understanding of others' goal-directed actions. To address these issues, the research will evaluate networks of neural activity as infants act and observe others' actions, and will assess whether these patterns of neural activity predict when infants are able to respond appropriately to others' goal-directed actions. Beyond addressing the focal research questions, the proposed studies will generate new approaches to analyzing infant neural and cognitive development, and the findings of these studies with typically-developing infants may help to shed light on developmental disorders that affect social cognition and social behavior. The project will provide unique multidisciplinary training opportunities for students and postdoctoral researchers.

Core A Project Summary The overall objectives of Core A, the administrative core are to: (1) Provide budgetary and administrative support for each of the Projects; (2) Support the programmatic and synergistic activities of the research teams from across the Projects; and (3) Support outreach activities related to the project. These objectives will be accomplished by (a) providing overall administrative leadership for the Program Project. This will be the primary responsibility of the two PIs, Nathan Fox and Amanda Woodward; (b) creating an administrative structure for the Program Project. This structure will be required to serve the needs and develop the coordination of the different projects of the Program Project. It will consist of an executive committee and a steering committee; (c) creating an External Advisory Board that will provide input from outside scientists to the Center on the scientific and administrative issues associated with the Program Project. The advisory board will help guide the priorities we set for research and outreach initiatives for the Program Project. Establish rubrics for evaluation of Project and Core progress for formal evaluation; (d) overseeing all IRB activities related to the research programs which will allow data sharing across projects; (e) overseeing and monitoring the allocation of resources to each Project and Core; (f) facilitate cross-project interactions amongst postdoctoral fellows and graduate students; (g) coordinate yearly Program Project meeting for all personnel (and External Advisory Board); (g) coordinate outreach efforts across the projects; (h) maintaining and updating of the Program Project website, using it for messaging, file sharing, and outreach.

Core B Project Summary The development of reliable, valid and innovative measures of the functioning of the mirror neuron system (MNS), particularly for use with human infants and children is a critical task in order to understand the plasticity and development of this system and its influence on the emergence of social cognition. Core B's aims have been to develop methods for the acquisition and processing of EEG that could identify EEG Event Related Desychronization (ERD) in different age populations and to support the use of these methods in both human and non-human populations across the different projects for assessment of the MNS. These aims were achieved over the past five years. Methods for the acquisition, processing, and analysis of brain electrical activity in human and non-human primates were developed and form the basis for the ability of investigators in in all four projects in the current proposal to be able to acquire, process, and analyze EEG during different tasks and with different age populations. The goals for Core B in the current proposal are to first, build on the achievements of Core B over the past years, with continued support for fidelity of EEG acquisition, processing and analysis of data in the projects; second, develop methods for modeling brain activity acquired with fMRI and EEG to enhance source localization; third, engage in the development of novel and innovative methods for the analysis of EEG network activity and fMRI functional connectivity during tasks involving action execution and observation; and fourth, provide statistical support to the projects in the core. Innovative methods for both source localization and brain network connectivity will be made available to members of the Program Project and ultimately disseminated to the scientific community.

Function and Development of the Mirror Neuron System Project Summary Two fundamental abilities are central to adaptive human functioning: the ability to deploy actions strategically in the service of goals, and the ability to apprehend the goals of social partners in order to produce adaptive social responses. These abilities emerge in infancy and undergo foundational developments across childhood. Evidence from diverse scientific approaches indicates that these capacities may be supported by a common underlying neural network known as the mirror neuron system (MNS). This system is comprised of a network of inter-connected brain regions some of which may contain mirror neurons (MNs) and others that involve feedback loops across brain regions supporting these complex capabilities. The MNS responds both when we perform an action and when we observe someone else perform that action. The discovery of MNs, first made in non-human primates, holds the potential to revolutionize scientific understanding of goal-directed action, social perception and their development. During the initial award period, this Program Project began studies that investigated integrating the complex neural circuitry and functional aspects of the MNS in human infants and children, which arguably are some of the most powerful potential effects of the MNS. Our work highlighted the need for systematic investigations of the neural and functional aspects of the MNS during development, both for understanding typical developmental pathways and for shedding light on developmental disorders in which the development of social cognition and the potential functions of the MNS are disrupted, as in autism spectrum disorder (ASD). As well, it necessitates innovative methodological approaches to measure the networks activated during complex behaviors associated with the MNS. Advances in our work include description of an extended MNS, the result of a complex set of brain networks involved in action execution and observation; findings of significant changes in the MNS across development; and, not surprisingly, that the MNS is linked tightly to the emergence and integration of motor skills not only during infancy but across childhood. In the next five years we will advance an understanding of the neural networks of the MNS and relations to other cognitive systems; explore the potential contributions and limitations of the MNS for the development of social cognition; and investigate the modulation of the MNS via experience including active training. Finally, we will extend our approach to investigate factors that may drive the varied patterns of social deficit seen in autism spectrum disorder (ASD).

Project Summary/Abstract Over the past 17 years, we have conducted the first-ever randomized controlled trial (RCT) of foster care as an alternative to institutional care for young children, the Bucharest Early Intervention Project (BEIP). We now propose an assessment of the participants in this project at age 21 years. The new assessment period will provide novel and important data regarding the transition to adulthood and allow us to answer timely questions about the possibility that adolescence is a second period of marked sensitivity to environmental influences and neural reorganization during which positive caregiving experiences may mitigate, at least in part, the negative effects of early adversity on cognitive, emotional, and neurobiological processes as well as psychopathology. The proposed analyses will make use of the intensive repeated assessments that have occurred beginning when participants were infants and toddles still living in institutions, following them after randomization to care as usual or foster care placement through childhood and adolescence. The longitudinal design is unique in measuring multiple constructs over time spanning early, middle, and late childhood, as well as the pre-pubertal period and the transition to adolescence. This allows us to examine whether domains of development that were unaffected by the early intervention (e.g., Cognitive Control) may improve during adolescence among children in stable caregiving placements, as well as whether additional improvements occur in domains that were positively influenced by the intervention, but where children continued to show difficulties compared to typically developing children (e.g., Reward Responsiveness). These questions will be examined not only using behavioral data, but also in several neurobiological domains that no prior study of early adversity has assessed over such a long period. This includes EEG, ERP, MRI, and DTI data in the neuroimaging domain, as well as comprehensive measures of cognitive, social, and emotional functioning at every time point. Our longitudinal RCT design with repeated assessment of caregiving relationships, psychopathology, and cognitive, emotional, and brain development allows us to examine the joint influence of early and later caregiving experiences in shaping a wide range of developmental processes. We will examine relations between early and later caregiving experiences and risk for psychopathology during adolescence and early adulthood, periods characterized by markedly elevated risk for the onset of psychiatric disorders. Our unique data allow us to evaluate whether specific domains of cognitive, emotional, and neurobiological development ?recover? or ?catch up? for children who experienced severe early deprivation followed by stable caregiving in adolescence. We will also assess the effects of early adversity and positive caregiving experiences on the emergence of developmentally appropriate competencies during young adulthood. Determining the relevance of adolescent caregiving experiences in shaping psychopathology in emerging adulthood is essential to designing interventions that have the potential to buffer the effects of early adversity in the US and worldwide.

Project Summary Anxiety disorders affect a significant number of individuals and are a significant public health problem. Accurate identification of those who are at risk for the development of anxiety symptoms would allow early intervention and development of prevention strategies. The proposed supplement will collect electrophysiological measures of cognitive control on a large number of participants (N = 291) who have been followed longitudinally since age two. Prior assessments of temperament, social interaction and social anxiety have already been collected on these children, but up until now, have not been assessed for cognitive control. These children have been followed as part of an ongoing grant focused on a separate group of children (N = 291), originally recruited at 4 months of age, for which electrophysiological measures of cognitive control have already been assessed. Collection of these new data will allow us to test the robustness and generalizability of our findings across samples, as well as increase the statistical power of our longitudinal study to identify developmental pathways of risk for social anxiety.

Abstract Anxiety disorders are the most prevalent form of pediatric psychopathology creating a significant burden on individuals and society. The overall goal of the funded R01 parent grant awarded to Dr. Nathan Fox is designed to examine the developmental pathways from early fearful temperament, Behavioral Inhibition (BI), to anxiety emerging during late adolescence. The parent grant examines how specific internal (e.g., reactive vs proactive cognitive control) and external (e.g., supportive friendships) factors, assessed during mid- adolescence (age 15), interact with BI to exacerbate or mitigate the development of anxiety by late adolescence (age 18) within a large sample of adolescents. However, the parent grant did not plan to (1) collect naturalistic measures of social interactions and anxiety, and (2) examine social rejection, a social scenario that may be particularly important for children at risk for anxiety because of BI. Accordingly, in this supplement to the parent grant, we propose to integrate ecological momentary assessment (EMA) methods to measure the real-world experiences of anxiety and neural measures of social rejection during a crucial developmental period, the transition to young adulthood. In Aim 1 of this grant, the candidate will investigate the mediating role of neural reactivity to social exclusion right after high-school graduation on the association between BI and real-world social anxiety outcomes during the transition to young adulthood. We hypothesize that the longitudinal relation between BI and social outcomes during the transition to young adulthood will be mediated by greater neural responses to social exclusion as indexed by increased frontal theta power. In Aim 2 of this grant, the candidate will utilize novel intensive sampling methods to examine the moderating role of BI on the effects of social context on the momentary experience of anxiety during the transition to young adulthood. We predict that the momentary effects of the social context on anxiety will be moderated by BI, such that the effects of the social context on anxiety will be larger for individuals high in BI. Specifically, individuals high in BI will display greater reductions in anxiety in the company of close companions (e.g., close friends or significant other) compared to when being alone or with distant others (e.g., strangers, co-workers, or acquaintances). For individuals low in BI, this difference will be less pronounced. This training project will provide a better understanding of the neural and contextual processes that lead to anxiety and aid the development of prevention and intervention strategies. Additionally, the training project will enhance Dr. Morales? career development by providing research training on advanced EEG and EMA methods. Ultimately, this training project will help accelerate Dr. Morales? transition to research independence.

Project Summary Anxiety disorders affect one third of the US population, significantly burdening individuals and society. Although rates peak in late adolescence, anxiety disorders have origins in infant and early childhood temperament. Moreover, beyond predicting risk for later anxiety, early temperament even more strongly predicts later neural correlates of anxiety. As such, temperament may identify an enduring neural ?risk signature.? Precisely characterizing this signature may generate knowledge that would help reduce the burden of long-term mental health problems. However, most research quantifies such neural risk signatures in older children and adults. Thus, it remains unclear whether such a risk signature, involving temperament and brain function, manifests in infancy before predicting later behavior. Here, we propose to recruit a sample of typically developing 3-5-month-old infants screened to identify negative reactive temperament, characterize their brain networks using magnetic resonance imaging (MRI), and assess their Behavioral Inhibition (BI) at 13-15 months of age. Our prior work uses novelty-evoked motor activity and behavioral distress to quantify a temperamental bias called negative reactivity. This bias predicts later avoidance of unfamiliar stimuli or contexts during early childhood, a pattern called BI. BI, in turn, is associated with functioning in the brain?s salience and ventral attention networks. Moreover, BI is the best early-child behavioral predictor of later anxiety disorders, conditions also associated with functioning in the salience and ventral attention networks. We will test the hypothesis that behaviorally assessed negative reactivity in early infancy is associated with decreased functional connectivity in the salience and ventral attention networks relative to non-reactive infants. Identifying the neural underpinnings of heightened negative reactivity in infancy and links to BI will elucidate the neurobiological origins of risk for the development of anxiety.

Project Summary/Abstract 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 (HBCD-NC) has been formed to 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 24 sites across the United States (US). The HBCD-NC will carry out a common research protocol under direction of the HBCD-NC Administrative Core (HCAC) and will assemble and distribute a comprehensive and well-curated research dataset to the scientific community at large under the direction of the HBCD-NC Data Coordinating Center (HDCC). The overarching goal of the HBCD-NC 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 sample of women enrolled will include: 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. In addition, the HBCD-NC will identify key developmental windows during which both harmful and protective environments have the most influence on later neurodevelopmental outcomes. The large, multi-modal, longitudinal, and generalizable dataset that will be produced for the first time by this study will provide novel insights into child development using state- of-the-art methods. The HBCD-NC study will inform public policy to improve the health and development of children across the nation.