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Multi-electrode array technologies for neuroscience and cardiology

Nature Nanotechnology volume 8, pages 83–94 (2013)Cite this article

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Abstract

At present, the prime methodology for studying neuronal circuit-connectivity, physiology and pathology under in vitro or in vivo conditions is by using substrate-integrated microelectrode arrays. Although this methodology permits simultaneous, cell-non-invasive, long-term recordings of extracellular field potentials generated by action potentials, it is 'blind' to subthreshold synaptic potentials generated by single cells. On the other hand, intracellular recordings of the full electrophysiological repertoire (subthreshold synaptic potentials, membrane oscillations and action potentials) are, at present, obtained only by sharp or patch microelectrodes. These, however, are limited to single cells at a time and for short durations. Recently a number of laboratories began to merge the advantages of extracellular microelectrode arrays and intracellular microelectrodes. This Review describes the novel approaches, identifying their strengths and limitations from the point of view of the end users — with the intention to help steer the bioengineering efforts towards the needs of brain-circuit research.

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Figure 1: Schematic layout depicting the spatial relationships between a neuron and a substrate-integrated electrode and the analogue passive electrical circuit.
Figure 2: Simulation of the contribution of individual electrical components to the neuron-electrode electrical coupling coefficient.
Figure 3: Dependency of the electrical coupling on the junctional membrane resistance and pulse duration.
Figure 4: Different forms of the electrode/neuron interface configuration.
Figure 5: Recently developed MEA devices record intracellular potential from excitable cells.
Figure 6: From extracellular field-potential recordings to intracellular recordings and the recovery process.

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References

  1. Hodgkin, A. L. & Huxley, A. F. Action potentials recorded from inside a nerve fibre. Nature 144, 710–711 (1939).

    Article  Google Scholar 

  2. Grundfest, H. The mechanisms of discharge of the electric organs in relation to general and comparative electrophysiology. Prog. Biophys. Biophys. Chem. 7, 1–85 (1957).

    Article  CAS  Google Scholar 

  3. Sakmann, B. & Neher, E. Patch clamp techniques for studying ionic channels in excitable membranes. Annu. Rev. Physiol. 46, 455–472 (1984).

    Article  CAS  Google Scholar 

  4. Verkhratsky, A., Krishtal, O. A. & Petersen, O. H. From Galvani to patch clamp: the development of electrophysiology. Pflugers Arch. 453, 233–247 (2006).

    Article  CAS  Google Scholar 

  5. Hutzler, M. et al. High-resolution multitransistor array recording of electrical field potentials in cultured brain slices. J. Neurophysiol. 96, 1638–1645 (2006).

    Article  CAS  Google Scholar 

  6. Eytan, D. & Marom, S. Dynamics and effective topology underlying synchronization in networks of cortical neurons. J. Neurosci. 26, 8465–8476 (2006).

    Article  CAS  Google Scholar 

  7. Berdondini, L. et al. Active pixel sensor array for high spatio-temporal resolution electrophysiological recordings from single cell to large scale neuronal networks. Lab Chip 9, 2644–2651 (2009).

    Article  CAS  Google Scholar 

  8. Frey, U., Egert, U., Heer, F., Hafizovic, S. & Hierlemann, A. Microelectronic system for high-resolution mapping of extracellular electric fields applied to brain slices. Biosens. Bioelectron. 24, 2191–2198 (2009).

    Article  CAS  Google Scholar 

  9. Hochberg, L. R. et al. Neuronal ensemble control of prosthetic devices by a human with tetraplegia. Nature 442, 164–171 (2006).

    Article  CAS  Google Scholar 

  10. Blanche, T. J., Spacek, M. A., Hetke, J. F. & Swindale, N. V. Polytrodes: high-density silicon electrode arrays for large-scale multiunit recording. J. Neurophysiol. 93, 2987–3000 (2005).

    Article  Google Scholar 

  11. Buzsaki, G., Anastassiou, C. A. & Koch, C. The origin of extracellular fields and currents — EEG, ECoG, LFP and spikes. Nature Rev. Neurosci. 13, 407–420 (2012).

    Article  CAS  Google Scholar 

  12. Shoham, S., O'Connor, D. H. & Segev, R. How silent is the brain: is there a “dark matter” problem in neuroscience? J. Comp. Physiol. 192, 777–784 (2006).

    Article  Google Scholar 

  13. Mayford, M., Siegelbaum, S. A. & Kandel, E. R. Synapses and memory storage. Cold Spring Harb. Perspect. Biol. 4, a005751 (2012).

    Article  CAS  Google Scholar 

  14. Thomas, C. A. Jr, Springer, P. A., Loeb, G. E., Berwald-Netter, Y. & Okun, L. M. A miniature microelectrode array to monitor the bioelectric activity of cultured cells. Exp. Cell Res. 74, 61–66 (1972).

    Article  Google Scholar 

  15. Gross, G. W., Williams, A. N. & Lucas, J. H. Recording of spontaneous activity with photoetched microelectrode surfaces from mouse spinal neurons in culture. J. Neurosci. Methods 5, 13–22 (1982).

    Article  CAS  Google Scholar 

  16. Regehr, W. G., Pine, J., Cohan, C. S., Mischke, M. D. & Tank, D. W. Sealing cultured invertebrate neurons to embedded dish electrodes facilitates long-term stimulation and recording. J. Neurosci. Methods 30, 91–106 (1989).

    Article  CAS  Google Scholar 

  17. Connolly, P., Clark, P., Curtis, A. S., Dow, J. A. & Wilkinson, C. D. An extracellular microelectrode array for monitoring electrogenic cells in culture. Biosens. Bioelectron. 5, 223–234 (1990).

    Article  CAS  Google Scholar 

  18. Nam, Y. & Wheeler, B. C. In vitro microelectrode array technology and neural recordings. Crit. Rev. Biomed. Eng. 39, 45–61 (2011).

    Article  Google Scholar 

  19. Huys, R. et al. Single-cell recording and stimulation with a 16k micro-nail electrode array integrated on a 0.18 μm CMOS chip. Lab Chip 12, 1274–1280 (2012).

    Article  CAS  Google Scholar 

  20. Schwartz, A. B. Cortical neural prosthetics. Annu. Rev. Neurosci. 27, 487–507 (2004).

    Article  CAS  Google Scholar 

  21. Fee, M. S., Mitra, P. P. & Kleinfeld, D. Automatic sorting of multiple unit neuronal signals in the presence of anisotropic and non-Gaussian variability. J. Neurosci. Methods 69, 175–188 (1996).

    Article  CAS  Google Scholar 

  22. Brown, E. N., Kass, R. E. & Mitra, P. P. Multiple neural spike train data analysis: state-of-the-art and future challenges. Nature Neurosci. 7, 456–461 (2004).

    Article  CAS  Google Scholar 

  23. Kauer, J. S., Senseman, D. M. & Cohen, L. B. Odor-elicited activity monitored simultaneously from 124 regions of the salamander olfactory bulb using a voltage-sensitive dye. Brain Res. 418, 255–261 (1987).

    Article  CAS  Google Scholar 

  24. Siegel, M. S. & Isacoff, E. Y. A genetically encoded optical probe of membrane voltage. Neuron 19, 735–741 (1997).

    Article  CAS  Google Scholar 

  25. Shoham, D. et al. Imaging cortical dynamics at high spatial and temporal resolution with novel blue voltage-sensitive dyes. Neuron 24, 791–802 (1999).

    Article  CAS  Google Scholar 

  26. Kralj, J. M., Douglass, A. D., Hochbaum, D. R., Maclaurin, D. & Cohen, A. E. Optical recording of action potentials in mammalian neurons using a microbial rhodopsin. Nature Methods 9, 90–95 (2012).

    Article  CAS  Google Scholar 

  27. Loew, L. M., Cohen, L. B., Salzberg, B. M., Obaid, A. L. & Bezanilla, F. Charge-shift probes of membrane potential. Characterization of aminostyrylpyridinium dyes on the squid giant axon. Biophys. J. 47, 71–77 (1985).

    Article  CAS  Google Scholar 

  28. Stosiek, C., Garaschuk, O., Holthoff, K. & Konnerth, A. In vivo two-photon calcium imaging of neuronal networks. Proc. Natl Acad. Sci. USA 100, 7319–7324 (2003).

    Article  CAS  Google Scholar 

  29. Higley, M. J. & Sabatini, B. L. Calcium signaling in dendrites and spines: practical and functional considerations. Neuron 59, 902–913 (2008).

    Article  CAS  Google Scholar 

  30. Rothschild, G., Nelken, I. & Mizrahi, A. Functional organization and population dynamics in the mouse primary auditory cortex. Nature Neurosci. 13, 353–360 (2010).

    Article  CAS  Google Scholar 

  31. Grinvald, A., Lieke, E., Frostig, R. D., Gilbert, C. D. & Wiesel, T. N. Functional architecture of cortex revealed by optical imaging of intrinsic signals. Nature 324, 361–364 (1986).

    Article  CAS  Google Scholar 

  32. Nagel, G. et al. Channelrhodopsin-1: a light-gated proton channel in green algae. Science 296, 2395–2398 (2002).

    Article  CAS  Google Scholar 

  33. Bernstein, J. G. & Boyden, E. S. Optogenetic tools for analyzing the neural circuits of behavior. Trends Cogn. Sci. 15, 592–600 (2011).

    Article  Google Scholar 

  34. Homma, R. et al. Wide-field and two-photon imaging of brain activity with voltage- and calcium-sensitive dyes. Phil. Trans. R. Soc. Lond. B 364, 2453–2467 (2009).

    Article  CAS  Google Scholar 

  35. Spatz, J. P. & Geiger, B. Molecular engineering of cellular environments: cell adhesion to nano-digital surfaces. Methods Cell Biol. 83, 89–111 (2007).

    Article  CAS  Google Scholar 

  36. Rutten, W. L. Selective electrical interfaces with the nervous system. Annu. Rev. Biomed. Eng. 4, 407–452 (2002).

    Article  CAS  Google Scholar 

  37. Fromherz, P. Three levels of neuroelectronic interfacing: silicon chips with ion channels, nerve cells, and brain tissue. Ann. NY Acad. Sci. 1093, 143–160 (2006).

    Article  CAS  Google Scholar 

  38. Jones, I. L. et al. The potential of microelectrode arrays and microelectronics for biomedical research and diagnostics. Anal. Bioanal. Chem. 399, 2313–2329 (2011).

    Article  CAS  Google Scholar 

  39. Bershadsky, A. D., Balaban, N. Q. & Geiger, B. Adhesion-dependent cell mechanosensitivity. Annu. Rev. Cell Dev. Biol. 19, 677–695 (2003).

    Article  CAS  Google Scholar 

  40. Wrobel, G. et al. Transmission electron microscopy study of the cell-sensor interface. J. R. Soc. Interface 5, 213–222 (2008).

    Article  Google Scholar 

  41. Braun, D. & Fromherz, P. Fluorescence interference-contrast microscopy of cell adhesion on oxidized silicon. Appl. Phys. A 65, 341–348 (1997).

    Article  CAS  Google Scholar 

  42. Iwanaga, Y., Braun, D. & Fromherz, P. No correlation of focal contacts and close adhesion by comparing GFP-vinculin and fluorescence interference of Dil. Eur. Biophysics J. Biophysics Lett. 30, 17–26 (2001).

    Article  CAS  Google Scholar 

  43. Lambacher, A. & Fromherz, P. Luminescence of dye molecules on oxidized silicon and fluorescence interference contrast microscopy of biomembranes. J. Opt. Soc. Am. B 19, 1435–1453 (2002).

    Article  CAS  Google Scholar 

  44. Gleixner, R. & Fromherz, P. The extracellular electrical resistivity in cell adhesion. Biophys. J. 90, 2600–2611 (2006).

    Article  CAS  Google Scholar 

  45. Fromherz, P. in Neuroelectronic Interfacing: Semiconductor Chips with Ion Channels, Nerve Cells, and Brain (ed. Waser, P.) Ch. 32, 781–810 (Wiley, 2003).

    Google Scholar 

  46. Maccione, A. et al. Experimental investigation on spontaneously active hippocampal cultures recorded by means of high-density MEAs: analysis of the spatial resolution effects. Front. Neuroeng. 3, 1–12 (2010).

    Google Scholar 

  47. Buitenweg, J. R., Rutten, W. L. & Marani, E. Geometry-based finite-element modeling of the electrical contact between a cultured neuron and a microelectrode. IEEE Trans. Biomed. Eng. 50, 501–509 (2003).

    Article  Google Scholar 

  48. Pine, J. Recording action potentials from cultured neurons with extracellular microcircuit electrodes. J. Neurosci. Methods 2, 19–31 (1980).

    Article  CAS  Google Scholar 

  49. Oka, H., Shimono, K., Ogawa, R., Sugihara, H. & Taketani, M. A new planar multielectrode array for extracellular recording: application to hippocampal acute slice. J. Neurosci. Methods 93, 61–67 (1999).

    Article  CAS  Google Scholar 

  50. Grumet, A. E., Wyatt, J. L. Jr & Rizzo, J. F. 3rd Multi-electrode stimulation and recording in the isolated retina. J. Neurosci. Methods 101, 31–42 (2000).

    Article  CAS  Google Scholar 

  51. Kim, J. H., Kang, G., Nam, Y. & Choi, Y. K. Surface-modified microelectrode array with flake nanostructure for neural recording and stimulation. Nanotechnology 21, 85303 (2010).

    Article  CAS  Google Scholar 

  52. Bruggemann, D. et al. Nanostructured gold microelectrodes for extracellular recording from electrogenic cells. Nanotechnology 22, 265104 (2011).

    Article  CAS  Google Scholar 

  53. Shein, M. et al. Engineered neuronal circuits shaped and interfaced with carbon nanotube microelectrode arrays. Biomed. Microdevices 11, 495–501 (2009).

    Article  CAS  Google Scholar 

  54. Keefer, E. W., Botterman, B. R., Romero, M. I., Rossi, A. F. & Gross, G. W. Carbon nanotube coating improves neuronal recordings. Nature Nanotech. 3, 434–439 (2008).

    Article  CAS  Google Scholar 

  55. Akaike, N. & Harata, N. Nystatin perforated patch recording and its applications to analyses of intracellular mechanisms. Jpn. J. Physiol. 44, 433–473 (1994).

    Article  CAS  Google Scholar 

  56. Braeken, D. et al. Single-cell stimulation and electroporation using a novel 0.18 μ CMOS chip with subcellular-sized electrodes. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010, 6473–6476 (2010).

    Google Scholar 

  57. Xie, C., Lin, Z., Hanson, L., Cui, Y. & Cui, B. Intracellular recording of action potentials by nanopillar electroporation. Nature Nanotech. 7, 185–190 (2012).

    Article  CAS  Google Scholar 

  58. Hai, A. & Spira, M. E. On-chip electroporation, membrane repair dynamics and transient in-cell recordings by arrays of gold mushroom-shaped microelectrodes. Lab Chip 12, 2865–2873 (2012).

    Article  CAS  Google Scholar 

  59. Fendyur, A. & Spira, M. E. Toward on-chip, in-cell recordings from cultured cardiomyocytes by arrays of gold mushroom-shaped microelectrodes. Front. Neuroeng. 5, 21 (2012).

    Article  CAS  Google Scholar 

  60. Braeken, D. et al. Open-cell recording of action potentials using active electrode arrays. Lab Chip 12, 4397–4402 (2012).

    Article  CAS  Google Scholar 

  61. Spira, M. E. et al. Improved neuronal adhesion to the surface of electronic device by engulfment of protruding micro-nails fabricated on the chip surface. Transducers '07 and Eurosensors XXI 1247–1250 (IEEE, 2007).

  62. Hai, A. et al. Spine-shaped gold protrusions improve the adherence and electrical coupling of neurons with the surface of micro-electronic devices. J. R. Soc. Interface 6, 1153–1165 (2009).

    Article  CAS  Google Scholar 

  63. Hai, A. et al. Changing gears from chemical adhesion of cells to flat substrata toward engulfment of micro-protrusions by active mechanisms. J. Neural Eng. 6, 066009 (2009).

    Article  Google Scholar 

  64. Hai, A., Shappir, J. & Spira, M. E. Long-term, multisite, parallel, in-cell recording and stimulation by an array of extracellular microelectrodes. J. Neurophysiol. 104, 559–568 (2010).

    Article  CAS  Google Scholar 

  65. Hai, A., Shappir, J. & Spira, M. E. In-cell recordings by extracellular microelectrodes. Nature Methods 7, 200–202 (2010).

    Article  CAS  Google Scholar 

  66. Aderem, A. & Underhill, D. M. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17, 593–623 (1999).

    Article  CAS  Google Scholar 

  67. Hayashi, Y. & Majewska, A. K. Dendritic spine geometry: functional implication and regulation. Neuron 46, 529–532 (2005).

    Article  CAS  Google Scholar 

  68. May, R. C. & Machesky, L. M. Phagocytosis and the actin cytoskeleton. J. Cell Sci. 114, 1061–1077 (2001).

    CAS  Google Scholar 

  69. Cohen, A., Shappir, J., Yitzchaik, S. & Spira, M. E. Reversible transition of extracellular field potential recordings to intracellular recordings of action potentials generated by neurons grown on transistors. Biosensors Bioelectronics 23, 811–819 (2008).

    Article  CAS  Google Scholar 

  70. Fendyur, A., Mazurski, N., Shappir, J. & Spira, M. E. Formation of essential ultrastructural interface between cultured hippocampal cells and gold mushroom-shaped MEA — toward “IN-CELL” recordings from vertebrate neurons. Front. Neuroeng. 4, 14 (2011).

    Article  Google Scholar 

  71. Robinson, J. T. et al. Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits. Nature Nanotech. 7, 180–184 (2012).

    Article  CAS  Google Scholar 

  72. Schoen, I. & Fromherz, P. Extracellular stimulation of mammalian neurons through repetitive activation of Na+ channels by weak capacitive currents on a silicon chip. J. Neurophysiol. 100, 346–357 (2008).

    Article  Google Scholar 

  73. Hofmann, B., Katelhon, E., Schottdorf, M., Offenhausser, A. & Wolfrum, B. Nanocavity electrode array for recording from electrogenic cells. Lab Chip 11, 1054–1058 (2011).

    Article  CAS  Google Scholar 

  74. Almquist, B. D. & Melosh, N. A. Fusion of biomimetic stealth probes into lipid bilayer cores. Proc. Natl Acad. Sci. USA 107, 5815–5820 (2010).

    Article  Google Scholar 

  75. Almquist, B. D. & Melosh, N. A. Molecular structure influences the stability of membrane penetrating biointerfaces. Nano Lett. 11, 2066–2070 (2011).

    Article  CAS  Google Scholar 

  76. Almquist, B. D., Verma, P., Cai, W. & Melosh, N. A. Nanoscale patterning controls inorganic-membrane interface structure. Nanoscale 3, 391–400 (2011).

    Article  CAS  Google Scholar 

  77. Tian, B. et al. Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. Science 329, 830–834 (2010).

    Article  CAS  Google Scholar 

  78. Duan, X. et al. Intracellular recordings of action potentials by an extracellular nanoscale field-effect transistor. Nature Nanotech. 7, 174–179 (2012).

    Article  CAS  Google Scholar 

  79. Huys, R. et al. A novel 16k micro-nail CMOS-chip for in-vitro single-cell recording, stimulation and impedance measurements. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010, 2726–2729 (2010).

    Google Scholar 

  80. Doherty, G. J. & McMahon, H. T. Mechanisms of endocytosis. Annu. Rev. Biochem. 78, 857–902 (2009).

    Article  CAS  Google Scholar 

  81. Cohen-Karni, T., Timko, B. P., Weiss, L. E. & Lieber, C. M. Flexible electrical recording from cells using nanowire transistor arrays. Proc. Natl Acad. Sci. USA 106, 7309–7313 (2009).

    Article  Google Scholar 

  82. Sadiku, M. N. O. Elements of Electromagnetics (Oxford Univ. Press, 2000).

    Google Scholar 

  83. Tian, B. & Lieber, C. M. Design, synthesis, and characterization of novel nanowire structures for photovoltaics and intracellular probes. Pure Appl. Chem. 83, 2153–2169 (2011).

    Article  CAS  Google Scholar 

  84. Gao, R. et al. Outside looking in: nanotube transistor intracellular sensors. Nano Lett. 12, 3329–3333 (2012).

    Article  CAS  Google Scholar 

  85. Ionescu-Zanetti, C. et al. Mammalian electrophysiology on a microfluidic platform. Proc. Natl Acad. Sci. USA 102, 9112–9117 (2005).

    Article  CAS  Google Scholar 

  86. Lau, A. Y., Hung, P. J., Wu, A. R. & Lee, L. P. Open-access microfluidic patch-clamp array with raised lateral cell trapping sites. Lab Chip 6, 1510–1515 (2006).

    Article  CAS  Google Scholar 

  87. Martina, M. et al. Recordings of cultured neurons and synaptic activity using patch-clamp chips. J. Neural Eng. 8, 034002 (2011).

    Article  Google Scholar 

  88. Abidi, A. A. High-frequency noise measurements on FET's with small dimensions. Electron. Dev., IEEE Trans. on 33, 1801–1805 (1986).

    Article  Google Scholar 

  89. Voelker, M. & Fromherz, P. Nyquist noise of cell adhesion detected in a neuron-silicon transistor. Phys. Rev. Lett. 96, 228102 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

Spira's laboratory is currently supported by EU FP7 MERIDIAN Grant agreement no. 280778., EU FP7 Marie Curie ITG, Grant agreement no. 264872., and the Charles E. Smith and Prof. Elkes Laboratory for Collaborative Research in Psychobiology. A. Hai was supported by a scholarship from The Israel Council for Higher Education.

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  1. The Alexander Silberman Life Sciences Institute, and the Harvey M. Kruger Family Center for Nanoscience, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel

    Micha E. Spira & Aviad Hai

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Correspondence to Micha E. Spira.

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Spira, M., Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nature Nanotech 8, 83–94 (2013). https://doi.org/10.1038/nnano.2012.265

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