Jennifer Silk, PhD - US grants

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award (K01) will enable the candidate to independently conduct longitudinal high-risk research on emotion regulatory risk factors for child and adolescent depression. Early-onset depression is a disabling condition that is disturbingly common among adolescents of depressed parents. Research suggests that both neurobehavioral systems and social-interactional processes involved in emotional reactivity and regulation play a role in the transmission of risk for depression from parents to adolescents. Understanding the pathways by which these factors interact to contribute to depression onset is crucial for developing prevention and intervention approaches for this population. To address this need, the candidate will pursue training in developmental affective neuroscience, the assessment of dyadic affective behavior, and longitudinal statistical modeling. Training will be accomplished via (a) meetings and guided readings with mentor Ronald Dahl, M.D., co-mentor Daniel Shaw, Ph.D., and an expert team of internal and external consultants; (b) formal coursework; (c) supervised hands-on experience in the collection and analysis of data using behavioral observation and psychophysiological methodologies; and (d) attendance at local and national conferences, journal clubs, and research network meetings. The proposed research will utilize observational, psychophysiological (task-evoked pupillary responses, event- "elated potentials), and questionnaire measures to examine maternal socialization of emotion regulation and adolescent emotional reactivity among depressed and nondepressed mothers and their early adolescent offspring. The research will also examine the interplay of these factors in contributing to adolescents' depressive symptomatology over time. These training activities will complement the candidate's background in clinical/developmental psychology and place the candidate in a position to conduct integrative research on social and neurobehavioral factors in the etiology of child and adolescent depression.

[unreadable] DESCRIPTION (provided by applicant): Mental and behavioral health during adolescence is an area of critical public health concern because morbidity and mortality rates increase 200-300% from childhood to late adolescence. A major dimension of these serious health problems is related to difficulties with the control of emotions. In order to understand how challenges to emotion regulation during adolescence contribute to specific health problems, researchers need better tools for measuring emotional reactivity and regulation during this developmental period. This project applies a developmentally informed social affective neuroscience perspective to the development of a new "toolbox" for studying emotional reactivity and regulation in adolescence. This requires an integration of the fields of developmental psychopathology, social neuroscience, and affective neuroscience. Combining key elements of these disciplines will facilitate the development of tools grounded in neuroscience that also have broader developmental, clinical, and social relevance. Because of the importance of the social sphere in adolescence, we focus on socially relevant paradigms that will facilitate an understanding of how social influences (e.g. parents, peers, media) contribute to adolescents' emotionality, and how neurobiological substrates underlie social and emotional processes. Specifically, we will develop and refine 3 sets of tools: (a) laboratory pupillary and functional magnetic resonance imaging (fMRI) social-emotional information processing tasks; (b) behavioral observation of parent-child affective interactions with concurrent pupillary data; and (c) a cell-phone based Ecological Momentary Assessment (EMA) protocol measuring adolescents' emotional reactivity and regulation in natural social contexts. Our aims are to (1) develop and establish initial psychometric properties for these measures, (2) integrate these measurement approaches across levels of context and time, and (3) examine the validity of these approaches in discriminating clinical groups and detecting developmental/pubertal differences in emotional reactivity and regulation. As first steps, we will focus specifically on the utility of these methods in research on adolescent depression--a common and debilitating adolescent health problem associated with chronic and recurrent impairment into adulthood. Innovative aspects of this work include the development of new methodologies for sampling "real-world" phenomena, integration of neuroscience with the social environment by developing laboratory paradigms that tap social processes, and improvements in the assessment of co-occurring social and biological processes through the development of mood inductions and peer and parent-child interaction tasks that can be used to collect concurrent neurobiological, behavioral and observational data. Ultimately, these tools could be useful for investigators examining a wide range of adolescent health problems across disciplines, including researchers in the areas of high risk research, treatment and prevention, longitudinal developmental research, psychology, neuroscience, and behavioral medicine. Developing new biological and ecological tools for measuring emotional reactivity and regulation is relevant to the missions of NICHD, NIMH, NIDA, and NIAAA in that emotion regulation has been identified as a critical yet poorly understood domain in normative child and adolescent development and in the development of problems in mental health, drug and alcohol abuse, and risk-taking and reckless behavior that leads to a broad range of health consequences. Developing tools that can facilitate a better understanding of the mechanisms through which emotional reactivity and regulation contribute to adolescent health is critical because it could lead to improvements or adaptations of existing prevention and intervention programs, the development of new prevention and intervention programs based on new scientific discoveries, and better matching of patients to specific treatment protocols based on emotional profiles. Tools that can identify initial disruptions in emotion regulation and facilitate early intervention during this period of relative plasticity could lead to long-term reductions in health-related cost and suffering in adulthood. [unreadable] [unreadable] [unreadable]

GAD and related anxiety disorders in youth are chronic and highly impairing. Cognitive-behavioral therapy (CBT), and other active forms of psychotherapy (e.g. education, support), are associated with reductions in anxiety (Barrett et al 1996; Kendall et al 1997; Last et al 1998; Silverman et al 1999); however, approximately 44% of anxious children treated with CBT do not improve (James et al 2005). Understanding predictors and correlates of treatment response in child anxiety will allow us to: (1) target treatments to children most likely to benefit, (2) refine treatments by focusing on components shown to be associated with treatment response, and (3) develop new treatments tailored to CBT non-responders. We propose that child anxiety disorders, as exemplified by GAD (Rapee, 2002), are associated with a vigilance-avoidance pattern characterized by problems in monitoring and evaluating emotional information and modifying emotional reactions. This pattern can be reinforced by controlling and critical parenting behaviors, parental psychopathology, and negative interactions with peers. CBT treatments for child anxiety target disruptions in emotion regulation by teaching children skills for identifying and managing negative emotion and providing opportunities to practice these skills during exposures. These skills are then presumed to generalize to social interactions in daily life settings outside the clinic, including interactions with parents and peers. Although improvements in affective functioning in the social context are believed to play a role in anxious children's positive response to CBT, research has not yet clearly demonstrated links between children's or parents' affective behaviors and their response to treatment. We will examine how children's emotion regulation in the social context and their relationships with parents and peers (1) predict initial and long-term response to CBT treatment (individually and compared to an active comparison Child Centered treatment) and (2) change across the course of treatment. We will rely on two ecologically valid methods for assessing affective behaviors in naturalistic contexts: (a) Behavioral Observation and (b) Ecological Momentary Assessment.

DESCRIPTION (provided by applicant): Depression is a leading cause of worldwide disability that increases markedly during adolescence. The period surrounding pubertal maturation may represent a sensitive period for the development and prevention of depression, and also provides a valuable window of opportunity to better understand how depression develops. Having an anxiety disorder before reaching puberty seems to put youth at increased risk of developing depression during adolescence. Our goal is to better understand why so many anxious children become depressed as adolescents, and whether treatment of anxiety in early adolescence can prevent these children from becoming depressed. From an affective neuroscience perspective, we focus on problems in neural response to potential social evaluation and potential reward as two vulnerabilities that may link child anxiety to adolescent depression. These vulnerabilities (a) have been associated with depression (b) are likely to be problematic in many but not all anxious youth, (c) may be exacerbated by maturational processes that occur around pubertal development in ways that could create a negative spiral into a depressive disorder, and (d) if targeted through early intervention could alter the trajectory toward depression. We will build upon an existing Center for Intervention Development and Applied Research that provides cognitive behavioral therapy and supportive psychotherapy to 9-13 year old youth with generalized anxiety disorder, separation anxiety disorder, and social phobia. We will conduct annual psychiatric follow-up interviews and biannual assessments of depressive symptomatology for approximately 180 of these treated youth through mid-to-late adolescence (4 years after treatment; ages 13 to 17). Two years following treatment, youth will complete a battery of socially relevant laboratory tasks, such as a virtual peer interaction and a parental criticism and praise task, during functional neuroimaging of brain activity with concurrent assessment of pupil dilation. We will also assess social threat and reward-related behaviors and emotions in the home environment using an ecological momentary assessment battery administered via cell phone interviews with the youth. These assessments will allow us to track how treatment and threat- and reward-related vulnerabilities contribute to the onset of depression and growth in depressive symptoms throughout this high-risk period and to track changes in these vulnerabilities with pubertal maturation. Specifically, we will examine (1) whether successful early treatment of anxiety prevents depression in adolescence, (2) whether it does so by normalizing response to social threat and reward, and (3) whether residual vulnerabilities in response to social threat and reward immediately following treatment predict which youth develop depression in adolescence. We will also explore (4) whether these vulnerabilities increase as the youth advance in pubertal maturation, (5) whether this exacerbation is attenuated by successful treatment during pre-to-early puberty; and (6) whether the timing of the intervention relative to pubertal development influences later risk for depression and its neural underpinnings.

DESCRIPTION (provided by applicant): Anxiety disorders are extremely prevalent among children and adolescents, affecting 10-20% of school-aged youth. Cognitive behavioral therapy (CBT) is an efficacious treatment for child anxiety disorders, but approximately 40-50% of youth do not respond fully to treatment. It is not clear why these children and adolescents do not achieve full benefits from CBT. One possibility is that they don't apply the skills learned in therapy during their daily lives, either because they don't understand the concepts and skills well enough, or they don't remember to use the skills in real-world anxiety provoking situations. Recent advances in interactive mobile health (mHealth) technologies offer tremendous potential to enhance mental health treatments by improving skill acquisition and utilization in real-world contexts. Technology-enhanced therapeutics may be particularly fruitful in working with youth, given children and teens' comfort with technology and the large amount of time they spend engaged with technology. mHealth technologies may also help to improve youths' engagement in treatment by incorporating motivational messages from therapists, providing fun and interactive ways to learn new skills (i.e. games), and incorporating digital rewards to reinforce skill use and practice. We will refine and test an Ecological Momentary Intervention called SmartCAT (Smartphone-Enhanced Child Anxiety Treatment) that will provide daily opportunities for skill use between CBT sessions during real-world emotional experiences. SmartCAT consists of an app and an integrated clinician portal connected to the app for secure 2-way communication. The app and portal both contain a secure messaging interface and a digital reward bank to track points that the patient can earn by using the app. The app also contains a multi-media library for storing and accessing treatment relevant materials. In the present study, we will develop new interactive skillbuilder modules that can be activated by patients and/or triggered via GPS in pre-specified locations or at prespecified times, including an in vivo skill coach module to reinforce skill utilization, a series of interactive games and activities to reinfoce skill acquisition, and a customizable home challenge module to facilitate home-based exposures. In the development phase of the study (Phase 1), we will apply user- centered design principles to develop these new features based on feedback from 15 anxious youth ages 8-16. Feedback from youth, parents, and therapists will be incorporated and revisions will be made to the SmartCAT program for beta testing in Phase 2. Phase 2 will test the feasibility and acceptability of delivering CBT + SmartCAT in 20 anxious youth ages 8-16 with diagnoses of generalized anxiety disorder, separation anxiety disorder, and/or social phobia. Phase 2 will also provide initial data on whether SmartCAT effectively engages its target of improved CBT skill use, and whether better skill use is associated with better treatment response. This approach is consistent with treatment development pathways recommended in the R34 mechanism and also responsive to strategies outlined in the NIMH Strategic Plan for improving personalization of treatments.

? DESCRIPTION (provided by applicant): Depression and social anxiety are highly impairing disorders that often co-occur and are twice as frequent in women compared to men. These problems are common in adolescents with earlier symptoms of anxiety, but tend to emerge or increase during adolescence, especially in girls. Depression is known to be associated with reduced positive affect/reward responsiveness, and growing evidence indicates that individuals with social anxiety also show reduced positive affect. We test a model proposing that sensitivity to social threat during early adolescence leads to blunted responsiveness to social rewards in the environment, which in turn contributes to increases in social anxiety and depressive symptoms later in adolescence. A large body of research shows that youth with high levels of fearful temperament or trait anxiety display increased vigilance for threatening stimuli, especiall stimuli conveying potential social threat. Girls appear to be particularly sensitive to interpersonl threats. In animal studies, exposure to social threats leads to dopaminergic changes and blunted responsiveness to reward. Yet, little is known about how social threats contribute to reward functioning in human adolescents, particularly during the period surrounding pubertal maturation, when social threats become increasingly salient. We propose that early adolescent girls who are sensitive to social threat will exhibit increased activation to social threat in an affective salience network of ventral brain regions involved in attending to personally salient threats (e.g. amygdala, subgenual anterior cingulate cortex, medial prefrontal cortex, anterior insula, and nucleus accumbens). This reactivity will contribute to a behavioral tendency to avoid situations that carry potential for social threat even when these situations also carry potential fr reward (i.e. making new friends, trying a new activity). Over time, increased neural reactivity to social threats and associated behavioral avoidance of possible threatening scenarios could alter reward responsiveness through several inter- related mechanisms, including: (a) reduced striatal response to reward (b) reduced social approach motivation, (c) reduced attention toward social reward cues, and/or (d) reduced subjective experience of positive emotion during social interactions. These changes are proposed to play a role in the emergence and exacerbation of symptoms. We test this model in a longitudinal study of early adolescent girls oversampled for subthreshold symptoms of social anxiety at baseline. The study will include neuroimaging during simulated peer interaction tasks that probe neural response to social threat and reward, behavioral and eye tracking paradigms, and Eco- logical Momentary Assessment (EMA) of daily social interactions, along with concurrent assessment of clinical symptoms and pubertal hormones. The battery will be completed at baseline (T1; ages 11-13) and 2 years later (T2; ages 13-15), with an additional clinical assessment at T3 (ages 14-16). Results are expected to high- light potentially modifiable shared neurobehavioral risk factors for social anxiety and depression in girls that could be targeted through neuroscience-based interventions during a sensitive developmental window.

? DESCRIPTION (provided by applicant): Depression and social anxiety are highly impairing disorders that often co-occur and are twice as frequent in women compared to men. These problems are common in adolescents with earlier symptoms of anxiety, but tend to emerge or increase during adolescence, especially in girls. Depression is known to be associated with reduced positive affect/reward responsiveness, and growing evidence indicates that individuals with social anxiety also show reduced positive affect. We test a model proposing that sensitivity to social threat during early adolescence leads to blunted responsiveness to social rewards in the environment, which in turn contributes to increases in social anxiety and depressive symptoms later in adolescence. A large body of research shows that youth with high levels of fearful temperament or trait anxiety display increased vigilance for threatening stimuli, especiall stimuli conveying potential social threat. Girls appear to be particularly sensitive to interpersonl threats. In animal studies, exposure to social threats leads to dopaminergic changes and blunted responsiveness to reward. Yet, little is known about how social threats contribute to reward functioning in human adolescents, particularly during the period surrounding pubertal maturation, when social threats become increasingly salient. We propose that early adolescent girls who are sensitive to social threat will exhibit increased activation to social threat in an affective salience network of ventral brain regions involved in attending to personally salient threats (e.g. amygdala, subgenual anterior cingulate cortex, medial prefrontal cortex, anterior insula, and nucleus accumbens). This reactivity will contribute to a behavioral tendency to avoid situations that carry potential for social threat even when these situations also carry potential fr reward (i.e. making new friends, trying a new activity). Over time, increased neural reactivity to social threats and associated behavioral avoidance of possible threatening scenarios could alter reward responsiveness through several inter- related mechanisms, including: (a) reduced striatal response to reward (b) reduced social approach motivation, (c) reduced attention toward social reward cues, and/or (d) reduced subjective experience of positive emotion during social interactions. These changes are proposed to play a role in the emergence and exacerbation of symptoms. We test this model in a longitudinal study of early adolescent girls oversampled for subthreshold symptoms of social anxiety at baseline. The study will include neuroimaging during simulated peer interaction tasks that probe neural response to social threat and reward, behavioral and eye tracking paradigms, and Eco- logical Momentary Assessment (EMA) of daily social interactions, along with concurrent assessment of clinical symptoms and pubertal hormones. The battery will be completed at baseline (T1; ages 11-13) and 2 years later (T2; ages 13-15), with an additional clinical assessment at T3 (ages 14-16). Results are expected to high- light potentially modifiable shared neurobehavioral risk factors for social anxiety and depression in girls that could be targeted through neuroscience-based interventions during a sensitive developmental window.

PROJECT SUMMARY/ABSTRACT This application responds to Notice of Special Interest: Availability of Administrative Supplements for NIMH Grants to Expand Suicide Research. The supplemental funds will allow a new team to collect real-time ecological momentary assessment (EMA) data on suicidal and nonsuicidal self-injurious thoughts and behav- iors (SITB) in adolescent girls at risk for emerging suicidality. We focus on suicidal ideation and nonsuicidal self-injury as two of the earliest and strongest markers of future suicidal behavior. The parent grant utilizes functional neuroimaging and EMA to assess how sensitivity to social threats and rewards (such as rejection and acceptance from peers) from early- to mid-adolescence are associated with risk for depression and social anxiety disorder. Importantly, neurobehavioral responses to social threats and rewards also have potential rel- evance to understanding the development of SITB. The parent grant uses novel fMRI tasks to assess neural response to acceptance and rejection from virtual peers and a new EMA protocol that assesses daily percep- tions of socially threatening and rewarding interactions with peers. The study provides an ideal platform to ad- vance understanding of the development of SITB. First, interpersonal models of suicide propose that a threat- ened sense of social belonging is a key mechanistic factor in the suicide process. Our rich multilevel focus on how adolescents process positive and negative social interactions with peers could be leveraged to better un- derstand how SITB develops during adolescence. Second, the girls in our study (now ages 13-16) are currently going through a period of high risk for the onset of SITB. Additionally, two-thirds of the girls in the sample were recruited to be at temperamental risk for anxiety and depression, based on high shyness or fearfulness, which also places them at risk for SITB. Finally, suicide researchers have highlighted the need for data on near-term precipitants of SITB. The EMA design of the parent study provides an opportunity to obtain real-time data on factors theorized to play a proximal role in precipitating SITB, such as negative social interactions with peers. We propose to incorporate measures of SITB into the parent study for approximately 50 girls who will complete two-year follow-up assessments in Year 5 of the parent study. Measures will include structured clinical inter- views and questionnaires assessing suicidality and nonsuicidal self-injury (NSSI), and real-time measures of SI and NSSI integrated into a 16-day smartphone EMA protocol. This supplement will allow us to establish the acceptability of our EMA-based SITB protocol, build expertise in suicide within our team, and collect critical pi- lot data to generate future hypotheses. Specifically, we will use EMA of peer social threat/reward to identify proximal predictors of real-time SITB for further investigation, collect preliminary data testing whether height- ened neural sensitivity to social threat is a risk factor for concurrent and future SITB in adolescent girls, and explore brain-behavior interactions in the prediction of SITB. Results will be used to generate acceptability and pilot data to support a future larger scale investigation.

PROJECT SUMMARY/ABSTRACT Rates of suicide, self-harm, and depression are alarmingly high among adolescent girls, with a dramatic spike over the last decade, yet it is not clear which girls are at highest risk for these serious problems and when they might escalate. Some have argued that the dramatic rise in social media (SM) use may play a role, but more rigorous data are needed to evaluate the positive and negative effects of SM use in adolescent girls. Sensitivity to social evaluation, such as rejection or exclusion, is a potential cross-diagnostic risk factor for self-injurious thoughts and behaviors (SITB; including suicidal ideation and behavior and nonsuicidal self-injury) and de- pressive symptoms (DEPsx). This study examines how socially threatening and rewarding peer interactions? experienced online or in-person?contribute to real-time fluctuations in SITB, DEPsx, and well-being. The first aim is to use ecological momentary assessment (EMA) to identify how adolescent girls? daily subjective experi- ence of online and in-person social threat and reward predict proximal within-person changes and longer-term between-person differences in SITB and DEPsx, along with wellbeing. The sample will include 177 adolescent girls (ages 13-17), with 75% of the sample at high-risk for suicide (e.g. active ideation within past 6 weeks, at- tempt in past year, or ? five episodes of nonsuicidal self-injury in past year), with at least half of high-risk par- ticipants also reporting elevated DEPsx. Girls will complete three 10-day bursts of EMA and will also provide access to passively obtained data on SM use and digital social interactions (i.e. text, video-chat). Multilevel modeling analyses will be used to identify predictors of near-term changes in SITB, DEPsx, and positive affect (PA), as well as long-term outcomes assessed at 6- and 12-month follow-up. A second aim is to identify which girls are at highest risk for DEPsx and/or SITB when exposed to near-term precipitants, focusing on differences in brain activation to social evaluation within an affective salience network (ASN) that includes the amygdala, anterior insula, dorsal and subgenual anterior cingulate cortex, and nucleus accumbens. Building on the differ- ential susceptibility to context theory, the study proposes that heightened ASN activation to social evaluation is a susceptibility factor that could amplify both the positive and negative effects of daily social experience on SITB and DEPsx. Girls will complete neuroimaging tasks that assess brain response to social evaluation from virtual peers. It is hypothesized that within-person increases and higher rates of peer social threat experiences (online and in-person) will be most strongly associated with SITB and DEPsx for girls with heightened ASN activation to social evaluation, and that within-person increases and higher rates of peer social reward experi- ences will also be more strongly associated with PA/wellbeing and more protective against SITB and DEPsx for girls with heightened ASN activation to social evaluation. Finally, machine learning will be used to determine which objective features of SM use track in real-time with subjective experience and emotional health, and to identify the strongest set of predictors of short-term and long-term emotional health.