Through the looking glass
Adaptive optics is a game-changer in ocular imaging
Joseph Carroll, PhD ’02, is debunking myths.
“The stars don’t twinkle,” he said. “It is only in the last instance that light arriving from a star gets distorted by the atmosphere. So it has the perception of twinkling.”
Another myth lies closer to the cell biologist’s field of vision research – that rod photoreceptors cannot be imaged, that they are much too small to be visualized. It was a belief that was proven incorrect by research published this summer by Dr. Carroll, Associate Professor of Ophthalmology at The Medical College of Wisconsin, and Alfredo Dubra, PhD, Assistant Professor of Ophthalmology and Biophysics at the Medical College, previously with University of Rochester in New York.
These two fallacies in once-conventional wisdom actually share a scientific solution in the technology used to view the objects clearly. Adaptive optics – a field born from astronomy and kindled by the military is beginning to yield results that are likely to have significant bearing on eye disease research, diagnosis and treatment.
Astronomers trying to view objects in space and satellites trying to view objects on earth have essentially the same problem. The atmosphere is filled with turbulence – particles and changes in pressure and temperature that distort light on its journey between space and the earth. Similarly, the eye contains inherent imperfections that induce aberrations in the light path; they typically do not affect a person’s vision but they significantly hinder the ability to clearly visualize the tiny cells involved in sight.
Joseph Carroll, PhD ’02, reviews ocular images in the Froedtert & The Medical College of Wisconsin Eye Institute.
Adaptive optics is a method for characterizing these aberrations, then correcting for them so that the image returned is flawless. It is accomplished in virtually the same fashion for stargazing and satellites as it is for ocular imaging. Scientists use a wavefront sensor to establish the profile of a known light source. For the eye, Dr. Carroll and his team use a super luminescent diode. This provides the baseline or null state of the system.
Then, they take the same light and pass it through the eye, where it is reflected back, and compare the two light profiles – this provides a measurement of the imperfections. The ensuing step is to correct for those imperfections. The mechanism of choice is a deformable mirror, the reflective surface of which can be physically manipulated into any shape by the pushing or pulling of attached actuators that are activated by electric or magnetic current.
“The idea is to make that mirror take on a shape so as to perfectly compensate for those imperfections you just measured,” Dr. Carroll said. “Now, what you’ve got is what we call a diffraction-limited imaging system, a perfect imaging system, and you throw some light in the eye and capture a picture.”
The result is a high resolution visualization of the living retina that can be captured with an imaging tool, such as a confocal microscope or fundus camera.
It has been 50 years since Soviet biophysicist M.S. Smirnov first proposed adaptive optics as a way to perceive the eye, but it wasn’t until the 1990s that technology began to catch up to the concept enough to develop a system to do so. Dr. Carroll completed a postdoctoral fellowship under Dr. David Williams at the University of Rochester where many of the modern advances took shape. He brought his expertise back to The Medical College of Wisconsin, which is rapidly becoming a unique leader in this burgeoning field.
The Froedtert & The Medical College of Wisconsin Eye Institute is currently one of only a few places in the U.S. where adaptive optics tools are available to clinicians. Having clinicians engaged in the effort drives the research in a meaningful direction, and support from leadership, including Chairman of Ophthalmology Dale Heuer, MD, GME ’82, has enabled the rapid growth of the Advanced Ocular Imaging Program that Dr. Carroll directs with Dennis Han, MD, Fel ’87, the Jack A. & Elaine Klieger Professor of Ophthalmology.
“I don’t honestly think this would work anywhere else,” he said. “We really have a unique collection of resources in terms of space, people, philanthropy and the culture to try something different.”
The investment in innovation and collaboration was rewarded this summer when the research team became the first ever to image the tiny light-sensing rods in the living eye. Revealing the entire rod photoreceptor mosaic in cellular resolution represents a breakthrough in vision research as there is a whole cadre of diseases affecting the rods that previously had no avenue for intervention. Drs. Dubra, Carroll and colleagues described the advance in a paper published in July in The Optical Society’s open access journal Biomedical Optics Express.
An image of the (smaller) rod and (larger) cone photoreceptors captured using adaptive optics in a living human retina.
Working hand-in-hand with Eye Institute clinicians has been instrumental in showing the true value of the technology. Twice in recent months, the team collaborated with Kimberly Stepien, MD, Assistant Professor of Ophthalmology, who was able to detect pathology in two of her patients only after using adaptive optics. Conventional clinical tools came up empty.
“This is what we were waiting for, the real demonstration that there is clinical utility with this technology,” Dr. Carroll said. “With conventional clinical imaging, by the time you see pathology, a lot has already happened; there has been significant cellular damage. If you wait to intervene on a disease until after 50 percent of the cells have died, it is a pretty ineffective treatment strategy.”
Early detection is a key benefit derived from an adaptive optics approach, especially for progressive and inherited blinding diseases. It won’t provide answers for every disease, but it may have implications for many, including advanced macular degeneration, retinitis pigmentosa, diabetic retinopathy, and achromatopsia.
“What we learn in one disease is going to be broadly applicable to other diseases,” he said. “In general, the imaging strategies and approaches we develop for choroideremia are going to be applicable to albinism.”
Early detection means early intervention, and Dr. Carroll is encouraged by the emergence of gene therapy as a viable future treatment option for inherited retinal disorders. Adaptive optics could play an important role in determining not only what patients are candidates for a specific therapy but also in measuring the effectiveness of treatment.
Since it is non-invasive and captured in real time, adaptive optics enables both doctor and patient to review images, providing an opportunity to educate about their condition. The image clearly shows cells that are healthy vs. those that are damaged or missing, thus capable of providing subclinical evidence of a disorder. If treatments are available, images could be compared over time.
“With standard clinical tools, you might have to wait years before you can see the treatment response,” Dr. Carroll said. “That’s not efficient. If what you are doing is working or not working, you would like to know that right away so you can either do more of the same or stop and change course. Definitely, assessing the efficacy of treatments is key.”
The future of adaptive optics is likely to involve integrated approaches with other imaging modalities. Combining adaptive optics with photo acoustic microscopy or spectroscopic imaging, for example, may allow scientists to image cells currently thought too small to do so, such as ganglion cells.
Dr. Carroll’s team is also making strides in the functional imaging of the retina. Someday, they may be able to tell a patient not only how many cells they have, but how well they are functioning. That capability doesn’t exist yet, but before this year, no one had ever imaged the rod photoreceptors. It likely won’t be long before adaptive optics dispels another myth.
Adaptive optics at work
Unique adaptive optics provides the ability to visualize the cells of the human eye. Joseph Carroll, PhD ’02, and colleagues use adaptive optics at The Medical College of Wisconsin to see photoreceptors at a cellular level and identify cells involved in eye disease.
Comments are subject to approval. The Medical College reserves the right to edit comments for length, grammar, clarity and appropriateness.
Please include your first and last name. Alumni, please also feel free to include your class year(s). Your e-mail address will not be published.