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

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

The goal of this study is to understand how light sensitivity in the eye affects sleep, mood, alertness, and cognition in adults with glaucoma compared to healthy individuals aged 45-75 years.

The main questions it aims to answer are:

1. Do patients with glaucoma experience poorer sleep, mood, alertness, and cognitive function than age-matched healthy adults?
2. Are these changes related to reduced light sensitivity in special retinal cells called intrinsically photosensitive retinal ganglion cells (ipRGCs), lost in glaucoma?
3. Can exposure to safe, full-spectrum indoor light help improve these functions?

Researchers will compare patients with glaucoma and age-matched healthy controls to see if differences in light sensitivity can explain changes in non-visual light responses (i.e., sleep, mood, alertness, and cognition) and whether full-spectrum light exposure can enhance alertness and wellbeing.

Participants will:

1. Complete eye exams and baseline questionnaires about their sleep, daytime sleepiness, mood, and wellbeing.

2. Wear a wrist-worn device for 8-16 days to record their sleep patterns and light exposure.

3. Visit the laboratory for cognitive and attention tests following exposure to two lighting conditions (randomized, cross-over):

   • Standard indoor light (~300 lux)
   • Full-spectrum light (~1000 lux)

This study will help researchers understand how glaucoma affects the brain beyond vision and explore whether light-based interventions can improve quality of life for people living with glaucoma.

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.

Inclusion Criteria:

• Patients with glaucoma must meet all of the inclusion criteria to participate in this study.

  • Patients diagnosed with primary open-angle glaucoma (POAG), as indicated by Humphrey Visual Field (HVF) mean deviation (VFMD) scores better than -12 dB in at least one eye during their most recent clinic visit.
  • Patients having spared central vision.
  • Patients aged 45 to 75 years old.
  • Patients with a best-corrected visual acuity better than 6/12
  • English-speaking patients

Healthy controls must meet all of the inclusion criteria to participate in this study:

• Participants aged 50 to 70 years old.
• Participants with a best-corrected visual acuity better than 6/12
• Normal ophthalmic examination
• English-speaking participants

Exclusion Criteria:

• All subjects (patients and controls) meeting any of the exclusion criteria at baseline will be excluded from participation:

  • Participants with myopia exhibiting a refractive error exceeding -8.00 diopters (D)
  • Participants with a history of complicated previous intraocular surgery
  • Participants taking alpha-adrenergic agonist eye drops or other systemic medications or drugs that could affect the pupillary response
  • Participants with any past or current ocular condition (i.e., age-related retinal diseases (e.g., age-related macular degeneration), retinal pigment epithelium diseases (e.g., Best's disease), diabetic retinopathy, or other optic or generalized neuropathies, significant ocular trauma, or any eye condition affecting fixation (eg. Nystagmus)).
  • Participants diagnosed with cataracts at NS3+ (Nuclear Sclerosis) and above, as well as those with Posterior Subcapsular (PSC) cataracts
  • Participants with clinically diagnosed psychiatric or neurologic disorders, including cognitive impairment or dementia
  • Participants with diagnosed mood disorders
  • Participants engaged in night shift work within the past three months, are currently using sleeping pills, or have recently travelled across timezones within a month prior to the study
  • Participants with obstructive sleep apnea
  • Participants with abnormal auditory function
  • Participants with impaired color vision
  • Pre-menopausal women (last menstrual period < 1 year) (If applicable)
  • Patients having unilateral glaucoma, congenital glaucoma, non-glaucomatous optic neuropathy, abnormal central vision
  • Diabetics on treatment