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AMD Update 15: Visualization of Living Rods and Cones

Posted Jun 10 2011 12:57pm
Back in February 2009, I first wrote about David Williams and his research group at the Institute of Optics at the University of Rochester, and their announcement that they had used adaptive optics to image RPE cells in vivo. That report, AMD Update 4: Does Visualizing RPE Cells Hold the Key to Understanding AMD? gave us a first look at how adaptive optics could image some of the retinal cells in the back of the eye in helping to understand how the effect of new drugs and treatments could be visualized in the living eye, providing a diagnostic mechanism to see changes in RPE cells, possibly when applying some of the new retinal treatment techniques.

Well, another group of researchers at  the same Institute of Optics at the University of Rochester, along with colleagues from several other research institutions have done it again. This time using their knowledge of applying adaptive optics to visualizing the much smaller photoreceptor rod cells present in the living eye.

This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative retinal eye disorders sooner, leading to quicker intervention and more effective treatments.

Here is the complete press release from the OSA, describing the two papers recently published:


Historic First Images Of Rod Photoreceptors In The Living Human Eye

Adaptive optics technology likely to spur sight-saving interventions, usher in new era of eye disease research, diagnosis and treatment


08 Jun 2011 

Scientists today reported that the tiny light-sensing cells known as rods have been clearly and directly imaged in the living eye for the first time. Using adaptive optics (AO), the same technology astronomers use to study distant stars and galaxies, scientists can see through the murky distortion of the outer eye, revealing the eye's cellular structure with unprecedented detail. This innovation, described in two papers in the Optical Society's (OSA) open access journal Biomedical Optics Express, will help doctors diagnose degenerative eye disorders sooner, leading to quicker intervention and more effective treatments.

"While therapies are only emerging, the ability to see the cells you are trying to rescue represents a critical first step in the process of restoring sight," says researcher Alfredo Dubra of the University of Rochester in New York, who led the team of researchers from Rochester, Marquette University, and the Medical College of Wisconsin (MCW), Milwaukee. "It's impossible to overemphasize how important early detection is to eye disease."

"One of the major hurdles in detecting retinal disease is that by the time it can be perceived by the patient or detected with clinical tools, significant cellular damage has often already occurred," adds team member Joseph Carroll of MCW.

The breakthrough that is ushering in a new era of eye disease research, diagnosis, and treatment is an improved design of a non-invasive adaptive optics imaging system. Dubra and his colleagues were able to push the device's resolution to its optical limits of nearly 2 microns (a micron is 1/1,000 of a millimeter), or the approximate diameter of a single rod in the human eye.

Rods are much more numerous than cones and are vastly more sensitive to light. With the optical design method successfully demonstrated by Dubra's team, even the smallest cone cells at the center of the retina, known as the foveal center, can be seen very clearly. Rods can be seen clearly in a less central retinal location.

"This is a really exciting breakthrough," says Steve Burns, a professor in the School of Optometry at Indiana University, who is not involved in the Biomedical Optics Express research. "Imaging contiguous rod mosaics will allow us to study the impact of a whole new class of blinding disorders on the retina. Since many of the eye diseases most amenable to intervention affect the rods, this should become a major tool for determining what treatments work best for those disorders."

De-twinkling Stars, Visualizing Rods

In astronomy, adaptive optics is able to correct for the blurring effect of Earth's atmosphere, effectively removing the "twinkling" from starlight and rendering cosmic objects as very sharp points of light. To achieve this correction, the AO system requires a reference point-either a bright, nearby star or an artificial "guide star" produced in the upper atmosphere by lasers mounted on a telescope. By monitoring that reference point, AO systems use a deformable mirror to create the exact but opposite distortion that is happening in the atmosphere. The result is a clearer image with much greater resolution.

Just as light passing through the atmosphere becomes bent and distorted, so too does light passing through the front part of the eye. This distortion is inconsequential on the scale of human vision, but poses a significant barrier in the microscopic realm of medical imaging.

In 1997, David Williams of the University of Rochester led the group that first demonstrated using AO technology to study the interior of the human eye. In this system, called an adaptive optics ophthalmoscope, a laser creates a reference point that is used to correct the blurring of the image obtained with a fundus camera. Today the fundus camera is commonly replaced by a second laser for imaging, which is known as an adaptive optics scanning laser ophthalmoscope. By moving the laser point across the retina and correcting the distortion along the way, line-by-line an accurate image emerges, in much the same way that a CRT monitor renders an image.

Though earlier AO systems could effectively image cones and have become a mainstay of high-resolution retinal imaging research, the smaller rods, which outnumber cones 20 to 1 in the retina, have eluded clear and contiguous observation in the living eye.

Breakthrough Design

The breakthrough in the design of the AO instrument that led to clearly visualizing rods was, according to Dubra, "embarrassingly simple, and relied on well-known equations and concepts." By simply folding the spherical mirrors that act as lenses in the instrument into a three-dimensional structure, the image quality of the retina was improved sufficiently to clearly resolve the contiguous rod mosaic, as well as the entire cone mosaic at the foveal center.

"By combining careful optical engineering, excellent adaptive optics control, and knowledge of the visual system the authors have made a major advancement in both biomedical imaging and vision science," says Burns.

Improving Patient Care

According to the researchers, their next step is to develop a clinical model that could be widely available. A related task is simplifying and teaching the art of interpreting AO images to guide clinical decisions about diagnosis and treatment.

When that occurs, hopefully in the next 5 to 10 years, doctors will likely be able to routinely peer into a living human eye with such precision and clarity that they will be able to see and evaluate individual rods-and do three things never before possible: accurately describe the physical presentation of specific rod disorders-the "phenotype" of a disease, intervene with early treatment at the first sign of disease, and even determine how individual cells are responding to a specific treatment.

"That's what's really exciting about this imaging device: it can really make a difference in a patient's life," says Carroll. "The ability to now resolve these cells opens up new possibilities for improving care that researchers have been anticipating for a long time-such as using the information in these retinal images to aid in targeting, delivering, and evaluating therapies."


Paper: "Non-invasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 7, pp. 1864-1876.

Abstract:

The rod photoreceptors are implicated in a number of devastating retinal diseases. However, routine imaging of these cells has remained elusive, even with the advent of adaptive optics imaging. Here, we present the first in vivo images of the contiguous rod photoreceptor mosaic in nine healthy human subjects. The images were collected with three different confocal adaptive optics scanning ophthalmoscopes at two different institutions, using 680 and 775 nm superluminescent diodes for illumination. Estimates of photoreceptor density and rod:cone ratios in the 5°-15° retinal eccentricity range are consistent with histological findings, confirming our ability to resolve the rod mosaic by averaging multiple registered images, without the need for additional image processing. In one subject, we were able to identify the emergence of the first rods at approximately 190 μm from the foveal center, in agreement with previous histological studies. The rod and cone photoreceptor mosaics appear in focus at different retinal depths, with the rod mosaic best focus (i.e., brightest and sharpest) being at least 10 μm shallower than the cones at retinal eccentricities larger than 8°. This study represents an important step in bringing high-resolution imaging to bear on the study of rod disorders.


Paper: "Reflective afocal broadband adaptive optics scanning ophthalmoscope" Biomedical Optics Express, Volume 2, Issue 6, pp. 1757-1768.

Abstract:

A broadband adaptive optics scanning ophthalmoscope (BAOSO) consisting of four afocal telescopes, formed by pairs of off-axis spherical mirrors in a non-planar arrangement, is presented. The non-planar folding of the telescopes is used to simultaneously reduce pupil and image plane astigmatism. The former improves the adaptive optics performance by reducing the root-mean-square (RMS) of the wavefront and the beam wandering due to optical scanning. The latter provides diffraction limited performance over a 3 diopter (D) vergence range. This vergence range allows for the use of any broadband light source(s) in the 450-850 nm wavelength range to simultaneously image any combination of retinal layers. Imaging modalities that could benefit from such a large vergence range are optical coherence tomography (OCT), multi- and hyper-spectral imaging, single- and multi-photon fluorescence. The benefits of the non-planar telescopes in the BAOSO are illustrated by resolving the human foveal photoreceptor mosaic in reflectance using two different superluminescent diodes with 680 and 796 nm peak wavelengths, reaching the eye with a vergence of 0.76 D relative to each other.

The papers appear as part of a special feature issue of Biomedical Optics Express on "Cellular Imaging of the Retina."
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