Probing the Nexus: Unraveling Neuroinflammation's Link to Anhedonia

Project Summary / Abstract Anhedonia, a multifaceted construct encompassing reduced pleasure, decreased motivation, and impaired reward learning 1, represents a clinically relevant symptom dimension observed across diverse psychiatric disorders 2–13. Linked to poor therapeutic responses, anhedonia imposes significant economic and care burdens 14–16. Recent studies highlight inflammation's pivotal role in anhedonia's pathophysiology, with a primary focus on peripheral inflammation 17. However, only a limited number of PET studies delve into neuroinflammation in the central nervous system 17–20, and even fewer explore longitudinal associations 21–23, leaving critical gaps in our understanding of how inflammation precisely influences anhedonia. This R03 proposal addresses these gaps by utilizing the UK Biobank and Adolescent Brain Cognitive Development datasets, along with the innovative diffusion basis spectrum imaging technique. Our central hypothesis posits that neuroinflammation mediates the association between peripheral inflammation and anhedonia symptoms, with an examination of potential age-related effects on this mediation relationship. Building on existing evidence 17,24,25, this project focuses on reward processing brain regions, and investigates cross- sectional and longitudinal relationships between peripheral inflammation, regional neuroinflammation, and anhedonia symptoms. By examining neuroinflammation's role in anhedonia, this secondary analysis project aims to provide novel insights into the dimensional symptom's etiology across mental disorders and highlight potential age- specific patterns. Future studies could extend to patient cohorts, exploring anhedonia in diverse disorders with additional measures for brain structure and function in the reward circuitry, as well as modifiable environmental and psychosocial factors. These future investigations hold the potential to validate the clinical relevance of the neural and inflammatory phenotypes trans-diagnostically and may ultimately inform interventions and treatments.