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Katrina Norfleet
Posted: 5/4/2016

 Emerging trends and hot topics: Presented Wednesday, May 4 at the ARVO Annual Meeting

Seattle, Wash. ― In their own words, First Authors at the 2016 Annual Meeting of the Association for Research in Vision and Ophthalmology explain their findings. Their abstracts were designated as some of the newest and most innovative research presented on Wednesday, May 4.

Anatomy and Pathology/Oncology

#430 - 4741. Characterization of a novel retinaldehyde dehydrogenase selective inhibitor.  Angelica Harper. May 4, 11am.

Nearsightedness or myopia, the blurring of objects viewed at a distance, is one of the most common ocular disorders in the world.  Severe myopia, known as high myopia, can result in the development of other ocular diseases, such as glaucoma and can, ultimately, result in blindness.  Despite much research, the specific molecules that result in the development of nearsightedness are still poorly understood; thus, while glasses and contacts can correct blurred vision, no therapies have been developed to stop myopia progression.  Retinoic acid, a derivative of vitamin A, has been identified as a signaling molecule that can mediate myopia development.  Our lab has recently identified the key protein responsible for producing retinoic acid during myopia, RALDH2.  We have developed a compound that inhibits RALDH2 and the production of retinoic acid.  We hope to use this compound to better understand the role retinoic acid plays in the development of nearsightedness so that one day, therapies will be available to stop the progression of myopia when it starts.   

#430 - 4738. Alpha2-Adrenergic Agonists Inhibit Form-Deprivation Myopia (FDM) in the Chick. Brittany Carr. Toward (improved) myopia treatments. May 4, 11am.

Myopia (near-sightedness) is a growing global concern. Over the past few decades, there has been a significant increase in the number of children who require eyeglasses to see clearly at a distance1; thus, there is an urgent need for a solution that not only slows myopia progression, but prevents it. There are no universally approved therapies for myopia prevention, but drugs such as atropine and pirenzepine have shown promise as therapies2,3. They are thought to work by blocking muscarinic acetylcholine (mAChR) receptors; however, this mechanism of action has never been proven.

We tested the hypothesis that mAChRs are not the primary growth-regulating receptors, by investigating the effects of non-mAChR drugs on experimentally-induced animal myopia. We found that drugs that activate the alpha-adrenergic system – clonidine and guanfacine – prevent myopia similarly to atropine, even though they are not known or expected to interact with mAChRs.  Our data do not prove that either of these receptor classes is, or is not, responsible for regulating eye growth; instead, they provide evidence that receptors other than mAChRs might be important eye growth-regulators. Most importantly, these results could lead to the development of therapies which would prevent myopia, without the most commonly reported side-effects of atropine-treatment.

#478 - 5526 - D0016. Effects of Long-wavelength Lighting Combined with Positive Lens Wear on Emmetropization in Young Rhesus Monkeys. Li-Fang Hung. May 4, 3:45pm.

Biochemistry/Molecular Biology

#437 - 4791 - A0007. MicroRNAs: regulators in the development of refractive errors and myopia. Milly Tedja. May 4, 11am.

We know that genes play a role in the development of nearsightedness, together with other factors like time spent outdoors during childhood and level of education. Recently, we have found over 140 places in our DNA which are associated with the development of nearsightedness; they can alter the activation or function of genes. We want to know if some of these places in the DNA are coded for microRNAs (miRNAs) or places where a miRNA can bind on.

MicroRNAs can inhibit the formation of proteins; protein formation normally occurs when particular genes are read out in the DNA. One miRNA can affect multiple genes, and can thus inhibit the formation of multiple proteins. MiRNAs are only able to inhibit protein formation by interacting with the binding sites of their target gene(s) on a molecular level. Here, we found 77 of these binding sites for miRNAs in the >140 places associated with the development of nearsightedness. These miRNA binding sites could play a role in a future therapy for nearsightedness. 

#437 - 4799 - A0015. Comprehensive Genomewide Functional Characterization of Etiopathogenesis of Primary Congenital Glaucoma for Identification of Potential Therapeutic Agents and Targets. Muneeb Faiq. May 4, 11am.

Primary Congenital Glaucoma is one of the leading causes of irreversible childhood blindness worldwide accounting for almost 50% to 70% of all cases of childhood glaucoma. There is a considerable number of children in the world who are born with this disease or develop the ailment in the first year of their life. Many genes have already been implicated to be causative but there is, as of now, no cure available. Once the vision loss ensues, these children have to live all their lives as blind individuals. In the light of the present research study, effective treatment to this malady may be a reality in near future. Muneeb Faiq et al. working at All India Institute of Medical Sciences, New Delhi carried out a series of experiments including, but not limited to, genome wide data analysis, interactome identifications, reactome analyses, cloning and functional characterization of the genes and pathways involved in this disease. They have identified important set of genes that can be targeted for effective therapy. More importantly, they have also found the potential compounds that can be used as drugs to treat these children suffering from this ailment of irreversible vision loss. According to these researchers, the so identified 28 different compounds in various combinations and permutations can be a great hope for an effective therapy and a way to rescue vision in these children.


#412 - 4370 - A0173. Influence of light emitting diode-derived blue light overexposure on mouse ocular surface    Hyo Seok Lee. May 4, 8:30am.

The effect of blue light derived from a light emitting diode (LED) on the retina has been extensively investigated; however, not much is known about the effect of overexposure to such light on the ocular surface. Therefore, we aimed to study the effect of overexposure to LED-derived blue light on ocular surface health in a mouse model by measuring various clinical and experimental parameters.

Experimental animals were separated into four groups: in three groups, the mice were exposed to red, green, or blue visible light, with equivalent energy; one group was not exposed to this light emission and was used as a control. Blue light overexposure for 10 days resulted in a significant increase in inflammatory cells and molecules, and ocular surface cell death, compared with the other types of visible light. In addition, rapid tear film breakup and ocular surface epithelial damage were detected after overexposure to blue light.

Through this experiment, we found that overexposure to blue light may induce harmful changes in the tear film and ocular surface.

#440 - 4899 - A0115. Role of epithelial cell-derived exosomes in corneal wound healing. Jennifer Tran. May 4, 11am.

What happens when your eye gets scratched or injured? The first thing that gets affected is the cornea, a clear tissue that resides at the front of the eye. It plays a large role in our vision by focusing light onto our retina and by protecting our eyes from threats such as foreign objects and germs. The cornea has multiple layers of cells that work together to recover after injury. When it heals well, your vision remains clear. When it doesn’t, a scar can form and obscure your field of view. We don’t know exactly how different cells coordinate healing through cell-to-cell communication because it can be a very complex process. One possible answer lies in exosomes, which are extremely small packets of cellular material that are released and received between cells as a form of communication. They hold pieces of information that have been found to affect the actions of the cells that receive them. What if we could figure out a way to engineer corneal exosomes so they promote scar-free healing? We have started by studying how they normally work in the cornea. Next, we hope to determine how certain cell types transmit important information during healing. #440 - 4902 - A0118. Effects of mechanical stimulation of fluid shear stress in cultured corneal epithelial cells. Tsugiaki Utsunomiya. May 4, 11am.

Effects of mechanical stimulation of fluid shear stress in cultured corneal epithelial cells

Purpose: Blinking plays a vital role to spread tear fluid over ocular surface, meanwhile blinking can generate mechanical stimulation on the corneal epithelial cells. Mechanical stimulation by blinking is thought as stimulation of fluid flow on the corneal epithelial cells because blinking results in movement of the tear fluid covering the corneal surface. The mechanical stress can vary in ocular-surface disorders such as dry eye and cause corneal epithelial damage. The stress also can affect some signaling cascades, but the details of that activity have not been determined. We investigated the effects of fluid flow on cultured human corneal epithelial cells.

Methods: Human corneal epithelial cells was exposed to fluid flow. We evaluated the expressions of transforming growth factor beta (TGF-β) and matrix metalloproteinase (MMP).

Results: The expression of TGFβs and MMPs in cells exposed to fluid flow increased significantly compared to that in static cells.

Conclusion: Fluid flow affected the signaling cascade including TGFβ and MMP in cultured human corneal epithelial cells. The mechanical stress caused by blinking may involve these signaling cascades, which are related to cellular proliferation, migration, and inflammation.

#471 - 5286 - A0213. Defined Regional Analysis of Mitochondrial Activity in the Endothelium of Donor Corneal Tissue. Benjamin Aldrich. May 4, 3:45pm

A healthy cornea, the clear tissue at the front of the eye, is required for proper vision. Approximately 47,000 Americans each year receive donated corneal tissue for sight restoring transplant surgery. The inner cell layer that lines the cornea – the endothelium – is essential to maintaining the success and survival of a cornea transplant. Currently, there is no objective measure to identify which tissues may be at risk for reduced survival following transplantation.

Our group has developed a method to measure corneal endothelial cell mitochondrial respiration, which reflects a cornea’s capacity to maintain clarity. In this project, we performed detailed measurements of mitochondrial respiration in samples of corneal endothelial tissue from one central and four peripheral locations (superior, inferior, nasal, and temporal). We found that corneal endothelial cells in the temporal region are metabolically different than samples from the other four regions.

This research will dovetail with clinical efforts to improve cornea transplant outcomes, and eye banking efforts to improve the quality of the donor supply. We anticipate that our results will provide a foundation for future investigations aimed at detecting damage at the molecular level, and developing strategies to preserve the health of the cornea before and after transplant surgery.

Eye Movements/Strabismus/Amblyopia/Neuro-Ophthalmology

#419 - 4582 - B0368. Effect of Explorative Saccadic Training (EST) to scanning eye movements in children with Homonymous Hemianopia (HH). Iliya Ivanov. May 4, 8:30am.

Homonymous hemianopia (HH) is a severe condition, where half of the visual field is not functioning. It is caused by pre- and perinatal brain damage, trauma or tumor. Children with HH are not aware of the world on their non-functioning side and therefore facing navigation and communication problems. They are at high risk for all kinds of accidents, as they recognize objects on their blind side too late. They feel insecure in unfamiliar environments and are restricted in their social interaction. As HH recovers only rarely, the aim is to enhance patients' condition by training them to better use their remaining vision. We developed a simple computer-based game to improve their vision by learning to direct their intact vision to the non-seeing half-field. We measured eye movements of children during performing search tasks on a computer screen, e.g. to find the zebra stripes in an image, before and after training. We found that eye-movements were more effective after training indicated by faster target detection. Our findings indicate that specific computer game training is effective and helps children learn how to better use their residual vision. Most of them improved their social activities and some even started to play bowling.

#418 - 4563 - B0349. Smartphone-based Head-mounted Binocular High-Speed Pupillometer. Wolfgang Fink. May 4, 8:30am

The iris of an eye is what gives an eye its color. The purpose of the pupil, the central opening within the iris, is to regulate how much light enters the eye and to protect the eye from too much light exposure: pupils get smaller in bright day light, and larger during dark settings. More importantly, from a medical point of view, the pupil is the gateway to the brain. Monitoring both pupils of a person, merely with a flashlight (so-called “swinging-flashlight” test), especially as part of an emergency examination after an accident, will tell the first responder or emergency doctor whether the person has suffered critical brain damage in a completely non-invasive way. Moreover, monitoring the pupillary movement in darkness has the potential to reveal whether a person is suffering from sleep disorders (so-called sleep apnea). We have developed a portable device that snaps onto a smartphone to monitor and record the pupillary movement both after light exposure (i.e., “swinging-flashlight” test), or during darkness without the subject having to be in a darkened room. This pupillometer, paired with a powerful data analysis system, provides a non-invasive means to assess people’s brain functions and to screen for sleep disorders.

#446 - 5088 - B0318. Oxygen, Atmospheric Pressure and Non-arteritic Ischemic Optic Neuropathy. Anna Ter-Zakarian. May 4, 11:00am.

Travel by air subjects the human body to a variety of stresses. Key among these is the stress of decreased oxygen content at high altitudes. Commercial aircraft are pressurized to below 8,000 feet to help maintain a comfortable environment, however at 8000 ft. the oxygen content is only 76% of sea level. While most individuals can tolerate these changes, patients with underlying ischemic diseases, including non-arteritic optic neuropathy (NAION), may be at increased risk for a recurrent ischemic event. Our study measured commercial aircraft pressurization at cruising altitude for 35 planes, including 12 narrow-body (single-isle) planes and 23 wide-body (twin-isle) aircraft. Our study found that larger aircraft maintained a higher internal barometric pressure than the smaller aircraft, with average cruising altitude pressures of 620 mmHg. and 594 mmHg., respectively. The flight duration and aircraft type may be a consideration when choosing to travel by air for individuals with an underlying predisposition for NAION.


#402 - 4281. Effect of Yoga and Meditation Based Intervention on Intraocular Pressure, Quality of Life, Oxidative Stress and Gene Expression Pattern in Primary Open Angle Glaucoma: A Randomized. Controlled Trial. Tanuj Dada. May 4, 830am.

Glaucoma is the leading cause of irreversible vision loss and affects nearly 70 million globally. Patients with glaucoma often suffer from anxiety and depression and have a poor quality of life. There is no cure for this disease and the only proven therapy currently is to lower the eye pressure or intraocular pressure by using eye drops or surgery. This therapy itself may be associated with serious side effects which further compromise the quality of life of the patient.

YOGA (Ünion” of the mind-body-spirit) is an ancient science developed in India over 5000 years ago to cultivate holistic health (physical, mental, emotional & social) and happiness, along with greater sense of self-awareness and higher consciousness. YOGA involves physical postures & movement along with breath awareness and breathing exercises, relaxation and concentration, self-inquiry and meditation.

A group of vision scientists from the All India Institute of Medical Sciences, New Delhi lead by Prof. Tanuj Dada have found that Meditation performed along with breathing exercises may be effective in ameliorating the dismal condition of glaucoma patients. In a comprehensively designed clinical trial it was found that a three weeks course of YOGA therapy (30 minute breathing and relaxation exercises and 30 minutes meditation) lowered the eye pressure by 20%-30% (the major risk factor for glaucoma), improved quality of life and reduced biochemical markers for stress and inflammation in the body. There was an increase in endorphins and other neurotrophic factors which promote general well being and eye health. The study also reported positive changes in gene expression pattern as revealed by the whole genome microarray studies pointing to the significant holistic benefits of YOGA therapy.

The present study underscores the importance of YOGA therapy (esp. breathing exercises and meditation which can even be done very elderly/bed ridden patients) as an effective adjunct to complement standard medical therapy in glaucoma.

#426 - 4710. Optical Coherence Tomography (OCT) Demonstrates Deformation of Optic Cup and Peripapillary Tissues by Horizontal Duction. Melinda Chang. May 4, 11am.

One of the commonest causes of blindness is glaucoma, an optic nerve disorder.  Although elevated intraocular pressure (fluid pressure inside the eye) has been believed the main glaucoma cause, most patients have normal pressure. Many relentlessly lose sight despite treatment reducing pressure below normal. Causes of glaucoma in patients without high intraocular pressure (normal tension glaucoma) remain mysterious. Recent magnetic resonance imaging (MRI) studies found that eye rotation towards the nose (adduction) can mechanically strain the junction between optic nerve and eye wall (sclera).  This occurs because the optic nerve is too short to allow free eye adduction, so the nerve tethers the eyeball. The present study used noninvasive imaging by optical coherence tomography (OCT) to evaluate structure of the optic nerve and surrounding (peripapillary) tissues during eye movements.  As predicted, OCT showed significant optic nerve deformation and displacement during adduction, depending upon amount of eye rotation. Tissues at the junction of the optic nerve and eye wall were also distorted during adduction, suggesting that repetitive strain to the optic nerve during eye movement might be a major cause of glaucoma unrelated to pressure inside the eye. This finding may enable new diagnostic and treatment strategies for glaucoma.

#460 - 5195. Quantitative Speckle-variance Optical Coherence Tomography of Radial Periparpillary Capillaries in Glaucoma. Zaid Mammo. May 4, 3:45pm

#482 - 5634 - D0217. Genetic and pharmacological inhibition of ER stress-induced ATF4/CHOP prodeath pathway prevents myocilin misfolding and rescues mouse models of glaucoma. Ramesh Kasetti. May 4, 3:45pm.

Physiology/Pharmacology #475 - 5387 - B0127. Reliability of kinetic visual field testing in children with mutation-proven retinal dystrophies: implications in therapeutic clinical trials. Vaidehi Dedania. May 4, 3:45pm.

We evaluated the extent of vision in children with inherited retinal degenerations. Our findings suggest that visual field testing may not serve as an accurate assessment of changes in visual function in children under the age of 12. This research will help us better monitor and understand disease activity in children, especially in therapeutic trials, such as gene therapy.


#414 - 4441 - A0346. Topical dorzolamide-timolol with intravitreal anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Jayanth Sridhar. May 4, 8:30am

Many patients with the 'wet' form of macular degeneration require repeated drug injections to the eye. Despite this treatment swelling in the back part of the eye, the retina, can persist and affect vision. This study demonstrated that addition of a topical glaucoma medication drop to be used by the patient at home may reduce swelling in the retina in patients receiving consistent drug injections in the office

#427 - 4718. The novel bispecific monoclonal anti-VEGF/anti-Ang2 antibody RG7716 shows promise in wet age-related macular degeneration patients with suboptimal response to prior anti-VEGF monotherapy. Usha Chakravarthy. May 4, 11am.

The Roche / Genentech group is developing RG7716 as a potential new treatment for serious eye diseases such as wet age related macular degeneration (wAMD) and diabetic macular edema (DME). This is the first dual action molecule to target both VEGF (vascular endothelial growth factor) and Ang2 (angiopoietin 2).  Targeting both factors may be more effective than current treatments that target VEGF alone.

In a global Phase 1 study, clinicians evaluated patients with chronic disease and suboptimal response to current anti-VEGF treatments and switched them to RG7716.  This resulted in encouraging signs of visual improvement with no serious safety events observed during treatment or upon follow up.

Roche / Genentech are currently undertaking 2 larger, multi-centered studies to evaluate the potential benefits of this novel treatment.  The wAMD study (AVENUE), as well as the DME study (BOULEVARD), are currently recruiting patients to participate in understanding the possibilities for the next generation of treatment options for these vision-threatening diseases.

For more information, please see (Avenue: NCT02484690, Boulevard: NCT02699450)                                                                                                                       

#428 - 4726. Photo-mediated ultrasound therapy as a novel method to selectively treat small blood vessels. Yannis Paulus. May 4, 11am.

New and abnormal blood vessels in the eye play a pivotal role in the leading causes of blindness, including macular degeneration and diabetes. Current treatment involves laser therapy which closes the leaky blood vessels but damages the surrounding area. We devise a novel treatment using a combination of laser light and sound to selectively treat blood vessels without damaging surrounding tissue. We investigate this treatment on blood vessels and demonstrate its selectivity.

#474 - 5371 - B0042. Bone morphogenetic protein 4 inhibits transforming growth factor-β1-induced epithelial-mesenchymal transition in retinal pigment epithelial cells. Haipei Yao. May 4, 3:45pm

Proliferative vitreoretinopathy (PVR) is a serious blind-causing eye disease. The hallmark of PVR is the formation of fibrotic membranes that can lead to contraction and then destroy the tissue structure of the fundus. Retinal pigment epithelium (RPE) is major cell type present in these fibrotic membranes. So far, surgery is the first choice treatments for PVR. Despite great progress in surgical techniques, recurrent can lead to irreversible damage of visual acuity. Therefore, it is important to develop new molecular targeting strategy for PVR prevention and treatment. In our recent study, we found that bone morphogenetic protein-4 (BMP4), a kind of growth factor, could inhibit RPE cells mediated formation and contraction of fibrotic membranes during the pathological processed of PVR. Thus, BMP4 might be used as a novel therapeutic approach for the prevention or treatment of PVR in the future.

#474 - 5380 - B0051. A protein kinase C theta mutation causes early-onset exudative retinal detachment. Xiaojie Ji. May 4, 3:45pm.

Retinal detachment (RD) is defined as the separation of the retina, the light-sensing tissue layer lining the back of the eye necessary for proper vision, from its supportive structures. RD precipitates a medical emergency that can lead to partial vision loss or even blindness without prompt treatment. RD is associated with many different eye diseases and the lifetime risk of RD is very high in populations with severe near-sightedness (1 in 20) and cataract surgery (5-16 in 1000). The mechanisms underlying this disease remain largely unknown. To understand the mechanisms, an animal model that reproducibly develops RD would be extremely useful. We recently identified and investigated a novel mouse model of early-onset RD that is caused by a gene mutation leading to defects of the supportive monolayer of cells in the back of the eye called the retinal pigment epithelium. In all mice carrying two copies of the disrupted gene, RD is observed by 6 weeks of age and subsequently the cells in the retina degenerate. Careful study of this model is likely to reveal the mechanisms and pathways underlying RD.

#462 - 5203. One-Year Outcomes of 49-Channel Suprachoroidal-Transretinal Stimulation (STS) Retinal Prosthesis in Patients with Advanced Retinitis Pigmentosa. Takashi Fujikado. May 4, 3:45pm. A one-year study of a Japanese-style retinal prosthesis in which the stimulating electrode array was implanted in the sclera showed that it was feasible and safe for patients with advanced retinitis pigmentosa (RP). The ability to navigate and walk was better, and table tasks were performed quicker and more accurately when the electrode array was implanted closer to the posterior pole of the eye. The time to reach an object was shorter with the prosthesis in RP eyes with some residual natural vision, indicating that the retinal prosthesis is helpful for RP patients with some residual natural vision.

#462 - 5207. Successful delivery of rAAV8.CNGA3 in a patient with CNGA3 achromatopsia. M Dominik Fischer. May 4, 3:45pm.

A joint group of scientists and clinicians from Tubingen, Munich and New York (RD-CURE consortium, funded by the Tistou and Charlotte Kerstan Foundation) have developed a potential treatment for patients lacking color vision from birth. A genetic defect blocks an important class of light sensing cells inside the eye to transmit light detection and color coding onwards to the brain, leading to color blindness, poor vision and glare. This genetic defect is targeted with the use of nano-sized protein shells, which shuttle a healthy copy of the affected gene into these cells. In mice with defects in the same gene, this worked fairly well and studies in primates showed no safety concern even when applying a much higher dose of the gene therapeutic agent. Since November 11th last year, all three patients from the first (low dose) group have received the treatment without complications. Preliminary data demonstrate safety of application paving the way for the next group receiving an intermediate dose of the therapeutic agent. There are three dosing groups planned and each patient is closely followed-up for one year. Enrolment of the last patient is scheduled towards the end of 2016.

#473 - 5351 - B0022. Caspase-9 inhibition by Pen1-XBir3 abrogates retinal edema. Maria Avrutsky. May 4, 3:45pm.

Retinal Cell Biology

#444 - 5002 - B020. Interaction of Metabolome and Microbiome Contributes to Dietary Glycemia-induced Age-related Macular Degeneration in Aged C57BL/6J Mice. Sheldon Rowan. May 4, 11am.

Consuming diets that are high in refined carbohydrates and sugar (high glycemic index) is a significant risk factor for developing age-related macular degeneration (AMD), the leading cause of blindness in developed nations. We tested this epidemiologic association in a mouse model and found that mice who consumed high glycemia diets developed eye disease resembling AMD.  This was prevented by dietary change to a low glycemia diet, even late in life. To find out how the diet contributed to eye disease, we measured 358 different known metabolites from blood and urine (metabolome) and 592 different gut bacterial members from feces (microbiome). Our analyses identified biomolecules and bacteria that associated with eye disease.  We found that certain bacteria, whose abundance was affected by the kind of diet, impacted the production of metabolites that contribute to eye disease. We also determined how high glycemia diet-associated modifications to proteins and lipids form toxic species that accumulate directly in the eye and contribute to eye disease. Therefore, we can use this animal model and our results to understand disease pathways, to identify new disease biomarkers, and to conceive novel opportunities to delay or prevent AMD.

Visual Neuroscience

#423 - 4665 - D003. Modulating ipRGC Input to Improve Sleep and Regulate Circadian Rhythm. Lisa Ostrin. May 4, 8:30am.

Artificial light from televisions, computers, iphones and overhead lighting may be disrupting sleep by stimulating a recently discovered cell type in the eye, the intrinsically photosensitive retinal ganglion cell (ipRGC). The ipRGCs are a type of photoreceptor that control pupil size and circadian rhythm. They are most sensitive to blue light, which is prevalent in electronic devices. We found that wearing blue blocking glasses for 3 hours before bedtime (for 2 weeks) significantly increased nighttime melatonin levels, increased sleep duration by 30 minutes, and improved daytime alertness. In addition, morning ipRGC function was increased following glasses wear. Results suggest that minimizing artificial light following sunset may help in regulating circadian rhythms and increasing sleep quality by reducing nighttime input to the ipRGCs.