Abstract

Vision begins when light isomerizes the photopigments within photoreceptors. Noninvasive cellular-scale observation of the structure of the human photoreceptor mosaic is made possible through the use of adaptive optics (AO) enhanced ophthalmoscopes, but establishing noninvasive objective measures of photoreceptor function on a similar scale has been more difficult. AO ophthalmoscope images acquired with near-infrared light show that individual cone photoreceptor reflectance can change in response to a visible stimulus. Here we show that the intrinsic response depends on stimulus wavelength and intensity, and that its action spectrum is well-matched to the spectral sensitivity of cone-mediated vision. Our results demonstrate that the cone reflectance response is mediated by photoisomerization, thus making it a direct measure of photoreceptor function.

© 2017 Optical Society of America

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References

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2017 (1)

P. Zhang, R. J. Zawadzki, M. Goswami, P. T. Nguyen, V. Yarov-Yarovoy, M. E. Burns, and E. N. Pugh., “In vivo optophysiology reveals that G-protein activation triggers osmotic swelling and increased light scattering of rod photoreceptors,” Proc. Natl. Acad. Sci. U.S.A. 114(14), E2937–E2946 (2017).
[PubMed]

2016 (2)

D. Hillmann, H. Spahr, C. Pfäffle, H. Sudkamp, G. Franke, and G. Hüttmann, “In vivo optical imaging of physiological responses to photostimulation in human photoreceptors,” Proc. Natl. Acad. Sci. U.S.A. 113(46), 13138–13143 (2016).
[PubMed]

J. C. Giacalone, L. A. Wiley, E. R. Burnight, A. E. Songstad, R. F. Mullins, E. M. Stone, and B. A. Tucker, “Concise review: patient-specific stem cells to interrogate inherited eye disease,” Stem Cells Transl. Med. 5(2), 132–140 (2016).
[PubMed]

2014 (2)

J. I. Morgan, G. Han, E. Klinman, W. M. Maguire, D. C. Chung, A. M. Maguire, and J. Bennett, “High-resolution adaptive optics retinal imaging of cellular structure in choroideremia,” Invest. Ophthalmol. Vis. Sci. 55(10), 6381–6397 (2014).
[PubMed]

D. Dalkara and J. A. Sahel, “Gene therapy for inherited retinal degenerations,” C. R. Biol. 337(3), 185–192 (2014).
[PubMed]

2013 (3)

S. Zayit-Soudry, J. L. Duncan, R. Syed, M. Menghini, and A. J. Roorda, “Cone structure imaged with adaptive optics scanning laser ophthalmoscopy in eyes with nonneovascular age-related macular degeneration,” Invest. Ophthalmol. Vis. Sci. 54(12), 7498–7509 (2013).
[PubMed]

A. V. Cideciyan, R. B. Hufnagel, J. Carroll, A. Sumaroka, X. Luo, S. B. Schwartz, A. Dubra, M. Land, M. Michaelides, J. C. Gardner, A. J. Hardcastle, A. T. Moore, R. A. Sisk, Z. M. Ahmed, S. Kohl, B. Wissinger, and S. G. Jacobson, “Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy,” Hum. Gene Ther. 24(12), 993–1006 (2013).
[PubMed]

K. Ratnam, J. Carroll, T. C. Porco, J. L. Duncan, and A. Roorda, “Relationship between foveal cone structure and clinical measures of visual function in patients with inherited retinal degenerations,” Invest. Ophthalmol. Vis. Sci. 54(8), 5836–5847 (2013).
[PubMed]

2012 (1)

R. Garrioch, C. Langlo, A. M. Dubis, R. F. Cooper, A. Dubra, and J. Carroll, “Repeatability of in vivo parafoveal cone density and spacing measurements,” Optom. Vis. Sci. 89(5), 632–643 (2012).
[PubMed]

2011 (5)

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).
[PubMed]

O. Yizhar, L. E. Fenno, T. J. Davidson, M. Mogri, and K. Deisseroth, “Optogenetics in neural systems,” Neuron 71(1), 9–34 (2011).
[PubMed]

K. Zhang, J. J. Hopkins, J. S. Heier, D. G. Birch, L. S. Halperin, T. A. Albini, D. M. Brown, G. J. Jaffe, W. Tao, and G. A. Williams, “Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration,” Proc. Natl. Acad. Sci. U.S.A. 108(15), 6241–6245 (2011).
[PubMed]

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

R. F. Cooper, A. M. Dubis, A. Pavaskar, J. Rha, A. Dubra, and J. Carroll, “Spatial and temporal variation of rod photoreceptor reflectance in the human retina,” Biomed. Opt. Express 2(9), 2577–2589 (2011).
[PubMed]

2010 (3)

2009 (2)

A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
[PubMed]

J. Rha, B. Schroeder, P. Godara, and J. Carroll, “Variable optical activation of human cone photoreceptors visualized using a short coherence light source,” Opt. Lett. 34(24), 3782–3784 (2009).
[PubMed]

2008 (3)

Y. B. Zhao and X. C. Yao, “Intrinsic optical imaging of stimulus-modulated physiological responses in amphibian retina,” Opt. Lett. 33(4), 342–344 (2008).
[PubMed]

K. Grieve and A. Roorda, “Intrinsic signals from human cone photoreceptors,” Invest. Ophthalmol. Vis. Sci. 49(2), 713–719 (2008).
[PubMed]

J. I. W. Morgan, J. J. Hunter, B. Masella, R. Wolfe, D. C. Gray, W. H. Merigan, F. C. Delori, and D. R. Williams, “Light-induced retinal changes observed with high-resolution autofluorescence imaging of the retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 49(8), 3715–3729 (2008).
[PubMed]

2007 (2)

R. S. Jonnal, J. Rha, Y. Zhang, B. Cense, W. Gao, and D. T. Miller, “In vivo functional imaging of human cone photoreceptors,” Opt. Express 14, 16141–16160 (2007).

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).
[PubMed]

2006 (1)

W. Makous, J. Carroll, J. I. Wolfing, J. Lin, N. Christie, and D. R. Williams, “Retinal microscotomas revealed with adaptive-optics microflashes,” Invest. Ophthalmol. Vis. Sci. 47(9), 4160–4167 (2006).
[PubMed]

2005 (2)

H. Hofer, J. Carroll, J. Neitz, M. Neitz, and D. R. Williams, “Organization of the human trichromatic cone mosaic,” J. Neurosci. 25(42), 9669–9679 (2005).
[PubMed]

L. T. Sharpe, A. Stockman, W. Jagla, and H. Jägle, “A luminous efficiency function, V*(λ), for daylight adaptation,” J. Vis. 5(11), 948–968 (2005) doi:.
[Crossref] [PubMed]

2004 (1)

W. Drexler, “Ultrahigh-resolution optical coherence tomography,” J. Biomed. Opt. 9(1), 47–74 (2004).
[PubMed]

2003 (1)

A. Pallikaris, D. R. Williams, and H. Hofer, “The reflectance of single cones in the living human eye,” Invest. Ophthalmol. Vis. Sci. 44(10), 4580–4592 (2003).
[PubMed]

2002 (4)

C. M. Poloschek and E. E. Sutter, “The fine structure of multifocal ERG topographies,” J. Vis. 2(8), 577–587 (2002) doi:.
[Crossref] [PubMed]

J. Carroll, J. Neitz, and M. Neitz, “Estimates of L:M cone ratio from ERG flicker photometry and genetics,” J. Vis. 2(8), 531–542 (2002) doi:.
[Crossref] [PubMed]

V. Y. Arshavsky, T. D. Lamb, and E. N. Pugh., “G proteins and phototransduction,” Annu. Rev. Physiol. 64, 153–187 (2002).
[PubMed]

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]

1999 (1)

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

1997 (1)

1996 (1)

J. van de Kraats, T. T. Berendschot, and D. van Norren, “The pathways of light measured in fundus reflectometry,” Vision Res. 36(15), 2229–2247 (1996).
[PubMed]

1990 (1)

J. L. Schnapf, B. J. Nunn, M. Meister, and D. A. Baylor, “Visual transduction in cones of the monkey Macaca fascicularis,” J. Physiol. 427, 681–713 (1990).
[PubMed]

1987 (1)

P. K. Ahnelt, H. Kolb, and R. Pflug, “Identification of a subtype of cone photoreceptor, likely to be blue sensitive, in the human retina,” J. Comp. Neurol. 255(1), 18–34 (1987).
[PubMed]

1981 (2)

K. P. Hofmann, A. Schleicher, D. Emeis, and J. Reichert, “Light-induced axial and radial shrinkage effects and changes of the refractive index in isolated bovine rod outer segments and disc vesicles: physical analysis of near-infrared scattering changes,” Biophys. Struct. Mech. 8(1-2), 67–93 (1981).
[PubMed]

H. Kühn, N. Bennett, M. Michel-Villaz, and M. Chabre, “Interactions between photoexcited rhodopsin and GTP-binding protein: kinetic and stoichiometric analyses from light-scattering changes,” Proc. Natl. Acad. Sci. U.S.A. 78(11), 6873–6877 (1981).
[PubMed]

1976 (1)

K. P. Hofmann, R. Uhl, W. Hoffmann, and W. Kreutz, “Measurements on fast light-induced light-scattering and -absorption changes in outer segments of vertebrate light sensitive rod cells,” Biophys. Struct. Mech. 2(1), 61–77 (1976).
[PubMed]

Acerra, C.

A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
[PubMed]

Ahmed, Z. M.

A. V. Cideciyan, R. B. Hufnagel, J. Carroll, A. Sumaroka, X. Luo, S. B. Schwartz, A. Dubra, M. Land, M. Michaelides, J. C. Gardner, A. J. Hardcastle, A. T. Moore, R. A. Sisk, Z. M. Ahmed, S. Kohl, B. Wissinger, and S. G. Jacobson, “Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy,” Hum. Gene Ther. 24(12), 993–1006 (2013).
[PubMed]

Ahnelt, P. K.

P. K. Ahnelt, H. Kolb, and R. Pflug, “Identification of a subtype of cone photoreceptor, likely to be blue sensitive, in the human retina,” J. Comp. Neurol. 255(1), 18–34 (1987).
[PubMed]

Albini, T. A.

K. Zhang, J. J. Hopkins, J. S. Heier, D. G. Birch, L. S. Halperin, T. A. Albini, D. M. Brown, G. J. Jaffe, W. Tao, and G. A. Williams, “Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration,” Proc. Natl. Acad. Sci. U.S.A. 108(15), 6241–6245 (2011).
[PubMed]

Arshavsky, V. Y.

V. Y. Arshavsky, T. D. Lamb, and E. N. Pugh., “G proteins and phototransduction,” Annu. Rev. Physiol. 64, 153–187 (2002).
[PubMed]

Auricchio, A.

A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
[PubMed]

Banfi, S.

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H. Kühn, N. Bennett, M. Michel-Villaz, and M. Chabre, “Interactions between photoexcited rhodopsin and GTP-binding protein: kinetic and stoichiometric analyses from light-scattering changes,” Proc. Natl. Acad. Sci. U.S.A. 78(11), 6873–6877 (1981).
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A. V. Cideciyan, R. B. Hufnagel, J. Carroll, A. Sumaroka, X. Luo, S. B. Schwartz, A. Dubra, M. Land, M. Michaelides, J. C. Gardner, A. J. Hardcastle, A. T. Moore, R. A. Sisk, Z. M. Ahmed, S. Kohl, B. Wissinger, and S. G. Jacobson, “Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy,” Hum. Gene Ther. 24(12), 993–1006 (2013).
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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).
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A. V. Cideciyan, R. B. Hufnagel, J. Carroll, A. Sumaroka, X. Luo, S. B. Schwartz, A. Dubra, M. Land, M. Michaelides, J. C. Gardner, A. J. Hardcastle, A. T. Moore, R. A. Sisk, Z. M. Ahmed, S. Kohl, B. Wissinger, and S. G. Jacobson, “Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy,” Hum. Gene Ther. 24(12), 993–1006 (2013).
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Goswami, M.

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J. I. Morgan, G. Han, E. Klinman, W. M. Maguire, D. C. Chung, A. M. Maguire, and J. Bennett, “High-resolution adaptive optics retinal imaging of cellular structure in choroideremia,” Invest. Ophthalmol. Vis. Sci. 55(10), 6381–6397 (2014).
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A. V. Cideciyan, R. B. Hufnagel, J. Carroll, A. Sumaroka, X. Luo, S. B. Schwartz, A. Dubra, M. Land, M. Michaelides, J. C. Gardner, A. J. Hardcastle, A. T. Moore, R. A. Sisk, Z. M. Ahmed, S. Kohl, B. Wissinger, and S. G. Jacobson, “Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy,” Hum. Gene Ther. 24(12), 993–1006 (2013).
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A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
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Heier, J. S.

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Hillmann, D.

D. Hillmann, H. Spahr, C. Pfäffle, H. Sudkamp, G. Franke, and G. Hüttmann, “In vivo optical imaging of physiological responses to photostimulation in human photoreceptors,” Proc. Natl. Acad. Sci. U.S.A. 113(46), 13138–13143 (2016).
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Hofer, H.

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J. I. Morgan, G. Han, E. Klinman, W. M. Maguire, D. C. Chung, A. M. Maguire, and J. Bennett, “High-resolution adaptive optics retinal imaging of cellular structure in choroideremia,” Invest. Ophthalmol. Vis. Sci. 55(10), 6381–6397 (2014).
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K. P. Hofmann, R. Uhl, W. Hoffmann, and W. Kreutz, “Measurements on fast light-induced light-scattering and -absorption changes in outer segments of vertebrate light sensitive rod cells,” Biophys. Struct. Mech. 2(1), 61–77 (1976).
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Lin, J.

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A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
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J. I. Morgan, G. Han, E. Klinman, W. M. Maguire, D. C. Chung, A. M. Maguire, and J. Bennett, “High-resolution adaptive optics retinal imaging of cellular structure in choroideremia,” Invest. Ophthalmol. Vis. Sci. 55(10), 6381–6397 (2014).
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J. I. Morgan, G. Han, E. Klinman, W. M. Maguire, D. C. Chung, A. M. Maguire, and J. Bennett, “High-resolution adaptive optics retinal imaging of cellular structure in choroideremia,” Invest. Ophthalmol. Vis. Sci. 55(10), 6381–6397 (2014).
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W. Makous, J. Carroll, J. I. Wolfing, J. Lin, N. Christie, and D. R. Williams, “Retinal microscotomas revealed with adaptive-optics microflashes,” Invest. Ophthalmol. Vis. Sci. 47(9), 4160–4167 (2006).
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A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
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A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
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J. I. W. Morgan, J. J. Hunter, B. Masella, R. Wolfe, D. C. Gray, W. H. Merigan, F. C. Delori, and D. R. Williams, “Light-induced retinal changes observed with high-resolution autofluorescence imaging of the retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 49(8), 3715–3729 (2008).
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H. Kühn, N. Bennett, M. Michel-Villaz, and M. Chabre, “Interactions between photoexcited rhodopsin and GTP-binding protein: kinetic and stoichiometric analyses from light-scattering changes,” Proc. Natl. Acad. Sci. U.S.A. 78(11), 6873–6877 (1981).
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Mingozzi, F.

A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
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J. I. Morgan, G. Han, E. Klinman, W. M. Maguire, D. C. Chung, A. M. Maguire, and J. Bennett, “High-resolution adaptive optics retinal imaging of cellular structure in choroideremia,” Invest. Ophthalmol. Vis. Sci. 55(10), 6381–6397 (2014).
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J. I. W. Morgan, J. J. Hunter, B. Masella, R. Wolfe, D. C. Gray, W. H. Merigan, F. C. Delori, and D. R. Williams, “Light-induced retinal changes observed with high-resolution autofluorescence imaging of the retinal pigment epithelium,” Invest. Ophthalmol. Vis. Sci. 49(8), 3715–3729 (2008).
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J. L. Schnapf, B. J. Nunn, M. Meister, and D. A. Baylor, “Visual transduction in cones of the monkey Macaca fascicularis,” J. Physiol. 427, 681–713 (1990).
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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).
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P. K. Ahnelt, H. Kolb, and R. Pflug, “Identification of a subtype of cone photoreceptor, likely to be blue sensitive, in the human retina,” J. Comp. Neurol. 255(1), 18–34 (1987).
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A. M. Maguire, K. A. High, A. Auricchio, J. F. Wright, E. A. Pierce, F. Testa, F. Mingozzi, J. L. Bennicelli, G. S. Ying, S. Rossi, A. Fulton, K. A. Marshall, S. Banfi, D. C. Chung, J. I. Morgan, B. Hauck, O. Zelenaia, X. Zhu, L. Raffini, F. Coppieters, E. De Baere, K. S. Shindler, N. J. Volpe, E. M. Surace, C. Acerra, A. Lyubarsky, T. M. Redmond, E. Stone, J. Sun, J. W. McDonnell, B. P. Leroy, F. Simonelli, and J. Bennett, “Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial,” Lancet 374(9701), 1597–1605 (2009).
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P. Zhang, R. J. Zawadzki, M. Goswami, P. T. Nguyen, V. Yarov-Yarovoy, M. E. Burns, and E. N. Pugh., “In vivo optophysiology reveals that G-protein activation triggers osmotic swelling and increased light scattering of rod photoreceptors,” Proc. Natl. Acad. Sci. U.S.A. 114(14), E2937–E2946 (2017).
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Raffini, L.

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K. Ratnam, J. Carroll, T. C. Porco, J. L. Duncan, and A. Roorda, “Relationship between foveal cone structure and clinical measures of visual function in patients with inherited retinal degenerations,” Invest. Ophthalmol. Vis. Sci. 54(8), 5836–5847 (2013).
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Supplementary Material (1)

NameDescription
» Visualization 1       Image of the cone mosaic exposed to a two second, 390 nW/degree^2 (2.2·104 cd/m^2) 550nm stimulus in subject 11015. B) Cones’ reflectance signals responded to the stimulus in a highly variable manner. Some cones increased their reflectance (orange pr

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Figures (9)

Fig. 1
Fig. 1

The steps taken to determine which cones were included for reflectance analysis. A) The average image (cropped to 113x113 µm [~0.4x0.4°] for visualization) from the top half of a stimulus trial’s image sequence, with overlaid cone locations. For each image sequence, we created a map of the extent of the stimulus delivered to the photoreceptors (B), color coded to indicate the percentage of the total stimulus that was delivered to each retinal region. Warmer colors correspond to a delivery of a greater percentage of the stimulus. Cones that received greater than 90% of the stimulus were categorized as ‘stimulated’ cones; cones that received less than 90% of the stimulus (dashed line) were excluded from analysis. (C) A map of the categorized cone locations. Red points label stimulated cones and orange points label excluded cones. After the cells were categorized, a motion contrast image (D) was generated using Tam et al.’s algorithm [22]. The motion contrast image was thresholded to create a mask (E) of the capillaries present in the image. (F) This mask was used to further exclude cones (additional orange points) underlying capillaries. The remaining stimulated cones (red points in (F) were used in subsequent analyses. Scale bar is 30 µm.

Fig. 2
Fig. 2

The pre-processing steps used to standardize each cone’s reflectance. Raw cone reflectance signals were extracted from each included cone for the control (A, 569 cones) and stimulated (D, 675 cones) image sequences. For visualization here, we display each cone’s reflectance signal relative to its starting value. To remove the effect of frame-to-frame changes in image intensity, each cone’s reflectance was scaled by the mean cone reflectance at each time point for the control (B) and stimulated image sequences (E). As in (A) and (D), each cone’s reflectance signal is relative to its starting value for visualization only. (C, F) Finally, individual cone reflectance signals were standardized to their pre-stimulus behavior by subtracting each cone’s pre-stimulus mean from itself, then dividing by its pre-stimulus standard deviation. Stimulus duration indicated by the black bars.

Fig. 3
Fig. 3

Individual infrared cone reflectance responds idiosyncratically to visible light stimulation (See also Visualization 1). A) A 58x58 µm cropped section of an image of the cone mosaic exposed to a two-second, 390 nW/degree2 (2.2·104 cd/m2) 550 nm stimulus in subject 11015. B) Cones’ reflectance signals responded to the stimulus in a highly variable manner. Some cones increased their reflectance (orange profile) in response to the stimulus, others decreased their reflectance (purple profile), and some oscillated (cyan profile). C) The reflectance response of a single cone was also heterogeneous across trials. While the reflectance in the first trial increased (orange profile), following trials decreased (purple profile), increased (red, blue profiles), and showed minimal to no change (green profile). Stimulus duration indicated by the black bar. Scale bar is 15µm.

Fig. 4
Fig. 4

The aggregated cone reflectance response. The figure shows the cone intrinsic reflectance response measured from the stimulated and control trials using all data from the condition illustrated by Fig. 3. (A) Repeat control and stimulated trials show a clear, measureable and reliable intrinsic reflectance response. The baseline is centered at 1 because Eq. (2) standardizes the response to the mean and standard deviation of the stimulus behavior. The warmer colors correspond to stimulated trials and the cooler colors correspond to control trials. (B) All trials for a given condition were then combined using pooled standard deviation, and the stimulus-evoked intrinsic reflectance response was taken as the difference between the stimulated and control pooled standard deviations. Signal gaps correspond to frames within each image sequence where the cone reflectance could not be measured due to failed registration (e.g. resulting from blinks or excessive eye motion). Stimulus duration indicated by the black bar. Data shown are from subject 11015 using a 550 nm, 337 nW/deg2 stimuli.

Fig. 5
Fig. 5

The cone reflectance response increases with stimulus irradiance. A) The reflectance response as a function of time for four stimulus intensities, overlaid with piecewise function fits (dotted lines; Formula 3). The reflectance response amplitude was extracted from each function by subtracting the mean prestimulus value from the peak fit value. As the intensity of the stimulus increased, the amplitude of the response also increased. Moreover, a more intense stimulus appeared to cause the peak of the intrinsic response to occur earlier in time with a steeper response slope. Stimulus duration indicated by the black bar. (B) The reflectance response amplitudes from (A) as a function of stimulus intensity. Data shown are from subject 11015 using 550 nm stimuli. Error bars delineate the 5th through the 95th percentile of the bootstrapped values.

Fig. 6
Fig. 6

Intrinsic reflectance response action spectrum for each subject. To determine the action spectrum for each subject, we fit the amplitude-irradiance functions across all wavelengths using a sigmoid with a common amplitude and slope, but unique shifts along the abscissa for each wavelength. The fit derived for each subject and each wavelength (dashed lines) is overlaid on each subjects’ amplitude response. Displayed data points were obtained from each condition’s pooled reflectance response. Error bars delineate the 5th through the 95th percentile of the bootstrapped amplitude distribution.

Fig. 7
Fig. 7

The wavelength dependence of the reflectance response links it to phototransduction. (A) For each subject, the horizontal shifts of the sigmoid fits for each wavelength relative to the 550 nm fit were taken as the relative action. To assess the variability of the amplitude responses and the sigmoidal fits, we bootstrapped each reflectance response, extracted the reflectance response amplitudes and repeated the fitting process 1,000 times. Error bars delineate the 5th through the 95th percentile of the bootstrapped values. In cases where error bars are not visible, they are smaller than the plotted points. (B) The average (across subjects) action spectrum of the intrinsic reflectance response (gold) overlaid on the human luminosity function (black dashed line). Overall, the action spectrum of the intrinsic reflectance response is well-matched to the photopic luminosity function. Error bars are ± 2 standard deviations.

Fig. 8
Fig. 8

The cone photoreceptor intrinsic reflectance response as a function of analysis area. To examine the signal-to-noise characteristics of the response, we selected concentric 10,000, 2,500, 625, and 100 µm2 areas for analysis. As region area decreased, the signal to noise ratio of the reflectance response decreased. Despite this, a clear response was observed even from the smallest analysis area. Data was obtained from an irradiance of 337 nW/deg2 at 550 nm, from subject 11015.

Fig. 9
Fig. 9

An analysis of the mean reflectance signal content. To ensure that a mean-based intrinsic signal was not lost due our normalization approach, we examined the change in mean cone reflectance across all trials of a 550 nm, 382 nW/deg2 stimulus condition for subject 11049. Individual trials (gray lines) did not show a clear, repeatable change in mean reflectance during or following the stimulus. Averaging across trials (black line) also did not produce a change in the mean.

Tables (1)

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Table 1 Reflectance response amplitudes averaged over all trials of a stimulus condition for each subject.

Equations (4)

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R norm ( t ) i = R raw (t) i R raw (t) ¯
R (t) i  =  R norm ( t ) i   R pre i ¯ σ R pr e i
σ fit ( t )={ A Γ Γ( k ) θ k (td) k1 e (td) θ σ pre ¯ ,              t< t σ max σ max + A exp e Τ(t t σ max ) A exp ,           t t σ max
f( E lo g 10 )= α 1+ e β( E log10 S w ) ,

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