Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Multifunctional fibers for simultaneous optical, electrical and chemical interrogation of neural circuits in vivo

Subjects

Abstract

Brain function depends on simultaneous electrical, chemical and mechanical signaling at the cellular level. This multiplicity has confounded efforts to simultaneously measure or modulate these diverse signals in vivo. Here we present fiber probes that allow for simultaneous optical stimulation, neural recording and drug delivery in behaving mice with high resolution. These fibers are fabricated from polymers by means of a thermal drawing process that allows for the integration of multiple materials and interrogation modalities into neural probes. Mechanical, electrical, optical and microfluidic measurements revealed high flexibility and functionality of the probes under bending deformation. Long-term in vivo recordings, optogenetic stimulation, drug perturbation and analysis of tissue response confirmed that our probes can form stable brain-machine interfaces for at least 2 months. We expect that our multifunctional fibers will permit more detailed manipulation and analysis of neural circuits deep in the brain of behaving animals than achievable before.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Multimodality fiber probe fabrication and characterization.
Figure 2: Multimodality probes allow for chronic implantation; single-unit resolution; and simultaneous electrophysiological recording, optogenetic stimulation and drug delivery.
Figure 3: Multielectrode fiber probe fabrication and characterization.
Figure 4: Tissue response to the multielectrode fiber probes.

Similar content being viewed by others

References

  1. Holtmaat, A. & Svoboda, K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat. Rev. Neurosci. 10, 647–658 (2009).

    Article  CAS  Google Scholar 

  2. Gradinaru, V., Mogri, M., Thompson, K.R., Henderson, J.M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).

    Article  CAS  Google Scholar 

  3. Zhang, F., Aravanis, A.M., Adamantidis, A., de Lecea, L. & Deisseroth, K. Circuit-breakers: optical technologies for probing neural signals and systems. Nat. Rev. Neurosci. 8, 577–581 (2007).

    Article  CAS  Google Scholar 

  4. Ramirez, S. et al. Creating a false memory in the hippocampus. Science 341, 387–391 (2013).

    Article  CAS  Google Scholar 

  5. Znamenskiy, P. & Zador, A.M. Corticostriatal neurons in auditory cortex drive decisions during auditory discrimination. Nature 497, 482–485 (2013).

    Article  CAS  Google Scholar 

  6. Kravitz, A.V., Tye, L.D. & Kreitzer, A.C. Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat. Neurosci. 15, 816–818 (2012).

    Article  CAS  Google Scholar 

  7. Anikeeva, P. et al. Optetrode: a multichannel readout for optogenetic control in freely moving mice. Nat. Neurosci. 15, 163–170 (2012).

    Article  CAS  Google Scholar 

  8. Rubehn, B., Wolff, S.B., Tovote, P., Luthi, A. & Stieglitz, T. A polymer-based neural microimplant for optogenetic applications: design and first in vivo study. Lab Chip 13, 579–588 (2013).

    Article  CAS  Google Scholar 

  9. Zhang, J. et al. Integrated device for optical stimulation and spatiotemporal electrical recording of neural activity in light-sensitized brain tissue. J. Neural Eng. 6, 055007 (2009).

    Article  Google Scholar 

  10. Campbell, P.K., Jones, K.E., Huber, R.J., Horch, K.W. & Normann, R.A. A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array. IEEE Trans. Biomed. Eng. 38, 758–768 (1991).

    Article  CAS  Google Scholar 

  11. Jog, M.S. et al. Tetrode technology: advances in implantable hardware, neuroimaging, and data analysis techniques. J. Neurosci. Methods 117, 141–152 (2002).

    Article  CAS  Google Scholar 

  12. Kennedy, P.R. The cone electrode: a long-term electrode that records from neurites grown onto its recording surface. J. Neurosci. Methods 29, 181–193 (1989).

    Article  CAS  Google Scholar 

  13. McNaughton, B.L., O'Keefe, J. & Barnes, C.A. The stereotrode: a new technique for simultaneous isolation of several single units in the central nervous system from multiple unit records. J. Neurosci. Methods 8, 391–397 (1983).

    Article  CAS  Google Scholar 

  14. Seymour, J.P., Langhals, N.B., Anderson, D.J. & Kipke, D.R. Novel multi-sided, microelectrode arrays for implantable neural applications. Biomed. Microdevices 13, 441–451 (2011).

    Article  Google Scholar 

  15. Borschel, G.H., Kia, K.F., Kuzon, W.M. & Dennis, R.G. Mechanical properties of acellular peripheral nerve. J. Surg. Res. 114, 133–139 (2003).

    Article  Google Scholar 

  16. Green, M.A., Bilston, L.E. & Sinkus, R. In vivo brain viscoelastic properties measured by magnetic resonance elastography. NMR Biomed. 21, 755–764 (2008).

    Article  Google Scholar 

  17. Ward, M.P., Rajdev, P., Ellison, C. & Irazoqui, P.P. Toward a comparison of microelectrodes for acute and chronic recordings. Brain Res. 1282, 183–200 (2009).

    Article  CAS  Google Scholar 

  18. Polikov, V.S., Tresco, P.A. & Reichert, W.M. Response of brain tissue to chronically implanted neural electrodes. J. Neurosci. Methods 148, 1–18 (2005).

    Article  Google Scholar 

  19. Saxena, T. et al. The impact of chronic blood–brain barrier breach on intracortical electrode function. Biomaterials 34, 4703–4713 (2013).

    Article  CAS  Google Scholar 

  20. Seymour, J.P. & Kipke, D.R. Neural probe design for reduced tissue encapsulation in CNS. Biomaterials 28, 3594–3607 (2007).

    Article  CAS  Google Scholar 

  21. Lee, H., Bellamkonda, R.V., Sun, W. & Levenston, M.E. Biomechanical analysis of silicon microelectrode-induced strain in the brain. J. Neural Eng. 2, 81–89 (2005).

    Article  Google Scholar 

  22. Kim, D.H. et al. Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics. Nat. Mater. 9, 511–517 (2010).

    Article  CAS  Google Scholar 

  23. Kuo, J.T.W. et al. Novel flexible Parylene neural probe with 3D sheath structure for enhancing tissue integration. Lab Chip 13, 554–561 (2013).

    Article  CAS  Google Scholar 

  24. Minev, I.R., Moshayedi, P., Fawcett, J.W. & Lacour, S.P. Interaction of glia with a compliant, microstructured silicone surface. Acta Biomater. 9, 6936–6942 (2013).

    Article  CAS  Google Scholar 

  25. Takeuchi, S., Suzuki, T., Mabuchi, K. & Fujita, H. 3D flexible multichannel neural probe array. J. Micromech. Microeng. 14, 104–107 (2004).

    Article  Google Scholar 

  26. Goff, D.R. Fiber Optic Reference Guide: a Practical Guide to Communications Technology (Focal Press, 2002).

  27. Yaman, M. et al. Arrays of indefinitely long uniform nanowires and nanotubes. Nat. Mater. 10, 494–501 (2011).

    Article  CAS  Google Scholar 

  28. LeChasseur, Y. et al. A microprobe for parallel optical and electrical recordings from single neurons in vivo . Nat. Methods 8, 319–325 (2011).

    Article  CAS  Google Scholar 

  29. Abouraddy, A.F. et al. Towards multimaterial multifunctional fibres that see, hear, sense and communicate. Nat. Mater. 6, 336–347 (2007).

    Article  CAS  Google Scholar 

  30. Merolli, A. et al. Response to polyetherimide based composite materials implanted in muscle and in bone. J. Mater. Sci. Mater. Med. 10, 265–268 (1999).

    Article  CAS  Google Scholar 

  31. Yalon, M., Goldberg, E.P., Osborn, D., Stacholy, J. & Sheets, J.W. Polycarbonate intraocular lenses. J. Cataract Refract. Surg. 14, 393–395 (1988).

    Article  CAS  Google Scholar 

  32. Khanarian, G. & Celanese, H. Optical properties of cyclic olefin copolymers. Opt. Eng. 40, 1024–1029 (2001).

    Article  CAS  Google Scholar 

  33. Aden, M., Roesner, A. & Olowinsky, A. Optical characterization of polycarbonate: influence of additives on optical properties. J. Polym. Sci. B Polym. Phys. 48, 451–455 (2010).

    Article  CAS  Google Scholar 

  34. Tye, K.M. & Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat. Rev. Neurosci. 13, 251–266 (2012).

    Article  CAS  Google Scholar 

  35. Arenkiel, B.R. et al. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron 54, 205–218 (2007).

    Article  CAS  Google Scholar 

  36. Cardin, J.A. et al. Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of channelrhodopsin-2. Nat. Protoc. 5, 247–254 (2010).

    Article  CAS  Google Scholar 

  37. Schmitzer-Torbert, N., Jackson, J., Henze, D., Harris, K. & Redish, A.D. Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience 131, 1–11 (2005).

    Article  CAS  Google Scholar 

  38. Steenland, H.W., Liu, H. & Horner, R.L. Endogenous glutamatergic control of rhythmically active mammalian respiratory motoneurons in vivo . J. Neurosci. 28, 6826–6835 (2008).

    Article  CAS  Google Scholar 

  39. Kozai, T.D. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nat. Mater. 11, 1065–1073 (2012).

    Article  CAS  Google Scholar 

  40. Ferguson, J.E., Boldt, C. & Redish, A.D. Creating low-impedance tetrodes by electroplating with additives. Sens. Actuators A Phys. 156, 388–393 (2009).

    Article  CAS  Google Scholar 

  41. Williams, J.C., Hippensteel, J.A., Dilgen, J., Shain, W. & Kipke, D.R. Complex impedance spectroscopy for monitoring tissue responses to inserted neural implants. J. Neural Eng. 4, 410–423 (2007).

    Article  Google Scholar 

  42. Lind, G., Linsmeier, C.E. & Schouenborg, J. The density difference between tissue and neural probes is a key factor for glial scarring. Sci. Rep. 3, 2942 (2013).

    Article  Google Scholar 

  43. Prasad, A. et al. Comprehensive characterization and failure modes of tungsten microwire arrays in chronic neural implants. J. Neural Eng. 9, 056015 (2012).

    Article  Google Scholar 

  44. Woolley, A.J., Desai, H.A. & Otto, K.J. Chronic intracortical microelectrode arrays induce non-uniform, depth-related tissue responses. J. Neural Eng. 10, 026007 (2013).

    Article  Google Scholar 

  45. Karumbaiah, L. et al. Relationship between intracortical electrode design and chronic recording function. Biomaterials 34, 8061–8074 (2013).

    Article  CAS  Google Scholar 

  46. Yizhar, O., Fenno, L.E., Davidson, T.J., Mogri, M. & Deisseroth, K. Optogenetics in neural systems. Neuron 71, 9–34 (2011).

    Article  CAS  Google Scholar 

  47. Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).

    Article  CAS  Google Scholar 

  48. Chow, B.Y. et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 463, 98–102 (2010).

    Article  CAS  Google Scholar 

  49. Mattis, J. et al. Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. Nat. Methods 9, 159–172 (2012).

    Article  CAS  Google Scholar 

  50. Quian Quiroga, R., Nadasdy, Z. & Ben-Shaul, Y. Unsupervised spike detection and sorting with wavelets and superparamagnetic clustering. Neural Comput. 16, 1661–1687 (2004).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the National Science Foundation under a CAREER award to P.A. (CBET–1253890), the Center for Materials Science and Engineering (DMR-0819762), the Center for Sensorimotor Neural Engineering (EEC-1028725), the McGovern Institute for Brain Research, the US Army Research Laboratory and the US Army Research Office through the Institute for Soldier Nanotechnologies under contract number W911NF-13-D-0001, and a grant from the Simons Foundation to the Simons Center for the Social Brain at MIT. The authors are grateful to G. Feng for the generous donation of Thy1-ChR2-YFP mice, W. Jia and J. LaVine for initial help with microfluidic characterization and C. Moritz and L.H. Tsai for assistance with equipment.

Author information

Authors and Affiliations

Authors

Contributions

P.A., Y.F. and U.P.F. designed the study. X.J. and A.C. drew multifunctional and multielectrode fibers, respectively. X.J. and J.S. connectorized multimodality probes. A.C. and C.M.T. connectorized and characterized multielectrode probes. C.L., L.W., X.J., C.H. and J.S. evaluated optical properties. A.C., C.M.T. and X.J. obtained electrode impedance spectra. A.C. conducted mechanical tests. X.J. and U.P.F. performed microfluidic characterization. U.P.F., A.C., X.J. and P.A. performed in vivo experiments. R.A.K., U.P.F., A.C., J.S. and C.M.T. investigated tissue response. U.P.F., A.C., R.A.K., X.J., Y.F. and P.A. analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Polina Anikeeva.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16, Supplementary Table 1 and Supplementary References (PDF 20236 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Canales, A., Jia, X., Froriep, U. et al. Multifunctional fibers for simultaneous optical, electrical and chemical interrogation of neural circuits in vivo. Nat Biotechnol 33, 277–284 (2015). https://doi.org/10.1038/nbt.3093

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt.3093

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing