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Biomedical Optics Express

Biomedical Optics Express

  • Editor: Joseph A. Izatt
  • Vol. 2, Iss. 8 — Aug. 1, 2011
  • pp: 2189–2201
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Observation of cone and rod photoreceptors in normal subjects and patients using a new generation adaptive optics scanning laser ophthalmoscope

David Merino, Jacque L. Duncan, Pavan Tiruveedhula, and Austin Roorda  »View Author Affiliations


Biomedical Optics Express, Vol. 2, Issue 8, pp. 2189-2201 (2011)
http://dx.doi.org/10.1364/BOE.2.002189


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Abstract

We demonstrate the capability of a new generation adaptive optics scanning laser ophthalmoscope (AOSLO) to resolve cones and rods in normal subjects, and confirm our findings by comparing cone and rod spacing with published histology measurements. Cone and rod spacing measurements are also performed on AOSLO images from two different diseased eyes, one affected by achromatopsia and the other by acute zonal occult outer retinopathy (AZOOR). The potential of AOSLO technology in the study of these and other retinal diseases is illustrated.

© 2011 OSA

1. Introduction

In 1997, Liang et al. reported the first retinal imaging system equipped with adaptive optics (AO), showing high resolution images from retinas of several healthy subjects where the cone photoreceptor mosaic was clearly identified at different eccentricities [1

1. J. Liang, D. R. Williams, and D. T. Miller, “Supernormal vision and high-resolution retinal imaging through adaptive optics,” J. Opt. Soc. Am. A 14(11), 2884–2892 (1997). [CrossRef] [PubMed]

]. Although the cone photoreceptor mosaic had been observed before without the use of AO [2

2. D. T. Miller, D. R. Williams, G. M. Morris, and J. Liang, “Images of cone photoreceptors in the living human eye,” Vision Res. 36(8), 1067–1079 (1996). [CrossRef] [PubMed]

], using this technique increased the resolution of the images obtained compared to those of traditional fundus cameras.

AO imaging has been since widely used due to its potential to resolve microscopic structure in the in vivo human retina, and it has been successfully combined with scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) [3

3. A. Roorda, F. Romero-Borja, W. Donnelly III, H. Queener, T. Hebert, and M. Campbell, “Adaptive optics scanning laser ophthalmoscopy,” Opt. Express 10(9), 405–412 (2002). [PubMed]

7

7. D. Merino, C. Dainty, A. Bradu, and A. G. Podoleanu, “Adaptive optics enhanced simultaneous en-face optical coherence tomography and scanning laser ophthalmoscopy,” Opt. Express 14(8), 3345–3353 (2006). [CrossRef] [PubMed]

]. AO ophthalmoscopy systems have been used to study and characterize normal human retina [8

8. A. Roorda and D. R. Williams, “The arrangement of the three cone classes in the living human eye,” Nature 397(6719), 520–522 (1999). [CrossRef] [PubMed]

12

12. C. Torti, B. Považay, B. Hofer, A. Unterhuber, J. Carroll, P. K. Ahnelt, and W. Drexler, “Adaptive optics optical coherence tomography at 120,000 depth scans/s for non-invasive cellular phenotyping of the living human retina,” Opt. Express 17(22), 19382–19400 (2009). [CrossRef] [PubMed]

], to characterize changes in retinal structure caused by several different degenerative retinal diseases [13

13. J. I. Wolfing, M. Chung, J. Carroll, A. Roorda, and D. R. Williams, “High-resolution retinal imaging of cone-rod dystrophy,” Ophthalmology 113(6), 1014–1019.e1 (2006). [CrossRef] [PubMed]

23

23. S. Ooto, M. Hangai, A. Sakamoto, A. Tsujikawa, K. Yamashiro, Y. Ojima, Y. Yamada, H. Mukai, S. Oshima, T. Inoue, and N. Yoshimura, “High-resolution imaging of resolved central serous chorioretinopathy using adaptive optics scanning laser ophthalmoscopy,” Ophthalmology 117(9), 1800–1809.e2 (2010). [CrossRef] [PubMed]

], and to assess progression of these diseases and responses to treatment [24

24. K. E. Talcott, K. Ratnam, S. M. Sundquist, A. S. Lucero, B. J. Lujan, W. Tao, T. C. Porco, A. Roorda, and J. L. Duncan, “Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment,” Invest. Ophthalmol. Vis. Sci. 52(5), 2219–2226 (2011). [CrossRef] [PubMed]

].

Although the improvement in image quality produced with AO enhanced systems is clearly established [1

1. J. Liang, D. R. Williams, and D. T. Miller, “Supernormal vision and high-resolution retinal imaging through adaptive optics,” J. Opt. Soc. Am. A 14(11), 2884–2892 (1997). [CrossRef] [PubMed]

,3

3. A. Roorda, F. Romero-Borja, W. Donnelly III, H. Queener, T. Hebert, and M. Campbell, “Adaptive optics scanning laser ophthalmoscopy,” Opt. Express 10(9), 405–412 (2002). [PubMed]

7

7. D. Merino, C. Dainty, A. Bradu, and A. G. Podoleanu, “Adaptive optics enhanced simultaneous en-face optical coherence tomography and scanning laser ophthalmoscopy,” Opt. Express 14(8), 3345–3353 (2006). [CrossRef] [PubMed]

], it seems to have fallen behind the theoretical predictions of image resolution for aberration-free systems. Aberration-free systems are diffraction-limited, and therefore only the numerical aperture of the eye limits the resolution of the images obtained using them. In this sense, some retinal features such as foveal cones and rod photoreceptors should be visible when imaged using AO-enhanced systems if the pupil size of the subject imaged is large enough. Ongoing efforts to increase image quality of data obtained using AO enhanced systems have employed post-acquisition image processing, AO loop control development and the use of complex AO systems using more than one wavefront corrector [25

25. J. C. Christou, A. Roorda, and D. R. Williams, “Deconvolution of adaptive optics retinal images,” J. Opt. Soc. Am. A 21(8), 1393–1401 (2004). [CrossRef] [PubMed]

27

27. D. C. Chen, S. M. Jones, D. A. Silva, and S. S. Olivier, “High-resolution adaptive optics scanning laser ophthalmoscope with dual deformable mirrors,” J. Opt. Soc. Am. A 24(5), 1305–1312 (2007). [CrossRef] [PubMed]

].

In this article the results obtained with a new generation adaptive optics scanning laser ophthalmoscope (AOSLO) system are reported. In this system the optical design has been meticulously developed to minimize astigmatism in the pupil plane. To demonstrate its enhanced performance, the system has been used to image normal subjects and patients with retinal disease. This article presents data related to images of cone photoreceptors and structures that appear consistent with rod photoreceptors.

2. Optical design

In the new generation AOSLO system described here, the optical design has been based on that developed by Zhang et al. [28

28. Y. Zhang, S. Poonja, and A. Roorda, “MEMS-based adaptive optics scanning laser ophthalmoscopy,” Opt. Lett. 31(9), 1268–1270 (2006). [CrossRef] [PubMed]

], which is shown in Fig. 1a
Fig. 1 a) Optical design for a traditional AOSLO system with all the optical elements arranged along the same plane [28]. b) and c) show the optical design of the system presented in this paper from the light delivery beam and collection beam splitter (BS) to the eye. In b) and c) the beam reaches the different optical elements in the same order as in a), so the labels can help understand the light path. In b) and c) the optical elements are not arranged in just one plane, but they are placed at different heights. b) shows the projection of the system on the xy plane, and c) shows the same design projected on the yz plane.
. Usually, SLO systems are built using spherical mirrors rather than lenses. In this manner, back reflections from optical elements of the system are eliminated, avoiding their effect on the wavefront sensor measurements. However, in order to use spherical mirrors the light beam hits these elements at a certain angle with respect to the optical axis, introducing astigmatism in the beam. In traditional designs of retinal imaging systems, like the one shown in Fig. 1a, this incident angle is always contained in the same plane as the beam travels through the different optical elements. Astigmatism builds up after each reflection on a spherical mirror, and it is corrected at the eye pupil plane along with the subject’s prescription by means of trial lenses (TL in Fig. 1a). The back reflections of these trial lenses and the cornea are filtered by means of an iris labeled RF in Fig. 1a.

A consequence of avoiding astigmatism build up, as opposed to relying on its correction in the pupil plane using a trial lens, is an increase in the quality of the image of the pupil plane onto the wavefront sensor. The reconstruction of the wavefront of the probing beam should therefore be more accurate, and the quality of AO correction improved. The absence of astigmatism build up also reduces beam-wandering in the pupil plane. Beam wandering blurs the image of the wavefront pattern on the wavefront sensor, and reducing it improves the fidelity of the wavefront measurement.

As a consequence of optical design improvement, the size of the confocal pinhole was reduced in this system with respect to the system from Zhang et al. [28

28. Y. Zhang, S. Poonja, and A. Roorda, “MEMS-based adaptive optics scanning laser ophthalmoscopy,” Opt. Lett. 31(9), 1268–1270 (2006). [CrossRef] [PubMed]

], from 75μm to 25μm. This translates into an increase in the contrast of the acquired images due to better confocality of the system, and better resolution.

The deformable mirror used is a 140 actuator, 5.5μm maximum stroke MEMS mirror (Boston Micromachines, Cambridge, MA, USA). The high number of actuators in this deformable mirror allows good matching of the shape of the mirror with the wavefront measured by the wavefront sensor.

The wavelength of the illuminating beam chosen was 830nm. Although a shorter wavelength would produce a smaller diffraction spot, near infrared wavelengths such as the one chosen are much more comfortable for the subject under study. This is a very important point since imaging sessions are long and the results are better if the subject is comfortable, especially when they are not experienced in the imaging process. The optical power reaching the cornea was 300μW, which is more than 10 times below the maximum permissible exposure (MPE) set by the ANSI laser safety standards for a system like the one described.

According to the Rayleigh criterion, the resolution for a diffraction-limited imaging system like the one described here where the pupil is limited to a 6mm circle in the plane of the eye pupil, the lateral resolution would be of 2.8μm.

The system is at this moment being used routinely to image both normal subjects and patients with retinal diseases in a clinic environment.

3. Image acquisition methods

All research procedures described in this article were performed in accordance with the Declaration of Helsinki. The study protocol was approved by the institutional review boards of the University of California, San Francisco and the University of California at Berkeley. All subjects gave written informed consent before participation in the studies.

Pupils of 3 normal subjects were dilated with 1% tropicamide and 2.5% phenylephrine prior to AOSLO imaging. Videos of small patches (0.7° to 1.2° size squares) of the subjects’ retinas at different locations were recorded at 30 frames per second. Single frames of these videos were warped due to sinusoidal scanning in the horizontal axis from the resonant scanner used. The images were de-warped and scaled using images of a characterized model eye with MATLAB (MathWorks, Natik, MA, USA) software developed by Dubra et al. [33

33. A. Dubra, “Monochrome AVI desinusoid software,” http://www.cvs.rochester.edu/dubralab/image_processing/index.htm.

]. Involuntary eye movements were also corrected in order to average a number of stabilized images and reduce noise [34

34. S. B. Stevenson and A. Roorda, “Correcting for miniature eye movements in high resolution scanning laser ophthalmoscopy,” Proc. SPIE 5688A, 145–151 (2005). [CrossRef]

]. The number of images averaged to reduce noise depended on the subject, but more than 30 images were usually used. Images of different areas of the retina were then assembled together after averaging to create a montage of a retinal area that covered up to 13° eccentricity from the central fovea.

4. Study of normal healthy eyes

Figure 2
Fig. 2 Cone spacing vs eccentricity: 1. Cone spacing computed from AOSLO images of 3 different healthy subjects (◇ nasal direction, □◯ inferior direction); 2. Cone spacing computed from published histological images (black solid circles) by Curcio et al. [35]; 3. Cone spacing in the temporal (solid line) and nasal (dotted line) directions inferred from density data reported by Curcio et al. [35].
shows cone spacing measurements from these montages at different eccentricities. Cone spacing was calculated as described by Rodieck [16

16. J. L. Duncan, Y. Zhang, J. Gandhi, C. Nakanishi, M. Othman, K. E. H. Branham, A. Swaroop, and A. Roorda, “High-resolution imaging with adaptive optics in patients with inherited retinal degeneration,” Invest. Ophthalmol. Vis. Sci. 48(7), 3283–3291 (2007). [CrossRef] [PubMed]

,36

36. R. W. Rodieck, “The density recovery profile: a method for analysis of points in the plane applicable to retinal studies,” Vis. Neurosci. 20(3), 349 (2003). [CrossRef] [PubMed]

], and in order to transform angular separation in the retina into distances the assumption of 289 μm/deg was followed [37

37. A. G. Bennett, A. R. Rudnicka, and D. F. Edgar, “Improvements on Littmann’s method of determining the size of retinal features by fundus photography,” Graefes Arch. Clin. Exp. Ophthalmol. 232(6), 361–367 (1994). [CrossRef] [PubMed]

,38

38. E. A. Rossi, P. Weiser, J. Tarrant, and A. Roorda, “Visual performance in emmetropia and low myopia after correction of high-order aberrations,” J. Vis. 7(8), 14 (2007). [CrossRef] [PubMed]

]. The error bars show the range of cone-to-cone distances that include 95% of the measurements performed. The same method was used to characterize cone spacing from histological images from Curcio et al. [35

35. C. A. Curcio, K. R. Sloan, R. E. Kalina, and A. E. Hendrickson, “Human photoreceptor topography,” J. Comp. Neurol. 292(4), 497–523 (1990). [CrossRef] [PubMed]

]. Also, average cone density measurements obtained from histological images by Curcio et al. were used to calculate cone spacing at different eccentricities. No error bars could be determined for these data.

Since AOSLO images are obtained in vivo, the range of eccentricities where cone spacing can be measured is limited, in contrast to the range of regions that can be studied in histological sections. At high incidence angles, the subject’s pupil becomes effectively elliptical, clipping the probing beam, and obstructing wavefront sensor measurements to determine the aberrations of the eye. Also, oblique incidence in the eye introduces high amounts of astigmatism in the beam which degrade the image quality, making it difficult to obtain cone spacing measurements.

At low eccentricities (up to 10°), cone spacing measurements derived from AOSLO images, histological images and cone density measurements are in agreement. However, differences appear between data derived from histological images and cone density measurements at high eccentricities. Each of the points in the graph showing cone spacing data from histological images is obtained from a particular image of a single subject. However, cone density measurements are averaged over a series of subjects. This may explain the differences between these two sources at high eccentricities. It should be mentioned that AOSLO data presented here was collected at different directions from the fovea including nasal and inferior to the fovea.

The authors believe the results presented in Fig. 2 validate the technique used to calculate cone spacing, and similarly, distance measurements within the retinal images obtained using AOSLO.

However, the data presented here clearly shows that the smaller structures visible in AOSLO images do not correspond to cone photoreceptors, and that the data obtained from previously published histological images of rods is compatible in terms of spacing.

5. Study of diseased eyes

5.1. Achromatopsia

The left eye of a 39 year old male patient with incomplete achromatopsia caused by a mutation in the cyclic nucleotide-gated channel, beta 3 (CNGB3) gene was imaged using AOSLO following the procedures described in section 4.

Achromatopsia is a disease characterized by lack of color discrimination, low visual acuity beginning at birth, and nystagmus. Electroretinograms (ERGs) show very little or no cone function. Rod photoreceptors are responsible for visual function. Many genetic causes of achromatopsia have been identified, including mutations in the cyclic nucleotide-gated channel, beta-3 [43

43. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), “Online Mendelian inheritance in man, OMIM (TM),” http://www.ncbi.nlm.nih.gov/omim/.

].

Genomic DNA was obtained from the patient’s white blood cells. DNA was directly sequenced through the portions of the coding sequences of the CNGA3 and CNGB3 genes that have been previously reported to harbor achromatopsia-causing genetic variations. One homozygous sequence variation was present in the coding sequence of the CNGB3 gene, a homozygous 1 base pair deletion of C at codon 283, predicted to result in a high-penetrance disease-causing sequence variation. Color vision was examined using the Farnsworth Dichotomous Test D-15 [44

44. D. Farnsworth, “The Farnsworth dichotomous test for color blindness-Panel D-15,” Psychological Corporation (1947).

]. The data were analyzed using a web-based platform scoring method [45

45. B. Török, “WEB-based scoring software for the Farnsworth-Munsell 100-Hue, Roth 28-Hue, Farnsworth D-15, and the Lanthony D-15 desaturated color tests,” http://www.torok.info/colorvision.

], and the error scores were calculated using methods proposed by Bowman [46

46. K. J. Bowman, “A method for quantitative scoring of the Farnsworth Panel D-15,” Acta Ophthalmol. (Copenh.) 60(6), 907–916 (1982). [CrossRef] [PubMed]

]. The Total Color Difference Score was 374.9 in the right eye (OD) and 294.8 in the left eye (OS), and the Color Confusion Index (CCI = TCDS actual/TCDS normal) was 3.20 OD and 2.52 OS, consistent with pathologic color discrimination and a diffuse color discrimination error.

Pupils were dilated with 1% tropicamide and 2.5% phenylephrine prior to obtaining OCT and infrared SLO images (Spectralis HRA + OCT Laser Scanning Camera System, Heidelberg Engineering, Vista, CA, USA).

Figure 5
Fig. 5 AOSLO retinal images at different eccentricities for a normal subject and a 39 year old patient with achromatopsia. The patient’s prescription on the eye imaged was −4.50sph, +0.50cyl, axis105 deg. Scale bar is 20 μm.
shows images obtained using AOSLO as described in section 3, comparing patches of the retina at different eccentricities for a healthy subject and the patient with achromatopsia. In the OCT image of the patient in Fig. 6
Fig. 6 OCT image from a normal subject (left) and an achromatopsia patient (right). Due to nystagmus it was difficult to acquire an OCT image at the exact center of the anatomical fovea of the achromatopsia patient. The image presented is the closest to the anatomical fovea that could be acquired. The image shows ELM (bright), IS (dark) and OS (dark) layers visible throughout both images.
, reflections corresponding to an intact photoreceptor layer (external limiting membrane, ELM, and inner segment/outer segment, IS/OS, junction layers) are present throughout the macular area imaged. These intact structures provide support that the features seen in the AOSLO image are indeed photoreceptors. The figure also shows an OCT image obtained from a normal subject for comparison purposes.

Spacing between photoreceptors present in the AOSLO images was calculated at different eccentricities, and the results are shown in Fig. 7
Fig. 7 Cone (squares) and rod (circles) spacing calculated from AOLSO images for 3 different healthy subjects (open symbols), a patient with achromatopsia (black filled symbols) and a patient with AZOOR (grey filled symbols).
.

It is possible that the photoreceptors at the anatomic fovea are abnormal cones, since the patient perceived some color vision. However, Fig. 7 shows spacing for these cone photoreceptors is greater than normal at corresponding eccentricities. Also, the fovea in the AOSLO montage appeared darker than what is typically observed in normal subjects. The cause for this could perhaps be the fact that photoreceptors in that area are not normal cones, or because other factors may influence photoreceptor reflectivity in achromatopsia.

Figure 5 shows dark spots evident at eccentricities 7° and 11°. These dark spots are observed throughout the retina and, although they may represent cones, they are too far apart to be considered normally spaced. The low reflectivity areas observed in AOSLO images may be a consequence of diffuse abnormalities of cone function and structure caused by mutation in the CNGB3 gene [47

47. J. Carroll, S. S. Choi, and D. R. Williams, “In vivo imaging of the photoreceptor mosaic of a rod monochromat,” Vision Res. 48(26), 2564–2568 (2008). [CrossRef] [PubMed]

]. Figure 7 also shows photoreceptor spacing calculated for larger eccentricities. In this case spacing is too small for the photoreceptor cells identified to be considered cones, as reported by Carroll et al. [47

47. J. Carroll, S. S. Choi, and D. R. Williams, “In vivo imaging of the photoreceptor mosaic of a rod monochromat,” Vision Res. 48(26), 2564–2568 (2008). [CrossRef] [PubMed]

], and the cells imaged are more consistent with rods, albeit with larger spacing.

From all the data compiled, the scenario is compatible with the patient having abnormal cones at the anatomical fovea that have increased spacing and reduced density compared with normal subjects. However, the cones retain some function, which provide the patient with residual, but abnormal, color vision. These abnormal cones are not as reflective as normal cones, which is compatible with the fact that the patient’s fovea is darker than that of normal subjects studied using AOSLO. Also, low reflectivity of abnormal cones would appear at higher eccentricities as dark spots, also observed in AOSLO images. Finally, the measurements of photoreceptor spacing in the current image show structures that are larger than normal rods, although smaller than normal cones.

Histological studies on achromatopsia have come to different conclusions as to whether central photoreceptors in patients with achromatopsia represent abnormal foveal cones or rods [48

48. H. F. Falls, J. R. Wolter, and M. Alpern, “Typical total monochromacy. A histological and psychophysical study,” Arch. Ophthalmol. 74(5), 610–616 (1965). [PubMed]

50

50. M. Glickstein and G. G. Heath, “Receptors in the monochromat eye,” Vision Res. 15(6), 633–636 (1975). [CrossRef] [PubMed]

]. The findings in this paper are compatible with the conclusion that abnormal cones are observed in the fovea of this patient, and that photoreceptors imaged in the retinal periphery are most likely rods with abnormally increased spacing [48

48. H. F. Falls, J. R. Wolter, and M. Alpern, “Typical total monochromacy. A histological and psychophysical study,” Arch. Ophthalmol. 74(5), 610–616 (1965). [PubMed]

].

5.2. AZOOR

The left eye of a patient that was diagnosed with AZOOR was studied. This 46 year old woman presented with acute onset of photopsias within a relative scotoma beginning from 4 to 6 degrees nasal to fixation in the left eye. Figure 8
Fig. 8 Visual field, infrared scanning laser ophthalmoscope image and OCT B-scan of an AZOOR patient. The two visual fields on the top panel show the deviation from normal (pattern deviation) over a 60 degree visual field. The numbers on the left field indicate the sensitivity difference from normal in decibels. The right field plots the probability that the visual sensitivity is part of a normal distribution. The relative scotoma starts between 4 and 6 degrees to the right of the fovea. The SLO fundus image (middle panel) spans 30 degrees and the location of the OCT B-scan (bottom panel) is indicated by the dashed white line. The arrow at 4.5 degrees corresponds to the point beyond which the regular mosaic of cones is no longer visible (Fig. 9). The OCT B-scan shows reflections, corresponding to an intact ELM and IS/OS junction, that persist into the relative scotoma, although the magnitude of the reflection is reduced.
shows the visual field (Pattern Deviation plots, Humphrey 30-2, Carl Zeiss Meditec AG) as well as imaging results. OCT images of this eye showed reflections of the ELM and the IS/OS junction through the relative scotoma. Although the reflections were decreased in intensity within the relative scotoma, their presence was consistent with the presence of a contiguous array of waveguiding photoreceptors. AOSLO images at different eccentricities were also acquired as detailed in section 3 on the area of the retina corresponding to the OCT scan shown in Fig. 8. Some patches of the montage assembled with these images are shown in Fig. 9
Fig. 9 AOSLO images from an eye of a 46 year old female patient affected by AZOOR. The top images correspond to 4 different eccentricities. Images at 1.5° and 2.5° eccentricity are outside the scotoma, while images at 6° and 7° eccentricity are within it. The bottom image, centered at 4.5° eccentricity, corresponds to the edge of the area where cones are not visible. The patient’s prescription was −1.50 sph, +1.25 cyl, axis 90 deg. Scale bar is 20μm.
. Areas outside the relative scotoma (in this case 1.5° and 2.5°) show a typical photoreceptor mosaic, also seen in the pictures of a normal eye in Fig. 5. However, images within the relative scotoma (6° and 7° in this case), do not show the usual mosaic structure. The cone mosaic appears normal around the relative scotoma, but is not seen within it. The edge of the area of the relative scotoma was imaged and is shown in the bottom image of Fig. 9. The interface between the areas with and without cones is very well-defined.

Cone spacing was calculated in regions of the AOSLO montage, and the results are shown in Fig. 7. Cones appear normally spaced outside the relative scotoma, and correspond to retinal regions with normal visual function. Within the relative scotoma, cones are not visualized, and the spacing of the visible structures corresponds better with spacing from rods of healthy eyes, although with increased spacing. This suggests that, in this patient with AZOOR, significant loss of cone photoreceptors within the relative scotoma has occurred, while the rods have remained relatively unaffected. The increased spacing of the rods compared to normal may have occurred because they have spread out to fill in the spaces left behind by degenerated cones. A more extensive report of this and other AZOOR patients, including functional and structural testing, is part of a second manuscript [56

56. M. Mkrtchyan, B. J. Lujan, D. Merino, C. E. Thirkill, A. Roorda, and J. Duncan, “Outer retinal structure in patients with acute zonal occult outer retinopathy,” submitted toAm. J. Ophthalmol. .

].

6. Conclusion

AOSLO images from an eye affected by AZOOR were also analyzed. Normal retina was observed in the areas with normal visual function. Discontinuity in the cone photoreceptor mosaic in the area of the relative scotoma was observed [51

51. J. D. M. Gass, “Acute zonal occult outer retinopathy. Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992,” J. Clin. Neuroophthalmol. 13(2), 79–97 (1993). [PubMed]

,52

52. D. M. Monson and J. R. Smith, “Acute zonal occult outer retinopathy,” Surv. Ophthalmol. 56(1), 23–35 (2011). [CrossRef] [PubMed]

]. Photoreceptor spacing in the area of the relative scotoma is consistent with the existence of rod photoreceptors.

AOSLO has been shown to be able to detect not only the cone photoreceptor mosaic, but also that of rods. Both cone and rod photoreceptors were detected and characterized not only in healthy subjects but also in patients with different diseases. This feature opens the possibility of using AOSLO images to study new parameters in retinal diseases to improve understanding and to facilitate the development of possible treatments.

Acknowledgments

Thanks to Brandon Lujan and Marianna Mkrtchyan for their assistance with this manuscript. This publication was made possible by grants from the National Institutes of Health—National Eye Institute, numbers EY014375 (AR) and EY002162 (JLD), in addition to the Foundation Fighting Blindness, a Physician-Scientist Award, and unrestricted funds from Research to Prevent Blindness, That Man May See, Inc., The Bernard A. Newcomb Macular Degeneration Fund, and Hope for Vision.

References and links

1.

J. Liang, D. R. Williams, and D. T. Miller, “Supernormal vision and high-resolution retinal imaging through adaptive optics,” J. Opt. Soc. Am. A 14(11), 2884–2892 (1997). [CrossRef] [PubMed]

2.

D. T. Miller, D. R. Williams, G. M. Morris, and J. Liang, “Images of cone photoreceptors in the living human eye,” Vision Res. 36(8), 1067–1079 (1996). [CrossRef] [PubMed]

3.

A. Roorda, F. Romero-Borja, W. Donnelly III, H. Queener, T. Hebert, and M. Campbell, “Adaptive optics scanning laser ophthalmoscopy,” Opt. Express 10(9), 405–412 (2002). [PubMed]

4.

B. Hermann, E. J. Fernández, A. Unterhuber, H. Sattmann, A. F. Fercher, W. Drexler, P. M. Prieto, and P. Artal, “Adaptive-optics ultrahigh-resolution optical coherence tomography,” Opt. Lett. 29(18), 2142–2144 (2004). [CrossRef] [PubMed]

5.

Y. Zhang, J. Rha, R. S. Jonnal, and D. T. Miller, “Adaptive optics parallel spectral domain optical coherence tomography for imaging the living retina,” Opt. Express 13(12), 4792–4811 (2005). [CrossRef] [PubMed]

6.

R. J. Zawadzki, S. M. Jones, S. S. Olivier, M. Zhao, B. A. Bower, J. A. Izatt, S. Choi, S. Laut, and J. S. Werner, “Adaptive-optics optical coherence tomography for high-resolution and high-speed 3D retinal in vivo imaging,” Opt. Express 13(21), 8532–8546 (2005). [CrossRef] [PubMed]

7.

D. Merino, C. Dainty, A. Bradu, and A. G. Podoleanu, “Adaptive optics enhanced simultaneous en-face optical coherence tomography and scanning laser ophthalmoscopy,” Opt. Express 14(8), 3345–3353 (2006). [CrossRef] [PubMed]

8.

A. Roorda and D. R. Williams, “The arrangement of the three cone classes in the living human eye,” Nature 397(6719), 520–522 (1999). [CrossRef] [PubMed]

9.

K. Y. Li, P. Tiruveedhula, and A. Roorda, “Intersubject variability of foveal cone photoreceptor density in relation to eye length,” Invest. Ophthalmol. Vis. Sci. 51(12), 6858–6867 (2010). [CrossRef] [PubMed]

10.

R. S. Jonnal, J. R. Besecker, J. C. Derby, O. P. Kocaoglu, B. Cense, W. Gao, Q. Wang, and D. T. Miller, “Imaging outer segment renewal in living human cone photoreceptors,” Opt. Express 18(5), 5257–5270 (2010). [CrossRef] [PubMed]

11.

T. Y. Chui, H. Song, and S. A. Burns, “Adaptive-optics imaging of human cone photoreceptor distribution,” J. Opt. Soc. Am. A 25(12), 3021–3029 (2008). [CrossRef] [PubMed]

12.

C. Torti, B. Považay, B. Hofer, A. Unterhuber, J. Carroll, P. K. Ahnelt, and W. Drexler, “Adaptive optics optical coherence tomography at 120,000 depth scans/s for non-invasive cellular phenotyping of the living human retina,” Opt. Express 17(22), 19382–19400 (2009). [CrossRef] [PubMed]

13.

J. I. Wolfing, M. Chung, J. Carroll, A. Roorda, and D. R. Williams, “High-resolution retinal imaging of cone-rod dystrophy,” Ophthalmology 113(6), 1014–1019.e1 (2006). [CrossRef] [PubMed]

14.

S. S. Choi, N. Doble, J. L. Hardy, S. M. Jones, J. L. Keltner, S. S. Olivier, and J. S. Werner, “In vivo imaging of the photoreceptor mosaic in retinal dystrophies and correlations with visual function,” Invest. Ophthalmol. Vis. Sci. 47(5), 2080–2092 (2006). [CrossRef] [PubMed]

15.

Y. Kitaguchi, T. Fujikado, K. Bessho, H. Sakaguchi, F. Gomi, T. Yamaguchi, N. Nakazawa, T. Mihashi, and Y. Tano, “Adaptive optics fundus camera to examine localized changes in the photoreceptor layer of the fovea,” Ophthalmology 115(10), 1771–1777 (2008). [CrossRef] [PubMed]

16.

J. L. Duncan, Y. Zhang, J. Gandhi, C. Nakanishi, M. Othman, K. E. H. Branham, A. Swaroop, and A. Roorda, “High-resolution imaging with adaptive optics in patients with inherited retinal degeneration,” Invest. Ophthalmol. Vis. Sci. 48(7), 3283–3291 (2007). [CrossRef] [PubMed]

17.

S. S. Choi, R. J. Zawadzki, J. L. Keltner, and J. S. Werner, “Changes in cellular structures revealed by ultra-high resolution retinal imaging in optic neuropathies,” Invest. Ophthalmol. Vis. Sci. 49(5), 2103–2119 (2008). [CrossRef] [PubMed]

18.

M. K. Yoon, A. Roorda, Y. Zhang, C. Nakanishi, L.-J. C. Wong, Q. Zhang, L. Gillum, A. Green, and J. L. Duncan, “Adaptive optics scanning laser ophthalmoscopy images in a family with the mitochondrial DNA T8993C mutation,” Invest. Ophthalmol. Vis. Sci. 50(4), 1838–1847 (2009). [CrossRef] [PubMed]

19.

J. L. Duncan, K. E. Talcott, K. Ratnam, S. M. Sundquist, A. S. Lucero, S. Day, Y. Zhang, and A. Roorda, “Cone structure in retinal degeneration associated with mutations in the peripherin/RDS gene,” Invest. Ophthalmol. Vis. Sci. 52(3), 1557–1566 (2011). [CrossRef] [PubMed]

20.

P. Godara, A. M. Dubis, A. Roorda, J. L. Duncan, and J. Carroll, “Adaptive optics retinal imaging: emerging clinical applications,” Optom. Vis. Sci. 87(12), 930–941 (2010). [CrossRef] [PubMed]

21.

J. Rha, A. M. Dubis, M. Wagner-Schuman, D. M. Tait, P. Godara, B. Schroeder, K. Stepien, and J. Carroll, “Spectral domain optical coherence tomography and adaptive optics: imaging photoreceptor layer morphology to interpret preclinical phenotypes,” Adv. Exp. Med. Biol. 664, 309–316 (2010). [CrossRef] [PubMed]

22.

S. S. Choi, R. J. Zawadzki, M. C. Lim, J. D. Brandt, J. L. Keltner, N. Doble, and J. S. Werner, “Evidence of outer retinal changes in glaucoma patients as revealed by ultrahigh-resolution in vivo retinal imaging,” Br. J. Ophthalmol. 95(1), 131–141 (2011). [CrossRef] [PubMed]

23.

S. Ooto, M. Hangai, A. Sakamoto, A. Tsujikawa, K. Yamashiro, Y. Ojima, Y. Yamada, H. Mukai, S. Oshima, T. Inoue, and N. Yoshimura, “High-resolution imaging of resolved central serous chorioretinopathy using adaptive optics scanning laser ophthalmoscopy,” Ophthalmology 117(9), 1800–1809.e2 (2010). [CrossRef] [PubMed]

24.

K. E. Talcott, K. Ratnam, S. M. Sundquist, A. S. Lucero, B. J. Lujan, W. Tao, T. C. Porco, A. Roorda, and J. L. Duncan, “Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment,” Invest. Ophthalmol. Vis. Sci. 52(5), 2219–2226 (2011). [CrossRef] [PubMed]

25.

J. C. Christou, A. Roorda, and D. R. Williams, “Deconvolution of adaptive optics retinal images,” J. Opt. Soc. Am. A 21(8), 1393–1401 (2004). [CrossRef] [PubMed]

26.

K. Y. Li, S. Mishra, P. Tiruveedhula, and A. Roorda, “Comparison of control algorithms for a MEMS-based adaptive optics scanning laser ophthalmoscope,” in American Control Conference, 2009. ACC '09 (IEEE, 2009), pp. 3848–3853.

27.

D. C. Chen, S. M. Jones, D. A. Silva, and S. S. Olivier, “High-resolution adaptive optics scanning laser ophthalmoscope with dual deformable mirrors,” J. Opt. Soc. Am. A 24(5), 1305–1312 (2007). [CrossRef] [PubMed]

28.

Y. Zhang, S. Poonja, and A. Roorda, “MEMS-based adaptive optics scanning laser ophthalmoscopy,” Opt. Lett. 31(9), 1268–1270 (2006). [CrossRef] [PubMed]

29.

A. Gómez-Vieyra, A. Dubra, D. Malacara-Hernández, and D. R. Williams, “First-order design of off-axis reflective ophthalmic adaptive optics systems using afocal telescopes,” Opt. Express 17(21), 18906–18919 (2009). [CrossRef] [PubMed]

30.

S. A. Burns, R. Tumbar, A. E. Elsner, D. Ferguson, and D. X. Hammer, “Large-field-of-view, modular, stabilized, adaptive-optics-based scanning laser ophthalmoscope,” J. Opt. Soc. Am. A 24(5), 1313–1326 (2007). [CrossRef] [PubMed]

31.

A. Dubra and Y. Sulai, “Reflective afocal broadband adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(6), 1757–1768 (2011). [CrossRef] [PubMed]

32.

A. Dubra, Y. Sulai, J. L. Norris, R. F. Cooper, A. M. Dubis, D. R. Williams, and J. Carroll, “Non-invasive in vivo imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(7), 1864–1876 (2011). [CrossRef]

33.

A. Dubra, “Monochrome AVI desinusoid software,” http://www.cvs.rochester.edu/dubralab/image_processing/index.htm.

34.

S. B. Stevenson and A. Roorda, “Correcting for miniature eye movements in high resolution scanning laser ophthalmoscopy,” Proc. SPIE 5688A, 145–151 (2005). [CrossRef]

35.

C. A. Curcio, K. R. Sloan, R. E. Kalina, and A. E. Hendrickson, “Human photoreceptor topography,” J. Comp. Neurol. 292(4), 497–523 (1990). [CrossRef] [PubMed]

36.

R. W. Rodieck, “The density recovery profile: a method for analysis of points in the plane applicable to retinal studies,” Vis. Neurosci. 20(3), 349 (2003). [CrossRef] [PubMed]

37.

A. G. Bennett, A. R. Rudnicka, and D. F. Edgar, “Improvements on Littmann’s method of determining the size of retinal features by fundus photography,” Graefes Arch. Clin. Exp. Ophthalmol. 232(6), 361–367 (1994). [CrossRef] [PubMed]

38.

E. A. Rossi, P. Weiser, J. Tarrant, and A. Roorda, “Visual performance in emmetropia and low myopia after correction of high-order aberrations,” J. Vis. 7(8), 14 (2007). [CrossRef] [PubMed]

39.

T. Y. P. Chui, H. Song, and S. A. Burns, “Individual variations in human cone photoreceptor packing density: variations with refractive error,” Invest. Ophthalmol. Vis. Sci. 49(10), 4679–4687 (2008). [CrossRef] [PubMed]

40.

J. M. Enoch, “Wave-guide modes in retinal receptors,” Science 133(3461), 1353–1354 (1961). [CrossRef] [PubMed]

41.

C. A. Curcio and K. R. Sloan, “Packing geometry of human cone photoreceptors: variation with eccentricity and evidence for local anisotropy,” Vis. Neurosci. 9(2), 169–180 (1992). [CrossRef] [PubMed]

42.

N. Doble, S. S. Choi, J. L. Codona, J. Christou, J. M. Enoch, and D. R. Williams, “In vivo imaging of the human rod photoreceptor mosaic,” Opt. Lett. 36(1), 31–33 (2011). [CrossRef] [PubMed]

43.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), “Online Mendelian inheritance in man, OMIM (TM),” http://www.ncbi.nlm.nih.gov/omim/.

44.

D. Farnsworth, “The Farnsworth dichotomous test for color blindness-Panel D-15,” Psychological Corporation (1947).

45.

B. Török, “WEB-based scoring software for the Farnsworth-Munsell 100-Hue, Roth 28-Hue, Farnsworth D-15, and the Lanthony D-15 desaturated color tests,” http://www.torok.info/colorvision.

46.

K. J. Bowman, “A method for quantitative scoring of the Farnsworth Panel D-15,” Acta Ophthalmol. (Copenh.) 60(6), 907–916 (1982). [CrossRef] [PubMed]

47.

J. Carroll, S. S. Choi, and D. R. Williams, “In vivo imaging of the photoreceptor mosaic of a rod monochromat,” Vision Res. 48(26), 2564–2568 (2008). [CrossRef] [PubMed]

48.

H. F. Falls, J. R. Wolter, and M. Alpern, “Typical total monochromacy. A histological and psychophysical study,” Arch. Ophthalmol. 74(5), 610–616 (1965). [PubMed]

49.

R. Harrison, D. Hoefnagel, and J. N. Hayward, “Congenital total color blindness: a clincopathological report,” Arch. Ophthalmol. 64, 685–692 (1960). [PubMed]

50.

M. Glickstein and G. G. Heath, “Receptors in the monochromat eye,” Vision Res. 15(6), 633–636 (1975). [CrossRef] [PubMed]

51.

J. D. M. Gass, “Acute zonal occult outer retinopathy. Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992,” J. Clin. Neuroophthalmol. 13(2), 79–97 (1993). [PubMed]

52.

D. M. Monson and J. R. Smith, “Acute zonal occult outer retinopathy,” Surv. Ophthalmol. 56(1), 23–35 (2011). [CrossRef] [PubMed]

53.

D. Li and S. Kishi, “Loss of photoreceptor outer segment in acute zonal occult outer retinopathy,” Arch. Ophthalmol. 125(9), 1194–1200 (2007). [CrossRef] [PubMed]

54.

N. Zibrandtsen, I. C. Munch, K. Klemp, T. M. Jørgensen, B. Sander, and M. Larsen, “Photoreceptor atrophy in acute zonal occult outer retinopathy,” Acta Ophthalmol. (Copenh.) 86(8), 913–916 (2008). [CrossRef] [PubMed]

55.

H. F. Fine, R. F. Spaide, E. H. Ryan Jr, Y. Matsumoto, and L. A. Yannuzzi, “Acute zonal occult outer retinopathy in patients with multiple evanescent white dot syndrome,” Arch. Ophthalmol. 127(1), 66–70 (2009). [CrossRef] [PubMed]

56.

M. Mkrtchyan, B. J. Lujan, D. Merino, C. E. Thirkill, A. Roorda, and J. Duncan, “Outer retinal structure in patients with acute zonal occult outer retinopathy,” submitted toAm. J. Ophthalmol. .

OCIS Codes
(010.1080) Atmospheric and oceanic optics : Active or adaptive optics
(170.0110) Medical optics and biotechnology : Imaging systems
(170.4460) Medical optics and biotechnology : Ophthalmic optics and devices
(170.4470) Medical optics and biotechnology : Ophthalmology

ToC Category:
Ophthalmology Applications

History
Original Manuscript: May 27, 2011
Revised Manuscript: June 24, 2011
Manuscript Accepted: July 2, 2011
Published: July 8, 2011

Citation
David Merino, Jacque L. Duncan, Pavan Tiruveedhula, and Austin Roorda, "Observation of cone and rod photoreceptors in normal subjects and patients using a new generation adaptive optics scanning laser ophthalmoscope," Biomed. Opt. Express 2, 2189-2201 (2011)
http://www.opticsinfobase.org/boe/abstract.cfm?URI=boe-2-8-2189


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References

  1. J. Liang, D. R. Williams, and D. T. Miller, “Supernormal vision and high-resolution retinal imaging through adaptive optics,” J. Opt. Soc. Am. A 14(11), 2884–2892 (1997). [CrossRef] [PubMed]
  2. D. T. Miller, D. R. Williams, G. M. Morris, and J. Liang, “Images of cone photoreceptors in the living human eye,” Vision Res. 36(8), 1067–1079 (1996). [CrossRef] [PubMed]
  3. A. Roorda, F. Romero-Borja, W. Donnelly III, H. Queener, T. Hebert, and M. Campbell, “Adaptive optics scanning laser ophthalmoscopy,” Opt. Express 10(9), 405–412 (2002). [PubMed]
  4. B. Hermann, E. J. Fernández, A. Unterhuber, H. Sattmann, A. F. Fercher, W. Drexler, P. M. Prieto, and P. Artal, “Adaptive-optics ultrahigh-resolution optical coherence tomography,” Opt. Lett. 29(18), 2142–2144 (2004). [CrossRef] [PubMed]
  5. Y. Zhang, J. Rha, R. S. Jonnal, and D. T. Miller, “Adaptive optics parallel spectral domain optical coherence tomography for imaging the living retina,” Opt. Express 13(12), 4792–4811 (2005). [CrossRef] [PubMed]
  6. R. J. Zawadzki, S. M. Jones, S. S. Olivier, M. Zhao, B. A. Bower, J. A. Izatt, S. Choi, S. Laut, and J. S. Werner, “Adaptive-optics optical coherence tomography for high-resolution and high-speed 3D retinal in vivo imaging,” Opt. Express 13(21), 8532–8546 (2005). [CrossRef] [PubMed]
  7. D. Merino, C. Dainty, A. Bradu, and A. G. Podoleanu, “Adaptive optics enhanced simultaneous en-face optical coherence tomography and scanning laser ophthalmoscopy,” Opt. Express 14(8), 3345–3353 (2006). [CrossRef] [PubMed]
  8. A. Roorda and D. R. Williams, “The arrangement of the three cone classes in the living human eye,” Nature 397(6719), 520–522 (1999). [CrossRef] [PubMed]
  9. K. Y. Li, P. Tiruveedhula, and A. Roorda, “Intersubject variability of foveal cone photoreceptor density in relation to eye length,” Invest. Ophthalmol. Vis. Sci. 51(12), 6858–6867 (2010). [CrossRef] [PubMed]
  10. R. S. Jonnal, J. R. Besecker, J. C. Derby, O. P. Kocaoglu, B. Cense, W. Gao, Q. Wang, and D. T. Miller, “Imaging outer segment renewal in living human cone photoreceptors,” Opt. Express 18(5), 5257–5270 (2010). [CrossRef] [PubMed]
  11. T. Y. Chui, H. Song, and S. A. Burns, “Adaptive-optics imaging of human cone photoreceptor distribution,” J. Opt. Soc. Am. A 25(12), 3021–3029 (2008). [CrossRef] [PubMed]
  12. C. Torti, B. Považay, B. Hofer, A. Unterhuber, J. Carroll, P. K. Ahnelt, and W. Drexler, “Adaptive optics optical coherence tomography at 120,000 depth scans/s for non-invasive cellular phenotyping of the living human retina,” Opt. Express 17(22), 19382–19400 (2009). [CrossRef] [PubMed]
  13. J. I. Wolfing, M. Chung, J. Carroll, A. Roorda, and D. R. Williams, “High-resolution retinal imaging of cone-rod dystrophy,” Ophthalmology 113(6), 1014–1019.e1 (2006). [CrossRef] [PubMed]
  14. S. S. Choi, N. Doble, J. L. Hardy, S. M. Jones, J. L. Keltner, S. S. Olivier, and J. S. Werner, “In vivo imaging of the photoreceptor mosaic in retinal dystrophies and correlations with visual function,” Invest. Ophthalmol. Vis. Sci. 47(5), 2080–2092 (2006). [CrossRef] [PubMed]
  15. Y. Kitaguchi, T. Fujikado, K. Bessho, H. Sakaguchi, F. Gomi, T. Yamaguchi, N. Nakazawa, T. Mihashi, and Y. Tano, “Adaptive optics fundus camera to examine localized changes in the photoreceptor layer of the fovea,” Ophthalmology 115(10), 1771–1777 (2008). [CrossRef] [PubMed]
  16. J. L. Duncan, Y. Zhang, J. Gandhi, C. Nakanishi, M. Othman, K. E. H. Branham, A. Swaroop, and A. Roorda, “High-resolution imaging with adaptive optics in patients with inherited retinal degeneration,” Invest. Ophthalmol. Vis. Sci. 48(7), 3283–3291 (2007). [CrossRef] [PubMed]
  17. S. S. Choi, R. J. Zawadzki, J. L. Keltner, and J. S. Werner, “Changes in cellular structures revealed by ultra-high resolution retinal imaging in optic neuropathies,” Invest. Ophthalmol. Vis. Sci. 49(5), 2103–2119 (2008). [CrossRef] [PubMed]
  18. M. K. Yoon, A. Roorda, Y. Zhang, C. Nakanishi, L.-J. C. Wong, Q. Zhang, L. Gillum, A. Green, and J. L. Duncan, “Adaptive optics scanning laser ophthalmoscopy images in a family with the mitochondrial DNA T8993C mutation,” Invest. Ophthalmol. Vis. Sci. 50(4), 1838–1847 (2009). [CrossRef] [PubMed]
  19. J. L. Duncan, K. E. Talcott, K. Ratnam, S. M. Sundquist, A. S. Lucero, S. Day, Y. Zhang, and A. Roorda, “Cone structure in retinal degeneration associated with mutations in the peripherin/RDS gene,” Invest. Ophthalmol. Vis. Sci. 52(3), 1557–1566 (2011). [CrossRef] [PubMed]
  20. P. Godara, A. M. Dubis, A. Roorda, J. L. Duncan, and J. Carroll, “Adaptive optics retinal imaging: emerging clinical applications,” Optom. Vis. Sci. 87(12), 930–941 (2010). [CrossRef] [PubMed]
  21. J. Rha, A. M. Dubis, M. Wagner-Schuman, D. M. Tait, P. Godara, B. Schroeder, K. Stepien, and J. Carroll, “Spectral domain optical coherence tomography and adaptive optics: imaging photoreceptor layer morphology to interpret preclinical phenotypes,” Adv. Exp. Med. Biol. 664, 309–316 (2010). [CrossRef] [PubMed]
  22. S. S. Choi, R. J. Zawadzki, M. C. Lim, J. D. Brandt, J. L. Keltner, N. Doble, and J. S. Werner, “Evidence of outer retinal changes in glaucoma patients as revealed by ultrahigh-resolution in vivo retinal imaging,” Br. J. Ophthalmol. 95(1), 131–141 (2011). [CrossRef] [PubMed]
  23. S. Ooto, M. Hangai, A. Sakamoto, A. Tsujikawa, K. Yamashiro, Y. Ojima, Y. Yamada, H. Mukai, S. Oshima, T. Inoue, and N. Yoshimura, “High-resolution imaging of resolved central serous chorioretinopathy using adaptive optics scanning laser ophthalmoscopy,” Ophthalmology 117(9), 1800–1809.e2 (2010). [CrossRef] [PubMed]
  24. K. E. Talcott, K. Ratnam, S. M. Sundquist, A. S. Lucero, B. J. Lujan, W. Tao, T. C. Porco, A. Roorda, and J. L. Duncan, “Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment,” Invest. Ophthalmol. Vis. Sci. 52(5), 2219–2226 (2011). [CrossRef] [PubMed]
  25. J. C. Christou, A. Roorda, and D. R. Williams, “Deconvolution of adaptive optics retinal images,” J. Opt. Soc. Am. A 21(8), 1393–1401 (2004). [CrossRef] [PubMed]
  26. K. Y. Li, S. Mishra, P. Tiruveedhula, and A. Roorda, “Comparison of control algorithms for a MEMS-based adaptive optics scanning laser ophthalmoscope,” in American Control Conference, 2009. ACC '09 (IEEE, 2009), pp. 3848–3853.
  27. D. C. Chen, S. M. Jones, D. A. Silva, and S. S. Olivier, “High-resolution adaptive optics scanning laser ophthalmoscope with dual deformable mirrors,” J. Opt. Soc. Am. A 24(5), 1305–1312 (2007). [CrossRef] [PubMed]
  28. Y. Zhang, S. Poonja, and A. Roorda, “MEMS-based adaptive optics scanning laser ophthalmoscopy,” Opt. Lett. 31(9), 1268–1270 (2006). [CrossRef] [PubMed]
  29. A. Gómez-Vieyra, A. Dubra, D. Malacara-Hernández, and D. R. Williams, “First-order design of off-axis reflective ophthalmic adaptive optics systems using afocal telescopes,” Opt. Express 17(21), 18906–18919 (2009). [CrossRef] [PubMed]
  30. S. A. Burns, R. Tumbar, A. E. Elsner, D. Ferguson, and D. X. Hammer, “Large-field-of-view, modular, stabilized, adaptive-optics-based scanning laser ophthalmoscope,” J. Opt. Soc. Am. A 24(5), 1313–1326 (2007). [CrossRef] [PubMed]
  31. A. Dubra and Y. Sulai, “Reflective afocal broadband adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(6), 1757–1768 (2011). [CrossRef] [PubMed]
  32. A. Dubra, Y. Sulai, J. L. Norris, R. F. Cooper, A. M. Dubis, D. R. Williams, and J. Carroll, “Non-invasive in vivo imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express 2(7), 1864–1876 (2011). [CrossRef]
  33. A. Dubra, “Monochrome AVI desinusoid software,” http://www.cvs.rochester.edu/dubralab/image_processing/index.htm .
  34. S. B. Stevenson and A. Roorda, “Correcting for miniature eye movements in high resolution scanning laser ophthalmoscopy,” Proc. SPIE 5688A, 145–151 (2005). [CrossRef]
  35. C. A. Curcio, K. R. Sloan, R. E. Kalina, and A. E. Hendrickson, “Human photoreceptor topography,” J. Comp. Neurol. 292(4), 497–523 (1990). [CrossRef] [PubMed]
  36. R. W. Rodieck, “The density recovery profile: a method for analysis of points in the plane applicable to retinal studies,” Vis. Neurosci. 20(3), 349 (2003). [CrossRef] [PubMed]
  37. A. G. Bennett, A. R. Rudnicka, and D. F. Edgar, “Improvements on Littmann’s method of determining the size of retinal features by fundus photography,” Graefes Arch. Clin. Exp. Ophthalmol. 232(6), 361–367 (1994). [CrossRef] [PubMed]
  38. E. A. Rossi, P. Weiser, J. Tarrant, and A. Roorda, “Visual performance in emmetropia and low myopia after correction of high-order aberrations,” J. Vis. 7(8), 14 (2007). [CrossRef] [PubMed]
  39. T. Y. P. Chui, H. Song, and S. A. Burns, “Individual variations in human cone photoreceptor packing density: variations with refractive error,” Invest. Ophthalmol. Vis. Sci. 49(10), 4679–4687 (2008). [CrossRef] [PubMed]
  40. J. M. Enoch, “Wave-guide modes in retinal receptors,” Science 133(3461), 1353–1354 (1961). [CrossRef] [PubMed]
  41. C. A. Curcio and K. R. Sloan, “Packing geometry of human cone photoreceptors: variation with eccentricity and evidence for local anisotropy,” Vis. Neurosci. 9(2), 169–180 (1992). [CrossRef] [PubMed]
  42. N. Doble, S. S. Choi, J. L. Codona, J. Christou, J. M. Enoch, and D. R. Williams, “In vivo imaging of the human rod photoreceptor mosaic,” Opt. Lett. 36(1), 31–33 (2011). [CrossRef] [PubMed]
  43. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), “Online Mendelian inheritance in man, OMIM (TM),” http://www.ncbi.nlm.nih.gov/omim/ .
  44. D. Farnsworth, “The Farnsworth dichotomous test for color blindness-Panel D-15,” Psychological Corporation (1947).
  45. B. Török, “WEB-based scoring software for the Farnsworth-Munsell 100-Hue, Roth 28-Hue, Farnsworth D-15, and the Lanthony D-15 desaturated color tests,” http://www.torok.info/colorvision .
  46. K. J. Bowman, “A method for quantitative scoring of the Farnsworth Panel D-15,” Acta Ophthalmol. (Copenh.) 60(6), 907–916 (1982). [CrossRef] [PubMed]
  47. J. Carroll, S. S. Choi, and D. R. Williams, “In vivo imaging of the photoreceptor mosaic of a rod monochromat,” Vision Res. 48(26), 2564–2568 (2008). [CrossRef] [PubMed]
  48. H. F. Falls, J. R. Wolter, and M. Alpern, “Typical total monochromacy. A histological and psychophysical study,” Arch. Ophthalmol. 74(5), 610–616 (1965). [PubMed]
  49. R. Harrison, D. Hoefnagel, and J. N. Hayward, “Congenital total color blindness: a clincopathological report,” Arch. Ophthalmol. 64, 685–692 (1960). [PubMed]
  50. M. Glickstein and G. G. Heath, “Receptors in the monochromat eye,” Vision Res. 15(6), 633–636 (1975). [CrossRef] [PubMed]
  51. J. D. M. Gass, “Acute zonal occult outer retinopathy. Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992,” J. Clin. Neuroophthalmol. 13(2), 79–97 (1993). [PubMed]
  52. D. M. Monson and J. R. Smith, “Acute zonal occult outer retinopathy,” Surv. Ophthalmol. 56(1), 23–35 (2011). [CrossRef] [PubMed]
  53. D. Li and S. Kishi, “Loss of photoreceptor outer segment in acute zonal occult outer retinopathy,” Arch. Ophthalmol. 125(9), 1194–1200 (2007). [CrossRef] [PubMed]
  54. N. Zibrandtsen, I. C. Munch, K. Klemp, T. M. Jørgensen, B. Sander, and M. Larsen, “Photoreceptor atrophy in acute zonal occult outer retinopathy,” Acta Ophthalmol. (Copenh.) 86(8), 913–916 (2008). [CrossRef] [PubMed]
  55. H. F. Fine, R. F. Spaide, E. H. Ryan, Y. Matsumoto, and L. A. Yannuzzi, “Acute zonal occult outer retinopathy in patients with multiple evanescent white dot syndrome,” Arch. Ophthalmol. 127(1), 66–70 (2009). [CrossRef] [PubMed]
  56. M. Mkrtchyan, B. J. Lujan, D. Merino, C. E. Thirkill, A. Roorda, and J. Duncan, “Outer retinal structure in patients with acute zonal occult outer retinopathy,” submitted toAm. J. Ophthalmol. .

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