Multisystem Stress Response Biotypes: Deriving Novel Physiological and Neural Risk Factors for Anhedonia in Adolescence

PROJECT SUMMARY Anhedonia (ANH), the reduced ability to anticipate or experience pleasure, is a major transdiagnostic contributor to disability, inferior quality of life, and a core characteristic of multiple severe psychopathologies. ANH emerges in

adolescence prior to the onset of these disorders and is highly prevalent (up to 20%) in youth 13-15-years. However, ANH in adolescence is poorly understood and interventions remain few. A growing body of evidence suggests that stress exacerbates ANH and dysregulated acute stress response mechanisms may critically contribute to ANH. Yet, little is

known about the role of stress neurobiology in the emergence, course, and severity of ANH in adolescence, a critical developmental period marked by significant pubertal changes and steep maturation of neural circuits implicated in the recalibration of the stress-response systems and mood regulation.

The objective of the current proposal is to characterize how biological acute stress response mechanisms influence the severity and trajectory of ANH. ANH research to date has almost exclusively focused on single-system physiological responses to acute stress, such as autonomic nervous system (ANS - parasympathetic and sympathetic nervous system

branches - PNS-SNS) or endocrine (HPA - Hypothalamic Pituitary Adrenal) system responses. New evidence supports the need for multi-system approaches to detect clinically meaningful patterns of stress responses associated with ANH. Recent research from our labs (PI Belger and Co-PI Roubinov) has shown that (1) discrete physiological latent stress-

response profiles (Buffered, Vigilant, Sensitive) that integrate unique patterns of responses across HPA and ANS systems

have additional utility in predicting both clinical and functional development outcomes beyond single-system biomarkers. In this proposal, we will examine how a novel constellation of complex neurobiological stress response mechanisms interactively contributes to ANH in adolescence. Using a multimodal approach including functional MRI (Magnetic

Resonance Imaging), physiological HPA and ANS stress reactivity, and clinical and cognitive assessments, the proposed

study will be the first to integrate physiological and neural acute stress response mechanisms to derive multisystem stress response biotypes (MSRB) and explore their contributions to ANH severity and trajectory in adolescence. We will study 192 adolescents ages 13-15-years experiencing a range of ANH at baseline, 10 months, and 20 months across 2 aims. In

Aim 1 we will identify multisystem stress response biotypes (MSRBs) integrating physiological and neural responses to

acute stress in adolescents and examine their longitudinal stability. In Aim 2, we will determine the characteristics of multisystem latent stress profiles that predict the severity and trajectory of ANH in adolescence. Across both aims, we will examine age, sex, and pubertal stage as covariates. IMPACT: This project will contribute a novel framework for understanding and modeling the complex multisystemic

biological mechanisms governing stress responsivity during adolescence. Understanding the individual and interactive

contributions of physiological and neural systems to ANH presents a unique opportunity to develop specific interventions that target malleable stress systems in adolescents with ANH.