PROJECT SUMMARY/ABSTRACT Delayed Sleep Wake Phase Disorder (DSWPD) is a common circadian rhythm sleep-wake disorder that is characterized by difficulty in initiating sleep at night and subsequent difficulty in waking at times required for work or school. Consequently, DSWPD is often associated with excessive daytime sleepiness, reduced academic and work performance, mood disturbances and reduced quality of life. Considering the significant negative impact of DSWPD on sleep quality, performance, mental and physical health and well-being, the physiological basis of the disorder surprisingly remains unclear. Classically, DSWPD is assumed to stem from a delay of central circadian timing. However, recent evidence shows that those clinically diagnosed with DSWPD fall into at least two distinct phenotypes: those with delayed circadian timing and sleep (DSWPD1) and those with typical circadian timing but delayed sleep (DSWPD2). Using pupillometry, our group has shown differences in light sensitivity between the DSWPD1 and DSWPD2 subtypes, as well as within the DSWPD1 group (high (HLS) and low sensitivity to light (LLS)), indicating that clinically diagnosed DSWPD likely represents a complex interplay between underlying physiological differences and behaviors that can affect sleep timing. However, current diagnostic criteria do not consider these distinct phenotypes, which can limit diagnostic accuracy and hinder the development of personalized treatments that target the underlying alterations in physiology and behavior of these DSWPD subtypes. The overall goal of the proposed research is to identify the physiological basis of DSWPD subtypes, and to use these findings to inform development of mechanistically based approaches in circadian medicine. This project will enroll 220 patients with DSWPD who will undergo circadian physiological and behavioral phenotyping by actigraphy, dim light melatonin sampling, pupillary light sensitivity, as well as assessment of mood, alertness and meal timing using questionnaires. In addition, we will evaluate light sensitivity in LLS DSWPD1, as measured by the suppression of melatonin, and test whether the SSRI citalopram can enhance light sensitivity. Finally, mathematical modeling will be used to integrate physiological (pupillometry) and behavioral assessments to identify DSWPD subtypes. The proposed research will form the basis for the development of light sensitivity-based tools and algorithms that integrate physiological and behavioral biomarkers which can lead to a personalized multimodal approach for the care of patients with circadian rhythm disorders.