Abstract

Occlusions in single cortical microvessels lead to a reduction in oxygen supply, but this decrement has not been able to be quantified in three dimensions at the level of individual vessels using a single instrument. We demonstrate a combined optical system using two-photon phosphorescence lifetime and fluorescence microscopy (2PLM) to characterize the partial pressure of oxygen (pO2) in single descending cortical arterioles in the mouse brain before and after generating a targeted photothrombotic occlusion. Integrated real-time Laser Speckle Contrast Imaging (LSCI) provides wide-field perfusion maps that are used to monitor and guide the occlusion process while 2PLM maps changes in intravascular oxygen tension. We present the technique’s utility in highlighting the effects of vascular networking on the residual intravascular oxygen tensions measured after occlusion in three dimensions.

© 2013 OSA

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    [CrossRef] [PubMed]
  3. Q. Fang, S. Sakadžić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express16(22), 17530–17541 (2008).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  22. G. A. Armitage, K. G. Todd, A. Shuaib, and I. R. Winship, “Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke,” J. Cereb. Blood Flow Metab.30(8), 1432–1436 (2010).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  25. C. D. Klaassen, “Pharmacokinetics of rose bengal in the rat, rabbit, dog and guinea pig,” Toxicol. Appl. Pharmacol.38(1), 85–100 (1976).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef]
  35. A. J. Strong, E. L. Bezzina, P. J. B. Anderson, M. G. Boutelle, S. E. Hopwood, and A. K. Dunn, “Evaluation of laser speckle flowmetry for imaging cortical perfusion in experimental stroke studies: quantitation of perfusion and detection of peri-infarct depolarisations,” J. Cereb. Blood Flow Metab.26(5), 645–653 (2006).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  40. K. P. Ivanov, A. N. Derry, E. P. Vovenko, M. O. Samoilov, and D. G. Semionov, “Direct measurements of oxygen tension at the surface of arterioles, capillaries and venules of the cerebral cortex,” Pflugers Arch.393(1), 118–120 (1982).
    [CrossRef] [PubMed]
  41. M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, S. A. Vinogradov, and D. A. Boas, “Optically based quantification of absolute cerebral metabolic rate of oxygen (CMRO2) with high spatial resolution in rodents,” Proc. SPIE7548, 75483R, 75483R-9 (2010).
    [CrossRef]
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    [CrossRef] [PubMed]
  43. M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express4(2), 307–321 (2013).
    [CrossRef] [PubMed]
  44. K. A. Kasischke, E. M. Lambert, B. Panepento, A. Sun, H. A. Gelbard, R. W. Burgess, T. H. Foster, and M. Nedergaard, “Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions,” J. Cereb. Blood Flow Metab.31(1), 68–81 (2011).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]

2013 (4)

A. Parpaleix, Y. G. Houssen, and S. Charpak, “Imaging local neuronal activity by monitoring PO₂ transients in capillaries,” Nat. Med.19(2), 241–246 (2013).
[CrossRef] [PubMed]

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef]

S. M. S. Kazmi, A. B. Parthasarthy, N. E. Song, T. A. Jones, and A. K. Dunn, “Chronic imaging of cortical blood flow using Multi-Exposure Speckle Imaging,” J. Cereb. Blood Flow Metab.33(6), 798–808 (2013).
[CrossRef] [PubMed]

M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express4(2), 307–321 (2013).
[CrossRef] [PubMed]

2012 (4)

A. Y. Shih, P. Blinder, P. S. Tsai, B. Friedman, G. Stanley, P. D. Lyden, and D. Kleinfeld, “The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit,” Nat. Neurosci.16(1), 55–63 (2012).
[CrossRef] [PubMed]

S. S. Howard, A. Straub, N. G. Horton, D. Kobat, and C. Xu, “Frequency-multiplexed in vivo multiphoton phosphorescence lifetime microscopy,” Nat. Photonics7(1), 33–37 (2012).
[CrossRef] [PubMed]

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

A. Y. Shih, J. D. Driscoll, P. J. Drew, N. Nishimura, C. B. Schaffer, and D. Kleinfeld, “Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain,” J. Cereb. Blood Flow Metab.32(7), 1277–1309 (2012).
[CrossRef] [PubMed]

2011 (5)

A. Devor, S. Sakadžić, P. A. Saisan, M. A. Yaseen, E. Roussakis, V. J. Srinivasan, S. A. Vinogradov, B. R. Rosen, R. B. Buxton, A. M. Dale, and D. A. Boas, “‘Overshoot’ of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels,” J. Neurosci.31(38), 13676–13681 (2011).
[CrossRef] [PubMed]

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. G. Houssen, S. A. Vinogradov, and S. Charpak, “Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels,” Nat. Med.17(7), 893–898 (2011).
[CrossRef] [PubMed]

K. A. Kasischke, E. M. Lambert, B. Panepento, A. Sun, H. A. Gelbard, R. W. Burgess, T. H. Foster, and M. Nedergaard, “Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions,” J. Cereb. Blood Flow Metab.31(1), 68–81 (2011).
[CrossRef] [PubMed]

A. F. H. McCaslin, B. R. Chen, A. J. Radosevich, B. Cauli, and E. M. C. Hillman, “In vivo 3D morphology of astrocyte-vasculature interactions in the somatosensory cortex: implications for neurovascular coupling,” J. Cereb. Blood Flow Metab.31(3), 795–806 (2011).
[CrossRef] [PubMed]

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

2010 (5)

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, S. A. Vinogradov, and D. A. Boas, “Optically based quantification of absolute cerebral metabolic rate of oxygen (CMRO2) with high spatial resolution in rodents,” Proc. SPIE7548, 75483R, 75483R-9 (2010).
[CrossRef]

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, V. J. Srinivasan, K. Arai, S. Ruvinskaya, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue,” Nat. Methods7(9), 755–759 (2010).
[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]

A. B. Parthasarathy, S. M. S. Kazmi, and A. K. Dunn, “Quantitative imaging of ischemic stroke through thinned skull in mice with Multi Exposure Speckle Imaging,” Biomed. Opt. Express1(1), 246–259 (2010).
[CrossRef] [PubMed]

G. A. Armitage, K. G. Todd, A. Shuaib, and I. R. Winship, “Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke,” J. Cereb. Blood Flow Metab.30(8), 1432–1436 (2010).
[CrossRef] [PubMed]

2009 (3)

2008 (6)

O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem9(12), 1673–1679 (2008).
[CrossRef] [PubMed]

A. D. Estrada, A. Ponticorvo, T. N. Ford, and A. K. Dunn, “Microvascular oxygen quantification using two-photon microscopy,” Opt. Lett.33(10), 1038–1040 (2008).
[CrossRef] [PubMed]

Q. Fang, S. Sakadžić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express16(22), 17530–17541 (2008).
[CrossRef] [PubMed]

A. Y. Lebedev, T. Troxler, and S. A. Vinogradov, “Design of metalloporphyrin-based dendritic nanoprobes for two-photon microscopy of oxygen,” J. Porphyr. Phthalocyanines12(12), 1261–1269 (2008).
[CrossRef] [PubMed]

W. J. Tom, A. Ponticorvo, and A. K. Dunn, “Efficient processing of laser speckle contrast images,” IEEE Trans. Med. Imaging27(12), 1728–1738 (2008).
[CrossRef] [PubMed]

P. Li and T. H. Murphy, “Two-photon imaging during prolonged middle cerebral artery occlusion in mice reveals recovery of dendritic structure after reperfusion,” J. Neurosci.28(46), 11970–11979 (2008).
[CrossRef] [PubMed]

2007 (3)

A. Durukan and T. Tatlisumak, “Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia,” Pharmacol. Biochem. Behav.87(1), 179–197 (2007).
[CrossRef] [PubMed]

N. Nishimura, C. B. Schaffer, B. Friedman, P. D. Lyden, and D. Kleinfeld, “Penetrating arterioles are a bottleneck in the perfusion of neocortex,” Proc. Natl. Acad. Sci. U.S.A.104(1), 365–370 (2007).
[CrossRef] [PubMed]

S. Zhang and T. H. Murphy, “Imaging the impact of cortical microcirculation on synaptic structure and sensory-evoked hemodynamic responses in vivo,” PLoS Biol.5(5), e119 (2007).
[CrossRef] [PubMed]

2006 (3)

P. Hermán, H. K. F. Trübel, and F. Hyder, “A multiparametric assessment of oxygen efflux from the brain,” J. Cereb. Blood Flow Metab.26(1), 79–91 (2006).
[CrossRef] [PubMed]

C. B. Schaffer, B. Friedman, N. Nishimura, L. F. Schroeder, P. S. Tsai, F. F. Ebner, P. D. Lyden, and D. Kleinfeld, “Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion,” PLoS Biol.4(2), e22 (2006).
[CrossRef] [PubMed]

A. J. Strong, E. L. Bezzina, P. J. B. Anderson, M. G. Boutelle, S. E. Hopwood, and A. K. Dunn, “Evaluation of laser speckle flowmetry for imaging cortical perfusion in experimental stroke studies: quantitation of perfusion and detection of peri-infarct depolarisations,” J. Cereb. Blood Flow Metab.26(5), 645–653 (2006).
[CrossRef] [PubMed]

2003 (1)

A. G. Tsai, P. C. Johnson, and M. Intaglietta, “Oxygen gradients in the microcirculation,” Physiol. Rev.83(3), 933–963 (2003).
[PubMed]

2001 (3)

D. A. Beard and J. B. Bassingthwaighte, “Modeling advection and diffusion of oxygen in complex vascular networks,” Ann. Biomed. Eng.29(4), 298–310 (2001).
[CrossRef] [PubMed]

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab.21(3), 195–201 (2001).
[CrossRef] [PubMed]

M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods111(1), 29–37 (2001).
[CrossRef] [PubMed]

1999 (1)

E. Vovenko, “Distribution of oxygen tension on the surface of arterioles, capillaries and venules of brain cortex and in tissue in normoxia: an experimental study on rats,” Pflugers Arch.437(4), 617–623 (1999).
[CrossRef] [PubMed]

1998 (1)

K. A. Hossmann, “Experimental models for the investigation of brain ischemia,” Cardiovasc. Res.39(1), 106–120 (1998).
[CrossRef] [PubMed]

1995 (1)

I. G. Kassissia, C. A. Goresky, C. P. Rose, A. J. Schwab, A. Simard, P. M. Huet, and G. G. Bach, “Tracer oxygen distribution is barrier-limited in the cerebral microcirculation,” Circ. Res.77(6), 1201–1211 (1995).
[CrossRef] [PubMed]

1991 (1)

C. A. Wilson and D. L. Hatchell, “Photodynamic retinal vascular thrombosis. Rate and duration of vascular occlusion,” Invest. Ophthalmol. Vis. Sci.32(8), 2357–2365 (1991).
[PubMed]

1985 (1)

B. D. Watson, W. D. Dietrich, R. Busto, M. S. Wachtel, and M. D. Ginsberg, “Induction of reproducible brain infarction by photochemically initiated thrombosis,” Ann. Neurol.17(5), 497–504 (1985).
[CrossRef] [PubMed]

1982 (1)

K. P. Ivanov, A. N. Derry, E. P. Vovenko, M. O. Samoilov, and D. G. Semionov, “Direct measurements of oxygen tension at the surface of arterioles, capillaries and venules of the cerebral cortex,” Pflugers Arch.393(1), 118–120 (1982).
[CrossRef] [PubMed]

1979 (1)

B. R. Duling, W. Kuschinsky, and M. Wahl, “Measurements of the perivascular PO2 in the vicinity of the pial vessels of the cat,” Pflugers Arch.383(1), 29–34 (1979).
[CrossRef] [PubMed]

1976 (1)

C. D. Klaassen, “Pharmacokinetics of rose bengal in the rat, rabbit, dog and guinea pig,” Toxicol. Appl. Pharmacol.38(1), 85–100 (1976).
[CrossRef] [PubMed]

Anderson, P. J. B.

A. J. Strong, E. L. Bezzina, P. J. B. Anderson, M. G. Boutelle, S. E. Hopwood, and A. K. Dunn, “Evaluation of laser speckle flowmetry for imaging cortical perfusion in experimental stroke studies: quantitation of perfusion and detection of peri-infarct depolarisations,” J. Cereb. Blood Flow Metab.26(5), 645–653 (2006).
[CrossRef] [PubMed]

Aprelev, A.

O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem9(12), 1673–1679 (2008).
[CrossRef] [PubMed]

Arai, K.

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, V. J. Srinivasan, K. Arai, S. Ruvinskaya, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue,” Nat. Methods7(9), 755–759 (2010).
[CrossRef] [PubMed]

Armitage, G. A.

G. A. Armitage, K. G. Todd, A. Shuaib, and I. R. Winship, “Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke,” J. Cereb. Blood Flow Metab.30(8), 1432–1436 (2010).
[CrossRef] [PubMed]

Bach, G. G.

I. G. Kassissia, C. A. Goresky, C. P. Rose, A. J. Schwab, A. Simard, P. M. Huet, and G. G. Bach, “Tracer oxygen distribution is barrier-limited in the cerebral microcirculation,” Circ. Res.77(6), 1201–1211 (1995).
[CrossRef] [PubMed]

Bassingthwaighte, J. B.

D. A. Beard and J. B. Bassingthwaighte, “Modeling advection and diffusion of oxygen in complex vascular networks,” Ann. Biomed. Eng.29(4), 298–310 (2001).
[CrossRef] [PubMed]

Beard, D. A.

D. A. Beard and J. B. Bassingthwaighte, “Modeling advection and diffusion of oxygen in complex vascular networks,” Ann. Biomed. Eng.29(4), 298–310 (2001).
[CrossRef] [PubMed]

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M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express4(2), 307–321 (2013).
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A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab.21(3), 195–201 (2001).
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A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab.21(3), 195–201 (2001).
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B. D. Watson, W. D. Dietrich, R. Busto, M. S. Wachtel, and M. D. Ginsberg, “Induction of reproducible brain infarction by photochemically initiated thrombosis,” Ann. Neurol.17(5), 497–504 (1985).
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A. Parpaleix, Y. G. Houssen, and S. Charpak, “Imaging local neuronal activity by monitoring PO₂ transients in capillaries,” Nat. Med.19(2), 241–246 (2013).
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N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
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A. Devor, S. Sakadžić, P. A. Saisan, M. A. Yaseen, E. Roussakis, V. J. Srinivasan, S. A. Vinogradov, B. R. Rosen, R. B. Buxton, A. M. Dale, and D. A. Boas, “‘Overshoot’ of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels,” J. Neurosci.31(38), 13676–13681 (2011).
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A. Devor, S. Sakadžić, P. A. Saisan, M. A. Yaseen, E. Roussakis, V. J. Srinivasan, S. A. Vinogradov, B. R. Rosen, R. B. Buxton, A. M. Dale, and D. A. Boas, “‘Overshoot’ of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels,” J. Neurosci.31(38), 13676–13681 (2011).
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Q. Fang, S. Sakadžić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express16(22), 17530–17541 (2008).
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B. D. Watson, W. D. Dietrich, R. Busto, M. S. Wachtel, and M. D. Ginsberg, “Induction of reproducible brain infarction by photochemically initiated thrombosis,” Ann. Neurol.17(5), 497–504 (1985).
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A. K. Dunn, “Laser speckle contrast imaging of cerebral blood flow,” Ann. Biomed. Eng.40(2), 367–377 (2012).
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D. A. Boas and A. K. Dunn, “Laser speckle contrast imaging in biomedical optics,” J. Biomed. Opt.15(1), 011109 (2010).
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A. B. Parthasarathy, S. M. S. Kazmi, and A. K. Dunn, “Quantitative imaging of ischemic stroke through thinned skull in mice with Multi Exposure Speckle Imaging,” Biomed. Opt. Express1(1), 246–259 (2010).
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[CrossRef] [PubMed]

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab.21(3), 195–201 (2001).
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Foster, T. H.

K. A. Kasischke, E. M. Lambert, B. Panepento, A. Sun, H. A. Gelbard, R. W. Burgess, T. H. Foster, and M. Nedergaard, “Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions,” J. Cereb. Blood Flow Metab.31(1), 68–81 (2011).
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A. Y. Shih, P. Blinder, P. S. Tsai, B. Friedman, G. Stanley, P. D. Lyden, and D. Kleinfeld, “The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit,” Nat. Neurosci.16(1), 55–63 (2012).
[CrossRef] [PubMed]

P. S. Tsai, J. P. Kaufhold, P. Blinder, B. Friedman, P. J. Drew, H. J. Karten, P. D. Lyden, and D. Kleinfeld, “Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels,” J. Neurosci.29(46), 14553–14570 (2009).
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K. A. Kasischke, E. M. Lambert, B. Panepento, A. Sun, H. A. Gelbard, R. W. Burgess, T. H. Foster, and M. Nedergaard, “Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions,” J. Cereb. Blood Flow Metab.31(1), 68–81 (2011).
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B. D. Watson, W. D. Dietrich, R. Busto, M. S. Wachtel, and M. D. Ginsberg, “Induction of reproducible brain infarction by photochemically initiated thrombosis,” Ann. Neurol.17(5), 497–504 (1985).
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P. Hermán, H. K. F. Trübel, and F. Hyder, “A multiparametric assessment of oxygen efflux from the brain,” J. Cereb. Blood Flow Metab.26(1), 79–91 (2006).
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A. F. H. McCaslin, B. R. Chen, A. J. Radosevich, B. Cauli, and E. M. C. Hillman, “In vivo 3D morphology of astrocyte-vasculature interactions in the somatosensory cortex: implications for neurovascular coupling,” J. Cereb. Blood Flow Metab.31(3), 795–806 (2011).
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O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem9(12), 1673–1679 (2008).
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A. J. Strong, E. L. Bezzina, P. J. B. Anderson, M. G. Boutelle, S. E. Hopwood, and A. K. Dunn, “Evaluation of laser speckle flowmetry for imaging cortical perfusion in experimental stroke studies: quantitation of perfusion and detection of peri-infarct depolarisations,” J. Cereb. Blood Flow Metab.26(5), 645–653 (2006).
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N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
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S. S. Howard, A. Straub, N. G. Horton, D. Kobat, and C. Xu, “Frequency-multiplexed in vivo multiphoton phosphorescence lifetime microscopy,” Nat. Photonics7(1), 33–37 (2012).
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A. Parpaleix, Y. G. Houssen, and S. Charpak, “Imaging local neuronal activity by monitoring PO₂ transients in capillaries,” Nat. Med.19(2), 241–246 (2013).
[CrossRef] [PubMed]

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. G. Houssen, S. A. Vinogradov, and S. Charpak, “Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels,” Nat. Med.17(7), 893–898 (2011).
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S. S. Howard, A. Straub, N. G. Horton, D. Kobat, and C. Xu, “Frequency-multiplexed in vivo multiphoton phosphorescence lifetime microscopy,” Nat. Photonics7(1), 33–37 (2012).
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I. G. Kassissia, C. A. Goresky, C. P. Rose, A. J. Schwab, A. Simard, P. M. Huet, and G. G. Bach, “Tracer oxygen distribution is barrier-limited in the cerebral microcirculation,” Circ. Res.77(6), 1201–1211 (1995).
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P. Hermán, H. K. F. Trübel, and F. Hyder, “A multiparametric assessment of oxygen efflux from the brain,” J. Cereb. Blood Flow Metab.26(1), 79–91 (2006).
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A. G. Tsai, P. C. Johnson, and M. Intaglietta, “Oxygen gradients in the microcirculation,” Physiol. Rev.83(3), 933–963 (2003).
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S. M. S. Kazmi, A. B. Parthasarthy, N. E. Song, T. A. Jones, and A. K. Dunn, “Chronic imaging of cortical blood flow using Multi-Exposure Speckle Imaging,” J. Cereb. Blood Flow Metab.33(6), 798–808 (2013).
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P. S. Tsai, J. P. Kaufhold, P. Blinder, B. Friedman, P. J. Drew, H. J. Karten, P. D. Lyden, and D. Kleinfeld, “Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels,” J. Neurosci.29(46), 14553–14570 (2009).
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M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express4(2), 307–321 (2013).
[CrossRef] [PubMed]

K. A. Kasischke, E. M. Lambert, B. Panepento, A. Sun, H. A. Gelbard, R. W. Burgess, T. H. Foster, and M. Nedergaard, “Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions,” J. Cereb. Blood Flow Metab.31(1), 68–81 (2011).
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I. G. Kassissia, C. A. Goresky, C. P. Rose, A. J. Schwab, A. Simard, P. M. Huet, and G. G. Bach, “Tracer oxygen distribution is barrier-limited in the cerebral microcirculation,” Circ. Res.77(6), 1201–1211 (1995).
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P. S. Tsai, J. P. Kaufhold, P. Blinder, B. Friedman, P. J. Drew, H. J. Karten, P. D. Lyden, and D. Kleinfeld, “Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels,” J. Neurosci.29(46), 14553–14570 (2009).
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S. M. S. Kazmi, A. B. Parthasarthy, N. E. Song, T. A. Jones, and A. K. Dunn, “Chronic imaging of cortical blood flow using Multi-Exposure Speckle Imaging,” J. Cereb. Blood Flow Metab.33(6), 798–808 (2013).
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M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express17(25), 22341–22350 (2009).
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N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef]

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[CrossRef] [PubMed]

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[CrossRef] [PubMed]

A. Y. Shih, P. Blinder, P. S. Tsai, B. Friedman, G. Stanley, P. D. Lyden, and D. Kleinfeld, “The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit,” Nat. Neurosci.16(1), 55–63 (2012).
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S. M. S. Kazmi, A. B. Parthasarthy, N. E. Song, T. A. Jones, and A. K. Dunn, “Chronic imaging of cortical blood flow using Multi-Exposure Speckle Imaging,” J. Cereb. Blood Flow Metab.33(6), 798–808 (2013).
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A. Devor, S. Sakadžić, P. A. Saisan, M. A. Yaseen, E. Roussakis, V. J. Srinivasan, S. A. Vinogradov, B. R. Rosen, R. B. Buxton, A. M. Dale, and D. A. Boas, “‘Overshoot’ of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels,” J. Neurosci.31(38), 13676–13681 (2011).
[CrossRef] [PubMed]

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[CrossRef] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, S. A. Vinogradov, and D. A. Boas, “Optically based quantification of absolute cerebral metabolic rate of oxygen (CMRO2) with high spatial resolution in rodents,” Proc. SPIE7548, 75483R, 75483R-9 (2010).
[CrossRef]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express17(25), 22341–22350 (2009).
[CrossRef] [PubMed]

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A. Y. Shih, P. Blinder, P. S. Tsai, B. Friedman, G. Stanley, P. D. Lyden, and D. Kleinfeld, “The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit,” Nat. Neurosci.16(1), 55–63 (2012).
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S. S. Howard, A. Straub, N. G. Horton, D. Kobat, and C. Xu, “Frequency-multiplexed in vivo multiphoton phosphorescence lifetime microscopy,” Nat. Photonics7(1), 33–37 (2012).
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K. A. Kasischke, E. M. Lambert, B. Panepento, A. Sun, H. A. Gelbard, R. W. Burgess, T. H. Foster, and M. Nedergaard, “Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions,” J. Cereb. Blood Flow Metab.31(1), 68–81 (2011).
[CrossRef] [PubMed]

Tatlisumak, T.

A. Durukan and T. Tatlisumak, “Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia,” Pharmacol. Biochem. Behav.87(1), 179–197 (2007).
[CrossRef] [PubMed]

Todd, K. G.

G. A. Armitage, K. G. Todd, A. Shuaib, and I. R. Winship, “Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke,” J. Cereb. Blood Flow Metab.30(8), 1432–1436 (2010).
[CrossRef] [PubMed]

Tom, W. J.

W. J. Tom, A. Ponticorvo, and A. K. Dunn, “Efficient processing of laser speckle contrast images,” IEEE Trans. Med. Imaging27(12), 1728–1738 (2008).
[CrossRef] [PubMed]

Troxler, T.

A. Y. Lebedev, T. Troxler, and S. A. Vinogradov, “Design of metalloporphyrin-based dendritic nanoprobes for two-photon microscopy of oxygen,” J. Porphyr. Phthalocyanines12(12), 1261–1269 (2008).
[CrossRef] [PubMed]

O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem9(12), 1673–1679 (2008).
[CrossRef] [PubMed]

Trübel, H. K. F.

P. Hermán, H. K. F. Trübel, and F. Hyder, “A multiparametric assessment of oxygen efflux from the brain,” J. Cereb. Blood Flow Metab.26(1), 79–91 (2006).
[CrossRef] [PubMed]

Tsai, A. G.

A. G. Tsai, P. C. Johnson, and M. Intaglietta, “Oxygen gradients in the microcirculation,” Physiol. Rev.83(3), 933–963 (2003).
[PubMed]

Tsai, P. S.

A. Y. Shih, P. Blinder, P. S. Tsai, B. Friedman, G. Stanley, P. D. Lyden, and D. Kleinfeld, “The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit,” Nat. Neurosci.16(1), 55–63 (2012).
[CrossRef] [PubMed]

P. S. Tsai, J. P. Kaufhold, P. Blinder, B. Friedman, P. J. Drew, H. J. Karten, P. D. Lyden, and D. Kleinfeld, “Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels,” J. Neurosci.29(46), 14553–14570 (2009).
[CrossRef] [PubMed]

C. B. Schaffer, B. Friedman, N. Nishimura, L. F. Schroeder, P. S. Tsai, F. F. Ebner, P. D. Lyden, and D. Kleinfeld, “Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion,” PLoS Biol.4(2), e22 (2006).
[CrossRef] [PubMed]

Vinogradov, S. A.

A. Devor, S. Sakadžić, P. A. Saisan, M. A. Yaseen, E. Roussakis, V. J. Srinivasan, S. A. Vinogradov, B. R. Rosen, R. B. Buxton, A. M. Dale, and D. A. Boas, “‘Overshoot’ of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels,” J. Neurosci.31(38), 13676–13681 (2011).
[CrossRef] [PubMed]

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. G. Houssen, S. A. Vinogradov, and S. Charpak, “Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels,” Nat. Med.17(7), 893–898 (2011).
[CrossRef] [PubMed]

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, V. J. Srinivasan, K. Arai, S. Ruvinskaya, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue,” Nat. Methods7(9), 755–759 (2010).
[CrossRef] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, S. A. Vinogradov, and D. A. Boas, “Optically based quantification of absolute cerebral metabolic rate of oxygen (CMRO2) with high spatial resolution in rodents,” Proc. SPIE7548, 75483R, 75483R-9 (2010).
[CrossRef]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express17(25), 22341–22350 (2009).
[CrossRef] [PubMed]

O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem9(12), 1673–1679 (2008).
[CrossRef] [PubMed]

A. Y. Lebedev, T. Troxler, and S. A. Vinogradov, “Design of metalloporphyrin-based dendritic nanoprobes for two-photon microscopy of oxygen,” J. Porphyr. Phthalocyanines12(12), 1261–1269 (2008).
[CrossRef] [PubMed]

Vovenko, E.

E. Vovenko, “Distribution of oxygen tension on the surface of arterioles, capillaries and venules of brain cortex and in tissue in normoxia: an experimental study on rats,” Pflugers Arch.437(4), 617–623 (1999).
[CrossRef] [PubMed]

Vovenko, E. P.

K. P. Ivanov, A. N. Derry, E. P. Vovenko, M. O. Samoilov, and D. G. Semionov, “Direct measurements of oxygen tension at the surface of arterioles, capillaries and venules of the cerebral cortex,” Pflugers Arch.393(1), 118–120 (1982).
[CrossRef] [PubMed]

Wachtel, M. S.

B. D. Watson, W. D. Dietrich, R. Busto, M. S. Wachtel, and M. D. Ginsberg, “Induction of reproducible brain infarction by photochemically initiated thrombosis,” Ann. Neurol.17(5), 497–504 (1985).
[CrossRef] [PubMed]

Wahl, M.

B. R. Duling, W. Kuschinsky, and M. Wahl, “Measurements of the perivascular PO2 in the vicinity of the pial vessels of the cat,” Pflugers Arch.383(1), 29–34 (1979).
[CrossRef] [PubMed]

Wallace, D. J.

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Wang, K.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef]

Watson, B. D.

B. D. Watson, W. D. Dietrich, R. Busto, M. S. Wachtel, and M. D. Ginsberg, “Induction of reproducible brain infarction by photochemically initiated thrombosis,” Ann. Neurol.17(5), 497–504 (1985).
[CrossRef] [PubMed]

Wilson, C. A.

C. A. Wilson and D. L. Hatchell, “Photodynamic retinal vascular thrombosis. Rate and duration of vascular occlusion,” Invest. Ophthalmol. Vis. Sci.32(8), 2357–2365 (1991).
[PubMed]

Winship, I. R.

G. A. Armitage, K. G. Todd, A. Shuaib, and I. R. Winship, “Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke,” J. Cereb. Blood Flow Metab.30(8), 1432–1436 (2010).
[CrossRef] [PubMed]

Wise, F. W.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef]

Wong, A. W.

Wu, W.

M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express4(2), 307–321 (2013).
[CrossRef] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express17(25), 22341–22350 (2009).
[CrossRef] [PubMed]

Xu, C.

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef]

S. S. Howard, A. Straub, N. G. Horton, D. Kobat, and C. Xu, “Frequency-multiplexed in vivo multiphoton phosphorescence lifetime microscopy,” Nat. Photonics7(1), 33–37 (2012).
[CrossRef] [PubMed]

D. Kobat, M. E. Durst, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express17(16), 13354–13364 (2009).
[CrossRef] [PubMed]

Yaseen, M. A.

M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express4(2), 307–321 (2013).
[CrossRef] [PubMed]

A. Devor, S. Sakadžić, P. A. Saisan, M. A. Yaseen, E. Roussakis, V. J. Srinivasan, S. A. Vinogradov, B. R. Rosen, R. B. Buxton, A. M. Dale, and D. A. Boas, “‘Overshoot’ of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels,” J. Neurosci.31(38), 13676–13681 (2011).
[CrossRef] [PubMed]

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, V. J. Srinivasan, K. Arai, S. Ruvinskaya, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue,” Nat. Methods7(9), 755–759 (2010).
[CrossRef] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, S. A. Vinogradov, and D. A. Boas, “Optically based quantification of absolute cerebral metabolic rate of oxygen (CMRO2) with high spatial resolution in rodents,” Proc. SPIE7548, 75483R, 75483R-9 (2010).
[CrossRef]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express17(25), 22341–22350 (2009).
[CrossRef] [PubMed]

Zhang, S.

S. Zhang and T. H. Murphy, “Imaging the impact of cortical microcirculation on synaptic structure and sensory-evoked hemodynamic responses in vivo,” PLoS Biol.5(5), e119 (2007).
[CrossRef] [PubMed]

Ann. Biomed. Eng. (2)

D. A. Beard and J. B. Bassingthwaighte, “Modeling advection and diffusion of oxygen in complex vascular networks,” Ann. Biomed. Eng.29(4), 298–310 (2001).
[CrossRef] [PubMed]

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

Ann. Neurol. (1)

B. D. Watson, W. D. Dietrich, R. Busto, M. S. Wachtel, and M. D. Ginsberg, “Induction of reproducible brain infarction by photochemically initiated thrombosis,” Ann. Neurol.17(5), 497–504 (1985).
[CrossRef] [PubMed]

Biomed. Opt. Express (2)

A. B. Parthasarathy, S. M. S. Kazmi, and A. K. Dunn, “Quantitative imaging of ischemic stroke through thinned skull in mice with Multi Exposure Speckle Imaging,” Biomed. Opt. Express1(1), 246–259 (2010).
[CrossRef] [PubMed]

M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express4(2), 307–321 (2013).
[CrossRef] [PubMed]

Cardiovasc. Res. (1)

K. A. Hossmann, “Experimental models for the investigation of brain ischemia,” Cardiovasc. Res.39(1), 106–120 (1998).
[CrossRef] [PubMed]

ChemPhysChem (1)

O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem9(12), 1673–1679 (2008).
[CrossRef] [PubMed]

Circ. Res. (1)

I. G. Kassissia, C. A. Goresky, C. P. Rose, A. J. Schwab, A. Simard, P. M. Huet, and G. G. Bach, “Tracer oxygen distribution is barrier-limited in the cerebral microcirculation,” Circ. Res.77(6), 1201–1211 (1995).
[CrossRef] [PubMed]

IEEE Trans. Med. Imaging (1)

W. J. Tom, A. Ponticorvo, and A. K. Dunn, “Efficient processing of laser speckle contrast images,” IEEE Trans. Med. Imaging27(12), 1728–1738 (2008).
[CrossRef] [PubMed]

Invest. Ophthalmol. Vis. Sci. (1)

C. A. Wilson and D. L. Hatchell, “Photodynamic retinal vascular thrombosis. Rate and duration of vascular occlusion,” Invest. Ophthalmol. Vis. Sci.32(8), 2357–2365 (1991).
[PubMed]

J. Biomed. Opt. (1)

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

J. Cereb. Blood Flow Metab. (2)

A. Y. Shih, J. D. Driscoll, P. J. Drew, N. Nishimura, C. B. Schaffer, and D. Kleinfeld, “Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain,” J. Cereb. Blood Flow Metab.32(7), 1277–1309 (2012).
[CrossRef] [PubMed]

K. A. Kasischke, E. M. Lambert, B. Panepento, A. Sun, H. A. Gelbard, R. W. Burgess, T. H. Foster, and M. Nedergaard, “Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions,” J. Cereb. Blood Flow Metab.31(1), 68–81 (2011).
[CrossRef] [PubMed]

J. Cereb. Blood Flow Metab. (6)

P. Hermán, H. K. F. Trübel, and F. Hyder, “A multiparametric assessment of oxygen efflux from the brain,” J. Cereb. Blood Flow Metab.26(1), 79–91 (2006).
[CrossRef] [PubMed]

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab.21(3), 195–201 (2001).
[CrossRef] [PubMed]

G. A. Armitage, K. G. Todd, A. Shuaib, and I. R. Winship, “Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke,” J. Cereb. Blood Flow Metab.30(8), 1432–1436 (2010).
[CrossRef] [PubMed]

A. J. Strong, E. L. Bezzina, P. J. B. Anderson, M. G. Boutelle, S. E. Hopwood, and A. K. Dunn, “Evaluation of laser speckle flowmetry for imaging cortical perfusion in experimental stroke studies: quantitation of perfusion and detection of peri-infarct depolarisations,” J. Cereb. Blood Flow Metab.26(5), 645–653 (2006).
[CrossRef] [PubMed]

S. M. S. Kazmi, A. B. Parthasarthy, N. E. Song, T. A. Jones, and A. K. Dunn, “Chronic imaging of cortical blood flow using Multi-Exposure Speckle Imaging,” J. Cereb. Blood Flow Metab.33(6), 798–808 (2013).
[CrossRef] [PubMed]

A. F. H. McCaslin, B. R. Chen, A. J. Radosevich, B. Cauli, and E. M. C. Hillman, “In vivo 3D morphology of astrocyte-vasculature interactions in the somatosensory cortex: implications for neurovascular coupling,” J. Cereb. Blood Flow Metab.31(3), 795–806 (2011).
[CrossRef] [PubMed]

J. Neurosci. (3)

P. S. Tsai, J. P. Kaufhold, P. Blinder, B. Friedman, P. J. Drew, H. J. Karten, P. D. Lyden, and D. Kleinfeld, “Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels,” J. Neurosci.29(46), 14553–14570 (2009).
[CrossRef] [PubMed]

A. Devor, S. Sakadžić, P. A. Saisan, M. A. Yaseen, E. Roussakis, V. J. Srinivasan, S. A. Vinogradov, B. R. Rosen, R. B. Buxton, A. M. Dale, and D. A. Boas, “‘Overshoot’ of O₂ is required to maintain baseline tissue oxygenation at locations distal to blood vessels,” J. Neurosci.31(38), 13676–13681 (2011).
[CrossRef] [PubMed]

P. Li and T. H. Murphy, “Two-photon imaging during prolonged middle cerebral artery occlusion in mice reveals recovery of dendritic structure after reperfusion,” J. Neurosci.28(46), 11970–11979 (2008).
[CrossRef] [PubMed]

J. Neurosci. Methods (1)

M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods111(1), 29–37 (2001).
[CrossRef] [PubMed]

J. Porphyr. Phthalocyanines (1)

A. Y. Lebedev, T. Troxler, and S. A. Vinogradov, “Design of metalloporphyrin-based dendritic nanoprobes for two-photon microscopy of oxygen,” J. Porphyr. Phthalocyanines12(12), 1261–1269 (2008).
[CrossRef] [PubMed]

Nat. Med. (2)

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. G. Houssen, S. A. Vinogradov, and S. Charpak, “Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels,” Nat. Med.17(7), 893–898 (2011).
[CrossRef] [PubMed]

A. Parpaleix, Y. G. Houssen, and S. Charpak, “Imaging local neuronal activity by monitoring PO₂ transients in capillaries,” Nat. Med.19(2), 241–246 (2013).
[CrossRef] [PubMed]

Nat. Methods (1)

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, V. J. Srinivasan, K. Arai, S. Ruvinskaya, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue,” Nat. Methods7(9), 755–759 (2010).
[CrossRef] [PubMed]

Nat. Neurosci. (2)

A. Y. Shih, P. Blinder, P. S. Tsai, B. Friedman, G. Stanley, P. D. Lyden, and D. Kleinfeld, “The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit,” Nat. Neurosci.16(1), 55–63 (2012).
[CrossRef] [PubMed]

W. Mittmann, D. J. Wallace, U. Czubayko, J. T. Herb, A. T. Schaefer, L. L. Looger, W. Denk, and J. N. D. Kerr, “Two-photon calcium imaging of evoked activity from L5 somatosensory neurons in vivo,” Nat. Neurosci.14(8), 1089–1093 (2011).
[CrossRef] [PubMed]

Nat. Photonics (2)

N. G. Horton, K. Wang, D. Kobat, C. G. Clark, F. W. Wise, C. B. Schaffer, and C. Xu, “In vivo three-photon microscopy of subcortical structures within an intact mouse brain,” Nat. Photonics7(3), 205–209 (2013).
[CrossRef]

S. S. Howard, A. Straub, N. G. Horton, D. Kobat, and C. Xu, “Frequency-multiplexed in vivo multiphoton phosphorescence lifetime microscopy,” Nat. Photonics7(1), 33–37 (2012).
[CrossRef] [PubMed]

Opt. Express (3)

Opt. Lett. (1)

Pflugers Arch. (1)

K. P. Ivanov, A. N. Derry, E. P. Vovenko, M. O. Samoilov, and D. G. Semionov, “Direct measurements of oxygen tension at the surface of arterioles, capillaries and venules of the cerebral cortex,” Pflugers Arch.393(1), 118–120 (1982).
[CrossRef] [PubMed]

Pflugers Arch. (2)

E. Vovenko, “Distribution of oxygen tension on the surface of arterioles, capillaries and venules of brain cortex and in tissue in normoxia: an experimental study on rats,” Pflugers Arch.437(4), 617–623 (1999).
[CrossRef] [PubMed]

B. R. Duling, W. Kuschinsky, and M. Wahl, “Measurements of the perivascular PO2 in the vicinity of the pial vessels of the cat,” Pflugers Arch.383(1), 29–34 (1979).
[CrossRef] [PubMed]

Pharmacol. Biochem. Behav. (1)

A. Durukan and T. Tatlisumak, “Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia,” Pharmacol. Biochem. Behav.87(1), 179–197 (2007).
[CrossRef] [PubMed]

Physiol. Rev. (1)

A. G. Tsai, P. C. Johnson, and M. Intaglietta, “Oxygen gradients in the microcirculation,” Physiol. Rev.83(3), 933–963 (2003).
[PubMed]

PLoS Biol. (2)

C. B. Schaffer, B. Friedman, N. Nishimura, L. F. Schroeder, P. S. Tsai, F. F. Ebner, P. D. Lyden, and D. Kleinfeld, “Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion,” PLoS Biol.4(2), e22 (2006).
[CrossRef] [PubMed]

S. Zhang and T. H. Murphy, “Imaging the impact of cortical microcirculation on synaptic structure and sensory-evoked hemodynamic responses in vivo,” PLoS Biol.5(5), e119 (2007).
[CrossRef] [PubMed]

Proc. Natl. Acad. Sci. U.S.A. (1)

N. Nishimura, C. B. Schaffer, B. Friedman, P. D. Lyden, and D. Kleinfeld, “Penetrating arterioles are a bottleneck in the perfusion of neocortex,” Proc. Natl. Acad. Sci. U.S.A.104(1), 365–370 (2007).
[CrossRef] [PubMed]

Proc. SPIE (1)

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, S. A. Vinogradov, and D. A. Boas, “Optically based quantification of absolute cerebral metabolic rate of oxygen (CMRO2) with high spatial resolution in rodents,” Proc. SPIE7548, 75483R, 75483R-9 (2010).
[CrossRef]

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C. D. Klaassen, “Pharmacokinetics of rose bengal in the rat, rabbit, dog and guinea pig,” Toxicol. Appl. Pharmacol.38(1), 85–100 (1976).
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Supplementary Material (7)

» Media 1: PDF (89 KB)     
» Media 2: MOV (4832 KB)     
» Media 3: MOV (22736 KB)     
» Media 4: MOV (34058 KB)     
» Media 5: MOV (40165 KB)     
» Media 6: PDF (550 KB)     
» Media 7: PDF (42 KB)     

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Figures (7)

Fig. 1
Fig. 1

(a) Custom two-photon microscope with integrated laser speckle contrast imaging and photothrombotic light delivery. EOM: electro-optic modulator; PCB: photon counting board; D1, D2, D3 dichroic mirrors with transmissions: T > 740 nm, T > 795 nm, and T > 570 nm, respectively. (b) Laser modulation paradigm for phosphorescence measurements. Pulsed laser train is temporally gated (ON: 20 µs, OFF: 180 µs) at a 5 kHz modulation rate for measuring phosphorescence signals (see optimization in Media 1) (c) Top: Sample calibration of PtP-C343. Bottom: Probe sensitivity derived from differentiating calibration curve. (d) Speckle contrast image of cortical perfusion and two photon projection of labeled vasculature over 400 µm of depth. Scale bar = 150 µm. (e) Normoxic and hypoxic phosphorescent decays from a surface arteriole (left, green circle). Scale bar = 50 µm.

Fig. 2
Fig. 2

(a) Two-photon linescan from a cortical arteriole and calculated RBC speed time-course. (b) Laser Speckle Contrast Imaging of cortical flow before and after occlusion. Images shown are real-time computed speckle contrast images (5ms exposure duration) using a 7x7 pixel window, where darker pixel intensities indicate higher flow. Green circle and triangle indicate two arterioles selected for occlusion. Scale bar = 400 µm. (c) Linescans taken from Arteriole 1 (circle) are shown pre- and post-occlusion. See Media 2 for real-time LSCI during photothrombosis. Intermediary halo of lower contrast around targeted vessel video are saturation artifacts of the excitation light used for photothrombosis.

Fig. 3
Fig. 3

Speckle contrast images of cortical flow from Mouse 1 (a) and Mouse 2 (c). Baseline pO2 in descending arterioles. Projections of three-dimensional vascular imaging to a depth of 400 µm (b) and 375 µm (d) with pO2 measurements taken in the arterioles of Mouse 1 and 2, respectively. Arrows indicate flow direction. Scale bar = 50 µm. See Media 3 for three-dimensional views of Mouse 1. (e) Baseline pO2 depth profile in descending arterioles from (b) and (d). First measurements (z = 50 µm) correspond to initial descent points. Data and error bars represent avg +/− s.d. over five measurements.

Fig. 4
Fig. 4

Targeted occlusion of an arteriole and resulting changes in oxygen tension and blood flow. (a) Baseline speckle contrast image. Two-photon imaging region is boxed and 'X' denotes photothrombosis location. Scale bar = 200 µm. (b) Baseline (Media 4) and (c) post-occlusion (Media 5) pO2 maps in descending arteriole. pO2 gradient downstream of occlusion significantly differs with baseline (p<002, repeated measures ANOVA). See Media 6 for selected pial measurements and linescans. pO2 depth profile under baseline and post-occlusion conditions in the (d) primary descending arteriole and in a (e) secondary descending segment. Arrows denote branch points. Error bars represent avg +/− s.d. over five measurements. (f) Cartoon depicting branch points from (d) and (e) and imaging plane selection at a depth of 110 µm for (g) two-photon image and linescans in the enumerated branches. Scale bar = 25 µm.

Fig. 5
Fig. 5

(a) Baseline and (c) post-occlusion LSCI; “X” marks location for targeted occlusion. (b) Baseline and (d) post-occlusion two-photon images and pO2 measurements in pial arteriole and venule. Arrows indicate flow direction. Scale bar = 50 µm. (e) pO2 depth profile in descending segment of pial arteriole in (a)-(d). Error bars represent avg +/− s.d. over five measurements. Baseline and occlusion pO2 gradients significantly differ (p<001, repeated measures ANOVA). (f) Partial z-projection with vascular outlines shows density of regional vasculature (left) and two photon image at z = 260 µm depicts branching point oxygen tensions (right). Cartoon (center) highlights projection depths and selected planes. Scale bar = 12 µm.

Fig. 6
Fig. 6

(a) Depiction of a descending arteriole with plane of first branch shown in gray at a depth of approximately 85µm. (b) Two photon images showing baseline oxygen measurements in descending arteriole and first branch before and after occlusion corresponding to plane noted in (a). Reversal or depression of oxygen gradient away from primary arteriole is observed after occlusion. (c) pO2 depth profile in descending arteriole under baseline and post-occlusion conditions. Arrow indicates first pO2 measurement after branch at z = 85µm in depth. Error bars represent avg +/− s.d. over five measurements. Co-registered baseline and occlusion pO2 gradients significantly differ (p<002, repeated measures ANOVA).

Fig. 7
Fig. 7

Partial pressure of O2 (pO2) depth profiles of descending arterioles under baseline (n = 9 vessels) and occlusion (n = 5 vessels) conditions across all animals. Symbols represent unique arterioles over 8 animals. “Early” branching is noted as occurring at z ≤ 150 µm, while “latent” occurring after this depth. See Media 7 for repeated baseline measurements in two arterioles.

Equations (1)

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I ( t ) = a + b exp ( t τ )

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