Susan B. Perlman - US grants

DESCRIPTION (provided by applicant): The goal of this research is to use functional magnetic resonance imaging (fMRI) to study the neural basis of attentional dyscontrol and emotion dysregulation in a sample of young children (ages 6-9) who are displaying early onset pervasive anger and irritability. These symptoms represent a significant mental health concern that some say requires a new diagnostic category in the DSM-V revision in order to secure the research and clinical services that these children require. The proposed study will be the first to examine brain mechanisms for attentional dyscontrol and emotion dysregulation, which signify key behavioral deficits, in these young school-age, unmedicated children upon first clinic presentation. Obtaining these measures of functional abnormalities in attentional control and emotion regulatory neural systems in young children presenting with pervasive anger and irritability relative to age-matched healthy counterparts will first help us to identify which children show greater levels of dysfunction within these neural systems. It is also a first step toward the longer term goal of examining the extent to which these neural system abnormalities may represent biological markers that can help distinguish relevant developmental trajectories of psychopathology, so that different treatments can be applied at this early stage of symptomatology. Well-validated experimental paradigms, including one paradigm developed by the PI, and behavioral measures will be employed. Primary analyses will probe the neural activity within specific regions related to attentional dyscontrol and emotion dysregulation, and connectivity amongst them, in order to define brain deficits for this illness. Exploratory analyses will examine the extent to which these neural system abnormalities may predict symptom severity and clinical diagnosis by correlating activity in these neural systems with parent reported symptom severity and clinician diagnostic report. Finally, long term plans for this research include a future proposal to complete a longitudinal neuroimaging study in which young children presenting with pervasive anger and irritability will be scanned yearly to increase our understanding of the neural and clinical trajectories of these symptoms. The P.I. already possesses general knowledge of developmental psychology with specific emphasis on emotional development and has extensive experience in the neuroimaging of young children, but lacks the clinical skill set necessary to become an independent scientist in the field of child psychiatry. Therefore, the proposed training plan is aimed at acquiring the relevant clinical skill set necessary to conduct neurodevelopmental research regarding early risk for child psychopathology. The P.I. will complete coursework, train with experts in the field, and author empirical and theoretical publications in order to develop an understanding of child clinical issues. This cross-disciplinary research and training plan, therefore, allows for a stepwise approach to a career in the cognitive and affective neuroscience of child psychopathology.

DESCRIPTION (provided by applicant): The goal of this research is to use functional Near Infrared Spectroscopy (fNIRS) to study the neural basis of irritability in a sample of preschool children (ages 3-5) who are being clinically treated for early onset psychopathology. Irritability exists on a dimension in every member of the population, however, it is also a significant mental health concern that is present in nearly every form of psychopathology. A new diagnostic category in the DSM-V revision has even been added in order to secure the research and clinical services that this symptom requires. The proposed study will be the first to examine brain mechanisms for frustration and inhibitory control, which signify key behavioral deficits, in young, highly irritable children. Obtaining these measures of functional abnormalities in the neural systems supporting frustration and inhibitory control in preschool children presenting with varying levels of irritability will first help us to identify which children show greater levels of dysfunction within these neural systems. It is also a first step toward the longer term goal of examining the extent to which these neural system abnormalities, identified at the age at which irritability first presents, may represent biological markers that can help distinguish relevant developmental trajectories of psychopathology, so that different treatments can be applied at this early stage of symptomatology. Children will be tested in the clinic setting using fNIRS, an optical imaging technique that is painless, non-restrictive, transportable, and allows for subject/experimenter interaction. Well-validated experimental paradigms will be employed. Primary analyses will probe the neural activity within specific regions related to frustration and inhibitory control, using state-of-the-art analysis techniques, in order to define brain deficits tat correlate with this symptom. Exploratory analyses will examine the extent to which these neural system abnormalities may predict symptom severity and clinical diagnosis by correlating activity in these neural systems with diagnostic report. Finally, long term plans for this research include a future proposal to complete a longitudinal R01 study, combining fNIRS and functional magnetic resonance imaging (fMRI). A large community sample of preschool children, across the range of irritability levels, will participate in yearly fNIRS measurement of neural systems fo frustration and inhibitory control using age appropriate tasks. In the later years of the project, when children have entered middle childhood, they will be scanned, using simultaneous fNIRS and fMRI to increase our understanding of the neural and clinical trajectories of this symptom. Our transdisciplinary research team unites developmental psychologists, neuroscientists, and child psychiatrists who are experts in their respective fields, but share a common interest in understanding the neural mechanisms for irritability as a predictor of child mental health outcomes.

? DESCRIPTION (provided by applicant): The goal of this application is to launch an innovative, multi-modal neuroimaging program that will investigate the longitudinal trajectory of the neurodevelopment of irritability across the preschool period. Irritability exists on a dimension in every member of the population, however, it is also a significant mental health concern that is present in nearly every form of psychopathology and spans the internalizing/externalizing gap. Differentiating clinically salient irritability from developmentally-normative temperamental variation has proven to be a difficult task. This is made even more challenging during the preschool period, when irritability has hit its normative peak and measuring neurodevelopment is impeded by methodological constraints. This state-of-the-art program of research will 1) identify specific biomarkers underlying preschool vulnerability for psychopathology by examining neural maturation in executive function as a predictor for clinical outcome and 2) examine how the parenting environment moderates this vulnerability, with the overarching objective of identifying aberrant from normative irritable trajectories as the foundation for future brain-based behavioral intervention. Our transdisciplinary research team will recruit a sample of 150 4 year-old children, enriched for high irritability to participate in a longitudinal project. At age 4, an again at age 5, the neural underpinnings of executive function will be assessed using functional near-infrared spectroscopy (fNIRS), an optical imaging technique that is painless, non-restrictive, and reliably employed in neuroimaging studies of the prefrontal cortex in preschool children. At the transition to school-age (age 6), where a 50% rate of psychopathological symptoms have been reported in irritable children, a third fNIRS assessment will occur along with simultaneous functional magnetic resonance imaging (fMRI) to probe frontal-cortical connectivity. Well- validated and child-friendly experimental paradigms will be employed. At age 4, we will also introduce dual- person fNIRS imaging to a standardized developmentally-based laboratory interaction task in order to investigate parent-child neural synchrony, a measure of the correlation between signals of brain activity of interacting individuals. Primary analyses will 1) probe the slope of increase in prefrontal activation underlying executive function as a predictor of clinical outcome and 2) examine parent-child neural synchrony as a predictor of executive function maturation and as a moderator of clinical outcome in highly irritable children. An ambitious program of longitudinal, multi-modal neuroimaging, combined with innovative and developmentally-sensitive behavioral data collection, has the potential to identify patterns of disruption in neural processes underlying executive function so that targeted therapeutic interventions, aimed at both the child individually, and the child and parent in an interactive context, can be developed to reestablish a normative developmental trajectory.

PROJECT SUMMARY/ABSTRACT Disruptive behavior is one of the most common reasons for mental health referral of preschool age children and is a marker of lifetime psychiatric risk. In addition, disruptive behavior has transdiagnostic import, is often a treatment target, and is a marker of lifetime risk for mental disorder. Meta-analytic studies indicate non- psychopharmacological, family-focused therapeutic strategies as the treatment of choice in this young population. However, substantial individual differences in treatment effectiveness and the need to enhance impact during this period of early brain plasticity suggest the need for incorporating a mechanistic perspective into treatment approaches for early childhood disruptive behavior. Parent-Child Interaction Therapy (PCIT), among the most widely used empirically validated treatments for early childhood disruptive behavior, is an intervention in which a parent in coached by a clinician on discrete behavioral parenting skills during parent- child interaction. While PCIT is effective for families who complete treatment, high drop-out rates are typically reported. The primary hypothesis of this study is that improvement in parent-child dyadic synchrony, a mutually focused and reciprocated exchange between interactional partners, is a core basic mechanism for PCIT effectiveness. Our novel approach explicates this mechanism by examining neural synchrony, which assesses coherence between the signals of brain activation of parent-child dyads, and links it to the clinically-observable behavioral synchrony and clinical improvement. In a sample of 50 preschool children and their parents, we will employ functional near infrared spectroscopy (fNIRS) to measure concomitant brain activation in key regions of social cognition circuitry during an initial assessment (Visit 1), PCIT midpoint (Visit 2), PCIT completion (Visit 3), and one month follow-up (Visit 4). This proposal brings together a team of neuroscientific, developmental and intervention experts as the critical first step in translating this basic line of research to clinical application with the ultimate goals of optimizing PCIT by training clinicians to focus upon fluctuations in dyadic synchrony. We theorize that explicating bidirectional neurodevelopmental mechanisms would make PCIT (1) more effective because it would enable operating directly on a specified biological target through modification at the clinically observable level; (2) more efficient by personalizing treatment, allowing clinicians the flexibility to select from the parenting skills that most immediately alter the target on the individual level, accelerating time to clinical improvement; and (3) more generalizable as its bidirectional emphasis would facilitate the child?s capacity to read social cues and respond adaptively to social partners, which more readily translates outside the parent-child context. This study will be the first to employ neuroscientific methods to elucidate the specific mechanisms by which PCIT reduces disruptive behavior, providing a more direct and efficient clinical target. Clinical translation of findings could serve as the basis for concentrating PCIT sessions, speed the time to improvement, and reduce time commitment, thus increasing patient compliance and decreasing attrition.

? DESCRIPTION (provided by applicant): The goal of this application is to launch an innovative, multi-modal neuroimaging program that will investigate the longitudinal trajectory of the neurodevelopment of irritability across the preschool period. Irritability exists on a dimension in every member of the population, however, it is also a significant mental health concern that is present in nearly every form of psychopathology and spans the internalizing/externalizing gap. Differentiating clinically salient irritability from developmentally-normative temperamental variation has proven to be a difficult task. This is made even more challenging during the preschool period, when irritability has hit its normative peak and measuring neurodevelopment is impeded by methodological constraints. This state-of-the-art program of research will 1) identify specific biomarkers underlying preschool vulnerability for psychopathology by examining neural maturation in executive function as a predictor for clinical outcome and 2) examine how the parenting environment moderates this vulnerability, with the overarching objective of identifying aberrant from normative irritable trajectories as the foundation for future brain-based behavioral intervention. Our transdisciplinary research team will recruit a sample of 150 4 year-old children, enriched for high irritability to participate in a longitudinal project. At age 4, an again at age 5, the neural underpinnings of executive function will be assessed using functional near-infrared spectroscopy (fNIRS), an optical imaging technique that is painless, non-restrictive, and reliably employed in neuroimaging studies of the prefrontal cortex in preschool children. At the transition to school-age (age 6), where a 50% rate of psychopathological symptoms have been reported in irritable children, a third fNIRS assessment will occur along with simultaneous functional magnetic resonance imaging (fMRI) to probe frontal-cortical connectivity. Well- validated and child-friendly experimental paradigms will be employed. At age 4, we will also introduce dual- person fNIRS imaging to a standardized developmentally-based laboratory interaction task in order to investigate parent-child neural synchrony, a measure of the correlation between signals of brain activity of interacting individuals. Primary analyses will 1) probe the slope of increase in prefrontal activation underlying executive function as a predictor of clinical outcome and 2) examine parent-child neural synchrony as a predictor of executive function maturation and as a moderator of clinical outcome in highly irritable children. An ambitious program of longitudinal, multi-modal neuroimaging, combined with innovative and developmentally-sensitive behavioral data collection, has the potential to identify patterns of disruption in neural processes underlying executive function so that targeted therapeutic interventions, aimed at both the child individually, and the child and parent in an interactive context, can be developed to reestablish a normative developmental trajectory.

Early life stress is associated with increased risk for psychiatric disorders that is long lasting into adulthood. Much of the research has focused on middle childhood and adolescence, however, there is mounting evidence that stressful life experiences occurring in early childhood set the foundation for dysregulation in biological stress responses that put children at risk for psychopathology. Our overarching aims are to examine the biological pathways through which early life stress affects risk for psychopathology in early childhood, and by which caregiving can alter biological and psychological stress responses . We propose to recruit 150 children, aged 4-6 years, within 3 months of parental divorce (stress group) and compare them to 75 control children from families with no history of parental divorce. Stress and control children will be followed at 6 and 18 months later. We choose divorce as a stressor because it is common in early childhood; represents the exacerbation of multiple stressful family processes; disrupts the caregiving environment; and is associated with internalizing and externalizing problems and long-lasting psychopathology in children. This population will allow us to study the unfolding of stress responses, which is almost impossible to capture for other more severe stressors. We focus on the 4-6 years period because it is a period of heightened neural plasticity and a transitional period from family to peer and teacher relationships, which makes children especially sensitive to a stressor that could disrupt their caregiving environment. We assess biological stress responses using: 1) hair cortisol concentrations (HCC), a retrospective measure of chronic HPA axis activity; 2) salivary cortisol, a measure of current HPA axis activity; and 3) MRI structural and functional connectivity in areas implicated in stress responses. We will assess pre-divorce factors (e.g., parental history of psychopathology, parental conflict), post-divorce parental adjustment using self-report and biological measures (HCC); parent-child behavioral and brain synchrony, a biological measure of the parent-child relationship; other post-divorce factors (e.g., ongoing conflict); and internalizing and externalizing symptoms in children. We hypothesize that the stress group will show higher HCC, salivary cortisol, and structural and functional connectivity early on following divorce compared to control children; and that pre-divorce factors will moderate these relationships. The stress group will show decreased HCC, salivary cortisol, and structural and functional connectivity over time; and parental reduced cortisol and increased psychiatric symptoms and decreased parent-child behavioral and brain synchrony and other post-divorce factors will mediate these relationships. Finally, early biological responses and changes in these responses over time will predict internalizing and externalizing symptoms. This study will examine the neurobiology of stress responses in early childhood and will improve our understanding of the biological mechanisms through which early life stress affects risk for psychopathology. It will help identify children at risk early on and guide novel biologically-based prevention and intervention approaches.

Project Summary Previous studies have identified three central pathways of parent-to-child anxiety transmission: (1) shared genetic load, (2) fetal programming through maternal experiences during pregnancy, and (3) parental behaviors that model and shape anxiety-linked cognitive, behavioral, and emotional profiles. To date, we have few tractable mechanisms by which we can intervene upon the first two pathways. However, a wide and robust literature has characterized specific parenting behaviors linked to the emergence of childhood anxiety, making it a translatable target. Much of this literature has focused on broad profiles based on questionnaire measures or aggregate summaries of behaviors averaged over time. As a result, we know little regarding the moment- by-moment interactions that serve as a behavioral conduit for intergenerational transmission. Repeated daily interactions with caregivers, channeled through dyadic social dynamics, attune the child to parental expressions of fear and distress influencing the child?s own responses to surrounding events. The current longitudinal study will focus on two instances of dyadic social dynamics as mechanisms for anxiety transmission. First is dyadic synchrony, a process captured in the temporal co-ordination of discrete microlevel signals between dyadic partners evident across levels of analysis. Second is emotion modeling, in which observed patterns of parental emotion, distress and coping are internalized by the child, supported by psychophysiological synchrony, and then reflected in their own subsequent behavior. Children ages 4 to 6 and their parent will be assessed at five time points, 6 months apart in a multi-modal battery. Parent-child dyads will engage in mildly stressful interactions that allow us to capture neural (fNIRS), psychophysiological (RSA), attentional (mobile eye-tracking), and behavioral (overt emotion and distress) patterns of synchrony. In addition, we will assess regulatory (EEG delta-beta coupling), cognitive (ERP N2 component), and attentional (threat bias) markers of socioemotional development and anxiety risk. Finally, we asses child fearful temperament, which is associated with greater sensitivity to the social environment and the later emergence of anxiety. Thus, we can ask (1) Concurrently, how do patterns of dyadic social dynamics vary across parent- child pairs? (2) Across tasks, to what extent does variation in dyadic patterns help predict anxiety risk? (3) Over time, can we predict socioemotional profiles and anxiety risk from earlier patterns of dynamic dyadic interactions? Reflecting the Research Domain Criteria, we integrate multilevel mechanisms by examining how social and arousal/regulatory systems are coupled through dyadic social dynamics to influence the emergence of anxiety via the cognitive (attention to threat, cognitive control), arousal/regulatory (delta-beta coupling), and negative valence (fearful temperament) systems. In doing so we heed the call to examine development and the environment as ?bidirectional influences? on transdiagnostic processes of psychopathology in order to translate our findings to dyadic treatment approaches.