Altered Non-Visual Photoreception in Patients With Glaucoma: Impacts on Sleep, Alertness, Mood, and Cognition
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Enrollment
- 120
- Locations
- 2
- Primary Endpoint
- Subjective Sleep Quality
Study Overview
Brief Summary
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:
- Do patients with glaucoma experience poorer sleep, mood, alertness, and cognitive function than age-matched healthy adults?
- Are these changes related to reduced light sensitivity in special retinal cells called intrinsically photosensitive retinal ganglion cells (ipRGCs), lost in glaucoma?
- 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:
- Complete eye exams and baseline questionnaires about their sleep, daytime sleepiness, mood, and wellbeing.
- Wear a wrist-worn device for 8-16 days to record their sleep patterns and light exposure.
- 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.
Detailed Description
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:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Supportive Care
- Masking
- None
Eligibility Criteria
- Ages
- 45 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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
Arms & Interventions
Patients with glaucoma
Patients undergoing both control and intervention light exposure in a cross-over randomized design.
Intervention: Full-spectrum light exposure (Other)
Patients with glaucoma
Patients undergoing both control and intervention light exposure in a cross-over randomized design.
Intervention: Standard indoor light exposure (Control) (Other)
Controls (healthy adults)
Healthy adults following the same procedures compared to patients with glaucoma
Intervention: Full-spectrum light exposure (Other)
Controls (healthy adults)
Healthy adults following the same procedures compared to patients with glaucoma
Intervention: Standard indoor light exposure (Control) (Other)
Outcomes
Primary Outcomes
Subjective Sleep Quality
Time Frame: Baseline (Visit 1)
Sleep quality is assessed using the Pittsburgh Sleep Quality Index (PSQI), a validated self-report questionnaire measuring subjective sleep quality, sleep latency, duration, efficiency, disturbances, use of sleep medication, and daytime dysfunction over the past month. Higher scores indicate poorer sleep quality.
Subjective Daytime Sleepiness
Time Frame: Baseline (Visit 1)
Daytime sleepiness is assessed using the Epworth Sleepiness Scale (ESS), a validated questionnaire evaluating the likelihood of dozing in common daytime situations. Higher scores indicate greater daytime sleepiness.
Depressive Symptoms
Time Frame: Baseline (Visit 1)
Depressive symptoms will be assessed using the Patient Health Questionnaire-9 (PHQ-9), a validated self-report questionnaire measuring the frequency and severity of depressive symptoms over the past two weeks. Higher scores indicate greater depressive symptom severity.
Global Cognitive Function
Time Frame: Baseline (Visit 1)
Global cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA), a standardized screening tool evaluating executive function, attention, memory, language, and visuospatial abilities.
Global Cognitive Function during light exposure
Time Frame: Immediately after the procedure
Global cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA), a standardized screening tool evaluating executive function, attention, memory, language, and visuospatial abilities. Alternate validated versions will be used across visits to minimize learning effects.
Median Reaction Time
Time Frame: Immediately after the procedure
Median reaction time will be assessed using a laboratory-based auditory Psychomotor Vigilance Task (aPVT). Participants will respond to auditory stimuli presented via headphones by pressing a key on a keyboard while viewing a fixation display on a monitor. Reaction time is defined as the interval between stimulus onset and the participant's button press. The primary outcome measure is the median reaction time calculated across all valid trials within the task.
Vigilance Lapses
Time Frame: Immediately after the procedure
Vigilance lapses will be assessed using a laboratory-based auditory Psychomotor Vigilance Task (aPVT). Participants will respond to auditory stimuli presented via headphones by pressing a key on a keyboard while viewing a fixation display on a monitor. Omission lapses are defined as trials in which no response is registered within the predefined response window following stimulus onset. The outcome measure is the total number of omission lapses across all valid trials.
Long Reation Time Lapses
Time Frame: Immediately after the procedure
Long reaction time lapses will be assessed using a laboratory-based auditory Psychomotor Vigilance Task (aPVT). Participants respond to auditory stimuli by pressing a key on a keyboard. A long reaction time lapse is defined as any trial in which the reaction time exceeds two times the participant's median reaction time for the task. The outcome measure is the total number of long reaction time lapses across all valid trials.
Anticipatory Responses
Time Frame: Immediately after the procedure
Anticipatory responses will be assessed using a laboratory-based auditory Psychomotor Vigilance Task (aPVT). Participants respond to auditory stimuli by pressing a key on a keyboard. An anticipatory response is defined as a button press occurring before stimulus onset, reflecting premature responding. The outcome measure is the total number of anticipatory responses across all valid trials.
Sustained Attention Variability
Time Frame: Immediately after the procedure
Additional reaction time metrics will be derived from the auditory Psychomotor Vigilance Task (aPVT) to characterize response speed distribution and variability. These metrics include reaction time slope across trials, fastest reaction times (e.g., fastest 10%), slowest reaction times (e.g., slowest 10%), and measures of intra-individual reaction time variability. These outcomes provide complementary information on vigilance stability and performance dynamics beyond central tendency measures.
Associative Learning
Time Frame: Immediately after the procedure
Associative Learning is assessed using a computerized variant of the Digital Symbol Substitution Task (DSST). Associative learning is quantifies by the proportion of correct responses across all trials (accuracy).
Processing Speed
Time Frame: Immediately after the procedure
Processing speed is assessed using a computerized variant of the Digital Symbol Substitution Task (DSST). Processing speed is quantifies by the median reaction time taken across trials to judge if the presented combination is correct or incorrect (button press).
Visual Attention Allocation
Time Frame: Immediately after the procedure
Visual attention allocation during the Digit Symbol Substitution Task (DSST) is assessed using eye tracking. Predefined areas of interest (AOIs), including the reference symbol-number set and the presented test pair, will be used to quantify visual strategy. Outcome measures include the number and sequence of visits to each AOI and the proportion of viewing time spent within each AOI across valid trials.
Eye-Movement Behavior
Time Frame: Immediately after the procedure
Eye-movement behavior during the Digital Symbol Substitution Task (DSST) will be assessed using video-based eye tracking. Metrics will characterize visual exploration and oculomotor behavior and include fixation count and duration, saccade frequency and amplitude, and related summary measures averaged across valid trials.
Selective Attention
Time Frame: Immediately after the procedure
Cognitive processing of infrequent auditory stimuli will be assessed using a laboratory-based auditory oddball task. Auditory tones will be presented via headphones while participants view a fixation display on a monitor and respond using a keyboard. Accuracy is defined as the proportion of correctly detected target tones and correctly ignored non-target tones across all trials.
Auditory Discrimination Performance
Time Frame: Immediately after the procedure
Auditory discrimination performance will be assessed using an auditory oddball task. Sensitivity (d') will be calculated based on hit rates (correct detection of target tones) and false alarm rates (responses to non-target tones). Higher d' values indicate greater ability to discriminate infrequent target tones from frequent non-target tones.
Task-Evoked Pupillary Responses
Time Frame: Immediately after the procedure
Task-evoked pupillary responses will be recorded during performance of the auditory Psychomotor Vigilance Task (aPVT) as well as the oddball task using eye-tracking pupillometry. Changes in pupil size measured during task performance, following stimulus presentation and participant response, will be quantified as indicators of cognitive effort and alertness. Outcome measures include pupil dilation amplitude and response dynamics averaged across valid trials.
Pupillary Responses to Shapes
Time Frame: Immediately after the procedure
Changes in pupil size during image presentation will be quantified as physiological correlates of the perceived features of a shape, independent of physical luminance.
Objective sleepiness
Time Frame: Immediately after the procedure
Objective sleepiness will be assessed using a computerized time estimation task. Participants will be instructed to press a button when they believe that a specified time interval has elapsed (10 seconds, 20 seconds, 30 seconds, 60 seconds, and 120 seconds). Time estimation accuracy will be quantified as the difference between the estimated and actual interval duration across trials.
Risk Taking Behavior
Time Frame: Immediately after the procedure
Risk-taking behavior is assessed using the Balloon Analogue Risk Task (BART), a computerized decision-making task. Adjusted average pumps is calculated as the mean number of pumps on balloons that do not burst (i.e., excluding balloons that explode), providing an index of risk-taking propensity.
Subjective Sleepiness, Mood, and Wellbeing
Time Frame: Immediately after the procedure
Change in subjective sleepiness, mood, and wellbeing assessed using the Stanford Sleepiness Scale (SSS) and Likert scales before each light exposure (baseline), immediately after exposure (acute effect), and following cognitive assessments (sustained effect).
Sleep Quantity
Time Frame: 8-16 days in between the visits
Night time sleep quantity (minutes) will be collected through actigraphy watches given to participants.
Sleep Efficiency
Time Frame: 8-16 days between the visits
Night time sleep efficiency (%) calculated as the amount of time spent asleep (in minutes) by the total amount of time in bed (in minutes) will be measured using actigraphy watches given to participants.
Phasic Pupil Constriction to Blue Light
Time Frame: Baseline (Visit 1)
Phasic pupil constriction to blue light will be quantified using chromatic pupillometry with a handheld chromatic pupillometer. Phasic pupil constriction to blue light refers to the rapid, transient decrease in pupil diameter that occurs immediately after the onset of a blue light stimulus. It is calculated as a percentage change from baseline.
Phasic Pupil Constriction to Red Light
Time Frame: Baseline (Visit 1)
Phasic pupil constriction to red light will be quantified using chromatic pupillometry with a handheld chromatic pupillometer. Phasic pupil constriction to red light refers to the rapid, transient decrease in pupil diameter that occurs immediately after the onset of a red light stimulus. It is calculated as a percentage change from baseline.
Maximum Pupil Constriction to Blue Light
Time Frame: Baseline (Visit 1)
Maximum pupil constriction to blue light will be quantified using chromatic pupillometry with a handheld chromatic pupillometer. Maximum pupil constriction to blue light refers to the greatest reduction in pupil diameter observed following the onset of a blue light stimulus. It is calculated as a percentage change from baseline.
Maximum Pupil Constriction to Red Light
Time Frame: Baseline (Visit 1)
Maximum pupil constriction to red light will be quantified using chromatic pupillometry with a handheld chromatic pupillometer. Maximum pupil constriction to red light refers to the greatest reduction in pupil diameter observed following the onset of a red light stimulus. It is calculated as a percentage change from baseline.
Pupil Constriction Latency to Blue Light
Time Frame: Baseline (Visit 1)
Maximum pupil constriction to blue light will be quantified using chromatic pupillometry with a handheld chromatic pupillometer. Constriction latency is defined as the time from blue light onset to the first detectable decrease in pupil diameter relative to baseline. It is measured in seconds.
Pupil Constriction Latency to Red Light
Time Frame: Baseline (Visit 1)
Maximum pupil constriction to red light will be quantified using chromatic pupillometry with a handheld chromatic pupillometer. Constriction latency is defined as the time from red light onset to the first detectable decrease in pupil diameter relative to baseline. It is measured in seconds.
Post-illumination Pupillary Responses
Time Frame: Baseline (Visit 1)
Post-illumination pupillary responses (PIPR) will be quantified using chromatic pupillometry with a handheld chromatic pupillometer. PIPR refers to the sustained pupil constriction that persists after the termination of a light stimulus.
Secondary Outcomes
- Anticipatory Pupil Size(Immediately after the procedure)
- Hit Rate(Immediately after the procedure)
- False Alarm Rate(Immediately after the procedure)
- Correct Rejection Rate(Immediately after the procedure)
- Miss Rate(Immediately after the procedure)
- Visual Behavior During Time Estimation Task(Immediately after the procedure)
- Secondary Risk Taking Metrcis(Immediately after the procedure)
- Reward Seeking Behavior(Immediately after the procedure)
- Risk/Reward-Related Visual Behavior(Immediately after the procedure)
- Daytime average light levels (lux)(8-16 days between the visits)
- Daytime average melanopic lux(8-16 days between the visits)
- Time spent outdoors(8-16 days between the visits)
- Nighttime average melanopic lux(8-16 days between the visits)
- Time spent over 250 or other melanopic EDI threshold during daytime(8-16 days between visits)
- Time spent under 10 or other melanopic EDI threshold during nighttime(8-16 days between visits)
Investigators
Raymond P. Najjar, PhD
Assistant Professor
National University of Singapore