Elizabeth G. Redcay, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Autism is a developmental disorder characterized by impairments in both language and social cognition. Despite much research on the neurobiological underpinnings of autism in adults, very few studies have examined the neural bases within a developmental framework. Those few studies that have often focus on the neural bases underlying either language or social cognition separately, but not both. Although language and social cognition are traditionally examined as independent behavioral domains, behavioral evidence from typical children suggests that language acquisition depends on social processes, such as responding to joint attention bids from a caregiver. In autism, joint attention deficits are severe and correlate with later language impairments. The goal of this proposal is to identify the shared and distinct neural substrates for social and language processing in typical development and in children with autism spectrum disorder (ASD). [unreadable] [unreadable] To achieve this goal, functional magnetic resonance imaging (fMRI) data will be acquired from 24 typical adults (12 male, 12 female), 24 typical 5-8 year-old children (12 male, 12 female), 24 typical 9-12 year-old children (12 male, 12 female), and 15 9-12 year-old children with autism spectrum disorder (ASD) (12 male, 3 female) during performance of two separate tasks: responding to joint attention bids and narrative comprehension. Analyses will be conducted to identify the neural bases underlying these separate tasks as well as the amount of shared neural overlap between these tasks within the same subjects. With this design age- and gender-related analyses in typical development and age- and performance-related analyses in autism can be conducted. The 15 ASD children (12 male, 3 female) will be compared to two gender-matched control groups: one age-matched control group (9-12 years) and one performance-matched control group (5-8 years). The control groups for the ASD children will be comprised of a subset of the typically developing children. PUBLIC HEALTH RELEVANCE: By addressing questions of both typical and atypical development in the same proposal, greater insights can be gained into the aberrant developmental trajectory underlying both social and linguistic development in ASD. Pinpointing the common neural bases of these primary deficits in ASD may help to guide early intervention and provide neural regions of focus to aid in the search for shared microstructural and genetic bases of these deficits. [unreadable] [unreadable] [unreadable]

Atypical reciprocal social interaction is a core diagnostic feature of autism spectrum disorder (ASD), but the brain network dynamics contributing to difficulties with social interactions remain unclear. Dominant theories suggest a role for social-motivational and social-cognitive brain networks. However, these theories have been tested in neuroimaging contexts divorced from social interaction (i.e., viewing photos of strangers). Because these detached, offline measures fail to capture the real-world social-interactive challenges faced by individuals with ASD, the critical question of what neural mechanisms underlie atypical social interaction remains unanswered. The current proposal takes an innovative, interactive approach by examining real-time social interaction during fMRI data acquisition to characterize the development and interaction of motivational (i.e., reward) and social-cognitive brain networks during middle childhood. Middle childhood presents an opportune time to address this question because this age is marked by increased social competence in neurotypical (NT) children but plateauing social abilities in ASD. At the neural level, middle childhood is a time of significant change in social brain networks in NT but relatively little data speak to these changes in ASD. Our central hypothesis is that atypical organization of social-motivational and social-cognitive networks during real- time social interactions predict social-interactive difficulties in autism. We will test this hypothesis with the following specific aims in NT and ASD children: 1) determine whether approval from a real-time social partner modulates motivational systems and 2) determine whether real-time social interaction modulates social- cognitive systems, and 3) determine how interactions between motivational and social-cognitive networks during real-time social interaction relate to measures of real-world social behaviors. To achieve these aims, 70 NT and 54 ASD children (7-12 years of age) will participate in a social reward and a social cognitive task in which they engage with an experimenter in real time during functional MRI data acquisition. Graph theoretic measures will be used to examine network organization and interactions within motivational and social- cognitive brain networks during the social interaction task and at rest. Successful completion of the proposed research will advance our understanding of how reward and social-cognitive networks are modulated by real- time social interaction in children with ASD and whether atypical modulation of these networks is related to real-world social impairments. These contributions will be significant to the scientific field and relevant to the strategic mission of NIMH because they will 1) provide critical missing information about the development of brain mechanisms underlying social interaction, 2) determine how individual differences in these brain circuits map onto directly observable behavior, and 3) examine differences in the course and mechanism of functional brain development between neurotypical and ASD children, which will address questions of how, when, and where to intervene.

The goal of this application is to develop a research program that, as stated in the call entitled The Neural Mechanisms of Multi-Dimensional Emotional and Social Representation (RFA-MH- 17-300), incorporates innovative approaches designed to move the fields of affective and social neuroscience beyond single region-based, modular, and static models of brain function and behavior. The RFA calls for research that is multi-dimensional, that is, that investigates the role of (among others) complex contexts, as well as distributed and/or dynamic processes that unfold over time. The objective of the present application is to jointly investigate emotional and social processes in a richly multi-dimensional manner. Aim 1: Network organization and evolution during emotional and social processing. The objective of this aim is to uncover how large-scale brain networks are organized and evolve temporally during emotional and social processing. Networks will include brain regions that robustly respond to the tasks proposed, and regions from well characterized networks, including the salience, executive control, and task-negative networks. Aim 2: Naturalistic processing during emotional and social processing. The objective of this aim is to understand naturalistic processing of emotional and social information. Although standard experimental designs afford great control over experimental conditions, they lack ecological validity and restrict the experiments that can be studied. We propose to investigate continuous (?naturalistic?) processing during movie watching involving emotional and social content. Continuous processing will be investigated via intersubject correlation analysis, which measures the extent to which signals are correlated across participants. Aim 3: Development of network organization/evolution and naturalistic processing. The objective of this aim is to investigate multi-dimensional emotional and social processes from a developmental perspective. Most developmental research in emotion has focused on observing amygdala responses and those of a few other brain regions during face perception. We focus on a question largely neglected in prior research, specifically sustained threat processing and the involvement of the bed nucleus of the stria terminalis. In the context of social processing, this aim examines the development of intersubject synchrony. Across the emotional and social domains, we propose to study middle childhood (8-9 y), early adolescence (12-13 y), and young adulthood (18-19 y).

ABSTRACT Loneliness, or the feeling of distress that accompanies perceived social disconnection, confers significant risk for negative physical and mental health outcomes, such as chronic disease, depression, and self-harm. Adolescence is a period of increasing loneliness and thus a critical time to identify risk and protective factors. Adolescents with autism spectrum disorder (ASD) demonstrate higher rates of loneliness than the typical population, making them especially vulnerable to these negative outcomes. While developmental research has identified peer relations as risk and protective factors in typically developing (TD) populations, gaps remain in our understanding of how peer relations relate to the development of loneliness in ASD. Thus, understanding the mechanisms that confer risk and protection in the development of loneliness in adolescence, and whether they differ in high-risk populations, is critical to effectively intervening and ameliorating loneliness before the onset of significant deleterious consequences. Research in adults points to several cognitive and neural factors associated with loneliness and social connection: social-cognitive systems, social reward systems, and dissimilarity from others. These brain mechanisms are also atypical in ASD and posited to relate to atypical social interaction. The current proposal will test a novel biopsychosocial model of the development of loneliness in which these posited neural mechanisms serve as predictors in the development of loneliness via their effects on social experiences. In our model, peer relations may confer both risk and protective factors between social experience and the development of loneliness. We will test this model using a prospective- longitudinal design to follow 75 ASD and 120 TD adolescents mean-matched in age and IQ, and followed every four months for twenty months. Importantly, this project will be the first to integrate across these neural, cognitive/affective, and behavioral levels of analysis to investigate risk and protective mechanisms in the developmental emergence of loneliness in adolescents with TD and ASD, and to examine whether these mechanisms differ between groups. The current proposal is innovative in its use of ecologically valid, naturalistic, and social-interactive fMRI approaches that the PI Dr. Redcay has developed. Further, the proposal builds on existing work from co-Is Drs. Shackman and Lemay and Consultant Dr. Silk to use ecological momentary assessment (EMA) to obtain real-world, in-the-moment assessments of social experiences and their effects on mood and loneliness. These contributions will be significant to the scientific field and relevant to the strategic mission of NIMH because they will provide novel, critical missing information on the developmental trajectory of loneliness in ASD and will identify mechanisms of risk for and protection against loneliness outcomes. Knowledge gained from this project has direct implications for treatment interventions to mitigate the experience of loneliness and associated negative outcomes in high-risk adolescents with ASD and TD.