Abstract

Retinal image quality from flood illumination adaptive optics (AO) ophthalmoscopes is adversely affected by out-of-focus light scatter due to the lack of confocality. This effect is more pronounced in small eyes, such as that of rodents, because the requisite high optical power confers a large dioptric thickness to the retina. A recently-developed structured illumination microscopy (SIM) technique called HiLo imaging has been shown to reduce the effect of out-of-focus light scatter in flood illumination microscopes and produce pseudo-confocal images with significantly improved image quality. In this work, we adopted the HiLo technique to a flood AO ophthalmoscope and performed AO imaging in both (physical) model and live rat eyes. The improvement in image quality from HiLo imaging is shown both qualitatively and quantitatively by using spatial spectral analysis.

© 2014 Optical Society of America

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2014 (2)

2013 (4)

J. B. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci.54(13), 8237–8250 (2013).
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Y. F. Jian, R. J. Zawadzki, and M. V. Sarunic, “Adaptive optics optical coherence tomography for in vivo mouse retinal imaging,” J. Biomed. Opt.18(5), 056007 (2013).
[CrossRef] [PubMed]

P. Bedggood and A. Metha, “Optical imaging of human cone photoreceptors directly following the capture of light,” PLoS ONE8(11), e79251 (2013).
[CrossRef] [PubMed]

A. Pinhas, M. Dubow, N. Shah, T. Y. Chui, D. Scoles, Y. N. Sulai, R. Weitz, J. B. Walsh, J. Carroll, A. Dubra, and R. B. Rosen, “In vivo imaging of human retinal microvasculature using adaptive optics scanning light ophthalmoscope fluorescein angiography,” Biomed. Opt. Express4(8), 1305–1317 (2013).
[CrossRef] [PubMed]

2012 (6)

2011 (5)

2010 (2)

A. Roorda, “Applications of adaptive optics scanning laser ophthalmoscopy,” Optom. Vis. Sci.87(4), 260–268 (2010).
[PubMed]

J. Tam, J. A. Martin, and A. Roorda, “Noninvasive visualization and analysis of parafoveal capillaries in humans,” Invest. Ophthalmol. Vis. Sci.51(3), 1691–1698 (2010).
[CrossRef] [PubMed]

2009 (4)

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, “Optically sectioned fluorescence endomicroscopy with hybrid-illumination imaging through a flexible fiber bundle,” J. Biomed. Opt.14(3), 030502 (2009).
[CrossRef] [PubMed]

B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
[CrossRef] [PubMed]

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Y. Geng, K. P. Greenberg, R. Wolfe, D. C. Gray, J. J. Hunter, A. Dubra, J. G. Flannery, D. R. Williams, and J. Porter, “In vivo imaging of microscopic structures in the rat retina,” Invest. Ophthalmol. Vis. Sci.50(12), 5872–5879 (2009).
[CrossRef] [PubMed]

2008 (5)

K. Kohzaki, A. J. Vingrys, and B. V. Bui, “Early inner retinal dysfunction in streptozotocin-induced diabetic rats,” Invest. Ophthalmol. Vis. Sci.49(8), 3595–3604 (2008).
[CrossRef] [PubMed]

Z. He, B. V. Bui, and A. J. Vingrys, “Effect of repeated iop challenge on rat retinal function,” Invest. Ophthalmol. Vis. Sci.49(7), 3026–3034 (2008).
[CrossRef] [PubMed]

R. E. Marc, B. W. Jones, C. B. Watt, F. Vazquez-Chona, D. K. Vaughan, and D. T. Organisciak, “Extreme retinal remodeling triggered by light damage: Implications for age related macular degeneration,” Mol. Vis.14, 782–806 (2008).
[PubMed]

M. Pircher, R. J. Zawadzki, J. W. Evans, J. S. Werner, and C. K. Hitzenberger, “Simultaneous imaging of human cone mosaic with adaptive optics enhanced scanning laser ophthalmoscopy and high-speed transversal scanning optical coherence tomography,” Opt. Lett.33(1), 22–24 (2008).
[CrossRef] [PubMed]

D. Lim, K. K. Chu, and J. Mertz, “Wide-field fluorescence sectioning with hybrid speckle and uniform-illumination microscopy,” Opt. Lett.33(16), 1819–1821 (2008).
[CrossRef] [PubMed]

2007 (2)

2005 (1)

B. V. Bui, B. Edmunds, G. A. Cioffi, and B. Fortune, “The gradient of retinal functional changes during acute intraocular pressure elevation,” Invest. Ophthalmol. Vis. Sci.46(1), 202–213 (2005).
[CrossRef] [PubMed]

2004 (1)

A. Abbott, “Laboratory animals: The renaissance rat,” Nature428(6982), 464–466 (2004).
[CrossRef] [PubMed]

2002 (1)

1997 (1)

1989 (1)

M. R. Capecchi, “Altering the genome by homologous recombination,” Science244(4910), 1288–1292 (1989).
[CrossRef] [PubMed]

1988 (1)

S. L. Mansour, K. R. Thomas, and M. R. Capecchi, “Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: A general strategy for targeting mutations to non-selectable genes,” Nature336(6197), 348–352 (1988).
[CrossRef] [PubMed]

1979 (1)

A. Hughes, “A schematic eye for the rat,” Vision Res.19(5), 569–588 (1979).
[CrossRef] [PubMed]

Abbott, A.

A. Abbott, “Laboratory animals: The renaissance rat,” Nature428(6982), 464–466 (2004).
[CrossRef] [PubMed]

Ahmad, K.

Anegon, I.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Bartoo, A. C.

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, “Optically sectioned fluorescence endomicroscopy with hybrid-illumination imaging through a flexible fiber bundle,” J. Biomed. Opt.14(3), 030502 (2009).
[CrossRef] [PubMed]

Bedggood, P.

Bonora, S.

Bozinovic, N.

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, “Optically sectioned fluorescence endomicroscopy with hybrid-illumination imaging through a flexible fiber bundle,” J. Biomed. Opt.14(3), 030502 (2009).
[CrossRef] [PubMed]

Buelow, R.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Bui, B. V.

B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
[CrossRef] [PubMed]

K. Kohzaki, A. J. Vingrys, and B. V. Bui, “Early inner retinal dysfunction in streptozotocin-induced diabetic rats,” Invest. Ophthalmol. Vis. Sci.49(8), 3595–3604 (2008).
[CrossRef] [PubMed]

Z. He, B. V. Bui, and A. J. Vingrys, “Effect of repeated iop challenge on rat retinal function,” Invest. Ophthalmol. Vis. Sci.49(7), 3026–3034 (2008).
[CrossRef] [PubMed]

B. V. Bui, B. Edmunds, G. A. Cioffi, and B. Fortune, “The gradient of retinal functional changes during acute intraocular pressure elevation,” Invest. Ophthalmol. Vis. Sci.46(1), 202–213 (2005).
[CrossRef] [PubMed]

Campbell, M.

Capecchi, M. R.

M. R. Capecchi, “Altering the genome by homologous recombination,” Science244(4910), 1288–1292 (1989).
[CrossRef] [PubMed]

S. L. Mansour, K. R. Thomas, and M. R. Capecchi, “Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: A general strategy for targeting mutations to non-selectable genes,” Nature336(6197), 348–352 (1988).
[CrossRef] [PubMed]

Carroll, J.

Choi, H. J.

Choi, S. S.

Choi, V. M.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Chu, K. K.

D. Lim, T. N. Ford, K. K. Chu, and J. Mertz, “Optically sectioned in vivo imaging with speckle illumination hilo microscopy,” J. Biomed. Opt.16(1), 016014 (2011).
[CrossRef] [PubMed]

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, “Optically sectioned fluorescence endomicroscopy with hybrid-illumination imaging through a flexible fiber bundle,” J. Biomed. Opt.14(3), 030502 (2009).
[CrossRef] [PubMed]

D. Lim, K. K. Chu, and J. Mertz, “Wide-field fluorescence sectioning with hybrid speckle and uniform-illumination microscopy,” Opt. Lett.33(16), 1819–1821 (2008).
[CrossRef] [PubMed]

Chui, T. Y.

Cioffi, G. A.

B. V. Bui, B. Edmunds, G. A. Cioffi, and B. Fortune, “The gradient of retinal functional changes during acute intraocular pressure elevation,” Invest. Ophthalmol. Vis. Sci.46(1), 202–213 (2005).
[CrossRef] [PubMed]

Cost, G. J.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Cui, X.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Davis, G. D.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Delori, F. C.

Donnelly, W.

Dubow, M.

Dubra, A.

Edmunds, B.

B. V. Bui, B. Edmunds, G. A. Cioffi, and B. Fortune, “The gradient of retinal functional changes during acute intraocular pressure elevation,” Invest. Ophthalmol. Vis. Sci.46(1), 202–213 (2005).
[CrossRef] [PubMed]

Eliceiri, K. W.

C. A. Schneider, W. S. Rasband, and K. W. Eliceiri, “Nih image to imagej: 25 years of image analysis,” Nat. Methods9(7), 671–675 (2012).
[CrossRef] [PubMed]

Evans, J. W.

Flannery, J. G.

Y. Geng, K. P. Greenberg, R. Wolfe, D. C. Gray, J. J. Hunter, A. Dubra, J. G. Flannery, D. R. Williams, and J. Porter, “In vivo imaging of microscopic structures in the rat retina,” Invest. Ophthalmol. Vis. Sci.50(12), 5872–5879 (2009).
[CrossRef] [PubMed]

Foeckler, J.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Ford, T. N.

T. N. Ford, D. Lim, and J. Mertz, “Fast optically sectioned fluorescence hilo endomicroscopy,” J. Biomed. Opt.17(2), 021105 (2012).
[CrossRef] [PubMed]

D. Lim, T. N. Ford, K. K. Chu, and J. Mertz, “Optically sectioned in vivo imaging with speckle illumination hilo microscopy,” J. Biomed. Opt.16(1), 016014 (2011).
[CrossRef] [PubMed]

S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, “Optically sectioned fluorescence endomicroscopy with hybrid-illumination imaging through a flexible fiber bundle,” J. Biomed. Opt.14(3), 030502 (2009).
[CrossRef] [PubMed]

Fortune, B.

B. V. Bui, B. Edmunds, G. A. Cioffi, and B. Fortune, “The gradient of retinal functional changes during acute intraocular pressure elevation,” Invest. Ophthalmol. Vis. Sci.46(1), 202–213 (2005).
[CrossRef] [PubMed]

Freyvert, Y.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

Geng, Y.

J. B. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci.54(13), 8237–8250 (2013).
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Y. Geng, L. A. Schery, R. Sharma, A. Dubra, K. Ahmad, R. T. Libby, and D. R. Williams, “Optical properties of the mouse eye,” Biomed. Opt. Express2(4), 717–738 (2011).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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Y. Geng, K. P. Greenberg, R. Wolfe, D. C. Gray, J. J. Hunter, A. Dubra, J. G. Flannery, D. R. Williams, and J. Porter, “In vivo imaging of microscopic structures in the rat retina,” Invest. Ophthalmol. Vis. Sci.50(12), 5872–5879 (2009).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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K. Kohzaki, A. J. Vingrys, and B. V. Bui, “Early inner retinal dysfunction in streptozotocin-induced diabetic rats,” Invest. Ophthalmol. Vis. Sci.49(8), 3595–3604 (2008).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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D. Lim, T. N. Ford, K. K. Chu, and J. Mertz, “Optically sectioned in vivo imaging with speckle illumination hilo microscopy,” J. Biomed. Opt.16(1), 016014 (2011).
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R. E. Marc, B. W. Jones, C. B. Watt, F. Vazquez-Chona, D. K. Vaughan, and D. T. Organisciak, “Extreme retinal remodeling triggered by light damage: Implications for age related macular degeneration,” Mol. Vis.14, 782–806 (2008).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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Mertz, J.

T. N. Ford, D. Lim, and J. Mertz, “Fast optically sectioned fluorescence hilo endomicroscopy,” J. Biomed. Opt.17(2), 021105 (2012).
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D. Lim, T. N. Ford, K. K. Chu, and J. Mertz, “Optically sectioned in vivo imaging with speckle illumination hilo microscopy,” J. Biomed. Opt.16(1), 016014 (2011).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
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J. B. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci.54(13), 8237–8250 (2013).
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R. E. Marc, B. W. Jones, C. B. Watt, F. Vazquez-Chona, D. K. Vaughan, and D. T. Organisciak, “Extreme retinal remodeling triggered by light damage: Implications for age related macular degeneration,” Mol. Vis.14, 782–806 (2008).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

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B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
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Roorda, A.

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S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, “Optically sectioned fluorescence endomicroscopy with hybrid-illumination imaging through a flexible fiber bundle,” J. Biomed. Opt.14(3), 030502 (2009).
[CrossRef] [PubMed]

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Schallek, J. B.

J. B. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci.54(13), 8237–8250 (2013).
[CrossRef] [PubMed]

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Schilling, R.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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C. A. Schneider, W. S. Rasband, and K. W. Eliceiri, “Nih image to imagej: 25 years of image analysis,” Nat. Methods9(7), 671–675 (2012).
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Shah, N.

Sharma, R.

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S. Santos, K. K. Chu, D. Lim, N. Bozinovic, T. N. Ford, C. Hourtoule, A. C. Bartoo, S. K. Singh, and J. Mertz, “Optically sectioned fluorescence endomicroscopy with hybrid-illumination imaging through a flexible fiber bundle,” J. Biomed. Opt.14(3), 030502 (2009).
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S. L. Mansour, K. R. Thomas, and M. R. Capecchi, “Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: A general strategy for targeting mutations to non-selectable genes,” Nature336(6197), 348–352 (1988).
[CrossRef] [PubMed]

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B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
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Tolcos, M.

B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
[CrossRef] [PubMed]

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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

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R. E. Marc, B. W. Jones, C. B. Watt, F. Vazquez-Chona, D. K. Vaughan, and D. T. Organisciak, “Extreme retinal remodeling triggered by light damage: Implications for age related macular degeneration,” Mol. Vis.14, 782–806 (2008).
[PubMed]

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R. E. Marc, B. W. Jones, C. B. Watt, F. Vazquez-Chona, D. K. Vaughan, and D. T. Organisciak, “Extreme retinal remodeling triggered by light damage: Implications for age related macular degeneration,” Mol. Vis.14, 782–806 (2008).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
[CrossRef] [PubMed]

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B. V. Bui, M. Loeliger, M. Thomas, A. J. Vingrys, S. M. Rees, C. T. Nguyen, Z. He, and M. Tolcos, “Investigating structural and biochemical correlates of ganglion cell dysfunction in streptozotocin-induced diabetic rats,” Exp. Eye Res.88(6), 1076–1083 (2009).
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[CrossRef] [PubMed]

Z. He, B. V. Bui, and A. J. Vingrys, “Effect of repeated iop challenge on rat retinal function,” Invest. Ophthalmol. Vis. Sci.49(7), 3026–3034 (2008).
[CrossRef] [PubMed]

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Watt, C. B.

R. E. Marc, B. W. Jones, C. B. Watt, F. Vazquez-Chona, D. K. Vaughan, and D. T. Organisciak, “Extreme retinal remodeling triggered by light damage: Implications for age related macular degeneration,” Mol. Vis.14, 782–806 (2008).
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Weiler, H.

A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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Werner, J. S.

Williams, D. R.

J. B. Schallek, Y. Geng, H. Nguyen, and D. R. Williams, “Morphology and topography of retinal pericytes in the living mouse retina using in vivo adaptive optics imaging and ex vivo characterization,” Invest. Ophthalmol. Vis. Sci.54(13), 8237–8250 (2013).
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Y. Geng, L. A. Schery, R. Sharma, A. Dubra, K. Ahmad, R. T. Libby, and D. R. Williams, “Optical properties of the mouse eye,” Biomed. Opt. Express2(4), 717–738 (2011).
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A. M. Geurts, G. J. Cost, Y. Freyvert, B. Zeitler, J. C. Miller, V. M. Choi, S. S. Jenkins, A. Wood, X. Cui, X. Meng, A. Vincent, S. Lam, M. Michalkiewicz, R. Schilling, J. Foeckler, S. Kalloway, H. Weiler, S. Ménoret, I. Anegon, G. D. Davis, L. Zhang, E. J. Rebar, P. D. Gregory, F. D. Urnov, H. J. Jacob, and R. Buelow, “Knockout rats via embryo microinjection of zinc-finger nucleases,” Science325(5939), 433 (2009).
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Yin, L.

Zawadzki, R. J.

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J. Tam, P. Tiruveedhula, and A. Roorda, “Characterization of single-file flow through human retinal parafoveal capillaries using an adaptive optics scanning laser ophthalmoscope,” Biomed. Opt. Express2(4), 781–793 (2011).
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A. Dubra and Y. Sulai, “Reflective afocal broadband adaptive optics scanning ophthalmoscope,” Biomed. Opt. Express2(6), 1757–1768 (2011).
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Y. Geng, A. Dubra, L. Yin, W. H. Merigan, R. Sharma, R. T. Libby, and D. R. Williams, “Adaptive optics retinal imaging in the living mouse eye,” Biomed. Opt. Express3(4), 715–734 (2012).
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P. Bedggood and A. Metha, “Direct visualization and characterization of erythrocyte flow in human retinal capillaries,” Biomed. Opt. Express3(12), 3264–3277 (2012).
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A. Pinhas, M. Dubow, N. Shah, T. Y. Chui, D. Scoles, Y. N. Sulai, R. Weitz, J. B. Walsh, J. Carroll, A. Dubra, and R. B. Rosen, “In vivo imaging of human retinal microvasculature using adaptive optics scanning light ophthalmoscope fluorescein angiography,” Biomed. Opt. Express4(8), 1305–1317 (2013).
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Y. Jian, J. Xu, M. A. Gradowski, S. Bonora, R. J. Zawadzki, and M. V. Sarunic, “Wavefront sensorless adaptive optics optical coherence tomography for in vivo retinal imaging in mice,” Biomed. Opt. Express5(2), 547–559 (2014).
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Figures (9)

Fig. 1
Fig. 1

Scaled (1:1) schematic layout of our non-planar design flood-illumination AO ophthalmoscope, flattened for visualization. All angles and distances are to scale. Representations of optical components are for illustrative purposes only. Two illumination arms are built in: the “wide-field illumination arm” and the “AO illumination arm”. The two arms can be switched by using the three flip mirrors marked with an asterisk (*FM). DPSS: diode-pumped solid-state laser. SPR: spatial phase randomizer. M: flat mirrors. BS: plate beam splitter. FM: flip mirrors. CM: curved mirrors. P: pupil planes conjugate to the wavefront sensor and deformable mirror. DM: Mirao 52d deformable mirror. WFS: wavefront sensor. Note that SPR1 (coupled to imaging light) was switched on and off for HiLo imaging (see description below), and SPR2 (coupled to wavefront sensing light) was left on throughout the experiment. Scale bar: 100 mm.

Fig. 2
Fig. 2

In vivo image of a human eye using our rat AO system. Image is located approximately 2° superior from fixation, averaged over 30 frames and linearly stretched to fill the colormap for display purposes. Cones are clearly visible at the centre of the image. The fovea is towards the bottom. Scale bar = 30 µm.

Fig. 3
Fig. 3

Example of AO images obtained using the 60 D model eye with an artificial “retina” made from a white piece of paper printed with ink spots, together with an intraocular scatterer. All images shown are the average of 50 frames and linearly stretched to fill the colormap for display purposes. Uniform (a) and Speckle (b) images were obtained with the scatterer in place and with uniform and speckle illumination, respectively. HiLo images were generated using two different values for the depth-of-field (DOF), with DOFx4 in (c) and DOFx8 in (d), with the circled areas showing greater enhancement of higher frequency details for the DOFx4 HiLo image in (c), and greater enhancement of lower frequency details for the DOFx8 HiLo image in (d) (see Fig. 4 for Fourier analysis). The Ideal image (e), which was obtained without the scatterer, is also shown for comparison. Scale bar = 50 µm.

Fig. 4
Fig. 4

Analysis showing improvement to the retinal image power spectrum following HiLo (with scatterer), compared to that obtained after physical removal of the scatterer (Ideal image) for the 60 D model eye. TOP CENTRE: Ratio plot of the normalized radial average energy of the FFT power spectrum of the images shown in Fig. 3. All results are normalized by the Uniform image power spectrum, represented by a horizontal dash-dot line at ratio = 1.0. The horizontal axis represents spatial frequency in units of cycles/mm. INSET TOP LEFT: Magnified view at lower spatial frequencies. Low frequency information occupies a lower fraction of the energy spectrum after HiLo, due to removal of veiling glare introduced by the scatterer. Performance approaches that of the ideal image. An example low frequency retinal feature (~4 cycles/mm) is highlighted in the Ideal image at BOTTOM. INSET TOP RIGHT: Magnified view of the higher spatial frequencies. High frequency information occupies a greater fraction of the energy spectrum after HiLo, due to removal of the low frequency veiling glare. An example high frequency retinal feature (~70 cycles/mm) is highlighted at BOTTOM.

Fig. 5
Fig. 5

Uniform and HiLo images obtained from the 220 D model eye, using a 45 µm thick lens cleaning tissue as the artificial retina. All images shown are the average of 50 frames and stretched to fill the colormap for display purposes. (a) and (c): Uniform and HiLo images for the most anterior surface of the cleaning tissue. It can be seen that light scatter from posterior layers is reduced greatly in the HiLo image. (b) and (d): Uniform and HiLo images for the most posterior surface. Scale bar = 20 µm.

Fig. 6
Fig. 6

An example of the Shack-Hartmann WFS spot quality from the rat eye prior to AO correction after optimization and, following adoption of the system modifications suggested by Geng et al. (2011) [32] summarized in the text. The spots appear well focussed at the centre, but become gradually blurry towards the periphery. The RMS wavefront error from the rat eye following adaptive optics correction ranged from 0.06 to 0.10 µm, measured over a 3.75 mm pupil.

Fig. 7
Fig. 7

Example of in vivo AO retinal images obtained from Long Evans rat #1, showing a large blood vessel. All images shown are the average of 80 frames and linearly stretched for display purposes. Uniform, Speckle and Hilo images were obtained as described in Fig. 3. For this data, DOFx4 gave the best overall contrast and details. DOFx1, 8 and 12 are also shown here for comparison. Scale bar = 10 µm.

Fig. 8
Fig. 8

Improvement to in vivo retinal image power spectrum following HiLo for rat #1. TOP CENTRE: Ratio plot of the normalized radial average energy of the FFT power spectrum of Uniform and HiLo images. All results are normalized by the Uniform image power spectrum, represented by a horizontal dash-dot line at ratio = 1.0. The horizontal axis represents spatial frequency in units of cycles/mm. INSET TOP LEFT: Magnified view at lower spatial frequencies. Low frequency information occupies a lower fraction of the energy spectrum after HiLo, due to removal of intra-ocular scatter. An example low frequency retinal feature - a blood vessel (~14 cycles/mm) is highlighted in the DOFx4 image at BOTTOM. INSET TOP RIGHT: Magnified view at medium spatial frequencies. Medium frequency information occupies a greater fraction of the energy spectrum after HiLo in DOFx4 compared to DOFx1. An example medium frequency feature - a nerve fibre bundle (86 cycles/mm) is highlighted at bottom.

Fig. 9
Fig. 9

Example of in vivo AO retinal images obtained from another Long Evans rat (rat #2), showing two large blood vessels near a bifurcation. All images shown are the average of 82 frames and linearly stretched to fill the colormap for display purposes. Similar to Fig. 7, DOFx4 was considered most useful to enhance visualization of retinal features at this location. DOFx1, 8 and 12 are also shown here for comparison. Sensing wavelength = 670 nm, imaging wavelength = 532 nm. Scale bar = 10 µm.

Equations (3)

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I hp =HP( I u )
I lp =LP( C δ I u )
I hilo =η I lp + I hp

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