Week in Review: Number 10

Unprecedented Imaging Resolution of the Retina
Imaging of the retina is limited by diffraction through apertures such as the pupil, which bends the light and essentially becomes a secondary source of waves. Diffraction limits image resolution. Additionally, the optics of refraction by the cornea and lens, such as transverse and longitudinal aberrations, further decrease image resolution. A team of researchers at the National Eye Institute developed a new adaptive optics technique called non-confocal split-detection to overcome some of these challenges for enhanced imaging of the photoreceptor mosaic of the retina. Interestingly, they did so by reducing the amount of light entering the eye, by strategically blocking the light in the center of a beam to form a hollow ring of light. Though this produced better transverse resolution of the retina, it also reduced axial resolution. The researchers compensated for this by blocking the light coming back from the retina using a sub-Airy disk, a tiny pinhole. The imaging tweak yielded 33% increase in transverse resolution and 13% improvement in axial resolution compared to traditional adaptive optics scanning light ophthalmoscopy. Unlike other methods of imaging that overcome the diffraction barrier by using more light, this technique reduces the amount of light to more safely image living human eyes. When applied to the eyes of five healthy volunteers (after theoretical simulations), the imaging technique could visualize "a circularly shaped subcellular structure in the center of cone photoreceptors that could not be clearly visualized previously." The enhanced resolution is particularly useful for imaging the cones tightly packed at the fovea as well as imaging the more numerous, but smaller, rods elsewhere. The researchers hope that this first step toward routine sub-diffraction imaging of subtleties and changes in size, shape, and distribution of photoreceptors will aid in early detection and intervention of retinal diseases.

Large Study Identified 50 New Genes for Eye Color
An international team of researchers conducted a genome-wide association study of the genes involved in eye color. The study comprising almost 195,000 people across Europe and Asia, the largest genetic study of its kind to date, identified 50 new genes for eye color. Additionally, the study found that eye color in Asians with different shades of brown is genetically similar to eye color in Europeans ranging from dark brown to light blue. While exploring the genetics of eye color might appear trivial on the surface, such a study has both societal and clinical relevance. As one of the senior authors states, “The findings are exciting because they bring us to a step closer to understanding the genes that cause one of the most striking features of the human faces, which has mystified generations throughout our history. This will improve our understanding of many diseases that we know are associated with specific pigmentation levels.” Clinically, this study contributes to a better understanding of eye diseases ranging from ocular albinism to uveal melanomas. Equally important to the basic sciences is the confirmation and further discovery that the genetic basis of a person's eye color are polygenic, much more so than previously thought. For simplicity, most of us were taught in grade school to consider eye color as an example of a simple monogenic (or bigenic) trait following Mendelian genetics, with brown being dominant over blue. Explorations into the topic in later years reveals a more complex picture with many other genes involved. Though the simplified conception of eye color will not likely leave the public eye anytime soon, the present study is valuable in providing a more nuanced expansion of that picture.

β-Amyloid Accumulation in RPE Lysosomes
Researchers in the U.K. recently published a study linking age-related macular degeneration (AMD) with the accumulation of β-amyloid proteins in the lysosomes of retinal pigment epithelial (RPE) cells. Beta amyloid is a hallmark of Alzheimer's disease, so this study also makes a connection between Alzheimer's and AMD, guided by prior research findings that donor eyes from patients who had suffered from AMD showed high levels of β-amyloid in their retinas. In their particular mouse model, the researchers were able to introduce β-amyloid to the mouse eyes, which subsequently developed retinal pathology similar to AMD in humans, without the use of transgenic mice. Though the lead researcher states that reducing the use of transgenic animals improves animal welfare, mouse models were still used, with the greatest practical benefit being a reduction in time to produce. More importantly, the researchers also used in vitro cell models to investigate the effect of β-amyloid on RPE cells. They found that β-amyloid accumulated in RPE cell lysosomes, and once invaded by β-amyloid, there were 20% fewer lysosomes available to perform recycling of photoreceptor discs, a necessary daily clean up process for vision at the cellular level. The experiments also found that once β-amyloid entered RPE cells, 85% of these toxic proteins remained in the lysosomes (rather than are cleared away) and accumulate over time. The finding of β-amyloid accumulation in RPE cells, thus linking AMD and Alzheimer's disease, seems to be a new connection that could guide additional anti-amyloid therapy pathways for both diseases.

Soft Contact Lenses for Electroretinograms
“Since the first conceptual invention by Leonardo da Vinci, there has been a great desire to utilize contact lenses for eye-wearable biomedical platforms,” reported a lead investigator of a project at Purdue University to engineer soft contact lenses with biosensors for improved patient comfort in electroretinograms. How this project differs from current corneal sensors is the seamless integration of ultrathin, stretchable biosensors with commercial soft contact lenses via “an electrochemical anchoring mechanism,” thus bypassing obstacles presented by the rigid planar surfaces of most electronics. As with electroretinogram sensors, these contact lenses would measure electrophysiological retinal activity from the corneal surface of human eyes; however, the contacts are an improvement over current sensors in both signal quality and patient comfort, that is, avoiding the need for a topical anesthetic or a speculum. It is tempting to imagine these contact lenses as the kind that could detect biomarkers of ocular diseases in the tear film, but this isn't quite that kind of project. Rather, it is an improved corneal interface for electroretinogram sensors using the more comfortable vehicle of the ubiquitous commercial soft contact lens. That being said, the fact that electronics could be so intimately integrated into the soft, curved surface of soft contact lenses is a big step forward for engineering of other biosensors for monitoring of ocular diseases.

Corneal Reflections Tell the Difference
This study lies at the intersection between computer science and optics. The slang term deepfake  usually refers to visual media that has been edited to replace the person in the original photo or video with another person, often a public figure, in a way that makes it look authentic; the "deep" in deepfake likely refers to deep learning algorithms. Computer scientists are looking into how the optics of the cornea can help to differentiate authentic photos from deepfakes. Because the cornea is foremost a transparent refracting surface, one often forgets that it is also a reflective surface, a convex mirror producing upright, virtual, minified images of the world. Because the two eyes are seeing and reflecting the same thing, the two images should be similar, for example, in shape and color. This is distinguished from the reflections seen in deepfake photos and videos, which are often generated by combining many images and thus produce corneal reflections that are not similar. By comparing the corneal reflections between the two eyes, the investigators' algorithm was reported to be 94% effective at telling the difference between authentic and deepfake portrait-like photos. In order for the tool to work, however, it requires that the photos have a reflected light source, that the original image not have been edited, and that there are two eyes to compare with one another. Additionally, the algorithm only compares differences at the level of pixels rather than broader shapes. Nonetheless, it is an interesting computer science application of corneal optics.

In Other News
(1) Pilocarpine to treat presbyopia submitted for FDA approval (Related)
(2) Visual attention in the immature brain of infants
(3) What your eyes can tell you about your health