Abstract

Removal of complex aberrations at millisecond time scales over millimeters in distance in multiphoton laser scanning microscopy limits the total spatiotemporal imaging throughput for deep tissue imaging. Using a single low resolution deformable mirror and time multiplexing (TM) adaptive optics, we demonstrate video rate aberration correction (5 ms update rate for a single wavefront mask) for a complex heterogeneous distribution of refractive index differences through a depth of up to 1.1 mm and an extended imaging FOV of up to 0.8 mm, with up to 167% recovery of fluorescence intensity 335 µm from the center of the FOV. The proposed approach, termed raster adaptive optics (RAO), integrates image-based aberration retrieval and video rate removal of arbitrarily defined regions of dominant, spatially varied wavefronts. The extended FOV was achieved by demonstrating rapid recovery of up to 50 distinct wavefront masks at 500 ms update rates that increased imaging throughput by 2.3-fold. Because RAO only requires a single deformable mirror with image-based aberration retrieval, it can be directly implemented on a standard laser scanning multiphoton microscope.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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References

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2019 (1)

2018 (3)

F. Soldevila, V. Durán, P. Clemente, J. Lancis, and E. Tajahuerce, “Phase imaging by spatial wavefront sampling,” Optica 5(2), 164–174 (2018).
[Crossref]

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

T. Kamal, L. Yang, and W. M. Lee, “In situ retrieval and correction of aberrations in moldless lenses using Fourier ptychography,” Opt. Express 26(3), 2708–2719 (2018).
[Crossref]

2017 (3)

G. Follain, L. Mercier, N. Osmani, S. Harlepp, and J. G. Goetz, “Seeing is believing – multi-scale spatio-temporal imaging towards in vivo cell biology,” J. Cell Sci. 130(1), 23–38 (2017).
[Crossref]

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

J.-H. Park, L. Kong, Y. Zhou, and M. Cui, “Large-field-of-view imaging by multi-pupil adaptive optics,” Nat. Methods 14(6), 581–583 (2017).
[Crossref]

2016 (2)

N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, e14472 (2016).
[Crossref]

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neurosci. 19(9), 1154–1164 (2016).
[Crossref]

2015 (3)

2014 (1)

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

2013 (1)

2012 (1)

2011 (1)

Mikael J. Pittet and R. Weissleder, “Intravital Imaging,” Cell 147(5), 983–991 (2011).
[Crossref]

2010 (1)

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods 7(2), 141–147 (2010).
[Crossref]

2007 (1)

R. Niesner, V. Andresen, J. Neumann, H. Spiecker, and M. Gunzer, “The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging,” Biophys. J. 93(7), 2519–2529 (2007).
[Crossref]

2005 (1)

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref]

2003 (1)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref]

2002 (1)

M. J. Booth, M. A. A. Neil, R. Juškaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U. S. A. 99(9), 5788–5792 (2002).
[Crossref]

1996 (1)

K. Visscher, S. P. Gross, and S. M. Block, “Construction of multiple-beam optical traps with nanometer-resolution position sensing,” IEEE J. Sel. Top. Quantum Electron. 2(4), 1066–1076 (1996).
[Crossref]

Allen, W. E.

Alt, C.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Andalman, A. S.

Andresen, V.

R. Niesner, V. Andresen, J. Neumann, H. Spiecker, and M. Gunzer, “The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging,” Biophys. J. 93(7), 2519–2529 (2007).
[Crossref]

Barankov, R.

Beaulieu, D. R.

Beaurepaire, E.

Betzig, E.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods 7(2), 141–147 (2010).
[Crossref]

Bifano, T. G.

Block, S. M.

K. Visscher, S. P. Gross, and S. M. Block, “Construction of multiple-beam optical traps with nanometer-resolution position sensing,” IEEE J. Sel. Top. Quantum Electron. 2(4), 1066–1076 (1996).
[Crossref]

Booth, M. J.

M. J. Booth, M. A. A. Neil, R. Juškaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U. S. A. 99(9), 5788–5792 (2002).
[Crossref]

Bronner, M. E.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

Brüstle, A.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Bumstead, J. R.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Chung, J.

Clemente, P.

Cockburn, I. A.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Côté, D. C.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Cui, M.

J.-H. Park, L. Kong, Y. Zhou, and M. Cui, “Large-field-of-view imaging by multi-pupil adaptive optics,” Nat. Methods 14(6), 581–583 (2017).
[Crossref]

Culver, J. P.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Daria, V. R.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Débarre, D.

Deisseroth, K.

Denk, W.

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref]

Diezmann, A. V.

Durán, V.

Engerer, P.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

Flickinger, D.

N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, e14472 (2016).
[Crossref]

Follain, G.

G. Follain, L. Mercier, N. Osmani, S. Harlepp, and J. G. Goetz, “Seeing is believing – multi-scale spatio-temporal imaging towards in vivo cell biology,” J. Cell Sci. 130(1), 23–38 (2017).
[Crossref]

Freeman, J.

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neurosci. 19(9), 1154–1164 (2016).
[Crossref]

Gaus, K.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Gautam, V.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Gillespie, C.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Goetz, J. G.

G. Follain, L. Mercier, N. Osmani, S. Harlepp, and J. G. Goetz, “Seeing is believing – multi-scale spatio-temporal imaging towards in vivo cell biology,” J. Cell Sci. 130(1), 23–38 (2017).
[Crossref]

Gross, S. P.

K. Visscher, S. P. Gross, and S. M. Block, “Construction of multiple-beam optical traps with nanometer-resolution position sensing,” IEEE J. Sel. Top. Quantum Electron. 2(4), 1066–1076 (1996).
[Crossref]

Gunzer, M.

R. Niesner, V. Andresen, J. Neumann, H. Spiecker, and M. Gunzer, “The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging,” Biophys. J. 93(7), 2519–2529 (2007).
[Crossref]

Harlepp, S.

G. Follain, L. Mercier, N. Osmani, S. Harlepp, and J. G. Goetz, “Seeing is believing – multi-scale spatio-temporal imaging towards in vivo cell biology,” J. Cell Sci. 130(1), 23–38 (2017).
[Crossref]

Helmchen, F.

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref]

Horstmeyer, R.

Ji, N.

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neurosci. 19(9), 1154–1164 (2016).
[Crossref]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods 7(2), 141–147 (2010).
[Crossref]

Juškaitis, R.

M. J. Booth, M. A. A. Neil, R. Juškaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U. S. A. 99(9), 5788–5792 (2002).
[Crossref]

Kamal, T.

Kauvar, I.

Kim, C. K.

King, J.

N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, e14472 (2016).
[Crossref]

Kong, L.

J.-H. Park, L. Kong, Y. Zhou, and M. Cui, “Large-field-of-view imaging by multi-pupil adaptive optics,” Nat. Methods 14(6), 581–583 (2017).
[Crossref]

Kraft, A. W.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Lancis, J.

Lee, M. Y.

Lee, W. M.

T. Kamal, L. Yang, and W. M. Lee, “In situ retrieval and correction of aberrations in moldless lenses using Fourier ptychography,” Opt. Express 26(3), 2708–2719 (2018).
[Crossref]

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Lencioni, K. C.

Lew, M. D.

Li, J.

Li, Y. X.

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

Mahou, P.

Marshel, J. H.

Martinez, G. W.

Mercier, L.

G. Follain, L. Mercier, N. Osmani, S. Harlepp, and J. G. Goetz, “Seeing is believing – multi-scale spatio-temporal imaging towards in vivo cell biology,” J. Cell Sci. 130(1), 23–38 (2017).
[Crossref]

Mertz, J.

Milkie, D. E.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods 7(2), 141–147 (2010).
[Crossref]

Misgeld, T.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

Moerner, W. E.

Mumm, J.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

Neil, M. A. A.

M. J. Booth, M. A. A. Neil, R. Juškaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U. S. A. 99(9), 5788–5792 (2002).
[Crossref]

Neumann, J.

R. Niesner, V. Andresen, J. Neumann, H. Spiecker, and M. Gunzer, “The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging,” Biophys. J. 93(7), 2519–2529 (2007).
[Crossref]

Niesner, R.

R. Niesner, V. Andresen, J. Neumann, H. Spiecker, and M. Gunzer, “The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging,” Biophys. J. 93(7), 2519–2529 (2007).
[Crossref]

Osmani, N.

G. Follain, L. Mercier, N. Osmani, S. Harlepp, and J. G. Goetz, “Seeing is believing – multi-scale spatio-temporal imaging towards in vivo cell biology,” J. Cell Sci. 130(1), 23–38 (2017).
[Crossref]

Ou, X.

Park, J. J.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Park, J.-H.

J.-H. Park, L. Kong, Y. Zhou, and M. Cui, “Large-field-of-view imaging by multi-pupil adaptive optics,” Nat. Methods 14(6), 581–583 (2017).
[Crossref]

Paudel, H.

Pittet, Mikael J.

Mikael J. Pittet and R. Weissleder, “Intravital Imaging,” Cell 147(5), 983–991 (2011).
[Crossref]

Reisman, M. D.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Rosen, I. A.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Sadda, S. R.

Saxena, A.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

Schanne-Klein, M.-C.

Smith, S. L.

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neurosci. 19(9), 1154–1164 (2016).
[Crossref]

Sofroniew, N. J.

N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, e14472 (2016).
[Crossref]

Soldevila, F.

Spiecker, H.

R. Niesner, V. Andresen, J. Neumann, H. Spiecker, and M. Gunzer, “The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging,” Biophys. J. 93(7), 2519–2529 (2007).
[Crossref]

Svoboda, K.

N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, e14472 (2016).
[Crossref]

Tajahuerce, E.

Visscher, K.

K. Visscher, S. P. Gross, and S. M. Block, “Construction of multiple-beam optical traps with nanometer-resolution position sensing,” IEEE J. Sel. Top. Quantum Electron. 2(4), 1066–1076 (1996).
[Crossref]

Wang, K.

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

Webb, W. W.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref]

Weissleder, R.

Mikael J. Pittet and R. Weissleder, “Intravital Imaging,” Cell 147(5), 983–991 (2011).
[Crossref]

Wetzstein, G.

Williams, R. M.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref]

Wilson, T.

M. J. Booth, M. A. A. Neil, R. Juškaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U. S. A. 99(9), 5788–5792 (2002).
[Crossref]

Wright, P. W.

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Yang, C.

Yang, L.

Yang, S. J.

Young, N. P.

Zeng, J.

Zheng, G.

Zhou, Y.

J.-H. Park, L. Kong, Y. Zhou, and M. Cui, “Large-field-of-view imaging by multi-pupil adaptive optics,” Nat. Methods 14(6), 581–583 (2017).
[Crossref]

Zipfel, W. R.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref]

Biomed. Opt. Express (1)

Biophys. J. (1)

R. Niesner, V. Andresen, J. Neumann, H. Spiecker, and M. Gunzer, “The power of single and multibeam two-photon microscopy for high-resolution and high-speed deep tissue and intravital imaging,” Biophys. J. 93(7), 2519–2529 (2007).
[Crossref]

Cell (1)

Mikael J. Pittet and R. Weissleder, “Intravital Imaging,” Cell 147(5), 983–991 (2011).
[Crossref]

eLife (1)

N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, e14472 (2016).
[Crossref]

IEEE J. Sel. Top. Quantum Electron. (1)

K. Visscher, S. P. Gross, and S. M. Block, “Construction of multiple-beam optical traps with nanometer-resolution position sensing,” IEEE J. Sel. Top. Quantum Electron. 2(4), 1066–1076 (1996).
[Crossref]

J. Biophotonics (1)

Y. X. Li, V. Gautam, A. Brüstle, I. A. Cockburn, V. R. Daria, C. Gillespie, K. Gaus, C. Alt, and W. M. Lee, “Flexible polygon-mirror based laser scanning microscope platform for multiphoton in-vivo imaging,” J. Biophotonics 10(11), 1526–1537 (2017).
[Crossref]

J. Cell Sci. (1)

G. Follain, L. Mercier, N. Osmani, S. Harlepp, and J. G. Goetz, “Seeing is believing – multi-scale spatio-temporal imaging towards in vivo cell biology,” J. Cell Sci. 130(1), 23–38 (2017).
[Crossref]

Nat. Biotechnol. (1)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref]

Nat. Methods (4)

N. Ji, D. E. Milkie, and E. Betzig, “Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues,” Nat. Methods 7(2), 141–147 (2010).
[Crossref]

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods 2(12), 932–940 (2005).
[Crossref]

J.-H. Park, L. Kong, Y. Zhou, and M. Cui, “Large-field-of-view imaging by multi-pupil adaptive optics,” Nat. Methods 14(6), 581–583 (2017).
[Crossref]

K. Wang, D. E. Milkie, A. Saxena, P. Engerer, T. Misgeld, M. E. Bronner, J. Mumm, and E. Betzig, “Rapid adaptive optical recovery of optimal resolution over large volumes,” Nat. Methods 11(6), 625–628 (2014).
[Crossref]

Nat. Neurosci. (1)

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neurosci. 19(9), 1154–1164 (2016).
[Crossref]

Neurophotonics (1)

J. R. Bumstead, J. J. Park, I. A. Rosen, A. W. Kraft, P. W. Wright, M. D. Reisman, D. C. Côté, and J. P. Culver, “Designing a large field-of-view two-photon microscope using optical invariant analysis,” Neurophotonics 5(02), 1–20 (2018).
[Crossref]

Opt. Express (3)

Optica (4)

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

M. J. Booth, M. A. A. Neil, R. Juškaitis, and T. Wilson, “Adaptive aberration correction in a confocal microscope,” Proc. Natl. Acad. Sci. U. S. A. 99(9), 5788–5792 (2002).
[Crossref]

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Figures (5)

Fig. 1.
Fig. 1. Raster Adaptive Optics (RAO). The basic framework of Raster Adaptive Optics (RAO) lies in image segmentation, wavefront retrieval and sequential update of wavefront masks (W) for video rate imaging. a) Digital selection of raster lines along the y-axis for each TM- time multiplexing segment. b) i) describes the image-based AO metric (a gradient search algorithm) used to iterate towards optimizing the appropriate wavefront mask. b) ii) All the retrieved wavefront mask (W1-W5) are saved in memory before the scanning mirror resumes to scan the whole area along with multiple wavefront masks updated by the DM. c) illustrates that the segmentation can be extended to fill the back aperture of the objective to correct aberrations, especially those in the off-axis FOV, which is subject to higher amounts of LA.
Fig. 2.
Fig. 2. Implementing RAO using a triple scanning mirrors multiphoton microscope and removing SA. a) A deformable mirror (DM), a polygon scanning mirror (PM) and 2 galvo scanning mirrors (GM-y(t) for the slow axis and GM-TMx for FOV x-axis extension) are placed on the pupil plane, which is conjugated to the back focal plane of the objective. b) The acquired image frame of a fluorescent sample is segmented and c) the wavefront pattern projected by the DM is changed over time, corresponding to the SA at different time sequences of each segment (TM) during the scan. d) The degree of improvement in fluorescence intensity under low light (3–7% of full signal) after applying 10-segment RAO is assessed from images of 540 nm quantum dots titrated and dried on a microscope slide. e) Measurement of intensity improvement with increasing RAO segmentation of a rhodamine-stained kidney section off-axis (more than 100 µm from the center of the FOV) or on-axis (less than 100 µm from the center of the FOV), where the FOV size is 256 µm x 275 µm. Average aberration optimization time: b) 10 TMy – 220 sec, e) 1 TMy segment- 22 sec, 2 TMy segments- 44 sec, 5 TMy segments- 110 sec, 10 TMy segments- 220 sec. Total imaging time: b, e) 50 ms.
Fig. 3.
Fig. 3. Removing SAA in refractive index inhomogeneity ∼1.1 mm thick sample. a) Diagram of the experimental setup: 3 µm yellow-green fluorescent beads in solidified PDMS overlaid by a glass coverslip were imaged at various depths (d) with a 20x objective with an effective excitation NA of 0.5 immersed in glycerol. Inhomogeneity of the refractive indexes (n) within the PDMS sample, and at the glass/glycerol interface scatter emitted photons, inducing aberration that increase with axial depth of the imaging plane. b) shows maximum intensity Z-projections of (i) a representative whole FOV and time-multiplexing sections (TM) at 1 mm z-depth and (ii-ix) TMy2 sections taken at various sample depths before and after 5-segment RAO. Images displayed are normalized to the maximum intensity of the RAO images for visualization. c) Axial maximum intensity projections of individual beads (colored boxes in (b)) at various sample depths along the axial direction before and after 5-segment RAO and d) the corresponding cross section plots and wavefront masks of the beads in (c) subtracted from the SA masks from Fig. 2c. e) Improvements in the axial FWHM and fluorescence intensity normalized to the RAO intensity maxima as shown in (d) are measured. FWHM is measured by applying Gaussian fitting (R2 > 0.9) to the cross-section plots. Data are the means and standard deviations of n = 3 beads and scale bars shown are b) i) 50 µm, ii-ix) 25 µm and c) 5 µm. Average aberration optimization time: a-c) 110 sec. Total imaging time: a-c) 50 ms.
Fig. 4.
Fig. 4. Removing field-dependent LA and extending FOV. a) Diagram of the experimental setup: 1 µm Tetraspeck beads embedded in gelatin and overlaid by a layer of gelatin sandwiched between two glass coverslips are imaged under an objective in PBS immersion medium. Photons emitted from beads at the periphery of the FOV exhibit increased scattering from spherical LA differences in sample refractive indexes. b) Maximum intensity Z-projection of the Tetraspeck beads before and after 5-segment RAO correction and the corresponding Zernike masks (W) applied in each TMy segment. Insets: 9.5X magnification showing changes in fluorescence intensity before and after RAO correction. c) Axial FWHM and normalized fluorescence intensity measurements of beads taken from the first and last (Fig. 4(b), TMy1 and TMy5, respectively) segments before and after RAO correction. d) and e) Imaging of fixed and permeabilized human fibroblast cells treated with SYTOX Green nucleic acid stain. d) The imaging FOV is shifted across the x-axis (∼100 µm per FOV or TMx) of the sample from the current FOV (TMx0) by control of the galvo mirror until the limits of the extended FOV (800 µm) of the objective are reached. 5-segment RAO correction is performed at each FOV to obtain a map of (d, i) Zernike modes implemented on each segment and maximum intensity projection of the overlaid and aligned FOV (d, ii) before, (d, iii) after RAO correction and (d, iv) the fold change in fluorescence intensity. Insets show a 17X magnification of selected TM(x,y) segments in the (d, v and vi) left, (d, vii and viii) center and (d, ix and x) right of the full FOV, before and after RAO correction. e) 10X magnification of a cell in late anaphase (e, i) before and (e, ii) after RAO correction. Data are the means and standard deviations of n = 3 beads. The summed fluorescence intensity of images were increased by (b) 1.25X, (d) 2X or (e) 1.7X above the raw image for visualization and scale bars are (b) 25 µm, (b, inset) 10 µm, (d, ii and iii) 50 µm, (d, insets and e) 5 µm. Average aberration optimization time: b, c), e) 110 sec, d) 1100 sec. Total imaging time: b, c), e) 50 ms, d) 500 ms.
Fig. 5.
Fig. 5. The effect of segment symmetry on RAO segment correction. A section of the cardiac tissue was imaged (i) before and after (ii) 5 TMy segments or (iii) 2 TMx with 5 TMy segments. The Zernike modes retrieved for each TMx,y segment is displayed next to the RAO images and the degree of improvement in fluorescence intensity is mentioned below each RAO image. Average aberration optimization time: ii) 110 sec and iii) 220 sec. Total imaging time: 50 ms.

Equations (2)

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Optimization time for each TMy = n lines t y n w
I m a g i n g t i m e f o r e a c h T M y = ( n lines t y ) ( 1 )

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