Margaret A. Sheridan - US grants

DESCRIPTION (provided by applicant): Current estimates place the prevalence of attention-deficit/hyperactivity disorder (ADHD) in the US at 3-5%. The usual age of first diagnosis is between 6-7 years of age when students are first entering school;however, many parents will argue that they observed signs/symptoms of ADHD much earlier. Intriguingly, of all 3-4 year old children diagnosed with ADHD (using traditional parent/teacher interview methods), only about 50% continue to meet diagnostic criteria at age 7. Previous attempts at achieving better diagnostic stability before the age of seven have expanded the number and kinds of behavior that are measured. Although these attempts have slightly improved predictability, no new gold standard for this age range has been achieved. The primary goal of this K01 research plan is to examine the development of the neural systems that mark the transition from signs and symptoms of ADHD to stable ADHD diagnosis. By using neuroimaging to better infer the underlying biology, better prediction of which children who exhibit elevated inattention and hyperactivity at age 3 will continue to exhibit these behaviors at age 7 and beyond may be achieved. Children who continue to meet diagnostic criteria for ADHD after the age of 7 are very likely to continue to meet diagnostic criteria across childhood, and in 40-70% of cases into adulthood. Even if they do not meet criteria for the disorder in adulthood they will, based on their childhood diagnosis, have increased risk for academic failure, social problems, substance use disorder, car accidents, and incarceration. Neuroimaging studies have associated deficits of cognitive control with differential activation of the prefrontal cortex in children and adolescents with and without ADHD ages 8 through adulthood. Less is known, however, about the neural basis of the development of cognitive control in younger children ages 3-7 and how this contributes to the development of ADHD. This is a major gap in knowledge, considering how crucial this time period may be to the continued expression of ADHD symptomology. Researchers have found it challenging to investigate the neuro-developmental roots of executive function because of limitations in our ability to image the brain in children this young. However, techniques allowing EEG data collection in 3-4 year olds and fMRI data collection in 5-7 year olds have recently been perfected and are proposed here. PUBLIC HEALTH RELEVANCE: The usual age of first diagnosis for attention-deficit/hyperactivity disorder (ADHD) is between 6-7 years of age when students are first entering school. However, parents and children can experience the negative effects of high ADHD symptomology long before they enter school, increasing the child's risk of social isolation, learning problems, and parental abuse. However current diagnostic techniques for children younger than 7 are inadequate;of all preschool children diagnosed with ADHD (using traditional methods), only about 50% continue to meet diagnostic criteria at age 7. At the moment, some physicians prescribe stimulant medications to children younger than 7 regardless of the diagnostic complications, other physicians do not. The current study would have the potential to reduce conflict around this issue by providing better diagnostic methods earlier.

DESCRIPTION (provided by applicant): Adolescence is a period of the lifespan when challenges to behavioral regulation can have critical short and long-term repercussions. During adolescence, burgeoning independence and exposure to situations that entail tangible risk (access to alcohol, drugs, or cigarettes) present a particular psychological challenge, whereby momentary motivation toward potential rewards comes into conflict with long-term goals that require inhibitory control processes. Though risky decision-making remains a key public health issue in adolescence, there is not a clear consensus on how to best design public health interventions to support decision making in adolescence. If we understood the mechanisms of inhibitory control, specifically in the face of rewarding stimuli we could create more effective interventions around risk in adolescence. Age related variability in self-regulatory behavior and resulting risky behavior during adolescence has been historically attributed to age-related deficits in inhibitory control and still-maturing lateral prefrontal systems, such as the right infrior frontal gyrus. However, recent neuroimaging studies have challenged this view (for a review, see Somerville, Jones, & Casey, 2010). For example, most motor inhibitory control tasks improve during adolescence, instead of declining. However, one study revealed that adolescents (relative to children and adults) were selectively less skilled at engaging in impulse control to positive social cues (happy faces) and showed different associated patterns of activity in the ventral striatum (VS). While this evidence suggests that increased risk behavior during adolescence may stem from adolescent-specific challenges in employing inhibitory control over rewarding cues, this task relies heavily on social stimuli (smiling faces), which come with their own variable reactions, known to be influenced by early childhood experiences and onset of adolescence. Here we address these gaps in the literature by introducing a novel test of inhibition of reward Learned Reward Inhibition Task (LRIT) and propose to investigate the neural correlates of the developmental progression of inhibition of reward across late childhood, early adolescence, late adolescence and adulthood using structural and functional MRI. Our preliminary data suggest differences between children and adolescents in control over previously rewarded, socially irrelevant stimuli. In children, inhibition is facilitated for these stimui, while it is selectively impaired in adolescents. That is, in the LRIT task, children are moe able to withhold a response from a previously rewarded cue. In contrast, adolescents are less able to withhold a response from a previously rewarded cue. This task, relative to other assessments of inhibitory control, appears to isolate a deficit in adolescent cognition, relative t children that more closely aligns with the dramatic uptick in risk taking and self reported impulsivity in adolescence.

Project Summary/Abstract Early adversity profoundly affects diverse aspects of child development, including brain development, physiological reactivity to stress, and long-term risk for mental illness. Most models of these effects focus on the number rather than character of adverse childhood experiences. The current proposal tests a novel conceptual model focused on the type of exposure, which differentiates two primary dimensions of experience underlying multiple forms of adversity: deprivation and threat. Deprivation involves a lack of enriching and species expectant cognitive and social inputs (e.g., neglect). Threat involves actual or perceived danger to the physical integrity of the child (e.g., exposure to violence). Here we test the hypothesis that deprivation and threat increase risk for psychopathology through separable neurobiological pathways. We identify these pathways using basic animal and human neuroscience and present them as compliments to existing models. The proposed project will examine the impact of deprivation and threat on the development of neural networks in Cognitive Control Systems and Negative Valance Systems. We predict that early deprivation exposure results in reduced cognitive control, and disruptions in the neural systems supporting cognitive control. Early threat exposure, in contrast, results in disrupted fear learning and alterations in fear circuitry. The current proposal extends our previous work to include longitudinal prediction of psychopathology during middle childhood and in depth evaluation of the proposed neurodevelopmental mechanisms. It is widely hypothesized that adversity primarily influences neural development during early childhood, yet these associations are most often studied in adolescence and adulthood. Here we propose investigating early adversity exposure in young children aged 4-7 years when these systems are undergoing peak development. To assess deprivation and threat in young children we will use in-depth home assessments including observational and parent-report measures. All children will complete structural MRI and functional neuroimaging using EEG and fMRI. The PI has extensive experience collecting such measures from children in this age range and this work follows directly from her recently completed K01 award. Understanding neurodevelopmental processes linking adversity to psychopathology will open up new pathways to prevention and intervention. The proposed research would directly address Objectives 1 and 2 of the NIMH strategic plan.

Consistent with the Biobehavioral Development objective of the NICHD strategic plan, we propose linking neural developmental trajectories in infancy with cognitive and neural function in middle childhood. Decades of work on sensitive periods from animal models predicts that early neurodevelopmental trajectories contribute to later behavior, cognitive, and neural function. Collectively, this research indicates that the brain is particularly sensitive to environmental inputs during early development, fundamentally altering developmental trajectories and later capacity. However, almost no studies in humans have explicitly examined the link between infant brain development and subsequent neural function and behavior, thus, it remains unclear what aspects of structural or functional development reflect these early periods of environmental sensitivity in the developing human brain. Attaining such information is a public health imperative, given that prevention efforts in early childhood rely on sensitive period theorizing. Information about neural development can neither contribute to nor be impacted by these efforts without these initial steps. The proposed study capitalizes on and extends an existing longitudinal neuroimaging study with neuroimaging data sampled frequently in early childhood (approximately at 0, 3, 6, 9, 12, 18, 24, 36, and 48 months of age). Previously this dataset has been used to develop novel imaging analysis techniques required to measure neural structure in the infant brain. Other studies of infant brain development have acquired data in a less dense fashion (e.g., at 0, 1, and 2 years). This unusually dense sampling approach which will allow us to use sophisticated longitudinal modeling techniques to characterize the developmental trajectories of brain development (between 0 and 4 years). We will use these trajectories to predict individual differences in neural function and cognitive task performance in middle childhood. Because we are beginning with an existing dataset, this is an efficient, highly innovative, and cost-effective proposal. We will need to acquire only a single additional neuroimaging and cognitive testing session between 7 and 8 years of age to complete this research study. This proof-of-concept study will serve as pilot data for a future application aimed at identifying how early neural trajectories predict function in a larger and more diverse sample of longitudinally-followed infants (currently being collected as part of U01-MH110274). Critically, information from this study will also immediately improve knowledge about how early neurodevelopmental trajectories predict later cognitive and neural function.

Project Summary/Abstract Preschool anxiety, while prevalent and impairing, is an imperfect predictor of future outcomes. For example, longitudinal data suggest that anxiety disorders in preschool predict not just future anxiety but also other internalizing disorders and comorbid disruptive behavior in adolescence. Similarly, early adversity increases risk for many forms of adolescent psychopathology. Using our current methods we cannot identify which preschool children will go on to acquire which disorders in adolescence. This is in part because most models focus primarily on continuity within diagnoses as opposed to transdiagnostic risk factors and in the case of adversity, on the number rather than character of adverse childhood experiences. The current proposal tests a novel conceptual model focused on the type of adverse exposure, which differentiates two primary dimensions of experience underlying multiple forms of adversity: deprivation and threat. Interpersonal violence or threat and decreased cognitive and social inputs or deprivation are differentiated by the kind of experiences children have and by the impact of those experiences on neural and cognitive function. Thus, this model of adversity allows a focus on transdiagnostic risk factors. Importantly, the neural pathways linked to deprivation and threat are the same neural circuits known to be disrupted in early anxiety disorders. Given this shared neural risk we expect that early adversity and anxiety will interact to increase risk for psychopathology in adolescence. We also expect further moderation by other preschool diagnoses (e.g., ODD, ADHD). These neural pathways may be the ?missing link? between preschool anxiety and adolescent psychopathology. To address this knowledge gap, we propose following a group of adolescents (now aged 15-17 years; N=502) who were first assessed in preschool (ages 2?5 years). A subsample of these children (N=93) underwent structural and functional imaging up to 3 times between 5-10 years of age. This innovative, cost-effective proposal will provide an unparalleled opportunity to answer central questions about the trajectory of neurodevelopmental processes linking early risk to specific forms of adolescent psychopathology in a highly vulnerable population. The proposed research directly addresses Objectives 1 and 2 of the NIMH strategic plan.

PROJECT SUMMARY/ABSTRACT This application, proposes an overarching theme to foster research into early life adversity (ELA) that will fundamentally develop and prepare the field for greater scientific discoveries, with a particular focus on interventions for population and patient benefits. Furthermore, we aim to raise awareness in the field about the importance of ELA, including ELA measurement, mechanisms, and interventions. Specific aims will be in three themes: (1) ELA Measures: Develop an ELA measurement toolkit that will include the best theoretically- embedded, prospectively- and retrospectively-assessed ELA measures, and will evolve as new discoveries on ELA measurement are made. (2) ELA Mechanisms: Catalyze research on key mechanisms through which ELA influences health and aging outcomes (e.g. biological, behavioral and self-report mechanisms). Target mechanisms will be evaluated as to whether they are both malleable to interventions and influence aging outcomes. (3) ELA Interventions: Foster research on: (a) Adult effects of early life interventions for those exposed to ELA; (b) Adult interventions for those who recall ELA and/or were objectively exposed to ELA. The approach to achieve these aims will be to extend an interdisciplinary, international Research Network on Interventions to Reverse Effects of Early Life Adversity (the ?Reversibility Network?) that was developed over the past five years. During the coming five years, the Reversibility Network will focus on ELA research capacity and community building, as well as on ELA knowledge dissemination, which will cut across the three themes outline above. This will be done through the following specific approaches: (1) Focused annual Reversibility Network investigator meetings, with an emphasis on building research capacity and community through bringing together senior and junior investigators, and new promising investigators. (2) Conference symposia and pre-conference workshops on three themes above, with major emphases of building the ELA research community (including bringing new researchers into the field), ELA knowledge dissemination, and utilizing existing expertise to enhance network productivity. (3) Fund pilot research, with an emphasis on ELA measurement, mechanisms, and interventions. (4) Develop an ELA measurement toolkit that will address the lack of precise ELA measurement across the lifespan, as well as enhance understanding of ELA mechanisms, and the moderation of interventions by ELA exposure. (5) Develop a website that will offer the ELA measurement toolkit, examples of effective ELA interventions, ELA intervention development frameworks, and opportunities for research and implementation. (6) Three peer-reviewed manuscripts outlining knowledge to date, theoretical frameworks, gaps in knowledge, and recommendations for the field within the three themes of ELA measures, mechanisms and interventions. In accomplishing these aims, the Reversibility Network will support and promote the interdisciplinary collaborations needed to develop effective interventions for mid- and later life adults that can reverse or remediate the effects of ELA.