Adaptive Optics and Its Clinical Implications for the Study and Understanding of Ocular Diseases

Adaptive optics (AO) is a set of technologies that allows optical system imperfections or limitations to be corrected. Adaptive optics technologies involve two aspects: a method for measuring imperfections or aberrations in an optical system (telescope, camera, the human eye) and a method for correcting the imperfections or distortions. Since there are no perfect optical systems, adaptive optics technologies are a way to circumvent some of the natural limitations inherent in an optical system.

Adaptive optics platforms were first developed by the U.S. Department of Defense decades ago for ground-based surveillance systems designed to monitor spy satellite activities in space. The first application of AO technology to study the human eye was achieved in the lab of David R. Williams, PhD, at the University of Rochester in New York. Adaptive optics is a revolutionary approach in the study of the human eye, one that has and will continue to be trans formative in the understanding of the eyes’ structural characteristics and disease pathogenesis.

AO and Eye Disease — New Research

Using adaptive optics technologies to study anatomical structures within the eye at the cellular level and disease processes within the eye for conditions like macular degeneration and glaucoma are the focal points of research for Ethan A. Rossi, PhD, director of the Advanced Ophthalmic Imaging Lab in the Department of Ophthalmology at the University of Pittsburgh School of Medicine.

Dr. Rossi joined the Department in 2016 as an assistant professor of ophthalmology. He also holds a secondary appointment as assistant professor in the Department of Bioengineering at the University of Pittsburgh Swanson School of Engineering and is a faculty member of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh.

Dr. Rossi completed his PhD in vision science at the University of California, Berkeley, followed by postdoctoral fellow-ships at Berkeley along with the University of Rochester in Dr. Williams’ lab, where he studied age-related macular degeneration (AMD) and developed improved techniques to image the cells of the retinal pigment epithelium (RPE), a layer of cells at the back of the eye that is crucial for vision, using adaptive optics.

Dr. Rossi’s work at its core is devoted to understanding the cellular organization and characteristics of the human retina in both the normal eye and in the presence of disease. His work and that of his collaborators have made significant advances over the last decade in the ability to image and study the layers and structural aspects of the human retina.

During his postdoctoral work, Dr. Rossi collaborated with the optics and imaging company Canon Inc. to design and develop new technologies for the commercial use of adaptive optics in ophthalmoscopy. This work led to more than a dozen patent applications, with Dr. Rossi being either a sole inventor or co-inventor on several, one of which was recently issued.

Transformative Technologies

Adaptive optics technologies can be applied to various types of cameras or optical systems for imaging internal structures of the eye. This technological approach allows for two distinct areas of scientific research, both of which are part of Dr. Rossi’s ongoing studies.

On the one hand, AO allows for sophisticated and detailed high-resolution imaging of living eye structures at cellular and micro - scopic levels. On the other hand, AO allows for the presentation of stimuli to the retina in a manner that is not possible through normal optical systems. This research is leading to new findings of the visual process- ing capabilities of the retina and the brain.

Dr. Rossi’s research explores both of these lines of investigation to probe the structural nature of the eye and how diseases that afflict it manifest in such areas as the RPE, or how disease states alter and damage components of the human visual system, such as the rods and cones.

“Because of the inherent limitations imposed by the optics of the human eye, we have not known the full potential of the human retina and brain to process visual stimuli. With adaptive optics, we can bypass these normal limitations and deliver visual stimuli that are of higher resolution than the visual system has ever experienced. This allows us to study how the retina and brain sample and process these stimuli,” says Dr. Rossi.

More Than Just AO

While a significant portion of Dr. Rossi’s past and current work is devoted to using AO to study retinal disease, his lab uses an extensive repertoire of technologies and conventional imaging modalities to study the eye.

“The use of AO has been central in my research, but it is one technology among many to help us understand and measure retinal structure and visual function, and the pathological states of diseased ocular structures. Our lab also uses conventional imaging and visual function testing tools, including visual psychophysics, to better understand how structure is related to function in the eye — a highly critical area for our overall understanding of disease processes. I have an incredible affinity for the science, technology, and engineering aspects of my work, but we are not tied 
to a particular technology. If another technology comes along that can better help us answer the questions we have related to structure, function, or disease processes, we will incorporate it into our studies. Ultimately, our goal is to definitively know how a disease manifests, propagates, and impairs vision, and to better understand the mechanism of the damage process if it has started so that we can develop ways to intervene to prevent vision loss or make repairs to restore visual function.”

Imaging Breakthroughs With Retinal Ganglion Cells and the RPE

Dr. Rossi’s past research has led to several significant breakthroughs in the ability to image structural components of the retina. In 2013, Dr. Rossi’s research group showed the ability of AO to image RPE cells in vivo in retinas with age-related macular degeneration. Imaging findings from the study proved to correlate highly with AMD changes in the retina as seen through postmortem histology exams. “The real clinical benefit of this technology is its ability to provide us with longitudinal observational power to see and characterize the changes and progression of AMD in the living retina — in human subjects over very short timescales at the level of single cells,” says Dr. Rossi.

More recently, in 2017, Dr. Rossi and colleagues published findings of a study designed to image in vivo aspects of the retinal ganglion cells.

Retinal ganglion cells, among other inner-retinal neurons, are among the most challenging classes of cells in the retina to image. The difficulty lies in the almost-complete trans parency of these cells.

Because light must pass through all of the layers of the retina to reach the photo-receptors (rods and cones) positioned at the back of the eye, evolutionary processes have made the intervening cells clear to allow for this light transmission.

“If you think about it, it makes perfect sense from a design standpoint. However, in order to image something, it has to scatter light and reflect it toward the imaging device. Since the retinal ganglion cells are virtually transparent, they scatter or reflect very little light, so traditional imaging systems cannot see them,” says Dr. Rossi.

Dr. Rossi and colleagues developed a technique to enhance the contrast of the retinal ganglion cells — and other inner- retinal cellular components — and do it in vivo without using fluorescent tracers or levels of light that could cause damage to the subject’s eye. Their findings were published in 2017 in the Proceedings of the National Academy of Sciences under the title “Imaging Individual Neurons in the Retinal Ganglion Cell Layer of the Living Eye.”

Since then, Dr. Rossi, along with collaborator Nils Loewen, MD, PhD, in the Department of Ophthalmology at the University of Pitts burgh, has secured a new grant from the BrightFocus® Foundation to perform in vivo imaging studies of the retinal ganglion cells in the presence of glaucoma.

“Most of my past research has involved studies related to AMD. This new grant is helping to expand our laboratory’s work into the world of glaucoma research where we hope to visualize some of the earliest changes occurring in the retinal ganglion cells in patients with glaucoma, and again, monitor and characterize those changes longitudinally to trace the disease process at the cellular level,” says Dr. Rossi.

Further Reading and References

Rossi EA, Granger CE, Sharma R, Yang Q, Saito K, Schwarz C, Walters S, Nozato K, Zhang J, Kawakami T, Fischer W, Latchney LR, Hunter JJ, Chung MM, Williams DR. Imaging Individual Neurons in the Retinal Ganglion Cell Layer of the Living Eye. PNAS. 2017; 114(3): 586-591.

Song H, Rossi EA, Stone E, Latchney LR, Williams DR, Dubra A, Chung MM. Adaptive Optics Demonstrates Phenotypic Diversity in Autosomal Dominant Cone-Rod Dystrophy Associated With a Single Mutation in the GUCA1A Gene. Br J Ophthalmol. 2018; 102: 136-141.

Williams ZW, Rossi EA, DiLoreto DA. In Vivo Adaptive Optics Ophthalmoscopy Correlated With Histopathology in Cancer Associated Retinopathy. Ophthalmology Retina. 2018; 2(2): 143-151.

Song H, Rossi EA, Latchney L, Bessette A, Stone E, Hunter JJ, Williams DR, Chung M. Cone and Rod Loss in Stargardt Disease Revealed by Adaptive Optics Scanning Light Ophthalmoscopy. JAMA Ophthalmol. 2015; 133(10): 1198–203.

Zhang J, Yang Q, Saito K, Nozato K, Roorda A, Williams DR, Rossi EA. An Adaptive Optics Imaging System Designed for Clinical Use. Biomedical Optics Express. 2015; 6(6): 2120.

Yang Q, Zhang J, Nozato K, Saito K, Williams DR, Roorda A, Rossi EA. Closed-loop Optical Stabilization and Digital Image Registration in Adaptive Optics Scanning Light Ophthalmoscopy. Biomedical Optics Express. 2014; 5(9): 3174.
Rossi EA, Rangel-Fonseca P, Parkins K, Fischer W, Latchney LR, Folwell MA, Williams DR, Dubra A, Chung MM. In Vivo Imaging of Retinal Pigment Epithelium Cells in Age-Related Macular Degeneration. Biomedical Optics Express. 2013; 4(11): 2527–2539.

Rossi EA, Roorda A. The Relationship Between Visual Resolution and Cone Spacing in the Human Fovea. 
Nat Neurosci. 2010; 13(2): 156–157.