Leah H. Somerville - US grants

DESCRIPTION (provided by applicant): Childhood anxiety disorders affect approximately one in ten children resulting in marked social impairment. These individuals also carry a heightened risk for mood and anxiety disorders in adulthood, rendering this a public health issue relevant to the entire lifespan. Work to date characterizing the pathophysiology of anxiety disorders has focused on one sphere of anxious symptoms- hypersensitivity to cues of potential threat such as emotional faces or negative images (e.g., phasic responses), while biological markers for other key symptoms of anxiety, such as sustained hypervigilance and arousal (e.g., tonic responses), remain relatively unexplored. The objectives of this program of research are: 1) to delineate the typical development of brain systems involved in phasic and tonic processes that map onto threat processing and vigilance, 2) to provide preliminary evidence for their differential roles in representing tonic anxious phenotypes characteristic of generalized anxiety disorder;and 3) to test their predictive merit for risk in familial cases. The proposed work will first use functional neuroimaging and psychophysiology to characterize the functional properties of brain networks that mediate tonic and phasic symptoms of anxiety in a cross-sectional, typically developing sample (K phase). Then, deviant neural and behavioral signatures will be identified in a sample of individuals with pediatric Generalized Anxiety Disorder (GAD), a clinical syndrome marked by chronic apprehension and vigilance (K phase). Using these samples, we will assess whether biobehavioral markers of GAD are also evident in a sample of children at heightened risk for developing anxiety disorders based on family history (R phase). To accomplish these objectives, the candidate will receive extensive training in testing pediatric and clinical populations bolstered by education in developmental and clinical neuroscience, and advanced neuroimaging techniques including resting-state connectivity, diffusion tensor connectivity and network modeling methodologies. This work and training will prepare the candidate for initiating an independent laboratory capable of developmental, clinical and advanced neuroimaging research. Irrespective of the observed findings, this work will serve as a natural precursor to future R01 funding applications to track high-risk individuals longitudinally and/or utilize identified biomarkers in clinical research evaluating new therapies targeting the tonic system and its associated chronic anxious symptomatology. This work is progressing toward the ultimate goal of identifying predictive markers of risk for anxiety disorders that will facilitate early identification and prevention. PUBLIC HEALTH RELEVANCE: Childhood anxiety disorders affect as many as one in ten children and confer a heightened risk for psychiatric disorders throughout the lifespan. The objective of work is expand our understanding of brain systems critical to different symptoms of anxiety by characterizing the neurobiological mechanisms of threat biases and vigilance across development. Brain networks that mediate these symptoms are predicted to play distinctive roles in the pathophysiology of anxiety disorders and will be evaluated for their predictive merit in identifying individuals at heightened risk for anxiety disorders based on family history. Ultimately, this work should provide biologically valid behavioral markers of risk for anxiety disorders that will facilitate early identification as well as new outcome measures for clinical trials for optimizing personalized treatment.

During adolescence, individuals begin to make increasingly independent decisions that involve weighing the potential risks and benefits of their actions. Although the decisions adolescents and adults make are similar in many situations, there are certain contexts that lead to more risky decisions by adolescents. This is the case in social contexts: adolescents (but not adults) tend to make riskier choices in the presence of peers. Although peers' influence on adolescent risk-taking is documented in real-world crime statistics, health statistics, and in controlled laboratory experiments, just how peers uniquely influence adolescents remains poorly understood. The overarching goals of this research are threefold: a) to refine understanding of adolescent risky behavior by demonstrating what aspects of decisions are vulnerable to peer influence, b) to identify how the developing brain contributes to peer influence on adolescent risk taking, and c) to evaluate how laboratory measures of peer influence relate to actual risky behavior in daily life.

To carry out this work, dyads of adolescents and dyads of young adults will complete a series of decision making-tasks designed to quantify components of risky choices. For instance, mathematical decomposition analyses can isolate how much risk an individual is willing to tolerate in order to obtain a potential reward. Participants complete these tasks in experimental configurations that vary in their degree of social evaluation. Peers are either absent, present and monitoring the participant's level of riskiness, or present but unable to monitor the participant's level of riskiness. These peer configurations build on recent findings by Leah Somerville and others showing that the mere presence of a peer may be sufficient to evoke riskier choices in adolescents. Comparisons of risky choices in these three contexts will disentangle the sources of peer influence that depend on the peer awareness of risky choices, compared to sources of peer influence that are evoked merely by the presence of a peer. In addition, confidential surveys will measure risk-taking in everyday life. They will be used to bridge the laboratory and the real world through analyses that ask what characteristics of the dyads, and what characteristics of individual's riskiness relate to their laboratory-based choices. Functional magnetic resonance imaging (fMRI) is used to measure how the still-developing brain uniquely processes information about social evaluation, and how these processes interact with decision-making processes. This project stands to build foundational knowledge about how neurodevelopment during adolescence shapes the development of complex social behavior. More broadly, this work can be extended to help predict the particular 'ingredients' of a situation that lead adolescents to take unhealthy risks. Further, this project generates key data to address legal-ethical issues of youth culpability for crimes committed with peers.

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