Efficacy of biologically-directed daylight therapy on sleep and circadian rhythm in Parkinson's disease: a randomised, double-blind, parallel-group, active-controlled, phase 2 clinical trial.

Background: New non-pharmacological treatments for improving non-motor symptoms in Parkinson's disease (PD) are urgently needed. Previous light therapies for modifying sleep behaviour lacked standardised protocols and were not personalised for an individual patient chronotype. We aimed to assess the efficacy of a biologically-directed light therapy in PD that targets retinal inputs to the circadian system on sleep, as well as other non-motor and motor functions. Methods: In this randomised, double-blind, parallel-group, active-controlled trial at the Queensland University of Technology, Australia, participants with mild to moderate PD were computer randomised (1:1) to receive one of two light therapies that had the same photometric luminance and visual appearance to allow blinding of investigators and participants to the intervention. One of these biologically-directed lights matched natural daylight (Day Mel), which is known to stimulate melanopsin cells. The light therapy of the other treatment arm of the study, specifically supplemented the stimulation of retinal melanopsin cells (Enhanced Mel), targeting deficits to the circadian system. Both lights were administered 30 min per day over 4-weeks and personalised to an individual patient's chronotype, while monitoring environmental light exposure with actigraphy. Co-primary endpoints were a change from baseline in mean sleep macrostructure (polysomnography, PSG) and an endocrine biomarker of circadian phase (dim light melatonin secretion onset, DLMO) at weeks 4 and 6. Participants data were analysed using an intention to treat principle. All endpoints were evaluated by applying a mixed model analysis. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12621000077864. Findings: Between February 4, 2021 and August 8, 2022, 144 participants with PD were consecutively screened, 60 enrolled and randomly assigned to a light intervention. There was no significant difference in co-primary outcomes between randomised groups overall or at any individual timepoint during follow-up. The mean (95% CI) for PSG, N3% was 24.15 (19.82-28.48) for Day Mel (n = 23) and 19.34 (15.20-23.47) for the Enhanced Mel group (n = 25) in week 4 (p = 0.12); and 21.13 (16.99-25.28) for Day Mel (n = 26) and 18.48 (14.34-22.62) for the Enhanced Mel group (n = 25) in week 6, (p = 0.37). The mean (95% CI) DLMO (decimal time) was 19.82 (19.20-20.44) for Day Mel (n = 22) and 19.44 (18.85-20.04) for the Enhanced Mel group (n = 24) in week 4 (p = 0.38); and 19.90 (19.27-20.53) for Day Mel (n = 23) and 19.04 (18.44-19.64) for the Enhanced Mel group (n = 25) in week 6 (p = 0.05). However, both the controlled daylight (Day Mel) and the enhanced melanopsin (Enhanced Mel) interventions demonstrated significant improvement in primary PSG sleep macrostructure. The restorative deep sleep phase (PSG, N3) significantly improved at week 6 in both groups [model-based mean difference to baseline (95% CI): -3.87 (-6.91 to -0.83), p = 0.04]. There was a phase-advance in DLMO in both groups which did not reach statistical significance between groups at any time-point. There were no safety concerns or severe adverse events related to the intervention. Interpretation: Both the controlled daylight and melanopsin booster light showed efficacy in improving measures of restorative deep sleep in people with mild to moderate PD. That there was no significant difference between the two intervention groups may be due to the early disease stage. The findings suggest that controlled indoor daylight that is personalised to the individuals' chronotype could be effective for improving sleep in early to moderate PD, and further studies evaluating controlled daylight interventions are now required utilising this standardised approach, including in advanced PD. Funding: The Michael J Fox Foundation for Parkinson's Research, Shake IT Up Australia, National Health and Medical Research Council, and Australian Research Council.

The role of melanopsin photoreception on visual attention linked pupil responses.

A decision during a visual task is marked by a task-evoked pupil dilation (TEPD) that is linked to the global cortical arousal state. Melanopsin expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) form the afferent pathway for this pupil response. Melanopsin activation also influences mood and arousal and increases activity in decision-making brain areas that receive direct ipRGC projections. Here, an optical photostimulation method controlled the excitations of all five photoreceptor classes in the human eye to isolate melanopsin-mediated photoreception. We hypothesised that the TEPD can be driven by directing active visual covert attention through the ipRGC pathway. When observers are completely certain of the stimulus presence, melanopsin-directed stimulation produces a TEPD of similar amplitude to a cone-directed stimulation, with their combination producing larger amplitudes. This dilation is satisfactorily modelled by linear addition with a higher melanopsin weighting in ipRGCs. Visual reaction times were longest in response to melanopsin-directed lights. Next, we asked whether the afferent photoreceptor input and decision certainty, controlled by priming the observer's a priori expectation, interact to drive the TEPD. Signal detection analysis showed that by fixing the predecision certainty (bias), the phasic arousal and TEPD amplitude vary with observer criterion (c') and sensitivity (d') but not with preferential activation of melanopsin. The signature feature of the melanopsin response during attention was a biphasic TEPD. We conclude that active covert attention can be modulated by visual information mediated via ipRGCs, but that phasic arousal responses marked using the TEPD are not increased by higher levels of melanopsin activation.

Student-led screening of school children for refractive error correction.

PURPOSE: Detection and correction of uncorrected refractive errors among 12 million children is an overwhelming task for the 500 currently available eye-care professionals in Nepal. A mid-term review of VISION 2020 goals in Nepal has recommended utilizing alternative human resources that could screen children for visual impairment. This study was conducted to assess the validity of vision screening of school children by trained high school students when compared to optometrist testing as the gold standard. METHODS: A total of 150 students were selected, based on their merit by the headmasters of 25 schools in Nepal and trained for two days by optometrists to screen visual acuity of their peers. Visual acuity ≤ 6/12 in either eye was referred as abnormal vision. A random sample of 1,209 screened students was selected and their visual acuity was reassessed by optometrists under the same settings adopted by trained students. Using optometrist scores as the gold standard, screening results of trained students were analyzed for validity. RESULTS: Mean age of screened students was 12.2 ± 3.03 years (range: 4-19 years) and 57.4% of them were female. Sensitivity of vision screening test done by trained students was 81.7% and the specificity was 97.6%. A positive predictive value of the test was 77.3% and negative predictive value was 98.2%. CONCLUSIONS: With high sensitivity and specificity values, vision screening done by trained students is effective for screening visual acuity of school children. Countries with limited eye-care professionals and infrastructures can effectively train and utilize students for timely detection of poor vision among children.

Ocular morbidity among porters at high altitudes.

INTRODUCTION: High altitude, often characterized by settings over 2400m, can be detrimental to the human body and pose a significant risk to ocular health. Reports concerning various ocular morbidities occurring as a consequence of high altitude are limited in the current literature. OBJECTIVES: This study was aimed at evaluating the ocular health of porters working at high altitudesof Himalayas in Nepal. MATERIALS AND METHODS: A mobile eye clinic was set up in Ghat and patient data were collected from its out- patient unit by a team of seven optometrists which was run for five days. Ghat is a small village in north-eastern Nepal, located at 2860 m altitude. Travellers walking through the trekking route were invited to get their eyes checked at the clinic. Comprehensive ocular examinations were performed, including visual acuities, objective and subjective refraction, anterior and posterior segment evaluations, and intraocular pressure measurements; blood pressure and blood glucose levels were also measured as required. Ocular therapeutics, prescription glasses, sunglasses and ocular health referrals were provided free of cost as necessary. A total of 1890 people visited the eye clinic, among which 57.4% (n=1084) were porters. CONCLUSIONS: Almost half of the porters had an ocular morbidity. Correctable refractive error was most prevalent, with other ocular health-related complications, including dry eye disease, infectious disorders, glaucoma and cataract. Proper provision of regular and effective eye care services should be made more available for those residing at these high altitudes in Nepal.

Causes of blindness and visual impairment among students in integrated schools for the blind in Nepal.

PURPOSE: To identify the causes of blindness and visual impairment among students in integrated schools for the blind in Nepal. METHODS: A total of 778 students from all 67 integrated schools for the blind in Nepal were examined using the World Health Organization/Prevention of Blindness Eye Examination Record for Children with Blindness and Low Vision during the study period of 3 years. RESULTS: Among 831 students enrolled in the schools, 778 (93.6%) participated in the study. Mean age of students examined was 13.7 years, and the male to female ratio was 1.4:1. Among the students examined, 85.9% were blind, 10% had severe visual impairment and 4.1% were visually impaired. The cornea (22.8%) was the most common anatomical site of visual impairment, its most frequent cause being vitamin A deficiency, followed by the retina (18.4%) and lens (17.6%). Hereditary and childhood factors were responsible for visual loss in 27.9% and 22.0% of students, respectively. Etiology could not be determined in 46% of cases. Overall, 40.9% of students had avoidable causes of visual loss. Vision could be improved to a level better than 6/60 in 3.6% of students refracted. CONCLUSION: More than one third of students were visually impaired for potentially avoidable reasons, indicating lack of eye health awareness and eye care services in the community. The cause of visual impairment remained unknown in a large number of students, which indicates the need for introduction of modern diagnostic tools.

Optical needs of students with low vision in integrated schools of Nepal.

PURPOSE: To identify the optical needs of students with low vision studying in the integrated schools for the blind in Nepal. METHODS: A total of 779 blind and vision-impaired students studying in 67 integrated schools for the blind across Nepal were examined using the World Health Organization/Prevention of Blindness Eye Examination Record for Children with Blindness and Low Vision. Glasses and low-vision devices were provided to the students with low vision who showed improvement in visual acuity up to a level that was considered sufficient for classroom learning. Follow-up on the use and maintenance of device provided was done after a year. RESULTS: Almost 78% of students studying in the integrated schools for the blind were not actually blind; they had low vision. Five students were found to be wrongly enrolled. Avoidable causes of blindness were responsible for 41% of all blindness. Among 224 students who had visual acuity 1/60 or better, distance vision could be improved in 18.7% whereas near vision could be improved in 41.1% students. Optical intervention provided improved vision in 48.2% of students who were learning braille. Only 34.8% students were found to be using the devices regularly after assessment 1 year later; the most common causes for nonuse were damage or misplacement of the device. CONCLUSIONS: A high proportion of students with low vision in integrated schools could benefit from optical intervention. A system of comprehensive eye examination at the time of school enrollment would allow students with low vision to use their available vision to the fullest, encourage print reading over braille, ensure appropriate placement, and promote timely adoption and proper usage of optical device.