As a method used to image the retina with a high degree of spatial sensitivity, it is helpful in the diagnosis of glaucoma, macular degeneration, and other retinal disorders. It has further been combined with adaptive optics technology to provide sharper images of the retina.[1][2]
Scanning laser ophthalmoscopy
SLO utilizes horizontal and vertical scanning mirrors to scan a specific region of the retina and create raster images viewable on a television monitor. While it is able to image the retina in real time, it has issues with reflections from eye astigmatism and the cornea. Eye movements additionally can confound the data from SLO.[3]
Adaptive optics scanning laser ophthalmoscopy
Adaptive optics scanning laser ophthalmoscopy (AOSLO) is a technique used to measure living retinal cells. It utilizes adaptive optics to remove optical aberrations from images obtained from scanning laser ophthalmoscopy of the retina.[citation needed]
History
Scanning laser ophthalmoscopy developed as a method to view a distinct layer of the living eye at the microscopic level. The use of confocal methods to diminish extra light by focusing detected light through a small pinhole made possible the imaging of individual layers of the retina with greater distinction than ever before.[4] However, using SLO for monitoring of individual retinal cells proved problematic because of optical aberrations created from the tissues of the anterior eye (specifically the cornea and lens). These aberrations (caused additionally by astigmatism and other factors affecting eye position) diminished lateral resolution and proved difficult to remove.[5]
Adaptive optics was first attempted for SLO in the 1980s. This first attempt did not use wavefront-detecting technology with its deformable mirror and estimated aberrations through pre-measured factors such as astigmatism.[6] However, this did not diffuse the small monochromatic aberrations resulting from light traveling through the anterior eye both into and out of the pupil during scanning. The invention and adaptation of the Shack–Hartmann wavefront sensor for the apparatus produced images of the retina with much higher lateral resolution.[7] The addition of microelectricalmechanical (MEMs) mirrors instead of larger, more expensive mirror deformable mirror systems to the apparatus made AOSLO further usable for a wider range of studies and for use in patients.[8]
Procedure
Diagram of the AOSLO setup
The subject is placed in a dental impression mount fixed in a way to make it possible to manipulate the head in three dimensions. The subject's pupils are dilated using a dilating agent to minimize fluctuations from accommodation. After the eyes are sufficiently dilated, the subject is told to fixate on a target while in the mount.[9]
Once the subject is properly placed, wavefront correction and imaging takes place. A laser is collimated and then reflected off of a beam-splitting mirror. As in confocal SLO, light must pass through both a horizontal and a vertical scanning mirror before and after the eye is scanned to align the moving beam for eventual retinal faster images of the retina. Additionally, the light is reflected off of a deformable mirror before and after exposure to the eye to diffuse optical aberrations. The laser enters the eye through the pupil to illuminate the region it has been focused onto and light reflected back leaves the same way. Light returning from the mirrors passes through the first beam splitter onto another beam splitter where it is directed simultaneously toward a photomultiplier tube (PMT) and toward a Shack–Hartmann wavefront sensor array. The light going toward the photomultiplier is focused through a confocal microscopy pinhole to remove light not reflecting off of the plane of interest and then recorded in the PMT. Light directed to the wavefront sensor array is split up by the lenslets in the array and then recorded onto a charge-coupled device (CCD) camera for detection of optical aberrations. These aberrations are then subtracted from the images recorded in the PMT to vastly increase lateral resolution.[3][4][7][9]
Applications
A major use of this increased lateral resolution from AOSLO has been the ability to determine the spatial distribution of cone cells around the fovea. Not only can the spatial density of these cells be found for a variety of regions within the retina, but the anisotropy of these cells can also be calculated to determine the axial orientation of retinal cells in the living subject. This represents a major benefit over typical histological examination of small numbers of donated human eyes.[10] AOSLO has also revealed significant decreases in foveal cone packing density for myopic eyes in comparison to emmetriopic eyes. This difference has been hypothesized to originate from a natural decrease in cone density with the increase in eye axial length associated with myopia.[11] Abnormalities in photoreceptor structure in regions damaged by macular dystrophy have additionally been imaged by AOSLO. In these subjects, a dark area has been visualized within the macular lesion and morphologically abnormal photoreceptors have been visible on the lesion perimeter.[12] Furthermore, scanning of subjects with cone dystrophy and retinitis pigmentosa (RP) has shown significant changes in cone packing density for these subjects compared to those with normal retinas. This presents a possible future use of AOSLO in phenotype tracking and confirmation for subjects with diseased genotypes.[13]
The imaging of retinal pigment epithelium (RPE) cells in patients with and without retinal disease has also proved possible with the use of AOSLO. With the loss of photoreceptor cells, background scattered light decreases and the light focused on the RPE can be analyzed more clearly.[14] As the loss of RPE cells represents the primary pathology of macular degeneration, this provides a possible future avenue for tracking RPE degradation in vivo. This has been further proved with the analysis of lipofuscin granule autofluoresence in normal human and rhesus macaque retinas by AOSLO. Comparison of this fluorescence in normal and diseased retinas with simultaneous imaging of cone structure and cone/retinal pigment cell ratio analysis has been shown to be possible and in the future may allow for the tracking of retinal damage from retinal dystrophies.[15] AOSLO has already been used in rhesus macaques to track light damage to the macula from particular wavelengths.[16]
Additionally, AOSLO provides a greater degree of accuracy for eye tracking than possible before with other techniques. Because of the short scan time involved in AOSLO, eye motion itself represents an obstacle to taking images of the retina. Computational adjustments and modeling have been able to correct for aberrations caused by eye motion between frames.[17] However, by tracking these aberrations based on changes to the retina between pictures, the effect of light on the individual orientation of the cone can be tracked. Research utilizing a visual stimulus and AOSLO eye tracking have yielded data on how the retina tracks movement at the microscopic level.[9]
The high degree of specificity and the ability to focus the laser on different levels of the eyes with AOSLO has additionally allowed for real time tracking of blood flow in the eye. By injecting fluorescin into macaques before scanning, fluorescence adaptive optics scanning laser ophthalmoscopy (FAOSLO) can be utilized to image individual capillaries in the nerve fiber layer and determine the thickness of the nerve fiber layer itself. Vessel pattern and diameter for these capillaries have been measured throughout the regions scanned by FAOSLO. This has future applications for monitoring glaucoma patients who either have changes in nerve fiber layer thickness or alterations in vasculature from damage to the retina.[18]
Comparison to retinal dissection and other imaging techniques
AOSLO represents an advantageous alternative to retinal dissection for a variety of reasons. Analysis of cone packing density before AOSLO was only possible on mounted eyes from eye donor banks.[19] As this method could not measure changes to cones in living eyes, it could not be used to track retinal changes over time or eye movements. With the use of living subjects, AOSLO allows for these measurements as well as easier control of age and other confounding factors while maintaining similar anatomical results for cone packing density.[10] Future clinical implications for AOSLO are also possible.
AOSLO compares favorably with other retinal imaging techniques as well. Fluorescein angiography uses injection of a fluorescein dye to image the back of the retina. It is a commonly used technique but it has a large number of side effects, including nausea in one fifth of patients and in some cases death from anaphylaxis.[20]Optical coherence tomography (OCT) represents a powerful clinical tool for monitoring retinal physiology in patients. OCT uses low coherence interferometry to differentiate tissues within the eye and create a cross section of a living patients’ retina non-invasively.[21] It actually has greater axial resolution than AOSLO.[22] However, AOSLO represents a method with much greater translational resolution than OCT and can thus be used to track minor lateral physical changes such as the effects of eye movements on the retina.[23] A combination of AOSLO and OCT has recently been attempted in one apparatus to produce the first three-dimensional images of individual cone cells and illustrate the overall cone mosaic near the fovea at high speeds.[24]
↑ Sharp P, Manivannan A. "The scanning laser ophthalmoscope" Physics in Medicine and Biology. 1997;42:951.
↑ Dreher AW, Bille JF, Weinreb RN. "Active optical depth resolution improvement of the laser tomographic scanner". Appl Opt. 1989;28(4):804-8.
1 2 Liang J, Williams DR, Miller DT. "Supernormal vision and high-resolution retinal imaging through adaptive optics". J Opt Soc Am A. 1997;14(11):2884-92.
↑ Doble N, Yoon G, Chen L, Bierden P, Singer B, Olivier S, et al. "Use of a microelectromechanical systems(MEMs) based mirror for adaptive optics in the human eye". Optics Letters. 2002;27(17):1537-9.
1 2 3 Roorda A. "Applications of adaptive optics scanning laser ophthalmoscopy". Optom Vis Sci. 2010 Apr;87(4):260-8.
1 2 Chui TY, Song H, Burns SA. "Adaptive-optics imaging of human cone photoreceptor distribution." J Opt Soc Am A Opt Image Sci Vis. 2008 Dec;25(12):3021-9.
↑ Chui TY, Song H, Burns SA. "Individual variations in human cone photoreceptor packing density: variations with refractive error." Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4679-87.
↑ Bessho K, Fujikado T, Mihashi T, Yamaguchi T, Nakazawa N, Tano Y. "Photoreceptor images of normal eyes and of eyes with macular dystrophy obtained in vivo with an adaptive optics fundus camera." Jpn J Ophthalmol. 2008 Sep-Oct;52(5):380-5.
↑ Duncan JL, Zhang Y, Gandhi J, Nakanishi C, Othman M, Branham KE, et al. "High-resolution imaging with adaptive optics in patients with inherited retinal degeneration." Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3283-91.
↑ Roorda A, Zhang Y, Duncan JL. "High-resolution in vivo imaging of the RPE mosaic in eyes with retinal disease". Invest Ophthalmol Vis Sci. 2007 May;48(5):2297-303.
↑ Morgan JI, Dubra A, Wolfe R, Merigan WH, Williams DR. "In vivo autofluorescence imaging of the human and macaque retinal pigment epithelial cell mosaic." Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1350-9.
↑ Morgan JI, Hunter JJ, Masella B, Wolfe R, Gray DC, Merigan WH, et al. "Light-induced retinal changes observed with high-resolution autofluorescence imaging of the retinal pigment epithelium". Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3715-29.
↑ Vogel C, Arathorn D, Roorda A, Parker A. "Retinal motion estimation in adaptive optics scanning laser ophthalmoscopy". Opt Express. 2006;14:487-97.
↑ Scoles D, Gray DC, Hunter JJ, Wolfe R, Gee BP, Geng Y, et al. "In vivo imaging of retinal nerve fiber layer vasculature: imaging histology comparison". BMC Ophthalmol. 2009;9:9.
↑ Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. "Human photoreceptor topography". J Comp Neurol. 1990 Feb 22;292(4):497-523.
↑ Antcliff RJ, Stanford MR, Chauhan DS, Graham EM, Spalton DJ, Shilling JS, et al. "Comparison between optical coherence tomography and fundus fluorescein angiography for the detection of cystoid macular edema in patients with uveitis". Ophthalmology. 2000;107(3):593-9.
↑ Huang D, Swanson E, Lin C, Schuman J, Stinson W, Chang W, et al. Optical coherence tomography. Spie Milestone Series MS. 1998;147:324-7.
↑ Romero-Borja F, Venkateswaran K, Roorda A, Hebert T. "Optical slicing of human retinal tissue in vivo with the adaptive optics scanning laser ophthalmoscope". Applied Optics. 2005;44(19):4032-40.
↑ Ferguson R, Bigelow C, Iftimia N, Ustun T, editors. Precision targeting with a tracking adaptive optics scanning laser ophthalmoscope2006.
↑ Pircher M, Zawadzki RJ, Evans JW, Werner JS, Hitzenberger CK. "Simultaneous imaging of human cone mosaic with adaptive optics enhanced scanning laser ophthalmoscopy and high-speed transversal scanning optical coherence tomography". Opt Lett. 2008 Jan 1;33(1):22-4.
The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.
Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and convert it into electro-chemical impulses in neurons (neurones). In higher organisms, the eye is a complex optical system which collects light from the surrounding environment, regulates its intensity through a diaphragm, focuses it through an adjustable assembly of lenses to form an image, converts this image into a set of electrical signals, and transmits these signals to the brain through complex neural pathways that connect the eye via the optic nerve to the visual cortex and other areas of the brain. Eyes with resolving power have come in ten fundamentally different forms, and 96% of animal species possess a complex optical system. Image-resolving eyes are present in molluscs, chordates and arthropods.
Adaptive optics (AO) is a technique of precisely deforming a mirror in order to compensate for light distortion. It is used in astronomical telescopes and laser communication systems to remove the effects of atmospheric distortion, in microscopy, optical fabrication and in retinal imaging systems to reduce optical aberrations. Adaptive optics works by measuring the distortions in a wavefront and compensating for them with a device that corrects those errors such as a deformable mirror or a liquid crystal array.
The macula (/ˈmakjʊlə/) or macula lutea is an oval-shaped pigmented area in the center of the retina of the human eye and in other animals. The macula in humans has a diameter of around 5.5 mm (0.22 in) and is subdivided into the umbo, foveola, foveal avascular zone, fovea, parafovea, and perifovea areas.
In visual physiology, adaptation is the ability of the retina of the eye to adjust to various levels of light. Natural night vision, or scotopic vision, is the ability to see under low-light conditions. In humans, rod cells are exclusively responsible for night vision as cone cells are only able to function at higher illumination levels. Night vision is of lower quality than day vision because it is limited in resolution and colors cannot be discerned; only shades of gray are seen. In order for humans to transition from day to night vision they must undergo a dark adaptation period of up to two hours in which each eye adjusts from a high to a low luminescence "setting", increasing sensitivity hugely, by many orders of magnitude. This adaptation period is different between rod and cone cells and results from the regeneration of photopigments to increase retinal sensitivity. Light adaptation, in contrast, works very quickly, within seconds.
Optical coherence tomography (OCT) is an imaging technique that uses interferometry with short-coherence-length light to obtain micrometer-level depth resolution and uses transverse scanning of the light beam to form two- and three-dimensional images from light reflected from within biological tissue or other scattering media. Short-coherence-length light can be obtained using a superluminescent diode (SLD) with a broad spectral bandwidth or a broadly tunable laser with narrow linewidth. The first demonstration of OCT imaging was published by a team from MIT and Harvard Medical School in a 1991 article in the journal Science. The article introduced the term "OCT" to credit its derivation from optical coherence-domain reflectometry, in which the axial resolution is based on temporal coherence. The first demonstrations of in vivo OCT imaging quickly followed.
The fovea centralis is a small, central pit composed of closely packed cones in the eye. It is located in the center of the macula lutea of the retina.
In physics, the wavefront of a time-varying wave field is the set (locus) of all points having the same phase. The term is generally meaningful only for fields that, at each point, vary sinusoidally in time with a single temporal frequency.
The blue field entoptic phenomenon is an entoptic phenomenon characterized by the appearance of tiny bright dots moving quickly along undulating pathways in the visual field, especially when looking into bright blue light such as the sky. The dots are short-lived, visible for about one second or less, and traveling short distances along seemingly random, undulating paths. Some of them seem to follow the same path as other dots before them. The dots may appear elongated along the path, like tiny worms. The dots' rate of travel appears to vary in synchrony with the heartbeat: they briefly accelerate at each beat. The dots appear in the central field of view, within 15 degrees from the fixation point. The left and right eye see different, seemingly random, dot patterns; a person viewing through both eyes sees a combination of both left and right visual field disturbances. While seeing the phenomenon, lightly pressing inward on the sides of the eyeballs at the lateral canthus causes the movement to stop being fluid and the dots to move only when the heart beats.
A cone dystrophy is an inherited ocular disorder characterized by the loss of cone cells, the photoreceptors responsible for both central and color vision.
Drusen, from the German word for node or geode, are tiny yellow or white accumulations of extracellular material that build up between Bruch's membrane and the retinal pigment epithelium of the eye. The presence of a few small ("hard") drusen is normal with advancing age, and most people over 40 have some hard drusen. However, the presence of larger and more numerous drusen in the macula is a common early sign of age-related macular degeneration (AMD).
The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to the underlying choroid and overlying retinal visual cells.
Epiretinal membrane or macular pucker is a disease of the eye in response to changes in the vitreous humor or more rarely, diabetes. Sometimes, as a result of immune system response to protect the retina, cells converge in the macular area as the vitreous ages and pulls away in posterior vitreous detachment (PVD).
Boston Micromachines Corporation is a US company operating out of Cambridge, Massachusetts. Boston Micromachines manufactures and develops instruments based on MEMS technology to perform open and closed-loop adaptive optics. The technology is applied in astronomy, beam shaping, vision science, retinal imaging, microscopy, laser communications, and national defense. The instruments developed at Boston Micromachines include deformable mirrors, optical modulators, and retinal imaging systems, all of which utilize adaptive optics technology to enable wavefront manipulation capabilities which enhance the quality of the final image.
Gholam A. Peyman is an Iranian American ophthalmologist, retina surgeon, and inventor. He is best known for his invention of LASIK eye surgery, a vision correction procedure designed to allow people to see clearly without glasses. He was awarded the first US patent for the procedure in 1989.
ALPAO is a company which manufactures a range of adaptive optics products for use in research and industry, including deformable mirrors with large strokes, wavefront sensors, and adaptive optics loops. These products are designed for astronomy, vision science, microscopy, wireless optical communications, and laser applications.
Microperimetry, sometimes called fundus-controlled perimetry, is a type of visual field test which uses one of several technologies to create a "retinal sensitivity map" of the quantity of light perceived in specific parts of the retina in people who have lost the ability to fixate on an object or light source. The main difference with traditional perimetry instruments is that, microperimetry includes a system to image the retina and an eye tracker to compensate eye movements during visual field testing.
Geographic atrophy (GA), also known as atrophic age-related macular degeneration (AMD) or advanced dry AMD, is an advanced form of age-related macular degeneration that can result in the progressive and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, choriocapillaris) which can lead to a loss of visual function over time. It is estimated that GA affects over 5 million people worldwide and approximately 1 million patients in the US, which is similar to the prevalence of neovascular (wet) AMD, the other advanced form of the disease.
Occult macular dystrophy (OMD) is a rare inherited degradation of the retina, characterized by progressive loss of function in the most sensitive part of the central retina (macula), the location of the highest concentration of light-sensitive cells (photoreceptors) but presenting no visible abnormality. "Occult" refers to the degradation in the fundus being difficult to discern. The disorder is called "dystrophy" instead of "degradation" to distinguish its genetic origin from other causes, such as age. OMD was first reported by Y. Miyake et al. in 1989.
Stem cell therapy for macular degeneration is the use of stem cells to heal, replace dead or damaged cells of the macula in the retina. Stem cell based therapies using bone marrow stem cells as well as retinal pigment epithelial transplantation are being studied. A number of trials have occurred in humans with encouraging results.
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