PROJECT ABSTRACT The proposed study seeks to examine the role of physiological threat dysregulation (TD) as a contributor to social impairment and psychotic-like experiences in youth at-risk for psychosis, and further examine the extent to which faulty cognitive and affective threat responses play a role in partially mediating this relationship. Although the “diathesis-stress model” is a well-established framework for the onset of psychosis and other forms of psychopathology, the exact mechanism as it applies to psychosis remains unclear. This is an important mechanism to examine because TD can generate chronic fear and arousal, states which interfere with social relationships and healthy development. The proposed study will address this gap in the literature by comprehensively examining physiological TD, including the function of the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Autonomic Nervous System (ANS). The current proposal uses multiple methods, including laboratory assessments, ecological momentary assessment (EMA), and ambulatory psychophysiology, to examine the link between TD and outcomes in the laboratory and in daily life. This proposal will utilize a longitudinal design to examine how TD is associated with the persistence or worsening of social impairment and psychotic-like experiences over 1 year. Given that the post-pubertal adolescent developmental stage is a sensitive period for the development of psychotic disorders, we propose to recruit a post-pubertal (age 14-17) sample of adolescents at clinical high-risk for psychosis (CHR; n = 105) and a group of age- and sex-matched controls (n = 70). Multi-method assessments will include 3 laboratory visits (Baseline, 6 months, and 1 year later) with clinical assessments and evaluation of TD before, during, and after a social threat induction task. Visits will be followed by 2 weeks of at-home EMA to investigate real-time ANS threat response (via cardiac wearable device), social impairment, stress, and psychotic-like experiences (via smartphone self-report). The proposed study would be novel in that it will to pair EMA with cutting-edge, ambulatory cardiovascular psychophysiology assessment. Thus, this proposal would unite established in vitro (laboratory) assessments of key variables with novel in vivo (EMA) assessments, the latter of which have high ecological and clinical validity. The aims of the project match well with the strategic goals of the National Institute of Mental Health (NIMH); in particular, Strategies 2 and 3. The proposed conceptual model is highly relevant to the NIMH Research Domain Criteria (RDoC) domains of the sustained and acute threat systems, as well as the “social processes” domain; thus, this research should have relevance to the study of psychopathology across diagnostic boundaries. The proposed award should 1) provide precision to investigation of a theoretical model of TD and its impacts on social impairment and psychotic-like experiences, 2) contribute to the development of an EMA- based “early warning system” to predict changes in psychosis, and 3) suggest new directions for improved prevention and intervention strategies for adolescents at-risk for psychosis.

PROJECT NARRATIVE Adolescence is typically when initial signs of psychosis develop, and social impairment is often one the first of these signs to emerge; however, little is known about specific factors that contribute to social impairment. The proposed study seeks to use cutting-edge ambulatory technology to examine physiologic threat dysregulation (TD) and its relation to social impairment and psychotic-like experiences in adolescence, and whether these relationships are partially mediated by aberrant cognitive and affective responses to threat. These results should develop ambulatory technology as a novel “early warning system” for assessing psychosis, thus contributing to reduced disability and early mortality associated with psychosis and other psychopathology.