Abstract

We propose a new optical coherence tomography (OCT) based method to measure red blood cell (RBC) velocities of single capillaries in the cortex of rodent brain. This OCT capillary velocimetry exploits quantitative laser speckle contrast analysis to estimate speckle decorrelation rate from the measured temporal OCT speckle signals, which is related to microcirculatory flow velocity. We hypothesize that OCT signal due to sub-surface capillary flow can be treated as the speckle signal in the single scattering regime and thus its time scale of speckle fluctuations can be subjected to single scattering laser speckle contrast analysis to derive characteristic decorrelation time. To validate this hypothesis, OCT measurements are conducted on a single capillary flow phantom operating at preset velocities, in which M-mode B-frames are acquired using a high-speed OCT system. Analysis is then performed on the time-varying OCT signals extracted at the capillary flow, exhibiting a typical inverse relationship between the estimated decorrelation time and absolute RBC velocity, which is then used to deduce the capillary velocities. We apply the method to in vivo measurements of mouse brain, demonstrating that the proposed approach provides additional useful information in the quantitative assessment of capillary hemodynamics, complementary to that of OCT angiography.

© 2016 Optical Society of America

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References

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2016 (2)

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
[Crossref] [PubMed]

K. L. Pepple, W. J. Choi, L. Wilson, R. N. Van Gelder, and R. K. Wang, “Quantitative assessment of anterior segment inflammation in a rat model of uveitis using spectral-domain optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 57(8), 3567–3575 (2016).
[Crossref] [PubMed]

2015 (2)

S. M. S. Kazmi, E. Faraji, M. A. Davis, Y.-Y. Huang, X. J. Zhang, and A. K. Dunn, “Flux or speed? Examining speckle contrast imaging of vascular flows,” Biomed. Opt. Express 6(7), 2588–2608 (2015).
[Crossref] [PubMed]

A. Zhang, Q. Zhang, C.-L. Chen, and R. K. Wang, “Methods and algorithms for optical coherence tomography-based angiography: a review and comparison,” J. Biomed. Opt. 20(10), 100901 (2015).
[Crossref] [PubMed]

2014 (4)

J. Lee, J. Y. Jiang, W. Wu, F. Lesage, and D. A. Boas, “Statistical intensity variation analysis for rapid volumetric imaging of capillary network flux,” Biomed. Opt. Express 5(4), 1160–1172 (2014).
[Crossref] [PubMed]

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

R. A. Leitgeb, R. M. Werkmeister, C. Blatter, and L. Schmetterer, “Doppler optical coherence tomography,” Prog. Retin. Eye Res. 41, 26–43 (2014).
[Crossref] [PubMed]

W. J. Choi, Z. Zhi, and R. K. Wang, “In vivo OCT microangiography of rodent iris,” Opt. Lett. 39(8), 2455–2458 (2014).
[Crossref] [PubMed]

2013 (4)

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

A. Nadort, R. G. Woolthuis, T. G. van Leeuwen, and D. J. Faber, “Quantitative laser speckle flowmetry of the in vivo microcirculation using sidestream dark field microscopy,” Biomed. Opt. Express 4(11), 2347–2361 (2013).
[Crossref] [PubMed]

X. Liu, Y. Huang, J. C. Ramella-Roman, S. A. Mathews, and J. U. Kang, “Quantitative transverse flow measurement using optical coherence tomography speckle decorrelation analysis,” Opt. Lett. 38(5), 805–807 (2013).
[Crossref] [PubMed]

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

2012 (5)

2011 (1)

M. Tomita, Y. Tomita, M. Unekawa, H. Toriumi, and N. Suzuki, “Oscillating neuro-capillary coupling during cortical spreading depression as observed by tracking of FITC-labeled RBCs in single capillaries,” Neuroimage 56(3), 1001–1010 (2011).
[Crossref] [PubMed]

2010 (4)

2009 (1)

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

2008 (3)

2007 (1)

2006 (3)

E. B. Hutchinson, B. Stefanovic, A. P. Koretsky, and A. C. Silva, “Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia,” Neuroimage 32(2), 520–530 (2006).
[Crossref] [PubMed]

G.-B. Lee, C.-C. Chang, S.-B. Huang, and R.-J. Yang, “The hydrodynamic focusing effect inside rectangular microchannels,” J. Micromech. Microeng. 16(5), 1024–1032 (2006).
[Crossref]

C. Simonnet and A. Groisman, “High-throughput and high-resolution flow cytometry in molded microfluidic devices,” Anal. Chem. 78(16), 5653–5663 (2006).
[Crossref] [PubMed]

2003 (2)

M. L. Schulte, J. D. Wood, and A. G. Hudetz, “Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat,” Brain Res. 963(1-2), 81–92 (2003).
[Crossref] [PubMed]

A. F. Fercher, W. Drexler, C. K. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,ˮ,” Rep. Prog. Phys. 66(2), 239–303 (2003).
[Crossref]

1998 (1)

D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, “Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex,” Proc. Natl. Acad. Sci. U.S.A. 95(26), 15741–15746 (1998).
[Crossref] [PubMed]

1997 (1)

A. G. Hudetz, “Blood flow in the cerebral capillary network: a review emphasizing observations with intravital microscopy,” Microcirculation 4(2), 233–252 (1997).
[Crossref] [PubMed]

1996 (1)

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Abounader, R.

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Agin, V.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Ali, C.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Alkayed, N. J.

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
[Crossref] [PubMed]

An, L.

Arathorn, D. W.

Attwell, D.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Baran, U.

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
[Crossref] [PubMed]

Barry, S.

Bartlett, L. A.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

Blatter, C.

R. A. Leitgeb, R. M. Werkmeister, C. Blatter, and L. Schmetterer, “Doppler optical coherence tomography,” Prog. Retin. Eye Res. 41, 26–43 (2014).
[Crossref] [PubMed]

Boas, D. A.

Bouma, B. E.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

Braaf, B.

Cable, A.

Cable, A. E.

Chang, C.-C.

G.-B. Lee, C.-C. Chang, S.-B. Huang, and R.-J. Yang, “The hydrodynamic focusing effect inside rectangular microchannels,” J. Micromech. Microeng. 16(5), 1024–1032 (2006).
[Crossref]

Chen, C.-L.

A. Zhang, Q. Zhang, C.-L. Chen, and R. K. Wang, “Methods and algorithms for optical coherence tomography-based angiography: a review and comparison,” J. Biomed. Opt. 20(10), 100901 (2015).
[Crossref] [PubMed]

Cheng, H.

Choi, W. J.

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
[Crossref] [PubMed]

K. L. Pepple, W. J. Choi, L. Wilson, R. N. Van Gelder, and R. K. Wang, “Quantitative assessment of anterior segment inflammation in a rat model of uveitis using spectral-domain optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 57(8), 3567–3575 (2016).
[Crossref] [PubMed]

W. J. Choi, Z. Zhi, and R. K. Wang, “In vivo OCT microangiography of rodent iris,” Opt. Lett. 39(8), 2455–2458 (2014).
[Crossref] [PubMed]

Davis, M. A.

de Boer, J. F.

Denk, W.

D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, “Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex,” Proc. Natl. Acad. Sci. U.S.A. 95(26), 15741–15746 (1998).
[Crossref] [PubMed]

Drexler, W.

A. F. Fercher, W. Drexler, C. K. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,ˮ,” Rep. Prog. Phys. 66(2), 239–303 (2003).
[Crossref]

Duelli, R.

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Dunn, A. K.

S. M. S. Kazmi, E. Faraji, M. A. Davis, Y.-Y. Huang, X. J. Zhang, and A. K. Dunn, “Flux or speed? Examining speckle contrast imaging of vascular flows,” Biomed. Opt. Express 6(7), 2588–2608 (2015).
[Crossref] [PubMed]

A. K. Dunn, “Laser speckle contrast imaging of cerebral blood flow,” Ann. Biomed. Eng. 40(2), 367–377 (2012).
[Crossref] [PubMed]

D. A. Boas and A. K. Dunn, “Laser speckle contrast imaging in biomedical optics,” J. Biomed. Opt. 15(1), 011109 (2010).
[Crossref] [PubMed]

Duong, T. Q.

Faber, D. J.

Faraji, E.

Fercher, A. F.

A. F. Fercher, W. Drexler, C. K. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,ˮ,” Rep. Prog. Phys. 66(2), 239–303 (2003).
[Crossref]

Fujimoto, J. G.

Fukumura, D.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

Gao, B. Z.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Gorczynska, I.

Groisman, A.

C. Simonnet and A. Groisman, “High-throughput and high-resolution flow cytometry in molded microfluidic devices,” Anal. Chem. 78(16), 5653–5663 (2006).
[Crossref] [PubMed]

Gruber, A.

Hall, C. N.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Hamilton, N. B.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Hanson, S. R.

Helmchen, F.

D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, “Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex,” Proc. Natl. Acad. Sci. U.S.A. 95(26), 15741–15746 (1998).
[Crossref] [PubMed]

Hitzenberger, C. K.

A. F. Fercher, W. Drexler, C. K. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,ˮ,” Rep. Prog. Phys. 66(2), 239–303 (2003).
[Crossref]

Hornegger, J.

Huang, D.

Huang, S.-B.

G.-B. Lee, C.-C. Chang, S.-B. Huang, and R.-J. Yang, “The hydrodynamic focusing effect inside rectangular microchannels,” J. Micromech. Microeng. 16(5), 1024–1032 (2006).
[Crossref]

Huang, T.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Huang, Y.

Huang, Y.-Y.

Hudetz, A. G.

M. L. Schulte, J. D. Wood, and A. G. Hudetz, “Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat,” Brain Res. 963(1-2), 81–92 (2003).
[Crossref] [PubMed]

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Hutchinson, E. B.

E. B. Hutchinson, B. Stefanovic, A. P. Koretsky, and A. C. Silva, “Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia,” Neuroimage 32(2), 520–530 (2006).
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Jacques, S. L.

Jain, R. K.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
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Jespersen, S. N.

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).
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Jia, Y.

Jiang, J.

Jiang, J. Y.

Kang, J. U.

Kazmi, S. M. S.

Khurana, M.

Kleinfeld, D.

D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, “Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex,” Proc. Natl. Acad. Sci. U.S.A. 95(26), 15741–15746 (1998).
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Koistinaho, J.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
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Koretsky, A. P.

E. B. Hutchinson, B. Stefanovic, A. P. Koretsky, and A. C. Silva, “Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia,” Neuroimage 32(2), 520–530 (2006).
[Crossref] [PubMed]

Kraus, M. F.

Kuschinsky, W.

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Lanning, R. M.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
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Lasser, T.

A. F. Fercher, W. Drexler, C. K. Hitzenberger, and T. Lasser, “Optical coherence tomography - principles and applications,ˮ,” Rep. Prog. Phys. 66(2), 239–303 (2003).
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Lee, G.-B.

G.-B. Lee, C.-C. Chang, S.-B. Huang, and R.-J. Yang, “The hydrodynamic focusing effect inside rectangular microchannels,” J. Micromech. Microeng. 16(5), 1024–1032 (2006).
[Crossref]

Lee, J.

Leitgeb, R. A.

R. A. Leitgeb, R. M. Werkmeister, C. Blatter, and L. Schmetterer, “Doppler optical coherence tomography,” Prog. Retin. Eye Res. 41, 26–43 (2014).
[Crossref] [PubMed]

Lesage, F.

Leung, M. K.

Liu, J. J.

Liu, X.

Lo, E. H.

Ma, Z.

Mandeville, E. T.

Mariampillai, A.

Mathews, S. A.

Mishra, A.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Mitra, P. P.

D. Kleinfeld, P. P. Mitra, F. Helmchen, and W. Denk, “Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex,” Proc. Natl. Acad. Sci. U.S.A. 95(26), 15741–15746 (1998).
[Crossref] [PubMed]

Montaner, J.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Morancho, A.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
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Moriyama, E. H.

Munce, N. R.

Munn, L. L.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

Nadort, A.

O’Farrell, F. M.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Omori, M.

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
[Crossref] [PubMed]

Osada, T.

M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Østergaard, L.

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]

Padera, T. P.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

Peng, X.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Pepple, K. L.

K. L. Pepple, W. J. Choi, L. Wilson, R. N. Van Gelder, and R. K. Wang, “Quantitative assessment of anterior segment inflammation in a rat model of uveitis using spectral-domain optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 57(8), 3567–3575 (2016).
[Crossref] [PubMed]

Potsaid, B.

Qin, J.

Qin, W.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Radhakrishnan, H.

Rahman, M.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Ramella-Roman, J. C.

Reynell, C.

A. Mishra, F. M. O’Farrell, C. Reynell, N. B. Hamilton, C. N. Hall, and D. Attwell, “Imaging pericytes and capillary diameter in brain slices and isolated retinae,” Nat. Protoc. 9(2), 323–336 (2014).
[Crossref] [PubMed]

Roorda, A.

Rosell, A.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Ruvinskaya, S.

Sakadzic, S.

Schmetterer, L.

R. A. Leitgeb, R. M. Werkmeister, C. Blatter, and L. Schmetterer, “Doppler optical coherence tomography,” Prog. Retin. Eye Res. 41, 26–43 (2014).
[Crossref] [PubMed]

Schmidt, L.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Schröck, H.

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Schulte, M. L.

M. L. Schulte, J. D. Wood, and A. G. Hudetz, “Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat,” Brain Res. 963(1-2), 81–92 (2003).
[Crossref] [PubMed]

Schwaninger, M.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Sheehy, C. K.

Silva, A. C.

E. B. Hutchinson, B. Stefanovic, A. P. Koretsky, and A. C. Silva, “Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia,” Neuroimage 32(2), 520–530 (2006).
[Crossref] [PubMed]

Simonnet, C.

C. Simonnet and A. Groisman, “High-throughput and high-resolution flow cytometry in molded microfluidic devices,” Anal. Chem. 78(16), 5653–5663 (2006).
[Crossref] [PubMed]

Srinivasan, V. J.

Standish, B. A.

Stefanovic, B.

E. B. Hutchinson, B. Stefanovic, A. P. Koretsky, and A. C. Silva, “Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia,” Neuroimage 32(2), 520–530 (2006).
[Crossref] [PubMed]

Stylianopoulos, T.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
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Subhash, H.

Suzuki, N.

M. Tomita, Y. Tomita, M. Unekawa, H. Toriumi, and N. Suzuki, “Oscillating neuro-capillary coupling during cortical spreading depression as observed by tracking of FITC-labeled RBCs in single capillaries,” Neuroimage 56(3), 1001–1010 (2011).
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M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Tan, O.

Tatarishvili, J.

M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Tearney, G. J.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
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Tiruveedhula, P.

Tokayer, J.

Tomita, M.

M. Tomita, Y. Tomita, M. Unekawa, H. Toriumi, and N. Suzuki, “Oscillating neuro-capillary coupling during cortical spreading depression as observed by tracking of FITC-labeled RBCs in single capillaries,” Neuroimage 56(3), 1001–1010 (2011).
[Crossref] [PubMed]

M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Tomita, Y.

M. Tomita, Y. Tomita, M. Unekawa, H. Toriumi, and N. Suzuki, “Oscillating neuro-capillary coupling during cortical spreading depression as observed by tracking of FITC-labeled RBCs in single capillaries,” Neuroimage 56(3), 1001–1010 (2011).
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M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Toriumi, H.

M. Tomita, Y. Tomita, M. Unekawa, H. Toriumi, and N. Suzuki, “Oscillating neuro-capillary coupling during cortical spreading depression as observed by tracking of FITC-labeled RBCs in single capillaries,” Neuroimage 56(3), 1001–1010 (2011).
[Crossref] [PubMed]

M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Tyrrell, J. A.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

Unekawa, M.

M. Tomita, Y. Tomita, M. Unekawa, H. Toriumi, and N. Suzuki, “Oscillating neuro-capillary coupling during cortical spreading depression as observed by tracking of FITC-labeled RBCs in single capillaries,” Neuroimage 56(3), 1001–1010 (2011).
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M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Vakoc, B. J.

B. J. Vakoc, R. M. Lanning, J. A. Tyrrell, T. P. Padera, L. A. Bartlett, T. Stylianopoulos, L. L. Munn, G. J. Tearney, D. Fukumura, R. K. Jain, and B. E. Bouma, “Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging,” Nat. Med. 15(10), 1219–1223 (2009).
[Crossref] [PubMed]

Van Gelder, R. N.

K. L. Pepple, W. J. Choi, L. Wilson, R. N. Van Gelder, and R. K. Wang, “Quantitative assessment of anterior segment inflammation in a rat model of uveitis using spectral-domain optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 57(8), 3567–3575 (2016).
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van Leeuwen, T. G.

Vienola, K. V.

Vitkin, I. A.

Vivien, D.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Vogel, J.

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Wang, R.

Wang, R. K.

K. L. Pepple, W. J. Choi, L. Wilson, R. N. Van Gelder, and R. K. Wang, “Quantitative assessment of anterior segment inflammation in a rat model of uveitis using spectral-domain optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 57(8), 3567–3575 (2016).
[Crossref] [PubMed]

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
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A. Zhang, Q. Zhang, C.-L. Chen, and R. K. Wang, “Methods and algorithms for optical coherence tomography-based angiography: a review and comparison,” J. Biomed. Opt. 20(10), 100901 (2015).
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W. J. Choi, Z. Zhi, and R. K. Wang, “In vivo OCT microangiography of rodent iris,” Opt. Lett. 39(8), 2455–2458 (2014).
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L. An, J. Qin, and R. K. Wang, “Ultrahigh sensitive optical microangiography for in vivo imaging of microcirculations within human skin tissue beds,” Opt. Express 18(8), 8220–8228 (2010).
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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).
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Wang, X.

A. Rosell, V. Agin, M. Rahman, A. Morancho, C. Ali, J. Koistinaho, X. Wang, D. Vivien, M. Schwaninger, and J. Montaner, “Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome?” Transl. Stroke Res. 4(3), 297–307 (2013).
[Crossref] [PubMed]

Wang, Y.

Wei, L.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Werkmeister, R. M.

R. A. Leitgeb, R. M. Werkmeister, C. Blatter, and L. Schmetterer, “Doppler optical coherence tomography,” Prog. Retin. Eye Res. 41, 26–43 (2014).
[Crossref] [PubMed]

Wilson, B. C.

Wilson, L.

K. L. Pepple, W. J. Choi, L. Wilson, R. N. Van Gelder, and R. K. Wang, “Quantitative assessment of anterior segment inflammation in a rat model of uveitis using spectral-domain optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 57(8), 3567–3575 (2016).
[Crossref] [PubMed]

Wood, J. D.

M. L. Schulte, J. D. Wood, and A. G. Hudetz, “Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat,” Brain Res. 963(1-2), 81–92 (2003).
[Crossref] [PubMed]

Woolthuis, R. G.

Wu, W.

Yan, Y.

Yang, Q.

Yang, R.-J.

G.-B. Lee, C.-C. Chang, S.-B. Huang, and R.-J. Yang, “The hydrodynamic focusing effect inside rectangular microchannels,” J. Micromech. Microeng. 16(5), 1024–1032 (2006).
[Crossref]

Yang, V. X.

Yang, X.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Yuan, J. X.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Yuan, X.

W. Qin, L. Schmidt, X. Yang, L. Wei, T. Huang, J. X. Yuan, X. Peng, X. Yuan, and B. Z. Gao, “Laser guidance-based cell detection in a microfluidic biochip,” J. Biomed. Opt. 18(6), 060502 (2013).
[Crossref] [PubMed]

Zeller, K.

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Zhang, A.

A. Zhang, Q. Zhang, C.-L. Chen, and R. K. Wang, “Methods and algorithms for optical coherence tomography-based angiography: a review and comparison,” J. Biomed. Opt. 20(10), 100901 (2015).
[Crossref] [PubMed]

Zhang, Q.

A. Zhang, Q. Zhang, C.-L. Chen, and R. K. Wang, “Methods and algorithms for optical coherence tomography-based angiography: a review and comparison,” J. Biomed. Opt. 20(10), 100901 (2015).
[Crossref] [PubMed]

Zhang, W.

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
[Crossref] [PubMed]

Zhang, X. J.

Zhi, Z.

Zhu, W.

U. Baran, W. Zhu, W. J. Choi, M. Omori, W. Zhang, N. J. Alkayed, and R. K. Wang, “Automated segmentation and enhancement of optical coherence tomography-acquired images of rodent brain,” J. Neurosci. Methods 270, 132–137 (2016).
[Crossref] [PubMed]

Am. J. Physiol. (1)

J. Vogel, R. Abounader, H. Schröck, K. Zeller, R. Duelli, and W. Kuschinsky, “Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia,” Am. J. Physiol. 270(4 Pt 2), H1441–H1445 (1996).
[PubMed]

Anal. Chem. (1)

C. Simonnet and A. Groisman, “High-throughput and high-resolution flow cytometry in molded microfluidic devices,” Anal. Chem. 78(16), 5653–5663 (2006).
[Crossref] [PubMed]

Ann. Biomed. Eng. (1)

A. K. Dunn, “Laser speckle contrast imaging of cerebral blood flow,” Ann. Biomed. Eng. 40(2), 367–377 (2012).
[Crossref] [PubMed]

Asian Biomed. (1)

M. Unekawa, M. Tomita, T. Osada, Y. Tomita, H. Toriumi, J. Tatarishvili, and N. Suzuki, “Frequency distribution function of red blood cell velocities in single capillaries of the rat cerebral cortex using intravital laser-scanning confocal microscopy with highspeed camera,” Asian Biomed. 2(3), 203–218 (2008).

Biomed. Opt. Express (5)

Brain Res. (1)

M. L. Schulte, J. D. Wood, and A. G. Hudetz, “Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat,” Brain Res. 963(1-2), 81–92 (2003).
[Crossref] [PubMed]

Invest. Ophthalmol. Vis. Sci. (1)

K. L. Pepple, W. J. Choi, L. Wilson, R. N. Van Gelder, and R. K. Wang, “Quantitative assessment of anterior segment inflammation in a rat model of uveitis using spectral-domain optical coherence tomography,” Invest. Ophthalmol. Vis. Sci. 57(8), 3567–3575 (2016).
[Crossref] [PubMed]

J. Biomed. Opt. (3)

D. A. Boas and A. K. Dunn, “Laser speckle contrast imaging in biomedical optics,” J. Biomed. Opt. 15(1), 011109 (2010).
[Crossref] [PubMed]

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Supplementary Material (1)

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Figures (6)

Fig. 1
Fig. 1 (a) Electro-coagulation of a distal MCA (dMCA) to induce permanent dMCA occlusion (dMCAO) in mouse with cranial window preparation. (b) Schematic of hindpaw electrical stimulation of mouse and (c) its experimental set-up in the OCT sample arm.
Fig. 2
Fig. 2 Procedure for estimating RBC velocity at single capillaries in the mouse brain cortex. (a) OCT B-scan of the mouse cortex through a cranial window. OCTA B-scan (b) at the same location as (a) and its binary image (c) are shown. (d) Capillary binary image isolated from (c). (e) Plots of intensity magnitudes extracted along with the ○ and × labeled points in (b) (solid lines) and their neighboring points in the static tissue (dotted lines). (f) Decorrelation time map. (g) Corresponding capillary absolute velocity map. Scale bars: 0.1mm.
Fig. 3
Fig. 3 Design of a single capillary flow phantom. (a) Layout of the hydrodynamic focusing microfluidic device for capillary flow simulation, where the two side sheath fluids hydrodynamically focus the blood cell suspension from blood reservoir to form a single-file flow. (b) Top view of the fabricated microfluidic device. (c) Illustration of the device fabrication process. (d) COMSOL simulation result of flow velocity distribution in the microflow channels for the inlet/outlet pumping flow rate of 10/10.8μl.
Fig. 4
Fig. 4 (a) Schematic of single capillary flow phantom imaging. Inset is a photograph of the set-up. (b) Time course snapshots captured by the inverted microscope (25fps) below the microfluidic device during hydrodynamic focusing of blood downstream. (c) (top) OCT B-scan of microfluidic device scanned at the location (arrow in the bottom snapshot in (b)), depicting a rectangle channel embedded in scattering PDMS, and (bottom) corresponding OCTA B-scan, highlighting the flow signal. (d) Extracted temporal profiles of OCT signals at the centroid of the focused blood streams in 100 consecutive OCT B-frames for each preset velocity: 1.0, 3.0, 5.0, and 8.0mm/s. (e) Distribution of decorrelation times repeatedly measured 15 times for each velocity. A curve fit of the average values in (e) shows the inverse relation of the decorrelation time to velocity in (f) with R2 = 0.987.
Fig. 5
Fig. 5 OCT capillary velocimetry in ischemic stroke model of mouse in vivo. OCT angiograms of the mouse cortex (surface to cortical layers II/III) through cranial window before (a) and 30min after (b) distal middle cerebral artery occlusion (dMCAO). Rarefaction of perfused capillaries is apparent after occlusion compared to pre-dMCAO. (c,d) OCT angiograms (boxes in (a) and (b)) (left) and corresponding capillary velocity maps (cortical layers II/III) (right) before (c) and after (d) occlusion, respectively. The velocity map post-dMCAO (d) shows reduction in velocity in the local perfused capillaries compared to pre-dMCAO (c). (e) Velocities in the capillary velocity maps before and after occlusion, plotted against the magnitude. For both pre/post-dMCAO, the RBC velocities are not constant but variable, clustered at around 1.0mm/s, but smearing at higher velocities up to 5.5mm/s before occlusion. R: rostral, C: caudal, M: medial, L: lateral.
Fig. 6
Fig. 6 OCT capillary velocimetry for monitoring capillary flow response to hindpaw electrical stimulation. (a) OCTA B-scan of brain cortex through cranial window with no stimulation. During electrical stimulation, OCTA visualizes increase in diameter of surface vessels (in red and green boxes in (a)) along with the longer tail artifacts with increment of stimulus amplitudes (from 1V to 10V), highlighted in (b) and (c), respectively. (d) Time course velocity graph taken at capillary region in the cortical layers II/III (white box in (a)) at 10V stimulus amplitude, where few capillaries showed gradual increase in RBC velocities 1-2 seconds after onset of stimulation. The capillary hemodynamics is represented with a velocity profile (e) at dotted line in (d). The gray bars in (d) and (e) indicate the electrical stimulation period.

Tables (1)

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Table 1 Speckle visibility with different scattering regimes and velocity distributions

Equations (3)

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K(T, τ c )= β 1/2 [ ρ 2 exp(2 x 2 )1+ 2π xerf( 2 x) 2 x 2 +2ρ(1ρ) exp( x 2 )1+ π xerf(x) x 2 + (1ρ) 2 ] 1/2 + C noise ,
K(T, τ c )= β 1/2 [ exp(2 x 2 )1+ 2π xerf( 2 x) 2 x 2 ] 1/2 ,
K(T, τ c )= K t (t, τ c )= σ t < I t > = β 1/2 [ exp(2 (t/ τ c ) 2 )1+ 2π (t/ τ c )erf( 2 (t/ τ c )) 2 (t/ τ c ) 2 ] 1/2 .

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