Dynamic contrast optical coherence tomography images transit time and quantifies microvascular plasma volume and flow in the retina and choriocapillaris

Conrad W. Merkle; Conor Leahy; Vivek J. Srinivasan

doi:10.1364/BOE.7.004289

Dynamic contrast optical coherence tomography images transit time and quantifies microvascular plasma volume and flow in the retina and choriocapillaris

Conrad W. Merkle, Conor Leahy, and Vivek J. Srinivasan

Biomedical Optics Express
Vol. 7,
Issue 10,
pp. 4289-4312
(2016)
•https://doi.org/10.1364/BOE.7.004289

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Conrad W. Merkle, Conor Leahy, and Vivek J. Srinivasan, "Dynamic contrast optical coherence tomography images transit time and quantifies microvascular plasma volume and flow in the retina and choriocapillaris," Biomed. Opt. Express 7, 4289-4312 (2016)

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Related Topics
Table of Contents Category
- Optical Coherence Tomography
Optics & Photonics Topics
?

The topics in this list come from the OSA Optics and Photonics Topics applied to this article.
Previously assigned OCIS codes
- Optical coherence tomography (110.4500)
- Blood or tissue constituent monitoring (170.1470)
- Medical and biological imaging (170.3880)
- Physiology (170.5380)
- Three-dimensional microscopy (170.6900)
- Retina scanning (170.5755)

About this Article
History
- Original Manuscript: June 30, 2016
- Revised Manuscript: August 19, 2016
- Manuscript Accepted: September 16, 2016
- Published: September 27, 2016

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Open Access

Abstract

Despite the prevalence of optical imaging techniques to measure hemodynamics in large retinal vessels, quantitative measurements of retinal capillary and choroidal hemodynamics have traditionally been challenging. Here, a new imaging technique called dynamic contrast optical coherence tomography (DyC-OCT) is applied in the rat eye to study microvascular blood flow in individual retinal and choroidal layers in vivo. DyC-OCT is based on imaging the transit of an intravascular tracer dynamically as it passes through the field-of-view. Hemodynamic parameters can be determined through quantitative analysis of tracer kinetics. In addition to enabling depth-resolved transit time, volume, and flow measurements, the injected tracer also enhances OCT angiograms and enables clear visualization of the choriocapillaris, particularly when combined with a post-processing method for vessel enhancement. DyC-OCT complements conventional OCT angiography through quantification of tracer dynamics, similar to fluorescence angiography, but with the important added benefit of laminar resolution.

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2016 (1)

C. W. Merkle and V. J. Srinivasan, “Laminar microvascular transit time distribution in the mouse somatosensory cortex revealed by Dynamic Contrast Optical Coherence Tomography,” Neuroimage 125, 350–362 (2016).
[Crossref] [PubMed]

2015 (1)

C. Leahy, H. Radhakrishnan, G. Weiner, J. L. Goldberg, and V. J. Srinivasan, “Mapping the 3D Connectivity of the Rat Inner Retinal Vascular Network Using OCT Angiography,” Invest. Ophthalmol. Vis. Sci. 56(10), 5785–5793 (2015).
[Crossref] [PubMed]

2014 (4)

Y. Pan, J. You, N. D. Volkow, K. Park, and C. Du, “Ultrasensitive detection of 3D cerebral microvascular network dynamics in vivo,” Neuroimage 103, 492–501 (2014).
[Crossref] [PubMed]

T. E. Kornfield and E. A. Newman, “Regulation of blood flow in the retinal trilaminar vascular network,” J. Neurosci. 34(34), 11504–11513 (2014).
[Crossref] [PubMed]

A. Biesemeier, T. Taubitz, S. Julien, E. Yoeruek, and U. Schraermeyer, “Choriocapillaris breakdown precedes retinal degeneration in age-related macular degeneration,” Neurobiol. Aging 35(11), 2562–2573 (2014).
[Crossref] [PubMed]

D. M. Schwartz, J. Fingler, D. Y. Kim, R. J. Zawadzki, L. S. Morse, S. S. Park, S. E. Fraser, and J. S. Werner, “Phase-variance optical coherence tomography: a technique for noninvasive angiography,” Ophthalmology 121(1), 180–187 (2014).
[Crossref] [PubMed]

2013 (10)

B. Braaf, K. V. Vienola, C. K. Sheehy, Q. Yang, K. A. Vermeer, P. Tiruveedhula, D. W. Arathorn, A. Roorda, and J. F. de Boer, “Real-time eye motion correction in phase-resolved OCT angiography with tracking SLO,” Biomed. Opt. Express 4(1), 51–65 (2013).
[Crossref] [PubMed]

H. C. Hendargo, R. Estrada, S. J. Chiu, C. Tomasi, S. Farsiu, and J. A. Izatt, “Automated non-rigid registration and mosaicing for robust imaging of distinct retinal capillary beds using speckle variance optical coherence tomography,” Biomed. Opt. Express 4(6), 803–821 (2013).
[Crossref] [PubMed]

H. Radhakrishnan and V. J. Srinivasan, “Compartment-resolved imaging of cortical functional hyperemia with OCT angiography,” Biomed. Opt. Express 4(8), 1255–1268 (2013).
[Crossref] [PubMed]

A. Bouwens, D. Szlag, M. Szkulmowski, T. Bolmont, M. Wojtkowski, and T. Lasser, “Quantitative lateral and axial flow imaging with optical coherence microscopy and tomography,” Opt. Express 21(15), 17711–17729 (2013).
[Crossref] [PubMed]

V. J. Srinivasan and H. Radhakrishnan, “Total average blood flow and angiography in the rat retina,” J. Biomed. Opt. 18(7), 076025 (2013).
[Crossref] [PubMed]

Y. Y. Shih, L. Wang, B. H. De La Garza, G. Li, G. Cull, J. W. Kiel, and T. Q. Duong, “Quantitative retinal and choroidal blood flow during light, dark adaptation and flicker light stimulation in rats using fluorescent microspheres,” Curr. Eye Res. 38(2), 292–298 (2013).
[Crossref] [PubMed]

E. A. Newman, “Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature,” J. Cereb. Blood Flow Metab. 33(11), 1685–1695 (2013).
[Crossref] [PubMed]

G. Li, J. W. Kiel, D. P. Cardenas, B. H. De La Garza, and T. Q. Duong, “Postocclusive reactive hyperemia occurs in the rat retinal circulation but not in the choroid,” Invest. Ophthalmol. Vis. Sci. 54(7), 5123–5131 (2013).
[Crossref] [PubMed]

D. Y. Kim, J. Fingler, R. J. Zawadzki, S. S. Park, L. S. Morse, D. M. Schwartz, S. E. Fraser, and J. S. Werner, “Optical imaging of the chorioretinal vasculature in the living human eye,” Proc. Natl. Acad. Sci. U.S.A. 110(35), 14354–14359 (2013).
[Crossref] [PubMed]

W. Choi, K. J. Mohler, B. Potsaid, C. D. Lu, J. J. Liu, V. Jayaraman, A. E. Cable, J. S. Duker, R. Huber, and J. G. Fujimoto, “Choriocapillaris and choroidal microvasculature imaging with ultrahigh speed OCT angiography,” PLoS One 8(12), e81499 (2013).
[Crossref] [PubMed]

2012 (10)

M. Miura, S. Makita, T. Iwasaki, and Y. Yasuno, “An approach to measure blood flow in single choroidal vessel using Doppler optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 53(11), 7137–7141 (2012).
[Crossref] [PubMed]

Y. Zhang, O. San Emeterio Nateras, Q. Peng, C. A. Rosende, and T. Q. Duong, “Blood flow MRI of the human retina/choroid during rest and isometric exercise,” Invest. Ophthalmol. Vis. Sci. 53(7), 4299–4305 (2012).
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L. V. Chinta, L. Lindvere, and B. Stefanovic, “Robust quantification of microvascular transit times via linear dynamical systems using two-photon fluorescence microscopy data,” J. Cereb. Blood Flow Metab. 32(9), 1718–1724 (2012).
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J. Kur, E. A. Newman, and T. Chan-Ling, “Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease,” Prog. Retin. Eye Res. 31(5), 377–406 (2012).
[Crossref] [PubMed]

G. Li, B. De La Garza, Y. Y. Shih, E. R. Muir, and T. Q. Duong, “Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats,” Exp. Eye Res. 101, 90–96 (2012).
[Crossref] [PubMed]

S. N. Jespersen and L. Østergaard, “The roles of cerebral blood flow, capillary transit time heterogeneity, and oxygen tension in brain oxygenation and metabolism,” J. Cereb. Blood Flow Metab. 32(2), 264–277 (2012).
[Crossref] [PubMed]

S. Ciechanowicz and V. Patil, “Lipid emulsion for local anesthetic systemic toxicity,” Anesthesiol. Res. Pract. 2012, 131784 (2012).
[Crossref] [PubMed]

Y. Jia, O. Tan, J. Tokayer, B. Potsaid, Y. Wang, J. J. Liu, M. F. Kraus, H. Subhash, J. G. Fujimoto, J. Hornegger, and D. Huang, “Split-spectrum amplitude-decorrelation angiography with optical coherence tomography,” Opt. Express 20(4), 4710–4725 (2012).
[Crossref] [PubMed]

V. J. Srinivasan, H. Radhakrishnan, E. H. Lo, E. T. Mandeville, J. Y. Jiang, S. Barry, and A. E. Cable, “OCT methods for capillary velocimetry,” Biomed. Opt. Express 3(3), 612–629 (2012).
[Crossref] [PubMed]

B. Braaf, K. A. Vermeer, K. V. Vienola, and J. F. de Boer, “Angiography of the retina and the choroid with phase-resolved OCT using interval-optimized backstitched B-scans,” Opt. Express 20(18), 20516–20534 (2012).
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2011 (5)

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. Express 2(4), 781–793 (2011).
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B. Baumann, B. Potsaid, M. F. Kraus, J. J. Liu, D. Huang, J. Hornegger, A. E. Cable, J. S. Duker, and J. G. Fujimoto, “Total retinal blood flow measurement with ultrahigh speed swept source/Fourier domain OCT,” Biomed. Opt. Express 2(6), 1539–1552 (2011).
[Crossref] [PubMed]

B. Braaf, K. A. Vermeer, V. A. D. P. Sicam, E. van Zeeburg, J. C. van Meurs, and J. F. de Boer, “Phase-stabilized optical frequency domain imaging at 1-µm for the measurement of blood flow in the human choroid,” Opt. Express 19(21), 20886–20903 (2011).
[Crossref] [PubMed]

D. R. Williams, “Imaging single cells in the living retina,” Vision Res. 51(13), 1379–1396 (2011).
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P. Cimalla, J. Walther, M. Mittasch, and E. Koch, “Shear flow-induced optical inhomogeneity of blood assessed in vivo and in vitro by spectral domain optical coherence tomography in the 1.3 μm wavelength range,” J. Biomed. Opt. 16(11), 116020 (2011).
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2010 (1)

V. J. Srinivasan, S. Sakadzić, I. Gorczynska, S. Ruvinskaya, W. Wu, J. G. Fujimoto, and D. A. Boas, “Quantitative cerebral blood flow with optical coherence tomography,” Opt. Express 18(3), 2477–2494 (2010).
[Crossref] [PubMed]

2009 (4)

X. Wen, V. V. Tuchin, Q. Luo, and D. Zhu, “Controling the scattering of intralipid by using optical clearing agents,” Phys. Med. Biol. 54(22), 6917–6930 (2009).
[Crossref] [PubMed]

B. J. Vakoc, G. J. Tearney, and B. E. Bouma, “Statistical properties of phase-decorrelation in phase-resolved Doppler optical coherence tomography,” IEEE Trans. Med. Imaging 28(6), 814–821 (2009).
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R. D. Braun, C. A. Wienczewski, and A. Abbas, “Erythrocyte flow in choriocapillaris of normal and diabetic rats,” Microvasc. Res. 77(3), 247–255 (2009).
[Crossref] [PubMed]

M. Pouliot, M. C. Deschênes, S. Hétu, S. Chemtob, M. R. Lesk, R. Couture, and E. Vaucher, “Quantitative and regional measurement of retinal blood flow in rats using N-isopropyl-p-[14C]-iodoamphetamine ([14C]-IMP),” Exp. Eye Res. 89(6), 960–966 (2009).
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2008 (5)

H. Ludot, J. Y. Tharin, M. Belouadah, J. X. Mazoit, and J. M. Malinovsky, “Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child,” Anesth. Analg. 106, 1572–1574 (2008).

A. Mariampillai, B. A. Standish, E. H. Moriyama, M. Khurana, N. R. Munce, M. K. K. Leung, J. Jiang, A. Cable, B. C. Wilson, I. A. Vitkin, and V. X. D. Yang, “Speckle variance detection of microvasculature using swept-source optical coherence tomography,” Opt. Lett. 33(13), 1530–1532 (2008).
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Y. K. Tao, A. M. Davis, and J. A. Izatt, “Single-pass volumetric bidirectional blood flow imaging spectral domain optical coherence tomography using a modified Hilbert transform,” Opt. Express 16(16), 12350–12361 (2008).
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Z. Zhong, B. L. Petrig, X. Qi, and S. A. Burns, “In vivo measurement of erythrocyte velocity and retinal blood flow using adaptive optics scanning laser ophthalmoscopy,” Opt. Express 16(17), 12746–12756 (2008).
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Y. Wang, B. A. Bower, J. A. Izatt, O. Tan, and D. Huang, “Retinal blood flow measurement by circumpapillary Fourier domain Doppler optical coherence tomography,” J. Biomed. Opt. 13(6), 064003 (2008).
[Crossref] [PubMed]

2007 (3)

G. Bjärnhall, L. Tomic, H. K. Mishima, H. Tsukamoto, and A. Alm, “Retinal mean transit time in patients with primary open-angle glaucoma and normal-tension glaucoma,” Acta Ophthalmol. Scand. 85(1), 67–72 (2007).
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R. K. Wang, S. L. Jacques, Z. Ma, S. Hurst, S. R. Hanson, and A. Gruber, “Three dimensional optical angiography,” Opt. Express 15(7), 4083–4097 (2007).
[Crossref] [PubMed]

L. Wang, B. Fortune, G. Cull, K. M. McElwain, and G. A. Cioffi, “Microspheres method for ocular blood flow measurement in rats: size and dose optimization,” Exp. Eye Res. 84(1), 108–117 (2007).
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2006 (3)

M. A. Rosenblatt, M. Abel, G. W. Fischer, C. J. Itzkovich, and J. B. Eisenkraft, “Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest,” Anesthesiology 105(1), 217–218 (2006).
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S. Makita, Y. Hong, M. Yamanari, T. Yatagai, and Y. Yasuno, “Optical coherence angiography,” Opt. Express 14(17), 7821–7840 (2006).
[Crossref] [PubMed]

H. Cheng, G. Nair, T. A. Walker, M. K. Kim, M. T. Pardue, P. M. Thulé, D. E. Olson, and T. Q. Duong, “Structural and functional MRI reveals multiple retinal layers,” Proc. Natl. Acad. Sci. U.S.A. 103(46), 17525–17530 (2006).
[Crossref] [PubMed]

2005 (1)

J. A. Martin and A. Roorda, “Direct and noninvasive assessment of parafoveal capillary leukocyte velocity,” Ophthalmology 112(12), 2219–2224 (2005).
[Crossref] [PubMed]

2003 (1)

B. White, M. Pierce, N. Nassif, B. Cense, B. Park, G. Tearney, B. Bouma, T. Chen, and J. de Boer, “In vivo dynamic human retinal blood flow imaging using ultra-high-speed spectral domain optical coherence tomography,” Opt. Express 11(25), 3490–3497 (2003).
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2001 (1)

L. Tomic, O. Mäepea, G. O. Sperber, and A. Alm, “Comparison of retinal transit times and retinal blood flow: a study in monkeys,” Invest. Ophthalmol. Vis. Sci. 42(3), 752–755 (2001).
[PubMed]

2000 (1)

L. Schmetterer, S. Dallinger, O. Findl, H. G. Eichler, and M. Wolzt, “A comparison between laser interferometric measurement of fundus pulsation and pneumotonometric measurement of pulsatile ocular blood flow. 1. Baseline considerations,” Eye (Lond.) 14(1), 39–45 (2000).
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1999 (4)

A. Roggan, M. Friebel, K. Dorschel, A. Hahn, and G. Muller, “Optical Properties of Circulating Human Blood in the Wavelength Range 400-2500 nm,” J. Biomed. Opt. 4(1), 36–46 (1999).
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R. G. Tilton, K. C. Chang, W. S. LeJeune, C. C. Stephan, T. A. Brock, and J. R. Williamson, “Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF,” Invest. Ophthalmol. Vis. Sci. 40(3), 689–696 (1999).
[PubMed]

D. C. Morris, Z. Zhang, K. Davies, J. Fenstermacher, and M. Chopp, “High resolution quantitation of microvascular plasma perfusion in non-ischemic and ischemic rat brain by laser-scanning confocal microscopy,” Brain Res. Brain Res. Protoc. 4(2), 185–191 (1999).
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J. Lin and S. Roth, “Ischemic preconditioning attenuates hypoperfusion after retinal ischemia in rats,” Invest. Ophthalmol. Vis. Sci. 40(12), 2925–2931 (1999).
[PubMed]

1998 (1)

W. M. Kuebler, A. Sckell, O. Habler, M. Kleen, G. E. Kuhnle, M. Welte, K. Messmer, and A. E. Goetz, “Noninvasive measurement of regional cerebral blood flow by near-infrared spectroscopy and indocyanine green,” J. Cereb. Blood Flow Metab. 18(4), 445–456 (1998).
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1997 (3)

T. M. Mayhew and D. Astle, “Photoreceptor number and outer segment disk membrane surface area in the retina of the rat: stereological data for whole organ and average photoreceptor cell,” J. Neurocytol. 26(1), 53–61 (1997).
[Crossref] [PubMed]

Z. Chen, T. E. Milner, D. Dave, and J. S. Nelson, “Optical Doppler tomographic imaging of fluid flow velocity in highly scattering media,” Opt. Lett. 22(1), 64–66 (1997).
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J. A. Izatt, M. D. Kulkarni, S. Yazdanfar, J. K. Barton, and A. J. Welch, “In vivo bidirectional color Doppler flow imaging of picoliter blood volumes using optical coherence tomography,” Opt. Lett. 22(18), 1439–1441 (1997).
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1996 (2)

L. Ostergaard, R. M. Weisskoff, D. A. Chesler, C. Gyldensted, and B. R. Rosen, “High resolution measurement of cerebral blood flow using intravascular tracer bolus passages. Part I: Mathematical approach and statistical analysis,” Magn. Reson. Med. 36, 715–725 (1996).

L. Ostergaard, A. G. Sorensen, K. K. Kwong, R. M. Weisskoff, C. Gyldensted, and B. R. Rosen, “High resolution measurement of cerebral blood flow using intravascular tracer bolus passages. Part II: Experimental comparison and preliminary results,” Magn. Reson. Med. 36, 726–736 (1996).

1994 (1)

A. Harris, R. C. Sergott, G. L. Spaeth, J. L. Katz, J. A. Shoemaker, and B. J. Martin, “Color Doppler analysis of ocular vessel blood velocity in normal-tension glaucoma,” Am. J. Ophthalmol. 118(5), 642–649 (1994).
[Crossref] [PubMed]

1993 (1)

R. W. Flower, “Extraction of choriocapillaris hemodynamic data from ICG fluorescence angiograms,” Invest. Ophthalmol. Vis. Sci. 34(9), 2720–2729 (1993).
[PubMed]

1991 (1)

D. Y. Yu, V. A. Alder, and S. J. Cringle, “Measurement of blood flow in rat eyes by hydrogen clearance,” Am. J. Physiol. 261(3 Pt 2), H960–H968 (1991).
[PubMed]

1990 (1)

S. S. Hayreh, “In vivo choroidal circulation and its watershed zones,” Eye (Lond.) 4(2), 273–289 (1990).
[Crossref] [PubMed]

1989 (1)

D. M. Silver, R. A. Farrell, M. E. Langham, V. O’Brien, and P. Schilder, “Estimation of pulsatile ocular blood flow from intraocular pressure,” Acta Ophthalmol. Suppl. 191, 25–29 (1989).
[PubMed]

1988 (1)

R. G. Tilton, K. Chang, C. Weigel, D. Eades, W. R. Sherman, C. Kilo, and J. R. Williamson, “Increased ocular blood flow and 125I-albumin permeation in galactose-fed rats: inhibition by sorbinil,” Invest. Ophthalmol. Vis. Sci. 29(6), 861–868 (1988).
[PubMed]

1987 (1)

C. Desjardins and B. R. Duling, “Microvessel hematocrit: measurement and implications for capillary oxygen transport,” Am. J. Physiol. 252(3 Pt 2), H494–H503 (1987).
[PubMed]

1972 (1)

A. Alm and A. Bill, “The oxygen supply to the retina. II. Effects of high intraocular pressure and of increased arterial carbon dioxide tension on uveal and retinal blood flow in cats. A study with radioactively labelled microspheres including flow determinations in brain and some other tissues,” Acta Physiol. Scand. 84(3), 306–319 (1972).
[Crossref] [PubMed]

1970 (1)

A. Alm and A. Bill, “Blood flow and oxygen extraction in the cat uvea at normal and high intraocular pressures,” Acta Physiol. Scand. 80(1), 19–28 (1970).
[Crossref] [PubMed]

1965 (1)

K. L. Zierler, “Equations for Measuring Blood Flow by External Monitoring of Radioisotopes,” Circ. Res. 16(4), 309–321 (1965).
[Crossref] [PubMed]

1961 (1)

H. R. Novotny and D. L. Alvis, “A method of photographing fluorescence in circulating blood in the human retina,” Circulation 24(1), 82–86 (1961).
[Crossref] [PubMed]

1954 (1)

P. Meier and K. L. Zierler, “On the theory of the indicator-dilution method for measurement of blood flow and volume,” J. Appl. Physiol. 6(12), 731–744 (1954).
[PubMed]

1931 (1)

R. Fahraeus and T. Lindqvist, “The viscosity of the blood in narrow capillary tubes,” Am. J. Physiol. 96, 562–568 (1931).

Abbas, A.

R. D. Braun, C. A. Wienczewski, and A. Abbas, “Erythrocyte flow in choriocapillaris of normal and diabetic rats,” Microvasc. Res. 77(3), 247–255 (2009).
[Crossref] [PubMed]

Abel, M.

Alder, V. A.

D. Y. Yu, V. A. Alder, and S. J. Cringle, “Measurement of blood flow in rat eyes by hydrogen clearance,” Am. J. Physiol. 261(3 Pt 2), H960–H968 (1991).
[PubMed]

Alm, A.

L. Tomic, O. Mäepea, G. O. Sperber, and A. Alm, “Comparison of retinal transit times and retinal blood flow: a study in monkeys,” Invest. Ophthalmol. Vis. Sci. 42(3), 752–755 (2001).
[PubMed]

A. Alm and A. Bill, “Blood flow and oxygen extraction in the cat uvea at normal and high intraocular pressures,” Acta Physiol. Scand. 80(1), 19–28 (1970).
[Crossref] [PubMed]

Alvis, D. L.

H. R. Novotny and D. L. Alvis, “A method of photographing fluorescence in circulating blood in the human retina,” Circulation 24(1), 82–86 (1961).
[Crossref] [PubMed]

Arathorn, D. W.

Astle, D.

Barry, S.

Barton, J. K.

Baumann, B.

Belouadah, M.

Biesemeier, A.

Bill, A.

A. Alm and A. Bill, “Blood flow and oxygen extraction in the cat uvea at normal and high intraocular pressures,” Acta Physiol. Scand. 80(1), 19–28 (1970).
[Crossref] [PubMed]

Bjärnhall, G.

Boas, D. A.

Bolmont, T.

Bouma, B.

Bouma, B. E.

Bouwens, A.

Bower, B. A.

Braaf, B.

Braun, R. D.

R. D. Braun, C. A. Wienczewski, and A. Abbas, “Erythrocyte flow in choriocapillaris of normal and diabetic rats,” Microvasc. Res. 77(3), 247–255 (2009).
[Crossref] [PubMed]

Brock, T. A.

Burns, S. A.

Cable, A.

Cable, A. E.

Cardenas, D. P.

Cense, B.

Chang, K.

Chang, K. C.

Chan-Ling, T.

Chemtob, S.

Chen, T.

Chen, Z.

Z. Chen, T. E. Milner, D. Dave, and J. S. Nelson, “Optical Doppler tomographic imaging of fluid flow velocity in highly scattering media,” Opt. Lett. 22(1), 64–66 (1997).
[Crossref] [PubMed]

Cheng, H.

Chesler, D. A.

Chinta, L. V.

Chiu, S. J.

Choi, W.

Chopp, M.

Ciechanowicz, S.

S. Ciechanowicz and V. Patil, “Lipid emulsion for local anesthetic systemic toxicity,” Anesthesiol. Res. Pract. 2012, 131784 (2012).
[Crossref] [PubMed]

Cimalla, P.

Cioffi, G. A.

Couture, R.

Cringle, S. J.

D. Y. Yu, V. A. Alder, and S. J. Cringle, “Measurement of blood flow in rat eyes by hydrogen clearance,” Am. J. Physiol. 261(3 Pt 2), H960–H968 (1991).
[PubMed]

Cull, G.

Dallinger, S.

Dave, D.

Z. Chen, T. E. Milner, D. Dave, and J. S. Nelson, “Optical Doppler tomographic imaging of fluid flow velocity in highly scattering media,” Opt. Lett. 22(1), 64–66 (1997).
[Crossref] [PubMed]

Davies, K.

Davis, A. M.

de Boer, J.

de Boer, J. F.

De La Garza, B.

G. Li, B. De La Garza, Y. Y. Shih, E. R. Muir, and T. Q. Duong, “Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats,” Exp. Eye Res. 101, 90–96 (2012).
[Crossref] [PubMed]

De La Garza, B. H.

Deschênes, M. C.

Desjardins, C.

C. Desjardins and B. R. Duling, “Microvessel hematocrit: measurement and implications for capillary oxygen transport,” Am. J. Physiol. 252(3 Pt 2), H494–H503 (1987).
[PubMed]

Dorschel, K.

Du, C.

Y. Pan, J. You, N. D. Volkow, K. Park, and C. Du, “Ultrasensitive detection of 3D cerebral microvascular network dynamics in vivo,” Neuroimage 103, 492–501 (2014).
[Crossref] [PubMed]

Duker, J. S.

Duling, B. R.

C. Desjardins and B. R. Duling, “Microvessel hematocrit: measurement and implications for capillary oxygen transport,” Am. J. Physiol. 252(3 Pt 2), H494–H503 (1987).
[PubMed]

Duong, T. Q.

G. Li, B. De La Garza, Y. Y. Shih, E. R. Muir, and T. Q. Duong, “Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats,” Exp. Eye Res. 101, 90–96 (2012).
[Crossref] [PubMed]

Eades, D.

Eichler, H. G.

Eisenkraft, J. B.

Estrada, R.

Fahraeus, R.

R. Fahraeus and T. Lindqvist, “The viscosity of the blood in narrow capillary tubes,” Am. J. Physiol. 96, 562–568 (1931).

Farrell, R. A.

Farsiu, S.

Fenstermacher, J.

Findl, O.

Fingler, J.

Fischer, G. W.

Flower, R. W.

R. W. Flower, “Extraction of choriocapillaris hemodynamic data from ICG fluorescence angiograms,” Invest. Ophthalmol. Vis. Sci. 34(9), 2720–2729 (1993).
[PubMed]

Fortune, B.

Fraser, S. E.

Friebel, M.

Fujimoto, J. G.

Goetz, A. E.

Goldberg, J. L.

Gorczynska, I.

Gruber, A.

R. K. Wang, S. L. Jacques, Z. Ma, S. Hurst, S. R. Hanson, and A. Gruber, “Three dimensional optical angiography,” Opt. Express 15(7), 4083–4097 (2007).
[Crossref] [PubMed]

Gyldensted, C.

Habler, O.

Hahn, A.

Hanson, S. R.

R. K. Wang, S. L. Jacques, Z. Ma, S. Hurst, S. R. Hanson, and A. Gruber, “Three dimensional optical angiography,” Opt. Express 15(7), 4083–4097 (2007).
[Crossref] [PubMed]

Harris, A.

Hayreh, S. S.

S. S. Hayreh, “In vivo choroidal circulation and its watershed zones,” Eye (Lond.) 4(2), 273–289 (1990).
[Crossref] [PubMed]

Hendargo, H. C.

Hétu, S.

Hong, Y.

S. Makita, Y. Hong, M. Yamanari, T. Yatagai, and Y. Yasuno, “Optical coherence angiography,” Opt. Express 14(17), 7821–7840 (2006).
[Crossref] [PubMed]

Hornegger, J.

Huang, D.

Huber, R.

Hurst, S.

R. K. Wang, S. L. Jacques, Z. Ma, S. Hurst, S. R. Hanson, and A. Gruber, “Three dimensional optical angiography,” Opt. Express 15(7), 4083–4097 (2007).
[Crossref] [PubMed]

Itzkovich, C. J.

Iwasaki, T.

Izatt, J. A.

Jacques, S. L.

R. K. Wang, S. L. Jacques, Z. Ma, S. Hurst, S. R. Hanson, and A. Gruber, “Three dimensional optical angiography,” Opt. Express 15(7), 4083–4097 (2007).
[Crossref] [PubMed]

Jayaraman, V.

Jespersen, S. N.

Jia, Y.

Jiang, J.

Jiang, J. Y.

Julien, S.

Katz, J. L.

Khurana, M.

Kiel, J. W.

Kilo, C.

Kim, D. Y.

Kim, M. K.

Kleen, M.

Koch, E.

Kornfield, T. E.

T. E. Kornfield and E. A. Newman, “Regulation of blood flow in the retinal trilaminar vascular network,” J. Neurosci. 34(34), 11504–11513 (2014).
[Crossref] [PubMed]

Kraus, M. F.

Kuebler, W. M.

Kuhnle, G. E.

Kulkarni, M. D.

Kur, J.

Kwong, K. K.

Langham, M. E.

Lasser, T.

Leahy, C.

LeJeune, W. S.

Lesk, M. R.

Leung, M. K. K.

Li, G.

G. Li, B. De La Garza, Y. Y. Shih, E. R. Muir, and T. Q. Duong, “Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats,” Exp. Eye Res. 101, 90–96 (2012).
[Crossref] [PubMed]

Lin, J.

J. Lin and S. Roth, “Ischemic preconditioning attenuates hypoperfusion after retinal ischemia in rats,” Invest. Ophthalmol. Vis. Sci. 40(12), 2925–2931 (1999).
[PubMed]

Lindqvist, T.

R. Fahraeus and T. Lindqvist, “The viscosity of the blood in narrow capillary tubes,” Am. J. Physiol. 96, 562–568 (1931).

Lindvere, L.

Liu, J. J.

Lo, E. H.

Lu, C. D.

Ludot, H.

Luo, Q.

X. Wen, V. V. Tuchin, Q. Luo, and D. Zhu, “Controling the scattering of intralipid by using optical clearing agents,” Phys. Med. Biol. 54(22), 6917–6930 (2009).
[Crossref] [PubMed]

Ma, Z.

R. K. Wang, S. L. Jacques, Z. Ma, S. Hurst, S. R. Hanson, and A. Gruber, “Three dimensional optical angiography,” Opt. Express 15(7), 4083–4097 (2007).
[Crossref] [PubMed]

Mäepea, O.

L. Tomic, O. Mäepea, G. O. Sperber, and A. Alm, “Comparison of retinal transit times and retinal blood flow: a study in monkeys,” Invest. Ophthalmol. Vis. Sci. 42(3), 752–755 (2001).
[PubMed]

Makita, S.

S. Makita, Y. Hong, M. Yamanari, T. Yatagai, and Y. Yasuno, “Optical coherence angiography,” Opt. Express 14(17), 7821–7840 (2006).
[Crossref] [PubMed]

Malinovsky, J. M.

Mandeville, E. T.

Mariampillai, A.

Martin, B. J.

Martin, J. A.

J. A. Martin and A. Roorda, “Direct and noninvasive assessment of parafoveal capillary leukocyte velocity,” Ophthalmology 112(12), 2219–2224 (2005).
[Crossref] [PubMed]

Mayhew, T. M.

Mazoit, J. X.

McElwain, K. M.

Meier, P.

P. Meier and K. L. Zierler, “On the theory of the indicator-dilution method for measurement of blood flow and volume,” J. Appl. Physiol. 6(12), 731–744 (1954).
[PubMed]

Merkle, C. W.

Messmer, K.

Milner, T. E.

Z. Chen, T. E. Milner, D. Dave, and J. S. Nelson, “Optical Doppler tomographic imaging of fluid flow velocity in highly scattering media,” Opt. Lett. 22(1), 64–66 (1997).
[Crossref] [PubMed]

Mishima, H. K.

Mittasch, M.

Miura, M.

Mohler, K. J.

Moriyama, E. H.

Morris, D. C.

Morse, L. S.

Muir, E. R.

G. Li, B. De La Garza, Y. Y. Shih, E. R. Muir, and T. Q. Duong, “Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats,” Exp. Eye Res. 101, 90–96 (2012).
[Crossref] [PubMed]

Muller, G.

Munce, N. R.

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Fig. 1 Dynamic Contrast Optical Coherence Tomography (DyC-OCT) protocol, DyC-OCT signal, and contrast-enhanced angiogram. A) In DyC-OCT, a blood plasma tracer is injected, continuous OCT imaging of the region-of-interest tracks tracer passage, and finally, data processing extracts hemodynamic information. B) The DyC-OCT signal from a single voxel consists of three phases: a “Baseline” phase before the tracer arrives, a “1st Bolus Passage” phase with a transient increase in signal followed by a decay as the tracer passes through the field-of-view, and a “Recirculation” phase during which the signal eventually settles at a “steady state” value above baseline. The model-based fit to the raw data (red line) excludes the recirculation phase. Transit-time metrics such as arrival time and peak time can be extracted from this model. C) The steady state signal from the tracer enhances OCT angiography after recirculation. A color-coded angiogram of the choroid and choriocapillaris is shown following tracer injection and computational Hessian-based “vesselness” enhancement, with proximal vessels in green, distal vessels in red, and overlapping regions in yellow.

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Fig. 2 DyC-OCT quantifies hemodynamics in the retinal vasculature based on measuring tracer content in different compartments. A) Rendering of trilaminar vasculature of the inner retina, showing the optic nerve fiber / ganglion cell layer (ONF/GCL), inner plexiform layer (IPL), and outer plexiform layer (OPL). B) The capillary compartment makes up the bulk of the vascular network with alternating supplying arteries and draining veins radiating from the optic nerve head. C) One approach (Section 2.5.5) to assess microvasculature uses an arterial input (c_a) and the total tracer signal within microvasculature (C_t) to determine the product of plasma flow (PF) and a residue function (R) that describes the fraction of tracer left in microvasculature after an impulsive arterial input. An alternative, but related, approach (Section 2.5.6) uses an arterial input (c_a) and venous output (c_v) to determine the arteriovenous transport function between them (h_av). The mean transit time, defined as the centroid of h_av(t), is marked.

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Fig. 3 Comparison of conventional OCT angiogram and DyC-OCT angiogram cross-sections is shown. A) Conventional OCT angiogram (A) reveals vasculature without the use of a contrast agent; however, the centers of large vessels in the choroid appear dark (*) with bright multiple scattering tails beneath them (arrow). The DyC-OCT angiogram also shows the vasculature (B) based on the mean signal change induced by the contrast agent during the first bolus passage. Choroidal vessels appear bright in DyC-OCT without multiple scattering artifacts. C) Both the conventional OCT angiogram (red) and the DyC-OCT angiogram (green) overlap well (yellow) in the large proximal vessels with some artifacts, while lumens of choroidal vessels are significantly enhanced by the contrast agent. D) Detailed contrast kinetics for the boxed region in A-C are shown. The angiogram (I_OCTA(z,x,t), first column), signal change (ΔI_OCTA(z,x,t), middle column), and relative signal (I_OCTA(z,x,t)/I_OCTA(z,x,0), last column), are shown at baseline (first row), at peak (middle row), and at steady-state (last row) after tracer recirculation. The large retinal artery (labeled “A”) shows a more uniform signal enhancement (middle column) than the large retinal vein (labeled “V”).

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Fig. 4 Maximum intensity projection angiograms across 4 vascular layers before contrast injection, after contrast injection (contrast-enhanced), and after applying the vesselness enhancement algorithm to the contrast-enhanced angiogram. Each pair of before and after angiograms in the same column have the same color scale. Red arrows point to large retinal vessels and the shadows that they cast in subsequent layers.

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Fig. 5 DyC-OCT measures laminar transit time kinetics. False color transit time maps are overlaid on grayscale structural OCT images with large arteries and veins marked (A and V respectively) at both the voxel level (A-C) and the vessel level (D-F). Statistics from vessels across 4 rats are shown (G-J). Metrics are arrival time (A,D, and G), peak time (B,E, and H), time to peak (C,F, and I), and mean transit time (J). The arrival and peak times shown in the first two rows are relative to the imaging start time. In the third row, the ONF/GCL, IPL, and OPL arrival and peak times are referenced, for each rat, to the earliest inner retinal arterial arrival time, while the CC and choroid arrival and peak times are similarly referenced to the earliest choroidal arterial arrival time. Medians (red lines) and means (red X’s) for each layer, with equal weighting for each vessel, are shown. The upper and lower quartile ranges are bounded by the blue box. Outliers (red points) fall outside of 2.5 times the upper or lower quartile range. The maximum and minimum points (dashed black lines), excluding outliers, are shown. Black bars show statistically significant pairwise comparisons (* p < 0.05 and *** p < 0.0005). ONF/GCL – Optic Nerve Fiber/Ganglion Cell Layer, IPL – Inner Plexiform Layer, OPL – Outer Plexiform Layer, and CC – Choriocapillaris.

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Fig. 6 RBC signal and plasma volume measurements are used to determine a hematocrit index. False color volume and hematocrit maps are overlaid on grayscale structural OCT images, with large arteries and veins marked A and V, respectively. A) Log scale red blood cell (RBC) content as measured by the qualitative baseline OCT angiogram. B) A quantitative map of plasma volume per vessel shown in log scale. C) Qualitative hematocrit index for individual vessels. D) Mean hematocrit index (red line) and individual hematocrit index measurements (blue lines) across the microvascular layers of four rats. IR – Total Inner Retina, ONF/GCL – Optic Nerve Fiber/Ganglion Cell Layer, IPL – Inner Plexiform Layer, OPL – Outer Plexiform Layer, and CC – Choriocapillaris.

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Fig. 7 Quantitative transit time metrics for individual microvascular layers show similar trends across animals. Kinetic measurements include arrival time (A), peak time (B), time to peak (C), and mean transit time (MTT), where MTT can be calculated from the arteriovenous transport function between artery-vein pairs in the inner retina and choroid (D), from a model-based residue deconvolution approach (E), or from a singular value decomposition (SVD) residue deconvolution solution (F). Measurements from individual animals are shown as blue lines with differently oriented triangles for each animal. Mean values are shown as red squares. Unfilled symbols represent measurements based on a retinal artery time reference (A-C, Section 2.6.5) or calibration (D-F, Section 2.5.3) while filled symbols used a choroidal artery time reference or calibration. IR – Total Inner Retina, ONF/GCL – Optic Nerve Fiber/Ganglion Cell Layer, IPL – Inner Plexiform Layer, OPL – Outer Plexiform Layer, and CC – Choriocapillaris.

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Fig. 8 Quantitative plasma volume metrics for individual microvascular layers show similar trends across animals. Two separate methods of quantifying plasma volume based on the DyC-OCT signal are compared: steady state signal (A) and integrated DyC-OCT signal (B). Measurements from individual animals are shown as blue lines with differently oriented triangles for each animal. Mean values are shown as red squares. Unfilled symbols represent measurements based on a retinal calibration (Section 2.5.3) while filled symbols are from a choroidal calibration. C) Both methods are correlated based on linear regression (red line), with all points near the line of equality (black). D) A Bland-Altman plot demonstrates agreement between the two methods. The black line shows the average difference, centered near zero, and the red lines show two standard deviations from this mean. IR – Total Inner Retina, ONF/GCL – Optic Nerve Fiber/Ganglion Cell Layer, IPL – Inner Plexiform Layer, OPL – Outer Plexiform Layer, and CC – Choriocapillaris.

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Fig. 9 Plasma flow metrics for individual microvascular layers show similar trends across animals: blood flow index (BFI) (A), central volume principle (CVP)-derived flow using arteriovenous mean transit times from Fig. 7(D) and plasma volumes from Fig. 8(A) (B), a model-based residue deconvolution method (C), and a model-free singular value decomposition (SVD) residue deconvolution method (D). Insets in C and D show respective plots of plasma flow (PF) times the residue (R(t)) for the choriocapillaris, determined by deconvolution. Measurements from individual animals are shown as blue lines with differently oriented triangles for each animal. Mean values are shown as red squares. Unfilled symbols represent measurements based on a retinal calibration (Section 2.5.3) while filled symbols are from a choroidal calibration. IR – Total Inner Retina, ONF/GCL – Optic Nerve Fiber/Ganglion Cell Layer, IPL – Inner Plexiform Layer, OPL – Outer Plexiform Layer, and CC – Choriocapillaris.

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Tables (2)

Table 1 Reference locations for the theory of DyC-OCT metrics.

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Table 2 Blood flow estimates of the inner retina and choroid using different DyC-OCT metrics.

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Equations (17)

Equations on this page are rendered with MathJax. Learn more.

I_{O C T A} (z, x, t) = h (z, x) [μ_{b, R B C} (z, x) + μ_{b, i} (z, x, t)]

h (z, x) = h_{s p e c} (z) h_{f o c u s} (z) h_{v i g n} (x) h_{a t t e n} (z, x)

μ_{b, i} (z, x, t) = c_{i} (z, x, t) σ_{b, i}

μ_{b, R B C} (z, x) = c_{R B C} (z, x) σ_{b, R B C}

Δ I_{O C T A} (z, x, t) = I_{O C T A} (z, x, t) - I_{O C T A} (z, x, 0) = h (z, x) μ_{b, i} (z, x, t) = K (z, x) c_{i} (z, x, t)

μ_{b, i, s s} (z, x) = c_{i, s s} (z, x) σ_{b, i}

Δ I_{O C T A, s s} (z, x) = I_{O C T A, s s} (z, x) - I_{O C T A} (z, x, 0) = h (z, x) μ_{b, i, s s} (z, x) = K_{s s} (z, x) c_{p} (z, x)

Δ I_{O C T A, s s, r e f} = \frac{1}{A_{R O I, r e f}} \iint_{R O I, r e f} Δ I_{O C T A, s s} (z, x) d z d x

K_{s s} (z, x) ≅ K_{s s, r e f} = \frac{Δ I_{O C T A, s s, r e f}}{c_{p, r e f}}

P V_{V, s s} = \iint_{R O I, v e s s e l ​} c_{p} (z, x) d z d x ≅ \iint_{R O I, v e s s e l ​} \frac{Δ I_{O C T A, s s} (z, x)}{K_{s s, r e f}} d z d x

P V_{L, s s} = \frac{1}{X_{l a y e r}} \iint_{R O I, l a y e r ​} c_{p} (z, x) d z d x ≅ \frac{1}{X_{l a y e r}} \iint_{R O I, l a y e r ​} \frac{Δ I_{O C T A, s s} (z, x)}{K_{s s, r e f}} d z d x

C_{t} (t) = \frac{1}{X_{l a y e r}} \iint_{R O I, l a y e r} c_{i} (z, x, t) d z d x

c_{a} (t) = \frac{1}{(1 - H) A_{a r t e r y}} \iint_{R O I, a r t e r y} c_{i} (z, x, t) d z d x

C_{t} (t) = c_{a} (t) * [P F \times R (t)]

P V = \frac{\int_{- \infty}^{\infty} C_{t} (t) d t}{\int_{- \infty}^{\infty} c_{a} (t) d t}

M T T = \int_{- \infty}^{\infty} t h_{a v} (t) d t = \frac{\int_{- \infty}^{\infty} t c_{a} (t) d t}{\int_{- \infty}^{\infty} c_{a} (t) d t} - \frac{\int_{- \infty}^{\infty} t c_{v} (t) d t}{\int_{- \infty}^{\infty} c_{v} (t) d t}

H_{i n d e x} (z, x) = \frac{I_{O C T A} (z, x, 0)}{I_{O C T A} (z, x, 0) + Δ I_{O C T A, s s} (z, x)} = \frac{σ_{b, R B C} c_{R B C} (z, x)}{σ_{b, R B C} c_{R B C} (z, x) + σ_{b, i} c_{i, s s} (z, x)}

Metric	Theory	Units	Sections	Equations
Individual Vessel Plasma Volume	Steady-State DyC-OCT Signal	Volume per unit length [pL/mm to nL/mm]	2.5.4	6-9, 10
Total Layer Plasma Volume	Steady-State DyC-OCT Signal	Volume per unit en face area [nL/mm²]	2.5.4	6-9, 11
	Integrated DyC-OCT Signal	Volume per unit en face area [nL/mm²]	2.5.5	12, 13, 15
Total Layer Plasma Flow	Central Volume Principle	Flow per unit en face area [μL/min/mm²]	2.5.5	Inline
	Model-Based Residue Deconvolution	Flow per unit en face area [μL/min/mm²]	2.5.5, 2.6.7	12, 13, 14
	Singular Value Decomposition Residue Deconvolution	Flow per unit en face area [μL/min/mm²]	2.5.5, 2.6.7	12, 13, 14
	Blood Flow Index	Arbitrary Units	2.5.7	N.A.
Hematocrit Index	Ratio Between Plasma Tracer and Baseline Angiogram Signals	Arbitrary Units	2.5.8	17
Mean Transit Time	Arteriovenous Transport Function Centroid	Time [s]	2.5.5	13, 16
	Model-Based Residue Deconvolution	Time [s]	2.5.5, 2.6.7	12-14, Inline
	Singular Value Decomposition Residue Deconvolution	Time [s]	2.5.5, 2.6.7	12-14, Inline
Other Transit Times	Arrival Time, Peak Time, Mean Transit Time, and Time to Peak from Fitted DyC-OCT Curve	Time [s]	2.6.2, 2.6.5	N.A.

	Inner Retina Blood Flow		Choriocapillaris Blood Flow
Technique	Mean	Std Dev	Mean	Std Dev	Ratio
BFI (AU)	2.3	0.8	14.1	19.1	6.1
CVP (µL/min)	7.5	5.9	41.7	17.7	6.5
Model-Based (µL/min)	22.7	6.3	70.9	8.2	3.7
SVD (µL/min)	9.1	4.3	40.0	18.3	5.2

Metric	Theory	Units	Sections	Equations
Individual Vessel Plasma Volume	Steady-State DyC-OCT Signal	Volume per unit length [pL/mm to nL/mm]	2.5.4	6-9, 10
Total Layer Plasma Volume	Steady-State DyC-OCT Signal	Volume per unit en face area [nL/mm²]	2.5.4	6-9, 11
	Integrated DyC-OCT Signal	Volume per unit en face area [nL/mm²]	2.5.5	12, 13, 15
Total Layer Plasma Flow	Central Volume Principle	Flow per unit en face area [μL/min/mm²]	2.5.5	Inline
	Model-Based Residue Deconvolution	Flow per unit en face area [μL/min/mm²]	2.5.5, 2.6.7	12, 13, 14
	Singular Value Decomposition Residue Deconvolution	Flow per unit en face area [μL/min/mm²]	2.5.5, 2.6.7	12, 13, 14
	Blood Flow Index	Arbitrary Units	2.5.7	N.A.
Hematocrit Index	Ratio Between Plasma Tracer and Baseline Angiogram Signals	Arbitrary Units	2.5.8	17
Mean Transit Time	Arteriovenous Transport Function Centroid	Time [s]	2.5.5	13, 16
	Model-Based Residue Deconvolution	Time [s]	2.5.5, 2.6.7	12-14, Inline
	Singular Value Decomposition Residue Deconvolution	Time [s]	2.5.5, 2.6.7	12-14, Inline
Other Transit Times	Arrival Time, Peak Time, Mean Transit Time, and Time to Peak from Fitted DyC-OCT Curve	Time [s]	2.6.2, 2.6.5	N.A.

	Inner Retina Blood Flow		Choriocapillaris Blood Flow
Technique	Mean	Std Dev	Mean	Std Dev	Ratio
BFI (AU)	2.3	0.8	14.1	19.1	6.1
CVP (µL/min)	7.5	5.9	41.7	17.7	6.5
Model-Based (µL/min)	22.7	6.3	70.9	8.2	3.7
SVD (µL/min)	9.1	4.3	40.0	18.3	5.2