Week in Review: Number 17

CYP39A1 Gene Confers Cholesterol Homeostasis Against Exfoliation Syndrome & Glaucoma
Singapore scientists conducted a genome-wide association study of exfoliation syndrome involving more than 20,000 participants from 14 countries across Asia, Europe, and Africa. Characterized by abnormal proteins in the anterior chamber of the eye, exfoliation syndrome is a major cause of glaucoma as these proteins accumulate in the trabecular meshwork and obstruct the normal flow of aqueous, leading to elevated intraocular pressure and subsequent optic nerve damage, i.e., glaucoma. According to the researchers, although exfoliation syndrome is the most common cause of glaucoma, little is known about the origins of the exfoliative material and the pathology of the disease. The research team identified genetic mutations in the CYP39A1 gene as being strongly associated with increased risk of exfoliation syndrome. People with exfoliation syndrome are twice as likely to carry damaging mutations to this gene. The CYP39A1 gene in particular encodes for the processing of cholesterol, which in turn is a major component of cell membranes. The researchers found that the epithelial cells of the ciliary body, responsible for producing aqueous humor as well as provide a barrier between the blood and the aqueous, were most affected by mutations in the CYP39A1 gene. When the blood-aqueous barrier is compromised, proteins from the blood can leak into the anterior chamber and accumulate, notably, in the trabecular meshwork. The presence of normal CYP39A1 thus has a significant stabilizing effect on cholesterol homeostasis, resulting in an intact blood-aqueous barrier that prevents leakage of exfoliative material into the anterior chamber.

Instrument for Detection of Carotenoids in the Eye
Originating as technology to measure how octopuses see polarized light, researchers in the U.K. then adapted the technology to develop a device that measures levels of carotenoids in human eyes. When tested on humans, the researchers found that people are able to see polarization patterns when the light was only 24% polarized. Humans can see polarized light due to birefringence of macular pigments such as the xanthophylls/carotenoids lutein, zeaxanthin, and meso-zeaxanthin in the radially arranged retinal nerve fiber layer of Henle. Birefringence is the refracting of light into two components, perpendicular to one another, and each having a different refractive index. The retardation of polarized light due to birefringence as a result of the thickness of the RNFL can be detected by ophthalmic instruments such as scanning laser polarimeters (GDx). Macular pigments play an antioxidant role in protecting the retina from ultraviolet light, which helps to prevent or delay retinal diseases such as age-related macular degeneration. Carotenoids are derived from food, thus the detection of the amount of macular pigment in the retina can help clinicians provide recommendations about consumption of foods containing carotenoids or wearing sun protection when outdoors. The lead researcher thinks that while there are existing methods to measure a person's amount of macular pigments, those techniques are time-consuming or expensive. His start-up company seeks to develop a device that enables rapid screening as part of regular eye exams.

Artificial Intelligence with Adaptive Optics Aids in the Detection and Treatment of Glaucoma
Biomedical engineers recently made progress in ophthalmic imaging through combining deep-learning artificial intelligence with optical coherence tomography (OCT) and adaptive optics to enable better diagnosis and monitoring of neuron-affecting diseases such as glaucoma. Traditional OCT is able to scan the thickness of retinal cell layers, but cannot visualize individual retinal ganglion cells. The new technique improves upon imaging by tracking changes in the number and shape of the eye's retinal ganglion cells. The axons of retinal ganglion cells form the optic nerve that relays visual information to the brain; it is also these axons that are damaged in neurodegenerative diseases such as glaucoma. With greater sensitivity of detecting changes to individual neurons conferred by adaptive optics, AO-OCT imaging can detect disease at earlier stages and monitor disease progression more rapidly. However, the higher resolution also generates a large amount of data that causes an image analysis bottleneck, which the research team solved with the addition of deep-learning algorithms, dubbed WeakGCSeg. As one of the researchers states, “Our experimental results showed that WeakGCSeg is actually superior to human experts, and it’s superior to other state-of-the-art networks that can process volumetric biomedical images.” A potential application of this technology is for use in clinical trials. Because the technique can detect disease at earlier stages and at shorter time spans, it can more precisely and more quickly monitor differences in a progressive disease that otherwise would take the death of hundreds or thousands of cells and months or years to manifest. The research team plans to expand their technique to the visualization of other cell types, such as photoreceptors, and other neurodegenerative diseases.

Interview with Two LCA Patients Treated with CRISPR
NPR  interviewed two patients with Leber congenital amaurosis (LCA) who participated in a landmark study using CRISPR gene editing. It was the first study to deliver CRISPR for gene editing inside the human body. Specifically, the two patients, Carlene Knight and Michael Kalberer, are affected by a version of LCA caused by a mutation in the CEP290 gene, affecting the photoreceptors of the eye. Both are legally blind with very limited tunnel vision centrally; Knight additionally has nystagmus. LCA was a suitable disease to test in vivo applications of CRISPR gene editing for two reasons: The retina is too fragile a tissue to remove, edit in vitro and then return to the eye. Furthermore, the healthy version of the gene is too large to use with viral vectors in traditional gene therapy. Instead, viral vectors, injected subretinally, were engineered to carry genetic instructions to manufacture the CRISPR gene-editor inside the retina. As a point of scientific interest, the news article also mentions safety precautions such as using the lowest number of viruses, beginning the clinical trials with older patients whose vision was already extensively damaged, and treating only one eye in each patient. At the same time, there was much consideration for the possibility that these patients would lose the little bit of vision they had remaining. The researchers have treated a total of four patients, and hope to add more with a wider age range. At this point in time, the effect of the treatment is yet to be seen. However, as Kalberer says, "But to even have the possibility — it's a gift."

Joint Synchronization of Vision and Hearing in the Brain
Physics tells us that light and sound travel at different speeds. Yet, visual and sound input from the same source arriving at our sense organs are then perceived as synchronous by the brain, even though they are processed at different speeds. The brain accounts for this difference through tricks such as temporal recalibration, altering our sense of time to synchronize the joint perception of sound and vision. This recalibration depends on brain signals constantly adapting to the environment to sample, order, and associate sensory inputs. Researchers in Canada used magnetoencephalography (MEG) to image the brain waves of volunteers asked to view short flashes of light paired with sounds with a variety of delays. The participants were then asked to report whether they thought both happened at the same time. The scientists found that the volunteers' perception of simultaneity in an audio-visual pair of stimuli was strongly affected by their perception of simultaneity in the preceding pair. For example, an audio-visual stimulus pair that was perceived as asynchronous might be followed by perceiving the next audio-visual stimulus pair as synchronous, even when it's not. The MEG signals revealed that such active temporal recalibration is the result of a unique interaction between fast and slow brain waves in auditory and visual regions of the brain, with the faster oscillations riding on top of slower fluctuations to create discrete and ordered time slots to register the order of sensory inputs. The relative delay between neural auditory and visual time slots, in turn, illustrates a dynamic process that constantly adapts to each participant’s recent exposure to audiovisual perception, resulting in judgments of perceived simultaneity. The neurophysiological mechanisms of temporal recalibration may be relevant in disorders that affect audio and other sensory perception, such as in autism and schizophrenia.

In Other News
(1) Improved color vision with psychedelic drug use
(2) Mantis shrimp vision inspires design of surgical camera
(3) Fossilized eye bones indicate this tiny dinosaur hunted at night (Related)

Joint Synchronization of Vision and Hearing in the Brain

Article: How Our Brains Sync Hearing With Vision
Source: McGill University (Canada), via Technology Networks
Published: May 11, 2021

Fast and slow brain waves in auditory and visual brain regions
enable temporal recalibration of audiovisual stimuli

Physics tells us that light and sound travel at different speeds. Yet, visual and sound input from the same source arriving at our sense organs are then perceived as synchronous by the brain, even though they are processed at different speeds. The brain accounts for this difference through tricks such as temporal recalibration, altering our sense of time to synchronize the joint perception of sound and vision. This recalibration depends on brain signals constantly adapting to the environment to sample, order, and associate sensory inputs. Researchers in Canada used magnetoencephalography (MEG) to image the brain waves of volunteers asked to view short flashes of light paired with sounds with a variety of delays. The participants were then asked to report whether they thought both happened at the same time. The scientists found that the volunteers' perception of simultaneity in an audio-visual pair of stimuli was strongly affected by their perception of simultaneity in the preceding pair. For example, an audio-visual stimulus pair that was perceived as asynchronous might be followed by perceiving the next audio-visual stimulus pair as synchronous, even when it's not. The MEG signals revealed that such active temporal recalibration is the result of a unique interaction between fast and slow brain waves in auditory and visual regions of the brain, with the faster oscillations riding on top of slower fluctuations to create discrete and ordered time slots to register the order of sensory inputs. The relative delay between neural auditory and visual time slots, in turn, illustrates a dynamic process that constantly adapts to each participant’s recent exposure to audiovisual perception, ultimately resulting in judgments of perceived simultaneity of audiovisual input. The neurophysiological mechanisms of temporal recalibration may be relevant in disorders that affect audio and other sensory perception, such as in autism and schizophrenia.

My rating of this study: ⭐⭐

Lennert T, Samiee S and Baillet S. "Coupled oscillations enable rapid temporal recalibration to audiovisual asynchrony." Communications Biology.  4(1):1-12. 11 May 2021. https://doi.org/10.1038/s42003-021-02087-0

Interview with Two LCA Patients Treated with CRISPR

Article: Blind Patients Hope Landmark Gene-Editing Experiment Will Restore Their Vision
Source: NPR, via Genetic Literacy Project
Published: May 10, 2021
Article: Gene editing clinical trial participant dreams of a future with sight
Source: Oregon Health & Science University
Published: May 10, 2021 (added August 6, 2021)

Kalberer visits with Dr. Jason Comander at Mass Eye and Ear in Boston

NPR  interviewed two patients with Leber congenital amaurosis (LCA) who participated in a landmark study using CRISPR gene editing. It was the first study to deliver CRISPR for gene editing inside the human body. Specifically, the two patients, Carlene Knight and Michael Kalberer, are affected by a version of LCA caused by a mutation in the CEP290 gene, affecting the photoreceptors of the eye. Both are legally blind with very limited tunnel vision centrally; Knight additionally has nystagmus. LCA was a suitable disease to test in vivo applications of CRISPR gene editing for two reasons: The retina is too fragile a tissue to remove, edit in vitro and then return to the eye. Furthermore, the healthy version of the gene is too large to use with viral vectors in traditional gene therapy. Instead, viral vectors, injected subretinally, were engineered to carry genetic instructions to manufacture the CRISPR gene-editor inside the retina. As a point of scientific interest, the news article also mentions safety precautions such as using the lowest number of viruses, beginning the clinical trials with older patients whose vision was already extensively damaged, and treating only one eye in each patient. At the same time, there was much consideration for the possibility that these patients would lose the little bit of vision they had remaining. The researchers have treated a total of four patients, and hope to add more with a wider age range. At this point in time, the effect of the treatment is yet to be seen. However, as Kalberer says, "But to even have the possibility — it's a gift."

My rating of this article: ⭐⭐

Artificial Intelligence with Adaptive Optics Aids in the Detection and Treatment of Glaucoma, Eye Disease

Article: AI Spots Individual Neurons in the Eye Better than Human Experts
Source: Duke University, via ScienceDaily  and NEI
Published: May 4, 2021

Biomedical engineers recently made progress in ophthalmic imaging through combining deep-learning artificial intelligence with optical coherence tomography (OCT) and adaptive optics to enable better diagnosis and monitoring of neuron-affecting diseases such as glaucoma. Traditional OCT is able to scan the thickness of retinal cell layers, but cannot visualize individual retinal ganglion cells. The new technique improves upon imaging by tracking changes in the number and shape of the eye's retinal ganglion cells. The axons of retinal ganglion cells form the optic nerve that relays visual information to the brain; it is also these axons that are damaged in neurodegenerative diseases such as glaucoma. With greater sensitivity of detecting changes to individual neurons conferred by adaptive optics, AO-OCT imaging can detect disease at earlier stages and monitor disease progression more rapidly. However, the higher resolution also generates a large amount of data that causes an image analysis bottleneck, which the research team solved with the addition of deep-learning algorithms, dubbed WeakGCSeg. As one of the researchers states, “Our experimental results showed that WeakGCSeg is actually superior to human experts, and it’s superior to other state-of-the-art networks that can process volumetric biomedical images.” A potential application of this technology is for use in clinical trials. Because the technique can detect disease at earlier stages and at shorter time spans, it can more precisely and more quickly monitor differences in a progressive disease that otherwise would take the death of hundreds or thousands of cells and months or years to manifest. The research team plans to expand their technique to the visualization of other cell types, such as photoreceptors, and other neurodegenerative diseases.

My rating of this study: ⭐⭐⭐

Soltanian-Zadeh S, Kurokawa K, Liu Z, et al. "Weakly supervised individual ganglion cell segmentation from adaptive optics OCT images for glaucomatous damage assessment." Optica.  8(5):642-651. 2021. https://doi.org/10.1364/OPTICA.418274

Instrument for Detection of Carotenoids in the Eye

Article: Insights from colour-blind octopus help fight human sight loss
Source: University of Bristol (U.K.), via ScienceDaily
Published: May 4, 2021

Haidinger's brush entoptic phenomenon

Originating as technology to measure how octopuses see polarized light, researchers in the U.K. then adapted the technology to develop a device that measures levels of carotenoids in human eyes. When tested on humans, the researchers found that people are able to see polarization patterns when the light was only 24% polarized. Humans can see polarized light due to birefringence of macular pigments such as the xanthophylls/carotenoids lutein, zeaxanthin, and meso-zeaxanthin in the radially arranged retinal nerve fiber layer of Henle. Birefringence is the refracting of light into two components, perpendicular to one another, and each having a different refractive index. The retardation of polarized light due to birefringence as a result of the thickness of the RNFL can be detected by ophthalmic instruments such as scanning laser polarimeters (GDx). Macular pigments play an antioxidant role in protecting the retina from ultraviolet light, which helps to prevent or delay retinal diseases such as age-related macular degeneration. Carotenoids are derived from food, thus the detection of the amount of macular pigment in the retina can help clinicians provide recommendations about consumption of foods containing carotenoids or wearing sun protection when outdoors. The lead researcher thinks that while there are existing methods to measure a person's amount of macular pigments, those techniques are time-consuming or expensive. His start-up company seeks to develop a device that enables rapid screening as part of regular eye exams.

Personal commentary: Macular pigments show up as the entoptic phenomenon known as Haidenger's brush, wherein polarized light is absorbed in one direction and transmitted in the perpendicular direction. In white light, both the blue and the yellow brushes are seen. The presence of Haidinger's brushes can be detected by instruments such as a Macula Integrity Tester to locate the fovea and assess (eccentric) fixation in clinical applications of vision therapy.

My rating of this study: ⭐⭐⭐

Temple SE, How MJ, Powell SB, et al. "Thresholds of polarization vision in octopuses." Journal of Experimental Biology.  224(7):jeb240812. 15 April 2021. https://doi.org/10.1242/jeb.240812

CYP39A1 Gene Confers Cholesterol Homeostasis Against Exfoliation Syndrome & Glaucoma

Article: Scientists find gene mutation linked to exfoliation syndrome, most common cause of glaucoma
Source: Agency for Science, Technology and Research (Singapore), via ScienceDaily
Published: May 4, 2021

Lens with exfoliative material deposits

Singapore scientists conducted a genome-wide association study of exfoliation syndrome involving more than 20,000 participants from 14 countries across Asia, Europe, and Africa. Characterized by abnormal proteins in the anterior chamber of the eye, exfoliation syndrome is a major cause of glaucoma as these proteins accumulate in the trabecular meshwork and obstruct the normal flow of aqueous, leading to elevated intraocular pressure and subsequent optic nerve damage, i.e., glaucoma. According to the researchers, although exfoliation syndrome is the most common cause of glaucoma, little is known about the origins of the exfoliative material and the pathology of the disease. The research team identified genetic mutations in the CYP39A1 gene as being strongly associated with increased risk of exfoliation syndrome. People with exfoliation syndrome are twice as likely to carry damaging mutations to this gene. The CYP39A1 gene in particular encodes for the processing of cholesterol, which in turn is a major component of cell membranes. The researchers found that the epithelial cells of the ciliary body, responsible for producing aqueous humor as well as provide a barrier between the blood and the aqueous, were most affected by mutations in the CYP39A1 gene. When the blood-aqueous barrier is compromised, proteins from the blood can leak into the anterior chamber and accumulate, notably, in the trabecular meshwork. The presence of normal CYP39A1 thus has a significant stabilizing effect on cholesterol homeostasis, resulting in an intact blood-aqueous barrier that prevents leakage of exfoliative material into the anterior chamber.

My rating of this study: ⭐⭐⭐⭐

Li Z, Wang Z, Lee MC, et al. "Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye." JAMA.  325(8):753-764. 23 February 2021. https://doi.org/10.1001/jama.2021.0507

Week in Review: Number 16

In the News: Special Edition 1
Thank you to Optometric Physician  for this piece. While I am neutral to both sides of politics, I very much enjoyed watching the congressman speak. I imagine that for his doctors, this congressman and former Navy Seal must be a great pleasure to work with as he takes steps toward a complete recovery.

Excerpt:
The other day I stumbled upon a YouTube video of Congressman Dan Crenshaw by chance. Crenshaw, for those who don’t know, is a former Navy Seal who lost an eye to an IED while serving in Afghanistan. What I didn’t know was that his other eye was severely damaged and recently required surgery for retinal detachment repair.

Regardless of your politics (which I don’t want to hear about), as a human being, fellow American and as an OD, I think you will be touched by Crenshaw’s humility and inner strength as he describes his ordeal and the impact it’s had on his life. Particularly poignant was his description of his vision both before the detachment when he was aphakic and now, as he waits for a gas bubble to dissipate before seeing the success or failure of the surgery. I sensed only determination and grace in his words and calm demeanor, but I was overcome with the magnitude of what he faced. I was also thankful for his service and sacrifice for our country.

Hearing Crenshaw’s words made me think about what we do every day and how important vision is, especially when one faces the prospect of life without sight. I was moved by the interview and urge you to take a moment to listen to it. For Rep. Crenshaw, I will be praying for a speedy and complete recovery. I would be obliged if you would as well.

Cone Photoreceptor Transplantation in Mice
Researchers in the U.K. conducted a proof-of-concept study that restored some degree of vision in mouse eyes transplanted with cone photoreceptors derived from human embryonic stem cells. Previous studies have transplanted stem cells that replaced the retina's pigmented epithelium, or converted mouse skin cells directly into rod photoreceptors. The present work is the first study to transplant retinal cells using using cone photoreceptors, which the authors emphasized for their importance in central and color vision. The researchers developed to variants of human cones: a normal type derived from human embryonic stem cells and a control derived from the peripheral blood of a 40-year-old person with achromatopsia. The functional cone photoreceptors were injected into the retinas of 32 mouse eyes, and the aberrant cones were injected into the retinas of 23 mouse eyes. As an additional study design quality measure, the mice were bred to have advanced eye disease with complete nonfunctional cones to control for the possibility of residual function from existing cones, rather than the transplanted cones. Both types of cones attached to the mice's retinas. Testing with microelectroretinogram, however, showed that only the functional human cones responded to light. Furthermore, only the mice that received functional cones exhibited behavioral responses to light, such as retreating to a dark room in the presence of light, a natural response for these nocturnal animals. The researchers next plan to improve the manufacturing capacity of cone photoreceptors, and they hope to start clinical trials several years in the future.

Digital Eye Strain During a Pandemic
This article in the Washington Post  reports on recent worrisome trends of eye strain and eye damage due to increased computer screen time during the COVID-19 pandemic. The effect is most prevalent in young children, who are susceptible to developing progressive myopia that puts them at increased risk of sight-threatening conditions such as retinal tears and macular degeneration later in life. In addition to extensive near work in a virtual learning environment, aspects such as viewing angle and screen glare/reflections force our eyes to work harder than they usually do when reading a printed page, a professor of neural science and psychology at NYU explains. Computer vision syndrome, also known as digital eye strain, is another contributor to vision problems, including blurred vision and dry eyes. Digital eye strain was also reported to have increased around the globe during the COVID-19 pandemic. The good news is that people can take steps to protect and heal their eyes. Taking frequent breaks from screen use, such as using the 20-20-20 rule of looking at least 20 feet in the distance for 20 seconds every 20 minutes spent on the screen, helps to mitigate eye strain. While taking into consideration precautions of distancing during the ongoing pandemic, the "bright and full-spectral light, rich spatial patterns across a wide range of scales, and sharp images of distant objects" of outdoor environments can help to reduce young children's risk of developing myopia.

Infratemporal Cortex Calibrates for Contrast in the Perception of Novel Visual Information
Visual information starts with the detection of incoming light at the retina's photoreceptors. The complex process is simplified here as then being relayed via the optic nerve to the visual cortex. The present research investigated the role of the intratemporal (IT) cortex in interpreting the complex patterns of visual information, specifically teasing apart the difference between the perception of novel and familiar patterns. According to an earlier theory known as repetition suppression, greater activation of the IT cortex meant that a person was viewing something new, while less activity in the IT cortex indicated familiarity. The researchers, however, note that different images produce different amounts of activity even when they are all novel, possibly influenced by factors such as brightness, contrast, and even memory. They instead propose a new theory called sensory reference suppression that suggests that the brain calibrates for the level of activation expected, correcting for these other factors and leaving behind the signal of familiarity. In particular, to explore the difference between memory and contrast, the researchers presented sequences of grayscale images to two adult rhesus monkeys and recorded the neural activity of their IT cortex, using a unique method that measures the spikes of hundreds of individual neurons. Using mathematical analysis, they found that both familiarity and contrast change the overall firing rate of neurons, and that the brain can tease apart one from the other. The researchers state that understanding how the brain builds memory in the presence of changes in sensory input could have implications for artificial intelligence and memory-impairing disorders such as Alzheimer's.

Naturalistic Driving Among Older Drivers Helps to Eliminate Bias in Traffic Accident Reports
Researchers using data from the Alabama VIP Older Driver Study found that naturalistic driving research confirmed that contrast sensitivity impairment, slowed visual processing speed and deficits in motion perception elevated crash and near-crash risk in older drivers. The study involved a great deal of cooperation from older driver participants, who had devices consisting of five-channel video, accelerometers, and GPS installed on their vehicles with continual recording over a six-month period. As the lead researcher explains, use of in-vehicle instrumentation eliminates biases and incomplete reports due to different perspectives from the drivers, witnesses, and law enforcement. She comments, “Witnesses can have different perspectives, meaning the driver may not feel they were responsible, but other witnesses may disagree. The police officer then has to piece it together and make notations on the accident report as to what they think happened, including whether a driver is at fault. Police officers can also have their own biases. Some may not want to blame an older adult driver, whereas others may hold older adults largely responsible due to stereotyping.” What is especially informative about naturalistic driving research is that it can identify near-crashes. Characterized by the "last-second" evasive maneuver by the driver, near crashes occur more frequently than actual crashes but have similar underlying causes. Furthermore, the study found associations between actual crashes and at-fault and the driver's visual capabilities. Naturalistic driving research can thus aid to provide more objective information for traffic accident reports as well as link at-fault crashes and near crashes with older drivers' vision impairment.

In Other News
(1) A new way of looking at concussions
(2) Christmas tree cataract
(3) Face masks and eye irritation

Naturalistic Driving Research Among Older Drivers Helps to Eliminate Bias in Traffic Accident Reports

Article: New research assesses naturalistic driving techniques to link vision impairment and traffic accidents
Source: University of Alabama at Birmingham, via NEI
Published: April 29, 2021

Researchers using data from the Alabama VIP Older Driver Study found that naturalistic driving research confirmed that contrast sensitivity impairment, slowed visual processing speed and deficits in motion perception elevated crash and near-crash risk in older drivers. The study involved a great deal of cooperation from older driver participants, who had devices consisting of five-channel video, accelerometers, and GPS installed on their vehicles with continual recording over a six-month period. As the lead researcher explains, use of in-vehicle instrumentation eliminates biases and incomplete reports due to different perspectives from the drivers, witnesses, and law enforcement. She comments, “Witnesses can have different perspectives, meaning the driver may not feel they were responsible, but other witnesses may disagree. The police officer then has to piece it together and make notations on the accident report as to what they think happened, including whether a driver is at fault. Police officers can also have their own biases. Some may not want to blame an older adult driver, whereas others may hold older adults largely responsible due to stereotyping.” What is especially informative about naturalistic driving research is that it can identify near-crashes. Characterized by the "last-second" evasive maneuver by the driver, near crashes occur more frequently than actual crashes but have similar underlying causes. Furthermore, the study found associations between actual crashes and at-fault and the driver's visual capabilities. Naturalistic driving research can thus aid to provide more objective information for traffic accident reports as well as link at-fault crashes and near crashes with older drivers' vision impairment.

My rating of this study: ⭐

Swain TA, McGwin G, Wood JM, et al. "Naturalistic Driving Techniques and Association of Visual Risk Factors With At-Fault Crashes and Near Crashes by Older Drivers With Vision Impairment." JAMA Ophthalmology. 139(6):639-645. 29 April 2021. https://doi.org/10.1001/jamaophthalmol.2021.0862

Infratemporal Cortex Calibrates for Contrast in the Perception of Novel Visual Information

Article: A new theory for what’s happening in the brain when something looks familiar
Source: University of Pennsylvania, via ScienceDaily  and NEI
Published: April 27, 2021

Visual information starts with the detection of incoming light at the retina's photoreceptors. The complex process is simplified here as then being relayed via the optic nerve to the visual cortex. The present research investigated the role of the intratemporal (IT) cortex in interpreting the complex patterns of visual information, specifically teasing apart the difference between the perception of novel and familiar patterns. According to an earlier theory known as repetition suppression, greater activation of the IT cortex meant that a person was viewing something new, while less activity in the IT cortex indicated familiarity. The researchers, however, note that different images produce different amounts of activity even when they are all novel, possibly influenced by factors such as brightness, contrast, and even memory. They instead propose a new theory called sensory reference suppression that suggests that the brain calibrates for the level of activation expected, correcting for these other factors and leaving behind the signal of familiarity. In particular, to explore the difference between memory and contrast, the researchers presented sequences of grayscale images to two adult rhesus monkeys and recorded the neural activity of their IT cortex, using a unique method that measures the spikes of hundreds of individual neurons. Using mathematical analysis, they found that both familiarity and contrast change the overall firing rate of neurons, and that the brain can tease apart one from the other. The researchers state that understanding how the brain builds memory in the presence of changes in sensory input could have implications for artificial intelligence and memory-impairing disorders such as Alzheimer's.

My rating of this study: ⭐⭐

Mehrpour V, Meyer T, Simoncelli EP, et al. "Pinpointing the neural signatures of single-exposure visual recognition memory." PNAS.  118(18):e2021660118. 4 May 2021. https://doi.org/10.1073/pnas.2021660118

Digital Eye Strain During a Pandemic

Article: Computer screen time is damaging eyes — especially for children
Source: Washington Post, via AOA
Published: April 25, 2021

This article in the Washington Post  reports on recent worrisome trends of eye strain and eye damage due to increased computer screen time during the COVID-19 pandemic. The effect is most prevalent in young children, who are susceptible to developing progressive myopia that puts them at increased risk of sight-threatening conditions such as retinal tears and macular degeneration later in life. In addition to extensive near work in a virtual learning environment, aspects such as viewing angle and screen glare/reflections force our eyes to work harder than they usually do when reading a printed page, a professor of neural science and psychology at NYU explains. Computer vision syndrome, also known as digital eye strain, is another contributor to vision problems, including blurred vision and dry eyes. Digital eye strain was also reported to have increased around the globe during the COVID-19 pandemic. The good news is that people can take steps to protect and heal their eyes. Taking frequent breaks from screen use, such as using the 20-20-20 rule of looking at least 20 feet in the distance for 20 seconds every 20 minutes spent on the screen, helps to mitigate eye strain. While taking into consideration precautions of distancing during the ongoing pandemic, the "bright and full-spectral light, rich spatial patterns across a wide range of scales, and sharp images of distant objects" of outdoor environments can help to reduce young children's risk of developing myopia.

My rating of this article: ⭐⭐

Cone Photoreceptor Transplantation in Mice

Article: Cones Derived from Human Stem Cells Help Mice See
Source: The Scientist, King's College London
Published: April 23, 2021

Wild-type cones generate widespread mERG
and light-evoked spiking activity

Researchers in the U.K. conducted a proof-of-concept study that restored some degree of vision in mouse eyes transplanted with cone photoreceptors derived from human embryonic stem cells. Previous studies have transplanted stem cells that replaced the retina's pigmented epithelium, or converted mouse skin cells directly into rod photoreceptors. The present work is the first study to transplant retinal cells using using cone photoreceptors, which the authors emphasized for their importance in central and color vision. The researchers developed to variants of human cones: a normal type derived from human embryonic stem cells and a control derived from the peripheral blood of a 40-year-old person with achromatopsia. The functional cone photoreceptors were injected into the retinas of 32 mouse eyes, and the aberrant cones were injected into the retinas of 23 mouse eyes. As an additional study design quality measure, the mice were bred to have advanced eye disease with complete nonfunctional cones to control for the possibility of residual function from existing cones, rather than the transplanted cones. Both types of cones attached to the mice's retinas. Testing with microelectroretinogram, however, showed that only the functional human cones responded to light. Furthermore, only the mice that received functional cones exhibited behavioral responses to light, such as retreating to a dark room in the presence of light, a natural response for these nocturnal animals. The researchers next plan to improve the manufacturing capacity of cone photoreceptors, and they hope to start clinical trials several years in the future.

Personal commentary: While there is no evidence or grounds to support a desire for clinical trials, the investigators' effort demonstrates the strength of their motivation to prevent disease.

My rating of this study: ⭐⭐⭐

Ribeiro J, Procyk CA, West  EL, et al. "Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors." Cell Reports.  35(3):109022. 20 April 2021. https://doi.org/10.1016/j.celrep.2021.109022

In the News: Special Edition 1

Article: Off the Cuff: Sometimes We Forget
Source: Optometric Physician
Published: May 15, 2021

Thank you to Optometric Physician  for this piece. While I am neutral to both sides of politics, I very much enjoyed watching the congressman speak. I imagine that for his doctors, this congressman and former Navy Seal must be a great pleasure to work with as he takes steps toward a complete recovery.

Excerpt:
The other day I stumbled upon a YouTube video of Congressman Dan Crenshaw by chance. Crenshaw, for those who don’t know, is a former Navy Seal who lost an eye to an IED while serving in Afghanistan. What I didn’t know was that his other eye was severely damaged and recently required surgery for retinal detachment repair.

Regardless of your politics (which I don’t want to hear about), as a human being, fellow American and as an OD, I think you will be touched by Crenshaw’s humility and inner strength as he describes his ordeal and the impact it’s had on his life. Particularly poignant was his description of his vision both before the detachment when he was aphakic and now, as he waits for a gas bubble to dissipate before seeing the success or failure of the surgery. I sensed only determination and grace in his words and calm demeanor, but I was overcome with the magnitude of what he faced. I was also thankful for his service and sacrifice for our country.

Hearing Crenshaw’s words made me think about what we do every day and how important vision is, especially when one faces the prospect of life without sight. I was moved by the interview and urge you to take a moment to listen to it. For Rep. Crenshaw, I will be praying for a speedy and complete recovery. I would be obliged if you would as well.

Review of Optology thanks science media and readership and will resume content next week.

Week in Review: Number 15

GUCY2D Gene Therapy for LCA Shows Positive Results
Researchers recently published initial results of a gene therapy for a form of Leber congenital amaurosis (LCA). Specifically, this gene therapy is the first-in-human clinical trial to target the GUCY2D gene in LCA, with initial results pertaining to three adult patients followed at nine months at this point. Normal copies of the GUCY2D gene encode an enzyme in the phototransduction pathway of the retina, allowing for light perception and vision. A lack of this enzyme prevents the recovery of this pathway, necessary for further signaling. Consequently, signals from the photoreceptors become very weak, manifesting as vision loss. However, despite weak signals and dysfunction, the photoreceptors often remain alive and structurally intact, spurring research into therapies via AAV viral vectors (injected subretinally in this case) to deliver functional copies of genes to those photoreceptors. The study reports that the first patient experienced substantial increase in rod sensitivity and improved pupillary response to light. The second patient experienced a smaller but sustained increase in rod sensitivity. And the third patient did not show improved rod sensitivity, although that patient did experience significantly improved visual acuity (a gain of 0.3 logMAR in the treated eye), which the researchers attribute to improved cone sensitivity and function. No toxicity effects were detected. These initial results demonstrate safety and efficacy for improved sensitivity of both rod and cone photoreceptors. The therapeutic dose used for these first three patients was the lowest dose the researchers intend to use in their study, and they hope to see continued safety and even greater efficacy at higher doses.

Vision Loss from Glaucoma in Some, but Not Most, if Untreated or Delayed Treatment
The Ocular Hypertension Treatment Study, a 7-year longitudinal clinical trial, recently published follow-up results 20 years after the initial launch of the trial evaluating the effect of glaucoma eye drops to preserve vision for patients with elevated eye pressure. The study involved 1,600 patients nationally who were at moderate to high risk for glaucoma due to elevated intraocular pressure (IOP). Although treatment was shown to be highly effective, reducing the incidence of glaucoma by 50% to 60% after five to seven years, the study found surprisingly that only 25% of study participants went on to develop vision loss from glaucoma in at least one eye, compared to the prior conventional wisdom that most patients would develop glaucoma if left untreated. This low incidence of vision loss was the case despite 46% of the study participants showing evidence of glaucoma in at least one eye. Furthermore, the risk of delayed treatment was relatively low. Participants who were randomly assigned to the observation group, before being switched to treatment after seven years, had only slightly greater risk of vision loss compared to participants who used eye-pressure-lowering drops from the start of the study. These findings of low incidence of vision loss due to elevated IOP is pertinent in the sense that while eye drops are effective, there can be obstacles due to cost, adverse effects, and adherence. The study also provided information regarding patient demographics. Although one-quarter of the study participants were African-American, a group with a higher incidence of vision loss from glaucoma, the study found that Black individuals had similar outcomes to other racial groups when matched for the same level of risk. The researchers caution that treatment is not a one-size-fits-all approach, and the sample size is small. Nonetheless, studies like these provide a starting point for conversations to arrive at the best approach.

Micromolded Scaffolds for Photoreceptor Transplantation
Scientists and engineers are working to design and fabricate scaffolds to improve photoreceptor transplantation in eyes with retinal diseases. While there are many advances to create photoreceptors from stem cells, the researchers remark that obstacles remain to precisely deliver those photoreceptors to diseased or damaged eyes in ways that would result in forming the appropriate connections so that they can "effectively reconstruct the retina." The research team had previously designed a micro-molded biodegradable polymer scaffolding "patch" with wine-glass-shaped pores to hold the photoreceptors in place. In the current iteration, they designed the shape of the scaffold pores to be more like "ice cube trays," increasing the capacity to hold three times as many cells as well as reducing the amount of biomaterial used. The latter benefit would facilitate faster degradation of the material in the eye. The researchers used poly(glycerol-sebacate), or PGS, a material that is strong, compatible with the retina, and degrades within two months. The process to fabricate scaffolds with microstructures was technically challenging, though the labs discovered that using isopropyl alcohol helped to demount and release the PGS material from the molds cleanly. Using these techniques, they created ice cube tray-shaped scaffolds capable of holding 300,000 photoreceptors in a patch roughly the area of the macula. They next plan to file a patent for the design as well as proceed to testing in large animals. While these designs are early, they provide information for later improvements. As one of the researchers concludes, “We didn’t start out with supercomputers on our wrists and we’re not going to start out by completely erasing blindness in our first attempt. But we’re very excited about taking a significant step in that direction.”

Eye Contact & Attention Influence Perception of Time
Researchers in Switzerland studying the social aspects of eye contact conducted a series of experiments exploring the influence of eye contact on the perception of time, with a focus on exploring connections with emotion and attention. The question they wanted to investigate was whether eye contact with others directly generates an emotional response without passing through attention, or whether eye contact activates attention processing that then generates an emotional response. To differentiate between the two hypotheses, the researchers looked at how either emotion and attention impact our evaluation of time, noting that it has been shown that we overestimate the passage of time (i.e., we perceive that time passes more quickly) when confronted with an unpleasant visual stimulus, such as a large spider. Emotions accelerate our perception of time. Attention, on the other hand, has the opposite and instead slows down our perception of time (i.e., we underestimate the passage of time). Thus, by examining a person's estimation of how long he or she has been looking at an object, we can determine if the eye contact is associated with emotions or with attention.

The experiments involved 22 participants, who observed a series of nearly 300 faces with gazes that either established eye contact (i.e., direct gaze) or did not establish eye contact (i.e., deviated gaze). The participants then subjectively assessed the duration of the social contact. The study found that deviated gazes did not distort the perception of time, whereas gazes where the eyes met, participants underestimated the duration of eye contact. In other words, it is not emotion but attention that distracts our evaluation of time. To further assess this finding, the researchers then carried out the same experiments with other participants using non-social objects that mimicked movements of gaze and with static faces. No distortions in time perception were seen in those situations. Interestingly, however, when the researchers used schematic eyes or stimuli showing parts of eyes without the rest of the face (a similar situation to wearing a mask), both scenarios also making eye movements, the time distortion effect was seen. This finding suggests that not only gaze but also movement elicits the distortion of time perception. The effect was replicated in an online experiment with 100 people. The researchers next plan to study the evolution of this effect at different ages, from childhood to older age. Though these experiments are on the smaller end in terms of sample size, they provide intriguing results to further studies into the connection between eye contact and social cognition, which are clinically relevant to patients suffering from disorders in processing social stimuli. These findings about our preferential processing of eye contact by attention also informs social interactions more broadly. As the lead researcher concludes, “This study gives meaning to the sensation that time stops when we meet another’s gaze.”

Highlights of the NEI's AGI Functional Imaging Consortium
The article summarized here is itself a kind of "Week in Review" highlighting updates to five projects from the National Eye Institute's AGI functional imaging consortium. The highlights include projects in (1) noninvasive methods to record nerve cell firing, (2) retinal camera technologies that compensate for eye movements, (3) two-photon excitation microscopy combined with adaptive optics to noninvasively and dynamically observe the integration of transplanted retinal cells, (4) two-photon excitation microscopy to noninvasively visualize vitamin A metabolic defects in the retina, and (5) diffusion basis spectrum imaging to noninvasively detect and quantify axonal injury and optic nerve damage. These five projects represent examples of advances in functional noninvasive imaging technologies to aid in the diagnosis and treatment of degenerative eye diseases and provide a foundation for enrolling patients in clinical trials for regenerative therapies.

In Other News
(1) In the News: Edition 5
(2) In the News: Supplemental 1
(3) A PhD student's perspective about social media

NEI's AGI Functional Imaging Consortium Highlights

Article: Audacious projects develop imaging technology to aid eye tissue regeneration
Source: National Eye Institute
Published: April 21, 2021

The article summarized here is itself a kind of "Week in Review" highlighting updates to five projects from the National Eye Institute's AGI functional imaging consortium. The highlights include projects in (1) noninvasive methods to record nerve cell firing, (2) retinal camera technologies that compensate for eye movements, (3) two-photon excitation microscopy combined with adaptive optics to noninvasively and dynamically observe the integration of transplanted retinal cells, (4) two-photon excitation microscopy to noninvasively visualize vitamin A metabolic defects in the retina, and (5) diffusion basis spectrum imaging to noninvasively detect and quantify axonal injury and optic nerve damage. These five projects represent examples of advances in functional noninvasive imaging technologies to aid in the diagnosis and treatment of degenerative eye diseases and provide a foundation for enrolling patients in clinical trials for regenerative therapies.

Micromolded Scaffolds for Photoreceptor Transplant

Article: Micro-molded ‘ice cube tray’ scaffold is next step in returning sight to injured retinas
Source: University of Wisconsin-Madison, via NEI
Published: April 21, 2021

Photoreceptors in the ice cube tray-shaped scaffold

Scientists and engineers are working to design and fabricate scaffolds to improve photoreceptor transplantation in eyes with retinal diseases. While there are many advances to create photoreceptors from stem cells, the researchers remark that obstacles remain to precisely deliver those photoreceptors to diseased or damaged eyes in ways that would result in forming the appropriate connections so that they can "effectively reconstruct the retina." The research team had previously designed a micro-molded biodegradable polymer scaffolding "patch" with wine-glass-shaped pores to hold the photoreceptors in place. In the current iteration, they designed the shape of the scaffold pores to be more like "ice cube trays," increasing the capacity to hold three times as many cells as well as reducing the amount of biomaterial used. The latter benefit would facilitate faster degradation of the material in the eye. The researchers used poly(glycerol-sebacate), or PGS, a material that is strong, compatible with the retina, and degrades within two months. The process to fabricate scaffolds with microstructures was technically challenging, though the labs discovered that using isopropyl alcohol helped to demount and release the PGS material from the molds cleanly. Using these techniques, they created ice cube tray-shaped scaffolds capable of holding 300,000 photoreceptors in a patch roughly the area of the macula. They next plan to file a patent for the design as well as proceed to testing in large animals. While these designs are early, they provide information for later improvements. As one of the researchers concludes, “We didn’t start out with supercomputers on our wrists and we’re not going to start out by completely erasing blindness in our first attempt. But we’re very excited about taking a significant step in that direction.”

My rating of this study: ⭐⭐⭐

Lee IK, Ludwig AL, Phillips MJ, et al. "Ultrathin micromolded 3D scaffolds for high-density photoreceptor layer reconstruction." Science Advances.  7(17):eabf0344. 21 April 2021. https://doi.org/10.1126/sciadv.abf0344

Eye Contact & Attention Influence Perception of Time

Article: Our attention is captured by eye-glance
Source: University of Geneva (Switzerland), via Technology Networks
Published: April 20, 2021

Researchers in Switzerland studying the social aspects of eye contact conducted a series of experiments exploring the influence of eye contact on the perception of time, with a focus on exploring connections with emotion and attention. The question they wanted to investigate was whether eye contact with others directly generates an emotional response without passing through attention, or whether eye contact activates attention processing that then generates an emotional response. To differentiate between the two hypotheses, the researchers looked at how either emotion and attention impact our evaluation of time, noting that it has been shown that we overestimate the passage of time (i.e., we perceive that time passes more quickly) when confronted with an unpleasant visual stimulus, such as a large spider. Emotions accelerate our perception of time. Attention, on the other hand, has the opposite and instead slows down our perception of time (i.e., we underestimate the passage of time). Thus, by examining a person's estimation of how long he or she has been looking at an object, we can determine if the eye contact is associated with emotions or with attention.

The experiments involved 22 participants, who observed a series of nearly 300 faces with gazes that either established eye contact (i.e., direct gaze) or did not establish eye contact (i.e., deviated gaze). The participants then subjectively assessed the duration of the social contact. The study found that deviated gazes did not distort the perception of time, whereas gazes where the eyes met, participants underestimated the duration of eye contact. In other words, it is not emotion but attention that distracts our evaluation of time. To further assess this finding, the researchers then carried out the same experiments with other participants using non-social objects that mimicked movements of gaze and with static faces. No distortions in time perception were seen in those situations. Interestingly, however, when the researchers used schematic eyes or stimuli showing parts of eyes without the rest of the face (a similar situation to wearing a mask), both scenarios also making eye movements, the time distortion effect was seen. This finding suggests that not only gaze but also movement elicits the distortion of time perception. The effect was replicated in an online experiment with 100 people. The researchers next plan to study the evolution of this effect at different ages, from childhood to older age. Though these experiments are on the smaller end in terms of sample size, they provide intriguing results to further studies into the connection between eye contact and social cognition, which are clinically relevant to patients suffering from disorders in processing social stimuli. These findings about our preferential processing of eye contact by attention also informs social interactions more broadly. As the lead researcher concludes, “This study gives meaning to the sensation that time stops when we meet another’s gaze.”

My rating of this study: ⭐🌸

Burra N, Kerzel D. "Meeting another's gaze shortens subjective time by capturing attention." Cognition. Published online 19 April 2021. https://doi.org/10.1016/j.cognition.2021.104734

GUCY2D Gene Therapy for LCA Shows Positive Results

Article: Gene Therapy Shows Promise in Initial Trial for Patients with Childhood Blindness
Source: Penn Medicine News, via Science Daily  and Technology Networks
Published: April 15, 2021

Structural differences in a normal retina
and in retinas with GUCY2D mutation

Researchers recently published initial results of a gene therapy for a form of Leber congenital amaurosis (LCA). Specifically, this gene therapy is the first-in-human clinical trial to target the GUCY2D gene in LCA, with initial results pertaining to three adult patients followed at nine months at this point. Normal copies of the GUCY2D gene encode an enzyme in the phototransduction pathway of the retina, allowing for light perception and vision. A lack of this enzyme prevents the recovery of this pathway, necessary for further signaling. Consequently, signals from the photoreceptors become very weak, manifesting as vision loss. However, despite weak signals and dysfunction, the photoreceptors often remain alive and structurally intact, spurring research into therapies via AAV viral vectors (injected subretinally in this case) to deliver functional copies of genes to those photoreceptors. The study reports that the first patient experienced substantial increase in rod sensitivity and improved pupillary response to light. The second patient experienced a smaller but sustained increase in rod sensitivity. And the third patient did not show improved rod sensitivity, although that patient did experience significantly improved visual acuity (a gain of 0.3 logMAR in the treated eye), which the researchers attribute to improved cone sensitivity and function. No toxicity effects were detected. These initial results demonstrate safety and efficacy for improved sensitivity of both rod and cone photoreceptors. The therapeutic dose used for these first three patients was the lowest dose the researchers intend to use in their study, and they hope to see continued safety and even greater efficacy at higher doses.

My rating of this study: ⭐⭐

Jacobson SG, Cideciyan AV, Ho AC, et al. "Safety and improved efficacy signals following gene therapy in childhood blindness caused by GUCY2D mutations." iScience. 10 April 2021. https://doi.org/10.1016/j.isci.2021.102409

Vision Loss from Glaucoma in Some, but Not Most, if Untreated or Delayed Treatment

Article: Treatment not always needed to prevent vision loss in patients with elevated eye pressure
Source: Washington University School of Medicine in St. Louis, via ScienceDaily  and NEI
Published: April 15, 2021

The Ocular Hypertension Treatment Study, a 7-year longitudinal clinical trial, recently published follow-up results 20 years after the initial launch of the trial evaluating the effect of glaucoma eye drops to preserve vision for patients with elevated eye pressure. The study involved 1,600 patients nationally who were at moderate to high risk for glaucoma due to elevated intraocular pressure (IOP). Although treatment was shown to be highly effective, reducing the incidence of glaucoma by 50% to 60% after five to seven years, the study found surprisingly that only 25% of study participants went on to develop vision loss from glaucoma in at least one eye, compared to the prior conventional wisdom that most patients would develop glaucoma if left untreated. This low incidence of vision loss was the case despite 46% of the study participants showing evidence of glaucoma in at least one eye. Furthermore, the risk of delayed treatment was relatively low. Participants who were randomly assigned to the observation group, before being switched to treatment after seven years, had only slightly greater risk of vision loss compared to participants who used eye-pressure-lowering drops from the start of the study. These findings of low incidence of vision loss due to elevated IOP is pertinent in the sense that while eye drops are effective, there can be obstacles due to cost, adverse effects, and adherence. The study also provided information regarding patient demographics. Although one-quarter of the study participants were African-American, a group with a higher incidence of vision loss from glaucoma, the study found that Black individuals had similar outcomes to other racial groups when matched for the same level of risk. The researchers caution that treatment is not a one-size-fits-all approach, and the sample size is small. Nonetheless, studies like these provide a starting point for conversations to arrive at the best approach.

Personal commentary: The mention of cost, adverse effects, and adherence difficulties is an opportunity to include that there are other first-line treatment options for glaucoma. Selective laser trabeculoplasty (SLT) is not effective in all patients, but if considering cost, adverse effects, and adherence, it is beneficial to suggest it as one of those starting point options.

My rating of this study: ⭐⭐⭐

Kass MA, Heuer DK, Higginbotham EJ, et al. "Assessment of Cumulative Incidence and Severity of Primary Open-Angle Glaucoma Among Participants in the Ocular Hypertension Treatment Study After 20 Years of Follow-up." JAMA Ophthalmology. 139(5):558-566. 15 April 2021. https://doi.org/doi:10.1001/jamaophthalmol.2021.0341

Week in Review: Number 14

Models for Precision & Color in Argus II Retinal Implant
The present pair of studies explored improvements to the Argus II retinal implant using electrical simulation wavefront models for greater precision of target stimulation as well as the encoding of basic color. The Argus II retinal prosthesis uses a camera mounted on special glasses to detect patterns of light. These signals are then relayed to an array of 60 electrodes that stimulate retinal ganglion cells (RGCs). The implant is used in patients whose photoreceptors no longer detect light, such as in severe cases of retinitis pigmentosa, by stimulating retinal ganglion cells downstream of the photoreceptors. The axons of retinal ganglion cells together form the optic nerve that relay the signal to the brain for visual perception. In some patients, off-target stimulation of the axons rather than the cell body results in the perception of elongated phosphenes rather than the intended dots of light. To address this issue, the researchers used a computer model of two types of retinal ganglion cells, D1-bistratified and A2-monostratified, at the single-cell level and in large networks. They identified a pattern of short pulses that preferentially targets the cell bodies with less off-target activation of axons. In a more recent study, the same team of researchers applied the same computer models to study the encoding of color by retinal ganglion cells. Prior tests in patients revealed that the perception of color depended on the frequency of electrical stimulation. The second study uses computer models to predict eliciting color perception, specifically by stimulating small bistratified cells that contribute to blue-yellow color opponency, i.e., blue and yellow color perception. These two studies provide information to guide improvements in the Argus II retinal prosthesis toward more precise and colorful visual perception for the blind.

Citicoline Supplementation as Neuroprotection Independent of IOP in a Rat Model of Glaucoma
Citicoline is a major source of choline, a building block of cell membranes, including those of the nerve cells that transmit information from the eye to the brain. The authors note that previous studies in humans and rodent models of glaucoma showed lower levels of choline in the brain, but there has been little research into the effectiveness of choline supplementation as a glaucoma therapy. The present study in rats found that ingesting citicoline restored optic nerve signals between the eye and the brain independent of intraocular pressure (IOP). As such, citicoline is of particular interest as a novel mechanism for the treatment of glaucoma. In the vast majority of cases, elevated eye pressure is a risk factor for damage to the optic nerve, resulting in glaucoma. However, many studies have shown that glaucoma progression continues despite good eye pressure control, suggesting additional mechanisms of the disease. Despite hints of alternative mechanisms, contributing to normal tension glaucoma, for example, eye pressure has been the only variable that can be modified clinically. Neural protection and reversal of optic nerve damage are the holy grails of glaucoma research. The fact that citicholine can reduce vision loss in mice independent of eye pressure is intriguing. In particular, the research team induced glaucoma in several dozen rats using a clear gel. For rats with mildly elevated IOP, optic nerve and other tissues decayed for up to five weeks after injury. In rats treated with oral doses of citicoline over a three-week period, nerve degradation was reduced by 74%, suggesting a neuroprotective effect. Furthermore, reduced vision loss was sustained for another three weeks after treatment was stopped. The researchers caution that there are several steps between lab research and commercial development of an effective drug. They next intend to further investigate the connection between choline and neural protection.

Txnip Gene Therapy for Three Types of RP in Mice
Retinitis pigmentosa (RP) is a genetic eye condition that results in progressive dysfunction or loss of the photoreceptors in the retina, beginning with loss of rod photoreceptors and later also affecting cone photoreceptors. Currently, more than 100 gene loci for retinitis pigmentosa have been mapped or identified. However, targeted gene therapies have only been able to treat specific gene defects rather than wider sets or families of the disease. As the lead author states, “A gene therapy that would preserve photoreceptors in people with retinitis pigmentosa regardless of their specific genetic mutation would help many more patients.” To find a gene-agnostic therapy that could apply more broadly, the researchers screened 20 potential therapies in mouse models of RP, selecting for therapies that target sugar metabolism based on the theory that cone photoreceptor degeneration in RP was due to loss of glucose supply. Their experiments found that a gene called Txnip, especially an allele called C247S, was most effective in treating RP across three different mouse models. C247S in particular helped the cone photoreceptors switch to alternative sources of energy and improved mitochondrial health. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), suggesting that this therapy improves cone photoreceptor health by enhancing lactate catabolism. Combining Txnip gene therapy with additional gene therapies that reduced oxidative stress and inflammation provided additional cellular protection. The researchers intend to further their studies in animal models beyond mice before starting clinical trials in humans.

Microgravity Manufacturing of Artificial Retina
Industry researchers are exploring the development of an artificial retina using bacteriorhodopsin, with intended manufacturing in the microgravity environment of space on the International Space Station. A representative for one of the companies explains, “When gravity is nearly eliminated, so too are forces such as surface tension, sedimentation, convection driven buoyancy, all of which can interfere with the orientation and alignment important in the creation of crystalline structures, nanoparticles, or improved uniformity in layering processes." Similar to rhodopsin in human photoreceptors, bacteriorhodopsin is a light-sensing protein found in extremomophile microorganisms of the Archaea domain of life. When activated by light, bacteriorhodopsin pumps hydrogen ions across a membrane, generating an ion gradient. Additionally, bacteriorhodopsin's molecular structure is highly ordered and thermally stable for nanotechnology applications. In the artificial retina, layers of purified bacteriorhodopsin generate an ion gradient across a permeable membrane, acting in place of photoreceptors, to stimulate bipolar cells and retinal ganglion cells. From there, the signal is relayed via the optic nerve to the brain as usual. The microgravity environment of space facilitates layering the bacteriorhodopsin in a more precise orientation to create a unidirectional ion gradient, which the companies anticipate would persist when returned to gravity on Earth. The companies are working toward FDA approval for the use of their artificial retina for retinitis pigmentosa, with preclinical data still underway prior to clinical trials.

Complement Factor H in C. Elegans Model of AMD
Researchers working with a laboratory model of C. elegans have found a potential new mechanism for age-related macular degeneration (AMD). Specifically, they looked at the contribution of protein complement factor H (CFH), after previous research showed that mutations related to it are seen in a large number of AMD patients. The role of complement factor H is to mark cells in the body as self to protect them from an immune attack. This link between CFH and AMD led some researchers to hypothesize that AMD is due to the immune system attacking the body's cells that were not marked as self. The researchers were curious to explore new mechanisms of the disease using nematode lab models. Roundworms have a version of CFH in the middle of their antennas, specifically in the cilia, which are responsible for sensing the environment. The CFH proteins are located next to another important antenna protein called inversin. In roundworms bred to lack CFH, inversin is spread throughout the antennas rather than located in the middle. Roundworm antennas have some structural similarities to the photoreceptors of the human eye. For example, CFH and inversin have the same positioning in the cilia of photoreceptors in healthy human retinal tissue. However, in people with CFH mutations, inversin was spread around rather than located in neat bands. The authors state, "The role of CFH in cilia compartment boundaries is conserved in vertebrate photoreceptors, suggesting that structural defects in photoreceptor cilia make a contribution to AMD progression in patients with CFH mutations that has not been appreciated previously."

In Other News
(1) Evolution of the eye-brain connection
(2) Adverum patient loses sight in eye treated with gene therapy
(3) A veterinarian explains comparative eye anatomy: owl eyes