Abstract

High-speed volumetric imaging represents a challenge in microscopy applications. We demonstrate a technique for acquiring volumetric images based on the extended depth of field microscopy with a fast focal scan and modulated illumination. By combining two frames with different illumination ramps, we can perform local depth ranging of the sample at speeds of up to half the camera frame rate. Our technique is light efficient, provides diffraction-limited resolution, enables axial localization that is largely independent of sample size, and can be operated with any standard widefield microscope based on fluorescence or darkfield contrast as a simple add-on. We demonstrate the accuracy of axial localization and applications of the technique to various dynamic extended samples, including in-vivo mouse brain.

© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

Full Article  |  PDF Article
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References

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2017 (4)

T. H. Chen, J. T. Ault, H. A. Stone, and C. B. Arnold, “High-speed axial-scanning wide-field microscopy for volumetric particle tracking velocimetry,” Exp. Fluids 58, 1–7 (2017).
[Crossref]

W. Yang and R. Yuste, “In vivo imaging of neural activity,” Nat. Meth. 14, 349–359 (2017).
[Crossref]

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

W. J. Shain, N. A. Vickers, B. B. Goldberg, T. Bifano, and J. Mertz, “Extended depth-of-field microscopy with a high-speed deformable mirror,” Opt. Lett. 42, 995–998 (2017).
[Crossref] [PubMed]

2016 (2)

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neuro. 19, 1154–1164 (2016).
[Crossref]

2015 (4)

2013 (1)

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Meth. 10, 413–420 (2013).
[Crossref]

2011 (2)

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

B. F. Grewe, F. F. Voigt, M. van ’t Hoff, and F. Helmchen, “Fast two-layer two-photon imaging of neuronal cell populations using an electrically tunable lens,” Biomed. Opt. Express 2, 2035–2046 (2011).
[Crossref] [PubMed]

2010 (1)

Z. Frentz, S. Kuehn, D. Hekstra, and S. Leibler, “Microbial population dynamics by digital in-line holographic microscopy,” Rev. Sci. Instrum. 81, 084301 (2010).
[Crossref] [PubMed]

2008 (1)

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

2006 (3)

P. Dufour, M. Piché, Y. De Koninck, and N. McCarthy, “Two-photon excitation fluorescence microscopy with a high depth of field using an axicon,” Appl. Opt. 45, 9246–9252 (2006).
[Crossref] [PubMed]

M. Levoy, “Light fields and computational imaging,” IEEE Comp. Soc.,  3945–55 (2006).
[Crossref]

S. Abrahamsson, S. Usawa, and M. Gustafsson, “A new approach to extended focus for high-speed, high-resolution biological microscopy,” Proc. SPIE 6090, 60900N (2006).
[Crossref]

2004 (1)

J. Huisken, J. Swoger, F. Del Benne, J. Wittbrodt, and E. H. K. Stelzer, “Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).
[Crossref] [PubMed]

1998 (1)

M. Watanabe and S. K. Nayar, “Rational filters for passive depth from defocus,” Int. J. Comp. Vision 27, 203–225 (1998).
[Crossref]

1995 (1)

1984 (1)

1972 (1)

G. Hausler, “A method to increase the depth of focus by two step image processing,” Opt. Commun. 6, 38–42 (1972).
[Crossref]

1960 (2)

A. Wang, R. F. Garmann, and V. N. Manoharan, “Tracking E. coli runs and tumbles with scattering solutions and digital holographic microscopy,” Optics Express 50, 23719–23725 (1960).

W. T. Welford, “Use of Annular Apertures to Increase Focal Depth,” J. Opt. Soc. Am. 50, 749–753 (1960).
[Crossref]

Abrahamsson, S.

S. Abrahamsson, S. Usawa, and M. Gustafsson, “A new approach to extended focus for high-speed, high-resolution biological microscopy,” Proc. SPIE 6090, 60900N (2006).
[Crossref]

Ahrens, M. B.

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Meth. 10, 413–420 (2013).
[Crossref]

Arnold, C. B.

T. H. Chen, J. T. Ault, H. A. Stone, and C. B. Arnold, “High-speed axial-scanning wide-field microscopy for volumetric particle tracking velocimetry,” Exp. Fluids 58, 1–7 (2017).
[Crossref]

Ault, J. T.

T. H. Chen, J. T. Ault, H. A. Stone, and C. B. Arnold, “High-speed axial-scanning wide-field microscopy for volumetric particle tracking velocimetry,” Exp. Fluids 58, 1–7 (2017).
[Crossref]

Baden, T.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Bai, H.

Berens, P.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Bertero, M.

M. Bertero and P. Boccacci, Introduction to Inverse Problems in Imaging (IOP Publishing, 1998).
[Crossref]

Bethge, M.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Bierfeld, J.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Bifano, T.

Bishara, W.

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Boccacci, P.

M. Bertero and P. Boccacci, Introduction to Inverse Problems in Imaging (IOP Publishing, 1998).
[Crossref]

Brady, D. J.

Carin, L.

Cathey, W. T.

Chen, T. H.

T. H. Chen, J. T. Ault, H. A. Stone, and C. B. Arnold, “High-speed axial-scanning wide-field microscopy for volumetric particle tracking velocimetry,” Exp. Fluids 58, 1–7 (2017).
[Crossref]

Coppola, G.

Cruz, L.

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

De Koninck, Y.

Del Benne, F.

J. Huisken, J. Swoger, F. Del Benne, J. Wittbrodt, and E. H. K. Stelzer, “Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).
[Crossref] [PubMed]

DiCaprio, G.

Dowski, E. R.

Dufour, P.

Eismann, S.

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

Euler, T.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Ferraro, P.

Fitzpatrick, D.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Freeman, J.

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neuro. 19, 1154–1164 (2016).
[Crossref]

Frentz, Z.

Z. Frentz, S. Kuehn, D. Hekstra, and S. Leibler, “Microbial population dynamics by digital in-line holographic microscopy,” Rev. Sci. Instrum. 81, 084301 (2010).
[Crossref] [PubMed]

Froudarakis, E.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Garmann, R. F.

A. Wang, R. F. Garmann, and V. N. Manoharan, “Tracking E. coli runs and tumbles with scattering solutions and digital holographic microscopy,” Optics Express 50, 23719–23725 (1960).

Goldberg, B. B.

Gong, Y.

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

Grewe, B. F.

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

B. F. Grewe, F. F. Voigt, M. van ’t Hoff, and F. Helmchen, “Fast two-layer two-photon imaging of neuronal cell populations using an electrically tunable lens,” Biomed. Opt. Express 2, 2035–2046 (2011).
[Crossref] [PubMed]

Gustafsson, M.

S. Abrahamsson, S. Usawa, and M. Gustafsson, “A new approach to extended focus for high-speed, high-resolution biological microscopy,” Proc. SPIE 6090, 60900N (2006).
[Crossref]

Hausler, G.

G. Hausler, “A method to increase the depth of focus by two step image processing,” Opt. Commun. 6, 38–42 (1972).
[Crossref]

Hekstra, D.

Z. Frentz, S. Kuehn, D. Hekstra, and S. Leibler, “Microbial population dynamics by digital in-line holographic microscopy,” Rev. Sci. Instrum. 81, 084301 (2010).
[Crossref] [PubMed]

Helmchen, F.

Hua, H.

Huang, C.

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

Huisken, J.

J. Huisken, J. Swoger, F. Del Benne, J. Wittbrodt, and E. H. K. Stelzer, “Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).
[Crossref] [PubMed]

Indebetouw, G.

Inglis, A.

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

Ji, N.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neuro. 19, 1154–1164 (2016).
[Crossref]

Keller, P. J.

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Meth. 10, 413–420 (2013).
[Crossref]

Kerlin, A.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Koyama, M.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Kuehn, S.

Z. Frentz, S. Kuehn, D. Hekstra, and S. Leibler, “Microbial population dynamics by digital in-line holographic microscopy,” Rev. Sci. Instrum. 81, 084301 (2010).
[Crossref] [PubMed]

Leibler, S.

Z. Frentz, S. Kuehn, D. Hekstra, and S. Leibler, “Microbial population dynamics by digital in-line holographic microscopy,” Rev. Sci. Instrum. 81, 084301 (2010).
[Crossref] [PubMed]

Levoy, M.

M. Levoy, “Light fields and computational imaging,” IEEE Comp. Soc.,  3945–55 (2006).
[Crossref]

Li, J. M.

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Meth. 10, 413–420 (2013).
[Crossref]

Li, J. Z. Z.

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

Liang, Y.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Llull, P.

Lu, R.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Lu, S.-H.

Luckhart, S.

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Manoharan, V. N.

A. Wang, R. F. Garmann, and V. N. Manoharan, “Tracking E. coli runs and tumbles with scattering solutions and digital holographic microscopy,” Optics Express 50, 23719–23725 (1960).

McCarthy, N.

Memmolo, P.

Mertz, J.

Miccio, L.

Mohar, B.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Mudanyali, O.

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Nayar, S. K.

M. Watanabe and S. K. Nayar, “Rational filters for passive depth from defocus,” Int. J. Comp. Vision 27, 203–225 (1998).
[Crossref]

Netti, P. A.

Orger, M. B.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Meth. 10, 413–420 (2013).
[Crossref]

Ozcan, A.

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Paturzo, M.

Pawley, J. E.

J. E. Pawley, Handbook of Biological Confocal Microscopy, 3rd. Ed. (Springer, 2006).
[Crossref]

Piché, M.

Reimer, J.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Robson, D. N.

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Meth. 10, 413–420 (2013).
[Crossref]

Roe, D. L.

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

Rosene, D. L.

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

Roson, M. R.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Schnitzer, M. J.

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

Scholl, B.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Seelig, J. D.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Shain, W. J.

Sikora, U.

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Smith, S. L.

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neuro. 19, 1154–1164 (2016).
[Crossref]

Stanley, H. E.

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

Stelzer, E. H. K.

J. Huisken, J. Swoger, F. Del Benne, J. Wittbrodt, and E. H. K. Stelzer, “Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).
[Crossref] [PubMed]

Stone, H. A.

T. H. Chen, J. T. Ault, H. A. Stone, and C. B. Arnold, “High-speed axial-scanning wide-field microscopy for volumetric particle tracking velocimetry,” Exp. Fluids 58, 1–7 (2017).
[Crossref]

Su, T.-W.

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Sun, W.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Swoger, J.

J. Huisken, J. Swoger, F. Del Benne, J. Wittbrodt, and E. H. K. Stelzer, “Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).
[Crossref] [PubMed]

Tanimoto, M.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Theis, L.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Tolias, A. S.

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Urbanc, B.

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

Usawa, S.

S. Abrahamsson, S. Usawa, and M. Gustafsson, “A new approach to extended focus for high-speed, high-resolution biological microscopy,” Proc. SPIE 6090, 60900N (2006).
[Crossref]

van ’t Hoff, M.

Vickers, N. A.

Voigt, F. F.

Wang, A.

A. Wang, R. F. Garmann, and V. N. Manoharan, “Tracking E. coli runs and tumbles with scattering solutions and digital holographic microscopy,” Optics Express 50, 23719–23725 (1960).

Watanabe, M.

M. Watanabe and S. K. Nayar, “Rational filters for passive depth from defocus,” Int. J. Comp. Vision 27, 203–225 (1998).
[Crossref]

Welford, W. T.

Wilson, D. E.

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Wittbrodt, J.

J. Huisken, J. Swoger, F. Del Benne, J. Wittbrodt, and E. H. K. Stelzer, “Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).
[Crossref] [PubMed]

Yaglidere, O.

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Yang, W.

W. Yang and R. Yuste, “In vivo imaging of neural activity,” Nat. Meth. 14, 349–359 (2017).
[Crossref]

Yuan, X.

Yuste, R.

W. Yang and R. Yuste, “In vivo imaging of neural activity,” Nat. Meth. 14, 349–359 (2017).
[Crossref]

Zhang, Y.

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

Adv. Opt. Photon. (1)

Appl. Opt. (3)

Biomed. Opt. Express (1)

Exp. Fluids (1)

T. H. Chen, J. T. Ault, H. A. Stone, and C. B. Arnold, “High-speed axial-scanning wide-field microscopy for volumetric particle tracking velocimetry,” Exp. Fluids 58, 1–7 (2017).
[Crossref]

IEEE Comp. Soc. (1)

M. Levoy, “Light fields and computational imaging,” IEEE Comp. Soc.,  3945–55 (2006).
[Crossref]

Int. J. Comp. Vision (1)

M. Watanabe and S. K. Nayar, “Rational filters for passive depth from defocus,” Int. J. Comp. Vision 27, 203–225 (1998).
[Crossref]

J. Microsc. (1)

A. Inglis, L. Cruz, D. L. Roe, H. E. Stanley, D. L. Rosene, and B. Urbanc, “Automated identification of neurons and their locations,” J. Microsc. 230, 339–352 (2008).
[Crossref] [PubMed]

J. Opt. Soc. Am. (1)

Lab Chip (1)

W. Bishara, U. Sikora, O. Mudanyali, T.-W. Su, O. Yaglidere, S. Luckhart, and A. Ozcan, “Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array,” Lab Chip 11, 1276–1279 (2011).
[Crossref] [PubMed]

Nat. Meth. (2)

W. Yang and R. Yuste, “In vivo imaging of neural activity,” Nat. Meth. 14, 349–359 (2017).
[Crossref]

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Meth. 10, 413–420 (2013).
[Crossref]

Nat. Neuro. (1)

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neuro. 19, 1154–1164 (2016).
[Crossref]

Nat. Neurosci. (1)

R. Lu, W. Sun, Y. Liang, A. Kerlin, J. Bierfeld, J. D. Seelig, D. E. Wilson, B. Scholl, B. Mohar, M. Tanimoto, M. Koyama, D. Fitzpatrick, M. B. Orger, and N. Ji, “Video-rate volumetric functional imaging of the brain at synaptic resolution,” Nat. Neurosci. 20, 620–628 (2017).
[Crossref] [PubMed]

Neuron (1)

L. Theis, P. Berens, E. Froudarakis, J. Reimer, M. R. Roson, T. Baden, T. Euler, A. S. Tolias, and M. Bethge, “Benchmarking Spike Rate Inference in Population Calcium Imaging,” Neuron 90, 471–482 (2016).
[Crossref] [PubMed]

Opt. Commun. (1)

G. Hausler, “A method to increase the depth of focus by two step image processing,” Opt. Commun. 6, 38–42 (1972).
[Crossref]

Opt. Express (1)

Opt. Lett. (1)

Optica (1)

Optics Express (1)

A. Wang, R. F. Garmann, and V. N. Manoharan, “Tracking E. coli runs and tumbles with scattering solutions and digital holographic microscopy,” Optics Express 50, 23719–23725 (1960).

Proc. SPIE (1)

S. Abrahamsson, S. Usawa, and M. Gustafsson, “A new approach to extended focus for high-speed, high-resolution biological microscopy,” Proc. SPIE 6090, 60900N (2006).
[Crossref]

Rev. Sci. Instrum. (1)

Z. Frentz, S. Kuehn, D. Hekstra, and S. Leibler, “Microbial population dynamics by digital in-line holographic microscopy,” Rev. Sci. Instrum. 81, 084301 (2010).
[Crossref] [PubMed]

Science (2)

J. Huisken, J. Swoger, F. Del Benne, J. Wittbrodt, and E. H. K. Stelzer, “Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).
[Crossref] [PubMed]

Y. Gong, C. Huang, J. Z. Z. Li, B. F. Grewe, Y. Zhang, S. Eismann, and M. J. Schnitzer, “High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor,” Science 350, 1361–1366 (2015).
[Crossref] [PubMed]

Other (2)

J. E. Pawley, Handbook of Biological Confocal Microscopy, 3rd. Ed. (Springer, 2006).
[Crossref]

M. Bertero and P. Boccacci, Introduction to Inverse Problems in Imaging (IOP Publishing, 1998).
[Crossref]

Supplementary Material (2)

NameDescription
» Visualization 1       Fluorescently-labeled E. Coli in water observed with 40x 0.8NA objective. Color corresponds to axial depth obtained by MI-EDOF.
» Visualization 2       Spontaneous activity of GCaMP-labeled neurons in mouse striatum. Two neurons overlap on another. Overlapping (middle) and non-overlapping (left/right) regions are highlighted. Scale bar is 20 microns. Frame rate is 2x real time.

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Figures (8)

Fig. 1
Fig. 1 Schematic for modulated-illumination EDOF system based on focal scanning with a deformable mirror. The illumination power is modulated with positive and negative ramps every other camera frame
Fig. 2
Fig. 2 EOTF (red) and MOTF (black) curves for a focal scan range of 60μm, as a function of spatial frequency normalized to the diffraction limit. Example regularization parameters (blue, purple) are shown for reference.
Fig. 3
Fig. 3 Verification of axial localization with an isolated 1μm bead (inset). Scale-bar is 5μm. Intensity of the bead as a function of stage position before (solid red) and after (solid black) deconvolution illustrates the range of the extended DOF of about 60μm. Axial localization of the bead before deconvolution (red) shows good agreement with the nominal stage position (dotted black) over the extended DOF (slope ≈ 0.8, r2 = 0.996). Axial localization with a single (blue) and double (black) parameter deconvolution shows improved axial accuracy (slope ≈ 0.9, r2 = 0.997).
Fig. 4
Fig. 4 Verification of axial localization with an extended cluster of 1μm beads (inset). Scale-bar is 5μm. Axial localization of the cluster before (red) deconvolution shows linearity but poor accuracy in estimating the axial position within the DOF, systematically underestimating deviations from Z = 0 (slope ≈ 0.4, r2 = 0.983). After applying deconvolution (blue) with a single regularization parameter the accuracy improves significantly (slope ≈ 0.8, r2 = 0.998). Two-parameter deconvolution (black) provides even higher accuracy (slope ≈ 0.9, r2 = 0.999) which extends even beyond the focal scan range of 60μm.
Fig. 5
Fig. 5 MI-EDOF images of 4μm beads embedded in PDMS acquired with a) fluorescence and b) darkfield imaging modes; scale bar is 50μm. Axial displacement from nominal focus is represented by the color axis (in units of microns). c) Comparison of the axial positions obtained in fluorescence and darkfield modes yields a linear fit of slope 1.02, and offset 3.2μm.
Fig. 6
Fig. 6 a) Cylindrospermum algae acquired with MI-EDOF in darkfield mode using a 20× 0.5NA Olympus objective. From the modulated-illumination image, two algae strands appear to overlap at two distinct points (A and B). b) Plots of the recorded axial location of each strand near point B reveal sharp variations that converge to a common axial location, indicative of an incorrect apparent co-localization of the strands. The convergence at point A occurs at much more slowly, suggesting the two strands are in fact co-localized at that point. c) Axial geometry is verified by an x–z projection obtained from an image stack, where we confirm that the strands are axially co-located point A but axially separated at point B. The different behaviors of axial plots about these points suggests that with prior information about the sample (such as continuity constraints), correct axial information can be inferred even in non-co-localized cases.
Fig. 7
Fig. 7 a–c) The monitoring of two E. Coli bacteria trajectories (obtained from a much larger FOV), with axial position represented by color. Bacteria are shown crossing the same lateral position but separated in height. d–e) 3D representations of the trajectories confirm height separation.
Fig. 8
Fig. 8 a) In-vivo MI-EDOF data from GCaMP-labeled neurons in a mouse striatum (three frames are shown from a video – see Visualization 2). Distinct neurons are observed (blue, green) in the indicated ROI that laterally overlap (purple); scalebar is 50μm. b,c) Intensity and depth variations are monitored simultaneously, facilitating the discrimination of neuronal activity. d1–3) MI-EDOF video frames show neurons firing either individually or together; scalebars are 20μm. e1–2) Intensity and depth of neurons firing almost simultaneously. f1–3) MI-EDOF video frames show near-simultaneous firing of neurons; scalebars are 20μm

Equations (18)

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M ± ( z s ) = 1 2 ± 1 D z s
I ˜ ± ( κ ) = 1 D D 2 D 2 d z s d z 0 M ± ( z s ) OTF ( κ ; z s z 0 ) O ˜ ( κ ; z 0 )
I ˜ Σ ( κ ) = I ˜ + ( κ ) + I ˜ ( κ ) I ˜ Δ ( κ ) = I ˜ + ( κ ) I ˜ ( κ )
I ˜ Σ ( κ ) = 1 D D 2 D 2 d z s d z 0 OTF ( κ ; z s z 0 ) O ˜ ( κ ; z 0 )
I ˜ Δ ( κ ) = 2 D 2 D 2 D 2 d z s d z 0 z s OTF ( κ ; z s z 0 ) O ˜ ( κ ; z 0 )
I ˜ Σ ( κ ) EOTF ( κ ; D ) d z 0 O ˜ ( κ ; z 0 )
EOTF ( κ ; D ) = 1 D D 2 D 2 d z OTF ( κ ; z )
d z 0 O ( ρ , z 0 ) = FT 1 { I ˜ Σ ( κ ) EOTF ( κ ; D ) }
I ˜ Δ ( κ ) = 2 D 2 d z 0 D 2 z 0 D 2 z 0 d z ( z 0 + z ) OTF ( κ ; z ) O ˜ ( κ ; z 0 )
D 2 z 0 D 2 z 0 d z z OTF ( κ ; z ) = ( D 2 D 2 z 0 D 2 z 0 D 2 ) d z z OTF ( κ ; z ) D z 0 OTF ( κ ; D 2 )
I ˜ Δ ( κ ) = 2 D MOTF ( κ ; D ) d z 0 z 0 O ˜ ( κ ; z 0 )
MOTF ( κ ; D ) = EOTF ( κ ; D ) OTF ( κ ; D 2 )
d z 0 z 0 O ( ρ , z 0 ) = D 2 FT 1 { I ˜ Δ ( κ ) MOTF ( κ ; D ) }
Z ( ρ ) = d z 0 z 0 O ( ρ , z 0 ) d z 0 O ( ρ , z 0 )
d z 0 O ( ρ , z 0 ) = FT 1 { I ˜ Σ ( κ ) EOTF * ( κ ; D ) | EOTF ( κ ; D ) | 2 + δ 2 }
d z 0 z 0 O ( ρ , z 0 ) = D 2 FT 1 { I ˜ Δ ( κ ) MOTF * ( κ ; D ) | MOTF ( κ ; D ) | 2 + δ 2 }
δ ( κ ) = { δ 1 ( κ > κ c ) δ 0 ( κ < κ c )
Z u ( ρ ) = D 2 I Δ ( ρ ) I Σ ( ρ )

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