Abstract

Improving our understanding of brain function requires novel tools to observe multiple physiological parameters with high resolution in vivo. We have developed a multimodal imaging system for investigating multiple facets of cerebral blood flow and metabolism in small animals. The system was custom designed and features multiple optical imaging capabilities, including 2-photon and confocal lifetime microscopy, optical coherence tomography, laser speckle imaging, and optical intrinsic signal imaging. Here, we provide details of the system’s design and present in vivo observations of multiple metrics of cerebral oxygen delivery and energy metabolism, including oxygen partial pressure, microvascular blood flow, and NADH autofluorescence.

© 2015 Optical Society of America

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2014 (2)

F. Scholkmann, S. Kleiser, A. J. Metz, R. Zimmermann, J. Mata Pavia, U. Wolf, and M. Wolf, “A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology,” Neuroimage 85(Pt 1), 6–27 (2014).
[Crossref] [PubMed]

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

2013 (3)

2012 (3)

C. Catana, A. Drzezga, W.-D. Heiss, and B. R. Rosen, “PET/MRI for neurologic applications,” J. Nucl. Med. 53(12), 1916–1925 (2012).
[Crossref] [PubMed]

A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (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 (6)

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, H. Radhakrishnan, I. Gorczynska, W. Wu, J. G. Fujimoto, and D. A. Boas, “Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation,” J. Cereb. Blood Flow Metab. 31(4), 1051–1063 (2011).
[Crossref] [PubMed]

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. Goulam 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]

B. V. Zlokovic, “Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders,” Nat. Rev. Neurosci. 12(12), 723–738 (2011).
[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. Tang, Y. Zhou, K. K. H. Chan, and T. Lai, “Multiscale multimodal imaging with multiphoton microscopy and optical coherence tomography,” Opt. Lett. 36(24), 4800–4802 (2011).
[Crossref] [PubMed]

B. Jeong, B. Lee, M. S. Jang, H. Nam, S. J. Yoon, T. Wang, J. Doh, B.-G. Yang, M. H. Jang, and K. H. Kim, “Combined two-photon microscopy and optical coherence tomography using individually optimized sources,” Opt. Express 19(14), 13089–13096 (2011).
[Crossref] [PubMed]

2010 (4)

R. B. Buxton, “Interpreting oxygenation-based neuroimaging signals: the importance and the challenge of understanding brain oxygen metabolism,” Front. Neuroenergetics 2, 8 (2010).

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Imaging of oxygen partial pressure in cerebral vasculature and tissue using a two-photon-enhanced phosphorescent nanoprobe,” Nat. Methods 7, 755–759 (2010).
[Crossref] [PubMed]

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

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

2009 (7)

M. B. Bouchard, B. R. Chen, S. A. Burgess, and E. M. C. Hillman, “Ultra-fast multispectral optical imaging of cortical oxygenation, blood flow, and intracellular calcium dynamics,” Opt. Express 17(18), 15670–15678 (2009).
[Crossref] [PubMed]

V. J. Srinivasan, S. Sakadzić, I. Gorczynska, S. Ruvinskaya, W. Wu, J. G. Fujimoto, and D. A. Boas, “Depth-resolved microscopy of cortical hemodynamics with optical coherence tomography,” Opt. Lett. 34(20), 3086–3088 (2009).
[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadzić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express 17(25), 22341–22350 (2009).
[Crossref] [PubMed]

M. E. Raichle, “A brief history of human brain mapping,” Trends Neurosci. 32(2), 118–126 (2009).
[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]

Q. Yu and A. A. Heikal, “Two-photon autofluorescence dynamics imaging reveals sensitivity of intracellular NADH concentration and conformation to cell physiology at the single-cell level,” J. Photochem. Photobiol. B 95(1), 46–57 (2009).
[Crossref] [PubMed]

S. Sakadzić, S. Yuan, E. Dilekoz, S. Ruvinskaya, S. A. Vinogradov, C. Ayata, and D. A. Boas, “Simultaneous imaging of cerebral partial pressure of oxygen and blood flow during functional activation and cortical spreading depression,” Appl. Opt. 48(10), D169–D177 (2009).
[Crossref] [PubMed]

2008 (5)

Q. Fang, S. Sakadzić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express 16(22), 17530–17541 (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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

T. H. Chia, A. Williamson, D. D. Spencer, and M. J. Levene, “Multiphoton fluorescence lifetime imaging of intrinsic fluorescence in human and rat brain tissue reveals spatially distinct NADH binding,” Opt. Express 16(6), 4237–4249 (2008).
[Crossref] [PubMed]

K. Bartlett, M. Saka, and M. Jones, “Polarographic Electrode Measures of Cerebral Tissue Oxygenation: Implications for Functional Brain Imaging,” Sensors (Basel Switzerland) 8(12), 7649–7670 (2008).
[Crossref]

J. J. Riera, A. Schousboe, H. S. Waagepetersen, C. Howarth, and F. Hyder, “The micro-architecture of the cerebral cortex: functional neuroimaging models and metabolism,” Neuroimage 40(4), 1436–1459 (2008).
[Crossref] [PubMed]

2007 (2)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

T. Kim, K. S. Hendrich, K. Masamoto, and S.-G. Kim, “Arterial versus total blood volume changes during neural activity-induced cerebral blood flow change: implication for BOLD fMRI,” J. Cereb. Blood Flow Metab. 27(6), 1235–1247 (2007).
[Crossref] [PubMed]

2006 (1)

M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature 443(7113), 787–795 (2006).
[Crossref] [PubMed]

2005 (3)

D. C. Wallace, “A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine,” Annu. Rev. Genet. 39(1), 359–407 (2005).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, A. M. Dale, and D. A. Boas, “Spatial extent of oxygen metabolism and hemodynamic changes during functional activation of the rat somatosensory cortex,” Neuroimage 27(2), 279–290 (2005).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational Dependence of Intracellular NADH on Metabolic State Revealed by Associated Fluorescence Anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

2004 (1)

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305(5680), 99–103 (2004).
[Crossref] [PubMed]

2003 (1)

2002 (1)

I. Dunphy, S. A. Vinogradov, and D. F. Wilson, “Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence,” Anal. Biochem. 310(2), 191–198 (2002).
[Crossref] [PubMed]

1999 (1)

1890 (1)

C. S. Roy and C. S. Sherrington, “On the regulation of the blood-supply of the brain,” J. Physiol. 11(1-2), 158 (1890).
[Crossref] [PubMed]

Amblard, F.

Andermann, M. L.

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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

Ayata, C.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

S. Sakadzić, S. Yuan, E. Dilekoz, S. Ruvinskaya, S. A. Vinogradov, C. Ayata, and D. A. Boas, “Simultaneous imaging of cerebral partial pressure of oxygen and blood flow during functional activation and cortical spreading depression,” Appl. Opt. 48(10), D169–D177 (2009).
[Crossref] [PubMed]

Bartlett, K.

K. Bartlett, M. Saka, and M. Jones, “Polarographic Electrode Measures of Cerebral Tissue Oxygenation: Implications for Functional Brain Imaging,” Sensors (Basel Switzerland) 8(12), 7649–7670 (2008).
[Crossref]

Beal, M. F.

M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature 443(7113), 787–795 (2006).
[Crossref] [PubMed]

Beaurepaire, E.

Becker, W.

Blinder, P.

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]

Boas, D. A.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[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. Express 4(2), 307–321 (2013).
[Crossref] [PubMed]

A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (2012).
[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, H. Radhakrishnan, I. Gorczynska, W. Wu, J. G. Fujimoto, and D. A. Boas, “Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation,” J. Cereb. Blood Flow Metab. 31(4), 1051–1063 (2011).
[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]

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

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Imaging of oxygen partial pressure in cerebral vasculature and tissue using a two-photon-enhanced phosphorescent nanoprobe,” Nat. Methods 7, 755–759 (2010).
[Crossref] [PubMed]

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

V. J. Srinivasan, S. Sakadzić, I. Gorczynska, S. Ruvinskaya, W. Wu, J. G. Fujimoto, and D. A. Boas, “Depth-resolved microscopy of cortical hemodynamics with optical coherence tomography,” Opt. Lett. 34(20), 3086–3088 (2009).
[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadzić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express 17(25), 22341–22350 (2009).
[Crossref] [PubMed]

S. Sakadzić, S. Yuan, E. Dilekoz, S. Ruvinskaya, S. A. Vinogradov, C. Ayata, and D. A. Boas, “Simultaneous imaging of cerebral partial pressure of oxygen and blood flow during functional activation and cortical spreading depression,” Appl. Opt. 48(10), D169–D177 (2009).
[Crossref] [PubMed]

Q. Fang, S. Sakadzić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express 16(22), 17530–17541 (2008).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, A. M. Dale, and D. A. Boas, “Spatial extent of oxygen metabolism and hemodynamic changes during functional activation of the rat somatosensory cortex,” Neuroimage 27(2), 279–290 (2005).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, H. Bolay, M. L. Andermann, M. A. Moskowitz, A. M. Dale, and D. A. Boas, “Simultaneous imaging of total cerebral hemoglobin concentration, oxygenation, and blood flow during functional activation,” Opt. Lett. 28(1), 28–30 (2003).
[Crossref] [PubMed]

Bolay, H.

Bouchard, M. B.

Burgess, S. A.

Buxton, R. B.

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]

R. B. Buxton, “Interpreting oxygenation-based neuroimaging signals: the importance and the challenge of understanding brain oxygen metabolism,” Front. Neuroenergetics 2, 8 (2010).

Catana, C.

C. Catana, A. Drzezga, W.-D. Heiss, and B. R. Rosen, “PET/MRI for neurologic applications,” J. Nucl. Med. 53(12), 1916–1925 (2012).
[Crossref] [PubMed]

Chan, K. K. H.

Charpak, S.

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. Goulam 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]

Chen, B. R.

Chia, T. H.

Chong, S. P.

Chung, E.

B. Kim, T. J. Wang, Q. Li, J. Nam, S. Hwang, E. Chung, S. Kim, and K. H. Kim, “Combined two-photon microscopy and angiographic optical coherence tomography,” J. Biomed. Opt. 18(8), 080502 (2013).
[Crossref] [PubMed]

Dale, A. M.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (2012).
[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]

Q. Fang, S. Sakadzić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express 16(22), 17530–17541 (2008).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, A. M. Dale, and D. A. Boas, “Spatial extent of oxygen metabolism and hemodynamic changes during functional activation of the rat somatosensory cortex,” Neuroimage 27(2), 279–290 (2005).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, H. Bolay, M. L. Andermann, M. A. Moskowitz, A. M. Dale, and D. A. Boas, “Simultaneous imaging of total cerebral hemoglobin concentration, oxygenation, and blood flow during functional activation,” Opt. Lett. 28(1), 28–30 (2003).
[Crossref] [PubMed]

Devor, A.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (2012).
[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, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Imaging of oxygen partial pressure in cerebral vasculature and tissue using a two-photon-enhanced phosphorescent nanoprobe,” Nat. Methods 7, 755–759 (2010).
[Crossref] [PubMed]

Q. Fang, S. Sakadzić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express 16(22), 17530–17541 (2008).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, A. M. Dale, and D. A. Boas, “Spatial extent of oxygen metabolism and hemodynamic changes during functional activation of the rat somatosensory cortex,” Neuroimage 27(2), 279–290 (2005).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, H. Bolay, M. L. Andermann, M. A. Moskowitz, A. M. Dale, and D. A. Boas, “Simultaneous imaging of total cerebral hemoglobin concentration, oxygenation, and blood flow during functional activation,” Opt. Lett. 28(1), 28–30 (2003).
[Crossref] [PubMed]

Dilekoz, E.

Doh, J.

Drew, P. J.

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]

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]

Driscoll, J. D.

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]

Drzezga, A.

C. Catana, A. Drzezga, W.-D. Heiss, and B. R. Rosen, “PET/MRI for neurologic applications,” J. Nucl. Med. 53(12), 1916–1925 (2012).
[Crossref] [PubMed]

Ducros, M.

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. Goulam 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]

Dunn, A. K.

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

A. K. Dunn, A. Devor, A. M. Dale, and D. A. Boas, “Spatial extent of oxygen metabolism and hemodynamic changes during functional activation of the rat somatosensory cortex,” Neuroimage 27(2), 279–290 (2005).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, H. Bolay, M. L. Andermann, M. A. Moskowitz, A. M. Dale, and D. A. Boas, “Simultaneous imaging of total cerebral hemoglobin concentration, oxygenation, and blood flow during functional activation,” Opt. Lett. 28(1), 28–30 (2003).
[Crossref] [PubMed]

Dunphy, I.

I. Dunphy, S. A. Vinogradov, and D. F. Wilson, “Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence,” Anal. Biochem. 310(2), 191–198 (2002).
[Crossref] [PubMed]

Eickhoff, J.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Eikermann-Haerter, K.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

Eliceiri, K. W.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Fang, Q.

Finikova, O. S.

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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

Fisher, P. J.

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305(5680), 99–103 (2004).
[Crossref] [PubMed]

Franceschini, M. A.

A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (2012).
[Crossref] [PubMed]

Friedman, B.

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]

Fujimoto, J. G.

Gagnon, L.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

Gao, F.

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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

Garnacho, C.

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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

Gendron-Fitzpatrick, A.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Gorczynska, I.

Goulam Houssen, Y.

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. Goulam 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]

Heikal, A. A.

Q. Yu and A. A. Heikal, “Two-photon autofluorescence dynamics imaging reveals sensitivity of intracellular NADH concentration and conformation to cell physiology at the single-cell level,” J. Photochem. Photobiol. B 95(1), 46–57 (2009).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational Dependence of Intracellular NADH on Metabolic State Revealed by Associated Fluorescence Anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

Heiss, W.-D.

C. Catana, A. Drzezga, W.-D. Heiss, and B. R. Rosen, “PET/MRI for neurologic applications,” J. Nucl. Med. 53(12), 1916–1925 (2012).
[Crossref] [PubMed]

Hendrich, K. S.

T. Kim, K. S. Hendrich, K. Masamoto, and S.-G. Kim, “Arterial versus total blood volume changes during neural activity-induced cerebral blood flow change: implication for BOLD fMRI,” J. Cereb. Blood Flow Metab. 27(6), 1235–1247 (2007).
[Crossref] [PubMed]

Hillman, E. M. C.

Hochstrasser, R. M.

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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

Howarth, C.

J. J. Riera, A. Schousboe, H. S. Waagepetersen, C. Howarth, and F. Hyder, “The micro-architecture of the cerebral cortex: functional neuroimaging models and metabolism,” Neuroimage 40(4), 1436–1459 (2008).
[Crossref] [PubMed]

Hwang, S.

B. Kim, T. J. Wang, Q. Li, J. Nam, S. Hwang, E. Chung, S. Kim, and K. H. Kim, “Combined two-photon microscopy and angiographic optical coherence tomography,” J. Biomed. Opt. 18(8), 080502 (2013).
[Crossref] [PubMed]

Hyder, F.

J. J. Riera, A. Schousboe, H. S. Waagepetersen, C. Howarth, and F. Hyder, “The micro-architecture of the cerebral cortex: functional neuroimaging models and metabolism,” Neuroimage 40(4), 1436–1459 (2008).
[Crossref] [PubMed]

Jang, M. H.

Jang, M. S.

Jeong, B.

Jones, M.

K. Bartlett, M. Saka, and M. Jones, “Polarographic Electrode Measures of Cerebral Tissue Oxygenation: Implications for Functional Brain Imaging,” Sensors (Basel Switzerland) 8(12), 7649–7670 (2008).
[Crossref]

Karten, H. J.

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]

Kasischke, K. 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. Express 4(2), 307–321 (2013).
[Crossref] [PubMed]

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational Dependence of Intracellular NADH on Metabolic State Revealed by Associated Fluorescence Anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305(5680), 99–103 (2004).
[Crossref] [PubMed]

Kaufhold, J. P.

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]

Kim, B.

B. Kim, T. J. Wang, Q. Li, J. Nam, S. Hwang, E. Chung, S. Kim, and K. H. Kim, “Combined two-photon microscopy and angiographic optical coherence tomography,” J. Biomed. Opt. 18(8), 080502 (2013).
[Crossref] [PubMed]

Kim, K. H.

B. Kim, T. J. Wang, Q. Li, J. Nam, S. Hwang, E. Chung, S. Kim, and K. H. Kim, “Combined two-photon microscopy and angiographic optical coherence tomography,” J. Biomed. Opt. 18(8), 080502 (2013).
[Crossref] [PubMed]

B. Jeong, B. Lee, M. S. Jang, H. Nam, S. J. Yoon, T. Wang, J. Doh, B.-G. Yang, M. H. Jang, and K. H. Kim, “Combined two-photon microscopy and optical coherence tomography using individually optimized sources,” Opt. Express 19(14), 13089–13096 (2011).
[Crossref] [PubMed]

Kim, S.

B. Kim, T. J. Wang, Q. Li, J. Nam, S. Hwang, E. Chung, S. Kim, and K. H. Kim, “Combined two-photon microscopy and angiographic optical coherence tomography,” J. Biomed. Opt. 18(8), 080502 (2013).
[Crossref] [PubMed]

Kim, S.-G.

T. Kim, K. S. Hendrich, K. Masamoto, and S.-G. Kim, “Arterial versus total blood volume changes during neural activity-induced cerebral blood flow change: implication for BOLD fMRI,” J. Cereb. Blood Flow Metab. 27(6), 1235–1247 (2007).
[Crossref] [PubMed]

Kim, T.

T. Kim, K. S. Hendrich, K. Masamoto, and S.-G. Kim, “Arterial versus total blood volume changes during neural activity-induced cerebral blood flow change: implication for BOLD fMRI,” J. Cereb. Blood Flow Metab. 27(6), 1235–1247 (2007).
[Crossref] [PubMed]

Kleinfeld, D.

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]

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]

Kleiser, S.

F. Scholkmann, S. Kleiser, A. J. Metz, R. Zimmermann, J. Mata Pavia, U. Wolf, and M. Wolf, “A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology,” Neuroimage 85(Pt 1), 6–27 (2014).
[Crossref] [PubMed]

Lai, T.

Lebedev, A. Y.

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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

Lecoq, J.

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. Goulam 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]

Lee, B.

Lefebvre, J.

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S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
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M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, H. Radhakrishnan, I. Gorczynska, W. Wu, J. G. Fujimoto, and D. A. Boas, “Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation,” J. Cereb. Blood Flow Metab. 31(4), 1051–1063 (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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S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Imaging of oxygen partial pressure in cerebral vasculature and tissue using a two-photon-enhanced phosphorescent nanoprobe,” Nat. Methods 7, 755–759 (2010).
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J. J. Riera, A. Schousboe, H. S. Waagepetersen, C. Howarth, and F. Hyder, “The micro-architecture of the cerebral cortex: functional neuroimaging models and metabolism,” Neuroimage 40(4), 1436–1459 (2008).
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C. S. Roy and C. S. Sherrington, “On the regulation of the blood-supply of the brain,” J. Physiol. 11(1-2), 158 (1890).
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Srinivasan, V. J.

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M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, H. Radhakrishnan, I. Gorczynska, W. Wu, J. G. Fujimoto, and D. A. Boas, “Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation,” J. Cereb. Blood Flow Metab. 31(4), 1051–1063 (2011).
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M. A. Yaseen, V. J. Srinivasan, S. Sakadzić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express 17(25), 22341–22350 (2009).
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Tsai, P. S.

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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A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (2012).
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[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadzić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express 17(25), 22341–22350 (2009).
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J. J. Riera, A. Schousboe, H. S. Waagepetersen, C. Howarth, and F. Hyder, “The micro-architecture of the cerebral cortex: functional neuroimaging models and metabolism,” Neuroimage 40(4), 1436–1459 (2008).
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B. Kim, T. J. Wang, Q. Li, J. Nam, S. Hwang, E. Chung, S. Kim, and K. H. Kim, “Combined two-photon microscopy and angiographic optical coherence tomography,” J. Biomed. Opt. 18(8), 080502 (2013).
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H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational Dependence of Intracellular NADH on Metabolic State Revealed by Associated Fluorescence Anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
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K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305(5680), 99–103 (2004).
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White, J. G.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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Wilson, D. F.

I. Dunphy, S. A. Vinogradov, and D. F. Wilson, “Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence,” Anal. Biochem. 310(2), 191–198 (2002).
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F. Scholkmann, S. Kleiser, A. J. Metz, R. Zimmermann, J. Mata Pavia, U. Wolf, and M. Wolf, “A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology,” Neuroimage 85(Pt 1), 6–27 (2014).
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F. Scholkmann, S. Kleiser, A. J. Metz, R. Zimmermann, J. Mata Pavia, U. Wolf, and M. Wolf, “A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology,” Neuroimage 85(Pt 1), 6–27 (2014).
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Yang, B.-G.

Yaseen, M. A.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[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. Express 4(2), 307–321 (2013).
[Crossref] [PubMed]

A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (2012).
[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, H. Radhakrishnan, I. Gorczynska, W. Wu, J. G. Fujimoto, and D. A. Boas, “Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation,” J. Cereb. Blood Flow Metab. 31(4), 1051–1063 (2011).
[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, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Imaging of oxygen partial pressure in cerebral vasculature and tissue using a two-photon-enhanced phosphorescent nanoprobe,” Nat. Methods 7, 755–759 (2010).
[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadzić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express 17(25), 22341–22350 (2009).
[Crossref] [PubMed]

Yoon, S. J.

Yu, Q.

Q. Yu and A. A. Heikal, “Two-photon autofluorescence dynamics imaging reveals sensitivity of intracellular NADH concentration and conformation to cell physiology at the single-cell level,” J. Photochem. Photobiol. B 95(1), 46–57 (2009).
[Crossref] [PubMed]

Yuan, S.

Yucel, M. A.

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

Zhou, Y.

Zimmermann, R.

F. Scholkmann, S. Kleiser, A. J. Metz, R. Zimmermann, J. Mata Pavia, U. Wolf, and M. Wolf, “A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology,” Neuroimage 85(Pt 1), 6–27 (2014).
[Crossref] [PubMed]

Zipfel, W. R.

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305(5680), 99–103 (2004).
[Crossref] [PubMed]

Zlokovic, B. V.

B. V. Zlokovic, “Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders,” Nat. Rev. Neurosci. 12(12), 723–738 (2011).
[PubMed]

Anal. Biochem. (1)

I. Dunphy, S. A. Vinogradov, and D. F. Wilson, “Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence,” Anal. Biochem. 310(2), 191–198 (2002).
[Crossref] [PubMed]

Annu. Rev. Genet. (1)

D. C. Wallace, “A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine,” Annu. Rev. Genet. 39(1), 359–407 (2005).
[Crossref] [PubMed]

Appl. Opt. (1)

Biomed. Opt. Express (2)

Chem. Phys. Chem. (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,” Chem. Phys. Chem. 9, 1673–1679 (2008).

Front. Neuroenergetics (1)

R. B. Buxton, “Interpreting oxygenation-based neuroimaging signals: the importance and the challenge of understanding brain oxygen metabolism,” Front. Neuroenergetics 2, 8 (2010).

J. Biol. Chem. (1)

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational Dependence of Intracellular NADH on Metabolic State Revealed by Associated Fluorescence Anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

J. Biomed. Opt. (2)

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

B. Kim, T. J. Wang, Q. Li, J. Nam, S. Hwang, E. Chung, S. Kim, and K. H. Kim, “Combined two-photon microscopy and angiographic optical coherence tomography,” J. Biomed. Opt. 18(8), 080502 (2013).
[Crossref] [PubMed]

J. Cereb. Blood Flow Metab. (4)

T. Kim, K. S. Hendrich, K. Masamoto, and S.-G. Kim, “Arterial versus total blood volume changes during neural activity-induced cerebral blood flow change: implication for BOLD fMRI,” J. Cereb. Blood Flow Metab. 27(6), 1235–1247 (2007).
[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]

M. A. Yaseen, V. J. Srinivasan, S. Sakadžić, H. Radhakrishnan, I. Gorczynska, W. Wu, J. G. Fujimoto, and D. A. Boas, “Microvascular oxygen tension and flow measurements in rodent cerebral cortex during baseline conditions and functional activation,” J. Cereb. Blood Flow Metab. 31(4), 1051–1063 (2011).
[Crossref] [PubMed]

A. Devor, S. Sakadžić, V. J. Srinivasan, M. A. Yaseen, K. Nizar, P. A. Saisan, P. Tian, A. M. Dale, S. A. Vinogradov, M. A. Franceschini, and D. A. Boas, “Frontiers in optical imaging of cerebral blood flow and metabolism,” J. Cereb. Blood Flow Metab. 32(7), 1259–1276 (2012).
[Crossref] [PubMed]

J. Neurosci. (2)

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. 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]

J. Nucl. Med. (1)

C. Catana, A. Drzezga, W.-D. Heiss, and B. R. Rosen, “PET/MRI for neurologic applications,” J. Nucl. Med. 53(12), 1916–1925 (2012).
[Crossref] [PubMed]

J. Photochem. Photobiol. B (1)

Q. Yu and A. A. Heikal, “Two-photon autofluorescence dynamics imaging reveals sensitivity of intracellular NADH concentration and conformation to cell physiology at the single-cell level,” J. Photochem. Photobiol. B 95(1), 46–57 (2009).
[Crossref] [PubMed]

J. Physiol. (1)

C. S. Roy and C. S. Sherrington, “On the regulation of the blood-supply of the brain,” J. Physiol. 11(1-2), 158 (1890).
[Crossref] [PubMed]

Nat. Commun. (1)

S. Sakadžić, E. T. Mandeville, L. Gagnon, J. J. Musacchia, M. A. Yaseen, M. A. Yucel, J. Lefebvre, F. Lesage, A. M. Dale, K. Eikermann-Haerter, C. Ayata, V. J. Srinivasan, E. H. Lo, A. Devor, and D. A. Boas, “Large arteriolar component of oxygen delivery implies a safe margin of oxygen supply to cerebral tissue,” Nat. Commun. 5, 5734 (2014).
[Crossref] [PubMed]

Nat. Med. (1)

J. Lecoq, A. Parpaleix, E. Roussakis, M. Ducros, Y. Goulam 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]

Nat. Methods (1)

S. Sakadžić, E. Roussakis, M. A. Yaseen, E. T. Mandeville, A. Devor, E. H. Lo, S. A. Vinogradov, and D. A. Boas, “Imaging of oxygen partial pressure in cerebral vasculature and tissue using a two-photon-enhanced phosphorescent nanoprobe,” Nat. Methods 7, 755–759 (2010).
[Crossref] [PubMed]

Nat. Rev. Neurosci. (1)

B. V. Zlokovic, “Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders,” Nat. Rev. Neurosci. 12(12), 723–738 (2011).
[PubMed]

Nature (1)

M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature 443(7113), 787–795 (2006).
[Crossref] [PubMed]

Neuroimage (3)

J. J. Riera, A. Schousboe, H. S. Waagepetersen, C. Howarth, and F. Hyder, “The micro-architecture of the cerebral cortex: functional neuroimaging models and metabolism,” Neuroimage 40(4), 1436–1459 (2008).
[Crossref] [PubMed]

F. Scholkmann, S. Kleiser, A. J. Metz, R. Zimmermann, J. Mata Pavia, U. Wolf, and M. Wolf, “A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology,” Neuroimage 85(Pt 1), 6–27 (2014).
[Crossref] [PubMed]

A. K. Dunn, A. Devor, A. M. Dale, and D. A. Boas, “Spatial extent of oxygen metabolism and hemodynamic changes during functional activation of the rat somatosensory cortex,” Neuroimage 27(2), 279–290 (2005).
[Crossref] [PubMed]

Opt. Express (6)

M. B. Bouchard, B. R. Chen, S. A. Burgess, and E. M. C. Hillman, “Ultra-fast multispectral optical imaging of cortical oxygenation, blood flow, and intracellular calcium dynamics,” Opt. Express 17(18), 15670–15678 (2009).
[Crossref] [PubMed]

Q. Fang, S. Sakadzić, L. Ruvinskaya, A. Devor, A. M. Dale, and D. A. Boas, “Oxygen advection and diffusion in a three- dimensional vascular anatomical network,” Opt. Express 16(22), 17530–17541 (2008).
[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, S. Sakadzić, W. Wu, S. Ruvinskaya, S. A. Vinogradov, and D. A. Boas, “Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy,” Opt. Express 17(25), 22341–22350 (2009).
[Crossref] [PubMed]

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

T. H. Chia, A. Williamson, D. D. Spencer, and M. J. Levene, “Multiphoton fluorescence lifetime imaging of intrinsic fluorescence in human and rat brain tissue reveals spatially distinct NADH binding,” Opt. Express 16(6), 4237–4249 (2008).
[Crossref] [PubMed]

B. Jeong, B. Lee, M. S. Jang, H. Nam, S. J. Yoon, T. Wang, J. Doh, B.-G. Yang, M. H. Jang, and K. H. Kim, “Combined two-photon microscopy and optical coherence tomography using individually optimized sources,” Opt. Express 19(14), 13089–13096 (2011).
[Crossref] [PubMed]

Opt. Lett. (4)

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

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

Science (1)

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305(5680), 99–103 (2004).
[Crossref] [PubMed]

Sensors (Basel Switzerland) (1)

K. Bartlett, M. Saka, and M. Jones, “Polarographic Electrode Measures of Cerebral Tissue Oxygenation: Implications for Functional Brain Imaging,” Sensors (Basel Switzerland) 8(12), 7649–7670 (2008).
[Crossref]

Trends Neurosci. (1)

M. E. Raichle, “A brief history of human brain mapping,” Trends Neurosci. 32(2), 118–126 (2009).
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A. Kumar and T. C. Foster, “Neurophysiology of old neurons and synapses,” in Brain Aging: Models, Methods, and Mechanisms, D. R. Riddle, ed. (Boca Raton, FL: CRC Press, 2007).

W. Becker, Advanced Time-Correlated Single Photon Counting Techniques (Berlin, Heidelberg, New York: Springer, 2005).

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Figures (4)

Fig. 1
Fig. 1 (a). Schematic featuring primary components of the custom multimodal optical microscope. EOM- electro-optic modulator, SH- shutter, APD- avalanche photodiode, xy- galvanometer scanners, Hg:Xe- arc lamp. (b) Magnified region of schematic illustrating how the TPM/confocal scanning beam path and OCT beam path are coupled together and how emitted fluorescence is separated. OCT and TPM/confocal modules were designed with separate scanning arms and their probing optical beams were coupled into the same microscope objective by a movable dichroic mirror. (c) Detailed model of detector array for TPM fluorescence. Some specifications ED: Epi dichroic after objective (FF735-Di01-25x36, Semrock Inc), IB: Infrared blocker (FF01-750/SP-50, Semrock Inc), MD: main dichroic mirror (t560lpxr-35x52, Chroma Technology Corp), FC1: Filter Cube 1 (dichroic mirror: t640lpxr; channel 1 emission filter: hq680-60m-TPM; channel 2 emission filter: et595/50m-TPM, Chroma Technology Corp), FC2: Filter Cube 2 (dichroic mirror: FF495-Di02-25x36; channel 3 emission filter: FF01-525/50-25; channel 4 emission filter: FF01-460/60-25, Semrock Inc), L1-L3: Lenses 1-3: 50 mm diameter; FL = 81 mm (026-1450, OptoSigma Corporation), L4-L7: Lenses 4-7: 25.4 mm diameter, FL = 19 mm (KBX043, Newport).
Fig. 2
Fig. 2 Intravascular measurements of pO2 and CBF (a) Color-coded, in vivo angiogram collected with confocal microscopy, green points represent locations at which pO2 (mmHg) and absolute CBF (µL/min) were measured simultaneously with confocal microscopy and OCT, respectively. Scalebar: 1mm. (b) Representative traces of pO2 and relative CBF collected during somatosensory stimulus (4-sec pulse train, 0.3 mS pulse duration, 3 Hz, administered to the forepaw during the shaded region) [14]. (c) and (d) Co-registration of the Two-Photon Microscopy and OCT data from the upper 650 um in a mouse somatosensory cortex. (c) The OCT measurements of blood flow. Measured blood flow values in penetrating arterioles and surfacing venules were color-coded and overlaid on the segmented microvascular structure. Positive CBF values correspond to upward flow in venules, while negative indicates downward flow in arterioles. The data were previously co-registered with the vascular stack in (d). (d) Segmented microvasculature with the intravascular pO2 measurements obtained by TPM. Mean vascular segment pO2 measurements were color-coded and overlaid on the segmented microvascular structure [15].
Fig. 3
Fig. 3 TPM-based, extravascular measurements of pO2 and NADH autofluorescence (a) pO2 traces recorded near an arteriole (red) and venule (blue) during a brief period (30s) of anoxia [13] (b) spatial distribution of pO2 in tissue surrounding a diving arteriole. (c) Representative traces of the normalized, amplitude-weighted lifetimes of distinct enzyme-bound formulations of NADH recorded with TPM FLIM during anoxic period (45s), averaged over the entire field of view [16] (d) spatial distribution of NADH intensity in tissue surrounding diving arterioles and a diving venule.
Fig. 4
Fig. 4 Spatial variability of relative cerebral blood flow (rCBF) and energy metabolism during focal ischemia (a) 580 nm reflectance image of the cranial window after distal occlusion of the middle cerebral artery, overlaid with color-coded relative cerebral blood flow measured with LSCI. Colored regions depict areas where rCBF stayed above 25% of the maximum rCBF value after occlusion. Dashed yellow rectangle represents the large field of view for 2-photon imaging over the entire cranial window (figs b and c). Dashed rectangles indicate areas imaged with higher magnification TPM FLIM of NADH, with red depicting well-perfused regions and blue indicating ischemic territory. Solid arrow identifies occluded MCA branch; dashed arrow indicates draining venule along the pial surface (b) Maximum intensity projection of intravascular FITC fluorescence, measured with TPM microscopy. (c) Corresponding NADH intensity fluorescence of the brain tissue, (d) mean lifetime values of intrinsic NADH, measured with TPM FLIM, in ischemic regions and perfused regions (e) Fractional fluorescence of the 4 “components” of NADH (c1 – c4 depict component 1 – component 4), observable by TPM-FLIM.

Tables (1)

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Table 1 Applications and characteristics of incorporated imaging modalities [5]

Metrics