Altered Non-Visual Photoreception in Patients With Glaucoma: Impacts on Sleep, Alertness, Mood, and Cognition

Glaucoma is a chronic eye disease that damages retinal ganglion cells (RGCs), leading to progressive loss of vision. Recent evidence suggests that glaucoma may also affect a special subset of RGCs called intrinsically photosensitive retinal ganglion cells (ipRGCs), which contain the light-sensitive pigment melanopsin. These cells are critical for regulating non-visual responses to light, such as sleep, mood, alertness, and cognition, by sending light signals from the eye to various regions of the brain. Patients with glaucoma often report sleep disturbances, fatigue, and mood changes, yet the biological mechanisms behind these symptoms are not fully understood. It remains unclear whether such non-visual effects result from damage to ipRGCs or from other disease-related factors. Understanding this relationship is important for improving the overall wellbeing and quality of life of individuals living with glaucoma. This study will therefore investigate how glaucoma affects non-visual responses to light and whether brief, safe exposure to full-spectrum light can improve alertness, sleepiness, and mood. The study combines observational and interventional components to comprehensively assess the link between light perception, brain function, and behavior in glaucoma. Study Design and Procedures A total of 120 participants will take part in the study: 1. 60 patients with bilateral primary open-angle glaucoma 2. 60 healthy control participants matched for age (45-75 years) Each participant attends two study visits: Visit 1 is done at the clinics (National University Hospital / Singapore National Eye Center) and covers the following: * Comprehensive eye examination including visual field testing, optical coherence tomography (OCT), fundus photography, autorefraction, visual acuity, color vision, slit-lamp examination and intraocular pressure measurement. * Evaluation of sleep quality, daytime sleepiness, and mood using validated questionnaires (Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Patient Health Questionnaire (PHQ-9)). * Assessment of cognitive function (Montreal Cognitive Assessment). * Measurement of non-visual light sensitivity using handheld chromatic pupillometry, a non-invasive test that evaluates ipRGC function through pupillary light responses. Participants are given a wrist-worn actigraphy device to record their daily sleep-wake cycles and light exposure for 8-16 days at home, along with a sleep diary. Visit 2 is done at the laboratory (National University of Singapore - Eye N' Brain Research Platform). After completing actigraphy, participants return for detailed testing of attention, cognition, and vigilance following exposure to two lighting conditions: 1. Control Light Condition: standard indoor lighting (\~300 lux) 2. Experimental Light Condition: full-spectrum white light (\~1000 lux), designed to mimic the spectral quality of daylight without ultraviolet or infrared radiation. Participants undergo two sessions of exposure to each of these lights (separated by a period of standard light during which they perform different versions of the MoCA test). The timing of the visit is individualized based on each participant's sleep/wake cycle. Participants go through the sessions in a cross-over manner and the order of lighting conditions will be randomized to control for order effects. Following light exposure, the following cognitive tasks are employed while doing eye tracking and cognitive pupillometry: 1. Auditory Psychomotor Vigilance Task (aPVT) to assess alertness or sustained attention 2. Auditory Oddball Task to assess selective attention 3. Time Estimation Task to assess sleepiness objectively 4. Balloon Analogue Risk Task (BART) to assess risk taking behavior 5. Digit Symbol Substitution Task (DSST) to evaluate processing speed and executive function 6. Cognitive pupillometry in response to different shapes. Subjective rating scales of mood, wellbeing, and sleepiness are administered before and after each lighting condition and after cognitive assessment to monitor fluctuations throughout the session.