Abstract

We demonstrate how optical coherence imaging techniques can detect intrinsic scattering changes that occur during action potentials in single neurons. Using optical coherence tomography (OCT), an increase in scattering intensity from neurons in the abdominal ganglion of Aplysia californica is observed following electrical stimulation of the connective nerve. In addition, optical coherence microscopy (OCM), with its superior transverse spatial resolution, is used to demonstrate a direct correlation between scattering intensity changes and membrane voltage in single cultured Aplysia bag cell neurons during evoked action potentials. While intrinsic scattering changes are small, OCT and OCM have potential use as tools in neuroscience research for non-invasive and non-contact measurement of neural activity without electrodes or fluorescent dyes. These techniques have many attractive features such as high sensitivity and deep imaging penetration depth, as well as high temporal and spatial resolution. This study demonstrates the first use of OCT and OCM to detect functionally-correlated optical scattering changes in single neurons.

© 2009 OSA

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2007 (2)

U. M. Rajagopalan and M. Tanifuji, “Functional optical coherence tomography reveals localized layer-specific activations in cat primary visual cortex in vivo,” Opt. Lett. 32(17), 2614–2616 (2007).
[CrossRef] [PubMed]

T. Akkin, C. Joo, and J. F. de Boer, “Depth-resolved measurement of transient structural changes during action potential propagation,” Biophys. J. 93(4), 1347–1353 (2007).
[CrossRef]

2006 (4)

2005 (3)

2004 (2)

2003 (3)

R. U. Maheswari, H. Takaoka, H. Kadono, R. Homma, and M. Tanifuji, “Novel functional imaging technique from brain surface with optical coherence tomography enabling visualization of depth resolved functional structure in vivo,” J. Neurosci. Methods 124(1), 83–92 (2003).
[CrossRef]

M. Lazebnik, D. L. Marks, K. Potgieter, R. Gillette, and S. A. Boppart, “Functional optical coherence tomography for detecting neural activity through scattering changes,” Opt. Lett. 28(14), 1218–1220 (2003).
[CrossRef]

B. H. Park, M. C. Pierce, B. Cense, and J. F. de Boer, “Real-time multi-functional optical coherence tomography,” Opt. Express 11(7), 782–793 (2003).
[CrossRef]

2002 (2)

M. A. Nicolelis and S. Ribeiro, “Multielectrode recordings: the next steps,” Curr. Opin. Neurobiol. 12(5), 602–606 (2002).
[CrossRef]

R. U. Maheswari, H. Takaoka, R. Homma, H. Kadono, and M. Tanifuji, “Implementation of optical coherence tomography (OCT) in visualization of functional structures of cat visual cortex,” Opt. Commun. 202(1-3), 47–54 (2002).
[CrossRef]

1997 (1)

1996 (1)

K. Holthoff and O. W. Witte, “Intrinsic optical signals in rat neocortical slices measured with near-infrared dark-field microscopy reveal changes in extracellular space,” J. Neurosci. 16(8), 2740–2749 (1996).
[PubMed]

1994 (1)

1991 (1)

R. A. Stepnoski, A. LaPorta, F. Raccuia-Behling, G. E. Blonder, R. E. Slusher, and D. Kleinfeld, “Noninvasive detection of changes in membrane potential in cultured neurons by light scattering,” Proc. Natl. Acad. Sci. U.S.A. 88(21), 9382–9386 (1991).
[CrossRef]

1985 (1)

D. Landowne, “Molecular motion underlying activation and inactivation of sodium channels in squid giant axons,” J. Membr. Biol. 88(2), 173–185 (1985).

1982 (1)

F. E. Dudek and A. Kossatz, “Conduction velocity and spike duration during afterdischarge in neuroendocrine bag cells of Aplysia,” J. Neurobiol. 13(4), 319–326 (1982).
[CrossRef]

1981 (1)

L. K. Kaczmarek and F. Strumwasser, “The expression of long lasting afterdischarge by isolated Aplysia bag cell neurons,” J. Neurosci. 1(6), 626–634 (1981).

1975 (1)

P. R. Harley, “A possible age-related decrement in the conduction velocity of Aplysia neuron R2,” Experientia 31(8), 901–902 (1975).
[CrossRef]

1972 (1)

L. B. Cohen, R. D. Keynes, and D. Landowne, “Changes in axon light scattering that accompany the action potential: current-dependent components,” J. Physiol. 224(3), 727–752 (1972).

1968 (1)

L. B. Cohen, R. D. Keynes, and B. Hille, “Light scattering and birefringence changes during nerve activity,” Nature 218(5140), 438–441 (1968).
[CrossRef]

1949 (1)

D. K. Hill and R. D. Keynes, “Opacity changes in stimulated nerve,” J. Physiol. 108, 278–281 (1949).
[PubMed]

Adler, D. C.

Aguirre, A. D.

Ahnelt, P.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Akkin, T.

T. Akkin, C. Joo, and J. F. de Boer, “Depth-resolved measurement of transient structural changes during action potential propagation,” Biophys. J. 93(4), 1347–1353 (2007).
[CrossRef]

T. Akkin, D. P. Dave, T. E. Milner, and H. Rylander Iii, “Detection of neural activity using phase-sensitive optical low-coherence reflectometry,” Opt. Express 12(11), 2377–2386 (2004).
[CrossRef]

Anger, E.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Baker, B. J.

B. J. Baker, E. K. Kosmidis, D. Vucinic, C. X. Falk, L. B. Cohen, M. Djurisic, and D. Zecevic, “Imaging brain activity with voltage- and calcium-sensitive dyes,” Cell. Mol. Neurobiol. 25(2), 245–282 (2005).
[CrossRef]

Bizheva, K.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Blonder, G. E.

R. A. Stepnoski, A. LaPorta, F. Raccuia-Behling, G. E. Blonder, R. E. Slusher, and D. Kleinfeld, “Noninvasive detection of changes in membrane potential in cultured neurons by light scattering,” Proc. Natl. Acad. Sci. U.S.A. 88(21), 9382–9386 (1991).
[CrossRef]

Boas, D. A.

Boppart, S. A.

Bouma, B. E.

Cense, B.

Chen, Y.

Chu, M. C.

Cohen, L. B.

B. J. Baker, E. K. Kosmidis, D. Vucinic, C. X. Falk, L. B. Cohen, M. Djurisic, and D. Zecevic, “Imaging brain activity with voltage- and calcium-sensitive dyes,” Cell. Mol. Neurobiol. 25(2), 245–282 (2005).
[CrossRef]

L. B. Cohen, R. D. Keynes, and D. Landowne, “Changes in axon light scattering that accompany the action potential: current-dependent components,” J. Physiol. 224(3), 727–752 (1972).

L. B. Cohen, R. D. Keynes, and B. Hille, “Light scattering and birefringence changes during nerve activity,” Nature 218(5140), 438–441 (1968).
[CrossRef]

Dasari, R. R.

Dave, D. P.

de Boer, J. F.

Devor, A.

Djurisic, M.

B. J. Baker, E. K. Kosmidis, D. Vucinic, C. X. Falk, L. B. Cohen, M. Djurisic, and D. Zecevic, “Imaging brain activity with voltage- and calcium-sensitive dyes,” Cell. Mol. Neurobiol. 25(2), 245–282 (2005).
[CrossRef]

Drexler, W.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Dudek, F. E.

F. E. Dudek and A. Kossatz, “Conduction velocity and spike duration during afterdischarge in neuroendocrine bag cells of Aplysia,” J. Neurobiol. 13(4), 319–326 (1982).
[CrossRef]

Duker, J. S.

Falk, C. X.

B. J. Baker, E. K. Kosmidis, D. Vucinic, C. X. Falk, L. B. Cohen, M. Djurisic, and D. Zecevic, “Imaging brain activity with voltage- and calcium-sensitive dyes,” Cell. Mol. Neurobiol. 25(2), 245–282 (2005).
[CrossRef]

Fang-Yen, C.

Feld, M. S.

Fujimoto, J. G.

George, J. S.

Gillette, R.

Harley, P. R.

P. R. Harley, “A possible age-related decrement in the conduction velocity of Aplysia neuron R2,” Experientia 31(8), 901–902 (1975).
[CrossRef]

Hee, M. R.

Hermann, B.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Hill, D. K.

D. K. Hill and R. D. Keynes, “Opacity changes in stimulated nerve,” J. Physiol. 108, 278–281 (1949).
[PubMed]

Hille, B.

L. B. Cohen, R. D. Keynes, and B. Hille, “Light scattering and birefringence changes during nerve activity,” Nature 218(5140), 438–441 (1968).
[CrossRef]

Holthoff, K.

K. Holthoff and O. W. Witte, “Intrinsic optical signals in rat neocortical slices measured with near-infrared dark-field microscopy reveal changes in extracellular space,” J. Neurosci. 16(8), 2740–2749 (1996).
[PubMed]

Homma, R.

R. U. Maheswari, H. Takaoka, H. Kadono, R. Homma, and M. Tanifuji, “Novel functional imaging technique from brain surface with optical coherence tomography enabling visualization of depth resolved functional structure in vivo,” J. Neurosci. Methods 124(1), 83–92 (2003).
[CrossRef]

R. U. Maheswari, H. Takaoka, R. Homma, H. Kadono, and M. Tanifuji, “Implementation of optical coherence tomography (OCT) in visualization of functional structures of cat visual cortex,” Opt. Commun. 202(1-3), 47–54 (2002).
[CrossRef]

Huber, R.

Izatt, J. A.

Joo, C.

T. Akkin, C. Joo, and J. F. de Boer, “Depth-resolved measurement of transient structural changes during action potential propagation,” Biophys. J. 93(4), 1347–1353 (2007).
[CrossRef]

Kaczmarek, L. K.

L. K. Kaczmarek and F. Strumwasser, “The expression of long lasting afterdischarge by isolated Aplysia bag cell neurons,” J. Neurosci. 1(6), 626–634 (1981).

Kadono, H.

R. U. Maheswari, H. Takaoka, H. Kadono, R. Homma, and M. Tanifuji, “Novel functional imaging technique from brain surface with optical coherence tomography enabling visualization of depth resolved functional structure in vivo,” J. Neurosci. Methods 124(1), 83–92 (2003).
[CrossRef]

R. U. Maheswari, H. Takaoka, R. Homma, H. Kadono, and M. Tanifuji, “Implementation of optical coherence tomography (OCT) in visualization of functional structures of cat visual cortex,” Opt. Commun. 202(1-3), 47–54 (2002).
[CrossRef]

Keynes, R. D.

L. B. Cohen, R. D. Keynes, and D. Landowne, “Changes in axon light scattering that accompany the action potential: current-dependent components,” J. Physiol. 224(3), 727–752 (1972).

L. B. Cohen, R. D. Keynes, and B. Hille, “Light scattering and birefringence changes during nerve activity,” Nature 218(5140), 438–441 (1968).
[CrossRef]

D. K. Hill and R. D. Keynes, “Opacity changes in stimulated nerve,” J. Physiol. 108, 278–281 (1949).
[PubMed]

Kleinfeld, D.

R. A. Stepnoski, A. LaPorta, F. Raccuia-Behling, G. E. Blonder, R. E. Slusher, and D. Kleinfeld, “Noninvasive detection of changes in membrane potential in cultured neurons by light scattering,” Proc. Natl. Acad. Sci. U.S.A. 88(21), 9382–9386 (1991).
[CrossRef]

Kosmidis, E. K.

B. J. Baker, E. K. Kosmidis, D. Vucinic, C. X. Falk, L. B. Cohen, M. Djurisic, and D. Zecevic, “Imaging brain activity with voltage- and calcium-sensitive dyes,” Cell. Mol. Neurobiol. 25(2), 245–282 (2005).
[CrossRef]

Kossatz, A.

F. E. Dudek and A. Kossatz, “Conduction velocity and spike duration during afterdischarge in neuroendocrine bag cells of Aplysia,” J. Neurobiol. 13(4), 319–326 (1982).
[CrossRef]

Landowne, D.

D. Landowne, “Molecular motion underlying activation and inactivation of sodium channels in squid giant axons,” J. Membr. Biol. 88(2), 173–185 (1985).

L. B. Cohen, R. D. Keynes, and D. Landowne, “Changes in axon light scattering that accompany the action potential: current-dependent components,” J. Physiol. 224(3), 727–752 (1972).

LaPorta, A.

R. A. Stepnoski, A. LaPorta, F. Raccuia-Behling, G. E. Blonder, R. E. Slusher, and D. Kleinfeld, “Noninvasive detection of changes in membrane potential in cultured neurons by light scattering,” Proc. Natl. Acad. Sci. U.S.A. 88(21), 9382–9386 (1991).
[CrossRef]

Lazebnik, M.

Maheswari, R. U.

R. U. Maheswari, H. Takaoka, H. Kadono, R. Homma, and M. Tanifuji, “Novel functional imaging technique from brain surface with optical coherence tomography enabling visualization of depth resolved functional structure in vivo,” J. Neurosci. Methods 124(1), 83–92 (2003).
[CrossRef]

R. U. Maheswari, H. Takaoka, R. Homma, H. Kadono, and M. Tanifuji, “Implementation of optical coherence tomography (OCT) in visualization of functional structures of cat visual cortex,” Opt. Commun. 202(1-3), 47–54 (2002).
[CrossRef]

Marks, D. L.

Milner, T. E.

Nelson, J. S.

Nicolelis, M. A.

M. A. Nicolelis and S. Ribeiro, “Multielectrode recordings: the next steps,” Curr. Opin. Neurobiol. 12(5), 602–606 (2002).
[CrossRef]

Owen, G. M.

Park, B. H.

Perry, B.

Pflug, R.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Pierce, M. C.

Popov, S.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Potgieter, K.

Povazay, B.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Qiu, P.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Raccuia-Behling, F.

R. A. Stepnoski, A. LaPorta, F. Raccuia-Behling, G. E. Blonder, R. E. Slusher, and D. Kleinfeld, “Noninvasive detection of changes in membrane potential in cultured neurons by light scattering,” Proc. Natl. Acad. Sci. U.S.A. 88(21), 9382–9386 (1991).
[CrossRef]

Rajagopalan, U. M.

Reitsamer, H.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Ribeiro, S.

M. A. Nicolelis and S. Ribeiro, “Multielectrode recordings: the next steps,” Curr. Opin. Neurobiol. 12(5), 602–606 (2002).
[CrossRef]

Ruvinskaya, L.

Rylander Iii, H.

Sattmann, H.

K. Bizheva, R. Pflug, B. Hermann, B. Povazay, H. Sattmann, P. Qiu, E. Anger, H. Reitsamer, S. Popov, J. R. Taylor, A. Unterhuber, P. Ahnelt, and W. Drexler, “Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography,” Proc. Natl. Acad. Sci. U.S.A. 103(13), 5066–5071 (2006).

Seung, H. S.

Slusher, R. E.

R. A. Stepnoski, A. LaPorta, F. Raccuia-Behling, G. E. Blonder, R. E. Slusher, and D. Kleinfeld, “Noninvasive detection of changes in membrane potential in cultured neurons by light scattering,” Proc. Natl. Acad. Sci. U.S.A. 88(21), 9382–9386 (1991).
[CrossRef]

Srinivasan, V. J.

Stepnoski, R. A.

R. A. Stepnoski, A. LaPorta, F. Raccuia-Behling, G. E. Blonder, R. E. Slusher, and D. Kleinfeld, “Noninvasive detection of changes in membrane potential in cultured neurons by light scattering,” Proc. Natl. Acad. Sci. U.S.A. 88(21), 9382–9386 (1991).
[CrossRef]

Strumwasser, F.

L. K. Kaczmarek and F. Strumwasser, “The expression of long lasting afterdischarge by isolated Aplysia bag cell neurons,” J. Neurosci. 1(6), 626–634 (1981).

Swanson, E. A.

Takaoka, H.

R. U. Maheswari, H. Takaoka, H. Kadono, R. Homma, and M. Tanifuji, “Novel functional imaging technique from brain surface with optical coherence tomography enabling visualization of depth resolved functional structure in vivo,” J. Neurosci. Methods 124(1), 83–92 (2003).
[CrossRef]

R. U. Maheswari, H. Takaoka, R. Homma, H. Kadono, and M. Tanifuji, “Implementation of optical coherence tomography (OCT) in visualization of functional structures of cat visual cortex,” Opt. Commun. 202(1-3), 47–54 (2002).
[CrossRef]

Tanifuji, M.

U. M. Rajagopalan and M. Tanifuji, “Functional optical coherence tomography reveals localized layer-specific activations in cat primary visual cortex in vivo,” Opt. Lett. 32(17), 2614–2616 (2007).
[CrossRef] [PubMed]

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Figures (6)

Fig. 1.
Fig. 1.

Schematic of a free-space spectral-domain OCT/OCM system. The output of the laser is split into the reference arm and the sample arm (region II). The combined reflections from the reference and sample arm are detected by the spectrometer (region I) giving a depth profile of the sample. The scanning mirrors move the beam across the sample to construct an image. (BS) beamsplitter, (M) mirror, (P) pinhole, (G) diffraction grating, (CCD) CCD line camera, (S) scanning mirrors, (O) objective.

Fig. 2.
Fig. 2.

Depth-resolved optical scattering changes over time from a single neuron in vitro. (A) Stereo microscope view of the Aplysia abdominal ganglion. (B,D) B-mode OCT images acquired from the ganglion. Orientation of B-mode images is shown by the red lines in (A). Numbers indicate specific neurons seen in the microscope image and the OCT images. (C) M-mode image showing the scattering over time from one position of the B-mode image, as indicated by the red arrow in (B).

Fig. 3.
Fig. 3.

M-mode image from a point on the in situ R14 cell during stimulation of the ganglion. Blue trace overlaying the M-mode image shows the action potential recorded by the electrode. An increase in scattering after the action potential from one depth is indicated by the black oval.

Fig. 4.
Fig. 4.

En face OCM image of a single cultured Aplysia bag cell neuron. The high transverse resolution offered by OCM allows individual cells to be imaged at high resolution. The red arrow points to the axon hillock, the location of M-mode image acquisition.

Fig. 5.
Fig. 5.

M-mode scattering image and membrane voltage of a single bag cell neuron in culture during a train of stimulation pulses. Beam was positioned over the axon hillock of the neuron. Stimulation of the neuron causes an increase in the scattering intensity from the cell membrane.

Fig. 6.
Fig. 6.

Comparison between membrane voltage and scattering intensity of a neuron during a single action potential. (A) M-mode scattering image. The top surface of the neuron is indicated by position 1 while reflection from the culture dish is seen at position 2. An increase in scattering from the neuron corresponding to the action potential is indicated by the blue arrow. (B) Membrane voltage and scattering from the neuron surface for a single stimulation. Scattering intensity is shown to closely follow the time course of the membrane voltage. The blue and green traces correspond to the voltage and optical scattering signals, respectively. (C) M-mode scattering image from same neuron without stimulation.

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