Michael Joseph Crowley - US grants

conduct disorder; male; psychophysiology; middle childhood (6-11); disease /disorder classification; emotions; psychometrics; behavioral /social science research tag; startle reaction; electroencephalography; human subject; clinical research;

DESCRIPTION (provided by applicant): This K01 application seeks support essential to my development as an independent interdisciplinary scientist. I am building a program of biopsychosocial research on self-regulation; particularly affect reduction and negative reinforcement (NR) as they relate to the development of substance use in adolescence. I have employed behavioral, electrophysiological, and hormonal assays (cortisol) to study risk-taking behavior. However, to fully understand avoidance and negative reinforcement processes, and their role in the risk for addictive behavior, I must deepen my understanding and broaden my technical skills in four core areas (a) developmental neuroimaging; (b) cognitive neuroscience; (c) substance use research; (d) statistical methods. This mentored scientist development award will provide me with the training to move onto an independent research career. While adolescence is a developmental period with increased risk-taking behavior and increased affect reduction motivation, we know relatively little about how the neural correlates of negative reinforcement processes relate to affect reduction motives and substance use behaviors. I address these gaps in our knowledge with three specific aims across two cross-sectional fMRI studies. I propose to study the neural and behavioral correlates of negative reinforcement for avoidance with two types of aversive stimulation (e.g., avoidance of incentive loss and avoidance of aversive sound) across two fMRI-friendly behavioral paradigms. The first study (n=48) will characterize the neural circuitry underlying negative reinforcement processes and behavior among children (8-11 yrs.), adolescents (13-17 yrs.), and adults (23-29 yrs.) The second study will examine the negative reinforcement-related neural correlates of affect reduction motives (negative affect, anxiety sensitivity) and substance use behaviors in a high-risk sample (14-18 yrs., n=70).

? DESCRIPTION: This is an application for a 5-year renewal of the Yale University's T32 Fellowship Training Program in Childhood Neuropsychiatric Disorders (T32 MH18268-30). Our program focuses on preparing scientists, including those in clinical sciences as well as those in basic sciences, for independent careers as field- leading investigators, conducting research on childhood neuropsychiatric disorders. Training programs like ours are urgently needed given: 1) the large number of children affected by or at risk to develop major mental illnesses; 2) the considerable costs to society associated with their care; 3) the limited efficacy and effectiveness of available treatment and prevention programs; 4) the small number of active investigators in the field; and 5) the emergence of relevant scientific and technological advances that have yet to be fully realized. Over the past 30 years, we have recruited 95 T32 Postdoctoral Fellows. A majority of these trainees have been women (54%) and close to a quarter (24%) have been underrepresented minorities. 98% of the trainees completed at least two years of the T32 Fellowship. The vast majority (85%) continues to be actively involved in research concerning Childhood Neuropsychiatric Disorders. Most trainees have published multiple peer-reviewed papers and many trainees have obtained numerous independent research grants and career development awards. Their work has garnered international acclaim and many of our graduates are leading figures in their respective fields. Uniquely, this T32 program is fully united with a highly successful six-year integrated child, adolescent and adult research and clinical residency training program in child psychiatry. Further, MD graduates are strongly encouraged to enroll in this residency program and pursue an advanced research degree in the Investigative Medicine Program or in another advanced degree program in the world-renowned Yale Graduate School of Arts and Sciences. In this renewal, we introduce explicit training in team science. We believe this training will augment the success of our trainees, reorienting the culture of the academic institution to better support, greater reward, and an enhanced quality of mentorship in clinical and translational research. We will continue to place a major emphasis on career development by providing individual mentoring along with experiential training in team science, complemented by didactic activities. A personalized training plan is developed for each trainee early during the course of the Fellowship and is monitored closely throughout. Enhancement of writing skills, guidance on balancing personal life and professional career, and exposure to cross-disciplinary co-mentors characterize our T32 Fellowship program.

PROJECT SUMMARY Anxiety disorders are near the top of the list of the most troublesome public health concerns we face, costing billions of dollars annually. Equally important are the many individual lives devastated by debilitating distress and chronic avoidance, leading to diminished quality of life, lost potential and emergent comorbid conditions (e.g. depression). Chronic, abnormally heightened threat processing is a linchpin in the pathophysiology and maintenance of anxiety disorders. Research to date on threat processing in anxiety has used passive viewing of static threat stimuli. However, real-life threats are not static?the nature of threats changes over time. We propose to remedy this important limitation of the extant research with a dynamic threat processing game (the Boom). The Boom is designed to assess a profile of neural responses to dynamically evolving threats among youth with and without elevated anxiety. The Boom is developmentally sensitive, engaging for youth, and calibrated for the detection of individual differences in threat processing. Employing child-friendly cartoon-like images, the game assesses youths? processing of successive, naturally-evolving threat contexts: vigilance for potential threats, followed by detection of direct or indirect acute threats, and an opportunity to reappraise indirect threats that do not require an immediate response. We propose a multi-method (EEG, behavior, and multi- informant phenotyping) study to evaluate the validity and reliability of the Boom for assessing 10- to 14- year-olds? neural responses to dynamically evolving threat contexts, to begin to unpack successive stages in a threat processing cascade among community and clinically-referred youth with varying anxiety severity. The Boom provides a unique lens into dynamic threat processing disruptions in anxiety that are not measured by existing assessments. However, establishing the reliability and validity of the Boom is a critical first step. Following psychometric validation, we expect the Boom will yield important insights into mechanisms contributing to the development and maintenance of anxiety disorders. This work may inform the design of novel or personalized interventions for anxiety disorders targeting dynamic threat processing disruptions. This study will deliver quantitative, developmentally informed brain-based biomarkers, for two key Research Domain Criteria (RDoC) negative valence constructs, Potential Threat and Acute Threat. Moreover, this project is well-aligned with the NIMH Strategic Plan Strategy 1.1, which includes identification and validation of novel assays to quantify changes in the activity of brain circuits.