Mitchell J. Prinstein, Ph.D. - US grants

social behavior; suicide; adolescence (12-20); middle childhood (6-11); conduct disorder; psychological stressor; social support network; peer group; social problems; behavioral /social science research tag; interview; human subject; clinical research;

DESCRIPTION (adapted from the investigator's abstract): This is the second revision of a new investigator proposal that seeks four years of funding for a longitudinal study of predictors of suicidal ideation and suicide attempts during the transition from early to mid-adolescence. The application targets 450 adolescents aged 12-14 years (225 clinically referred; 225 normative) who will participate in a baseline assessment followed by six telephone and home-based assessment at three-month intervals. The multiple-informant design will include adolescent self-reports parent reports, teacher reports and peer nomination. The study will focus on peer and family factors affecting suicide ideation and behaviors. It will test three conceptual models: incidental, causal, and transactional. Analyses will include MAC/SEM for evaluation of predictor variables across the normative and clinical samples and growth curve analyses to track effects of across time.

DESCRIPTION (provided by applicant): Prior work suggests that peer influence of adolescent health risk behavior is a remarkably pervasive phenomenon, but little is known about theory-based motivations underlying peer influence, or moderators that may affect adolescents' susceptibility or resistance to peer influence (DHHS, 1994). This application offers a theoretical model of peer influence and a series of two experimental studies that will examine this model and its implications for potential prevention efforts. Notably, these studies offer an opportunity for translational research, integrating theories and methods from developmental psychopathology and social psychology to elucidate directions for future preventive interventions. The proposed model suggests that adolescents' conformity to peers is motivated largely by a desire to achieve high levels of peer status, and consequently a favorable self-concept. Proposed studies each include an experimental and a longitudinal component to examine mechanisms and moderators of peer influence, as well as a potential preventive intervention to reduce peer conformity. Experimental studies use a simulated chat room context in which electronic confederates ostensibly communicate social norms endorsing risk or prosocial attitudes. Experimental studies allow for an examination of adolescents' public conformity and private acceptance of health risk behaviors (as well one measure of actual aggressive behavior measured in vivo). These studies also allow for the study of mechanisms (e.g., changes in self- esteem or perceived peer status) in real time, as conformity occurs. Longitudinal components to these studies allow for a long-term examination of peer influence susceptibility (Study 1) and the effects of a theoretically-based preventive intervention that may mitigate peer influence effects (Study 2) during the critical developmental interval associated with sharp increases in adolescents' health risk behavior engagement.

DESCRIPTION (provided by applicant): Especially among girls, the adolescent transition is associated with dramatic increases in the prevalence of suicidal ideation, and several forms of self-injury, including non-suicidal self-injury (NSSI;i.e., self-mutilation), suicidal gestures, threats, and attempts. This study proposes, and will test a theoretical model suggesting that biological and cognitive responses to social stressors explain the association between psychopathology (i.e., depression) and self-injury (i.e., mediation) and that specific interactions between stress responses (i.e., moderation) will help identify which girls with psychopathology are most likely to engage in self-injury longitudinally. Specific combinations of cognitive and biological stress responses are proposed to uniquely identify risks for different types of self-injury/suicidality (i.e., NSSI vs. suicidal ideation). Moreover, this study will examine trajectories of, and associations among self-injury constructs, addressing several limitations of past work. The aims of this research thus address several of the goals outlined in PA # 07-079, Research on the Reduction and Prevention of Suicidality as well as many of the goals articulated the NIMH Strategic Plan (NIMH, 2008) and the NAMHC Workgroup report on Transformative Neurodevelopmental Research (NAMHC, 2008). This study will use an innovative, lab-based methodological paradigm to examine cognitive (i.e., attributions, social problem solving) and biological (i.e., neuroendocrine, cardiovascular) responses to an in vivo social stressor. Participants will include 250 female adolescents from both outpatient and inpatient clinically-referred samples. Data will be collected from multiple informants (adolescents, parents) and multiple sources (observational methods, structured interviews, questionnaires, biological assays). It is expected that observed stress responses in the lab will interact with the experience of actual social stress measured during follow-up to predict self-injury trajectories over an 18 month interval. In other words, this study will address long-standing, but under-explored questions regarding why and how psychological symptoms, and/or the experience of stress, are associated with self-injurious behaviors. PUBLIC HEALTH RELEVANCE: Although much research has indicated that adolescents with a history of psychopathology are at increased risk for self-injury (e.g., self-mutilation;suicide attempts), little is known about why or how psychological symptoms lead to self-injury. Thus, there are few directions for evidence-based prevention/intervention. This research will examine specific psychological and biological responses to social stress that may increase the risk for girls'self- injury, and help to elucidate the development of self-injurious behaviors by exploring the course of these behaviors across a sensitive and critical developmental period.

DESCRIPTION (provided by applicant): Especially among girls, the adolescent transition is associated with dramatic increases in the prevalence of suicidal ideation, and several forms of self-injury, including non-suicidal self-injury (NSSI; i.e., self-mutilation), suicidal gestures, threats, and attempts. This study proposes, and will test a theoretical model suggesting that biological and cognitive responses to social stressors explain the association between psychopathology (i.e., depression) and self-injury (i.e., mediation) and that specific interactions between stress responses (i.e., moderation) will help identify which girls with psychopathology are most likely to engage in self-injury longitudinally. Specific combinations of cognitive and biological stress responses are proposed to uniquely identify risks for different types of self-injury/suicidality (i.e., NSSI vs. suicidal ideation). Moreover, this study will examine trajectories of, and associations among self-injury constructs, addressing several limitations of past work. The aims of this research thus address several of the goals outlined in PA # 07-079, Research on the Reduction and Prevention of Suicidality as well as many of the goals articulated the NIMH Strategic Plan (NIMH, 2008) and the NAMHC Workgroup report on Transformative Neurodevelopmental Research (NAMHC, 2008). This study will use an innovative, lab-based methodological paradigm to examine cognitive (i.e., attributions, social problem solving) and biological (i.e., neuroendocrine, cardiovascular) responses to an in vivo social stressor. Participants will include 250 female adolescents from both outpatient and inpatient clinically-referred samples. Data will be collected from multiple informants (adolescents, parents) and multiple sources (observational methods, structured interviews, questionnaires, biological assays). It is expected that observed stress responses in the lab will interact with the experience of actual social stress measured during follow-up to predict self-injury trajectories over an 18 month interval. In other words, this study will address long-standing, but under-explored questions regarding why and how psychological symptoms, and/or the experience of stress, are associated with self-injurious behaviors.

? DESCRIPTION (provided by applicant): In response to public calls from the US President, Congress, Surgeon General, and a recent NIMH-co- sponsored Suicide Research Prioritization Agenda, the proposed research will examine how suicidal ideation and attempts develop within one of the most vulnerable populations at risk for suicide (i.e., adolescent girls). This work will examine how girls' atypical acute stress responses to interpersonal stress at physiological, genomic, and behavioral units of analysis moderate the association between actual experiences of interpersonal stress and suicidal ideation among girls with distal suicide risk factors (i.e., elevated depressive symptoms/lifetime interpersonal adversity). Moreover, this research will examine how these distal risk factors transact with pubertal processes to produce risk for atypical acute stress responses. Last, inhibitory control will be examined as a moderator of the association between suicide ideation and suicide attempts. This research will identify numerous biomarkers of suicide risk, significantly advancing progress towards identification and prevention of an enormous public health issue that has been woefully understudied and for which no evidence- based approaches exist. Using a combination of a RDoC conceptual framework, experimental lab-based stressor paradigm, biological assays, performance-based assessments of executive function, longitudinal methods, and innovative bioinformatics approaches for measuring gene expression, this work offers a substantial advance within a field that almost exclusively has relied on cross-sectional, single-informant, retrospective reports of suicidality. Participants will include 200 girls (age 9-14 years) at pre-, peri-, and post-pubertal stages of development. Recruitment will oversample girls with elevated depressive symptoms/lifetime interpersonal adversity to participate in a lab-based study involving the assessment of physiological, genomic, and behavioral responses following an experimentally-induced social stressor. A multi-wave assessment occurring over a one-year longitudinal interval will be conducted to obtain extensive data on suicidal ideation and attempts over time. Biological data will be collected to measure the autonomic nervous system, hypothalamic-pituitary-adrenal axis system, gene expression (using microarray-based genome-wide transcriptional profiling), and pubertal development. Ongoing research conducted by this investigative team utilizing many of the same recruitment, data collection, and analytic procedures strongly supports the feasibility of the proposed research.

Project Summary/Abstract Suicide is the second leading cause of death (behind accidents) among those ages 10-34 years in the US and is the cause of mortality most strongly linked to mental illness. Starting at approximately age 12 years, the rate of suicidal thoughts and behaviors (STBs) increases dramatically, especially among girls, who experience STBs at twice the rate for boys. These pronounced increases for adolescents and for girls have been well-documented for decades and are seen in virtually every country/culture around the world, yet, there is no firm understanding of why they exist. Moreover, very little is known about when risk is highest. The proposed research extends our team?s prior work, funded by two prior R01 awards, examining adolescent girls? stress responses as prospective predictors of STB trajectories, and a K99/R00 award revealing that changes in reproductive hormones across the menstrual cycle produce specific periods of high STB risk (particularly during the peri-menstrual phase) among adult women. Specifically, we hypothesize that girls will report higher occurrence and severity of STBs on days in the peri-menstrual phase than on days in other cycle phases (mid-follicular, ovulatory, mid-luteal), that these increases will be mediated by daily changes in negative affect and stress-reactivity during the peri- menstrual phase, and that girls with greater cyclical hormone sensitivity are at greater long-term risk of STBs, particularly during times when interpersonal stress is elevated. We propose to test these hypotheses in a sample of 200 clinically-referred girls ages 12-17 years who are at least one year post-menarche. The design begins with 70 days (two cycles) of daily surveys to assess negative affect and STBs. In addition, girls will complete two counterbalanced laboratory visits (at high risk peri-menstrual and low risk mid-follicular phases) during which we will evaluate their affective and physiological (autonomic, cortisol, genomic) responses to a standardized laboratory stressor. Next, girls will complete weekly surveys measuring cycle phase, interpersonal stress, negative affect, and STBs through one year of follow up. The intensive two-month baseline phase allows us to examine how the menstrual cycle shapes daily affective and physiological risk for STBs and lets us diagnose each girl?s degree of hormone sensitivity. These baseline individual differences in hormone sensitivity then can be examined as a predictor of STBs across the follow-up year of assessments, particularly during periods of elevated social stress. This powerful design will clarify whether cyclical changes in daily STBs (Aim 1) are mediated by affective and physiological STB risk factors, such as negative affect (Aim 2a; measured via daily surveys) and social stress reactivity (Aim 2b; measured via lab-based behavioral, physiological, and molecular biomarker assays), while also acknowledging critical moderation by both individual differences in hormone sensitivity (i.e., not all girls will have severe cyclical mood changes) and time-varying interpersonal stress (Aim 3). This innovative study will address several long-standing questions in the literature, including why girls are at increased risk, when girls may be most at risk, and which girls are at highest risk for future STBs.

Project Summary/Abstract An alarming number of adolescents will engage in substance use (including alcohol, tobacco, marijuana and opioids) before they leave high school, a fact that has serious long-term health and societal impacts. Since most adolescents begin using substances with peers, an understanding of the processes that lead to peer influence susceptibility in the context of substance-using peers offers critical avenues for successful intervention in substance use. Our prior research developed a unique performance-based experimental paradigm for measuring peer influence susceptibility and found that individual differences in susceptibility interact with adolescents? perceptions of their peers? substance use to predict their own substance use engagement. However, it remains unclear why some adolescents are more susceptible to peer influence than others, and how development confers increased risk for susceptibility. This work will examine the neural correlates associated with individual differences in peer influence susceptibility. Specifically, we will assess how increased functional connectivity within and between neural networks subserving greater sensitivity to social rewards and punishments, motivation to attain rewards and avoid punishment, and representations of social others is associated with greater peer influence susceptibility. We will also examine a network involved in executive control as a protective factor against later substance use. Using a two-cohort, accelerated longitudinal design including adolescents spanning grades 6-12, we will investigate how individual differences in connectivity within and between candidate neural networks predict prospective substance use initiation in the context of peers. Eight hundred adolescents (age 11-13 years) will complete baseline assessments of substance use, and peer influence susceptibility using an innovative experimental paradigm. A subset (n = 250) of the initial sample will partake in longitudinal task-based functional imaging in year 1 and 3, as well as multi-wave longitudinal assessment occurring at one-year longitudinal intervals in subsequent years 2-5 to obtain extensive data on adolescents? and peers? substance use trajectories across a critical developmental period associated with substance use. By delineating the neurobiological markers of social influence susceptibility, project findings can characterize those individuals at greatest risk for substance use, which can inform interventions by targeting the psychological processes that contribute to peer influence susceptibility.