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:

Tapered fibertrodes for optoelectrical neural interfacing in small brain volumes with reduced artefacts

Nature Materials volume 21, pages 826–835 (2022)Cite this article

Subjects

Abstract

Deciphering the neural patterns underlying brain functions is essential to understanding how neurons are organized into networks. This deciphering has been greatly facilitated by optogenetics and its combination with optoelectronic devices to control neural activity with millisecond temporal resolution and cell type specificity. However, targeting small brain volumes causes photoelectric artefacts, in particular when light emission and recording sites are close to each other. We take advantage of the photonic properties of tapered fibres to develop integrated ‘fibertrodes’ able to optically activate small brain volumes with abated photoelectric noise. Electrodes are positioned very close to light emitting points by non-planar microfabrication, with angled light emission allowing the simultaneous optogenetic manipulation and electrical read-out of one to three neurons, with no photoelectric artefacts, in vivo. The unconventional implementation of two-photon polymerization on the curved taper edge enables the fabrication of recoding sites all around the implant, making fibertrodes a promising complement to planar microimplants.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Fabrication process.
Fig. 2: Electrical characterization and extracellular recordings.
Fig. 3: Light emission properties in quasi-transparent solutions and related Monte Carlo simulations in scattering brain tissue.
Fig. 4: Light-induced photoelectric noise in PBS.
Fig. 5: In vivo test of the fibertrode.
Fig. 6: Scalability of the 2PP-based patterning process.

Similar content being viewed by others

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding authors on reasonable request and are available in the Zenodo repository (https://doi.org/10.5281/zenodo.6477861). Data on the optrode fabrication and in vitro optical measurements are available from B.S., A.B., L.S., F. Pisanello and M.D.V. Data on the in vivo use of tapered fibres are available from B.S., R.T.P., B.L.S. and F. Pisanello.

Code availability

The scripts related to the Monte Carlo simulations used in the current study are available from the corresponding authors on reasonable request and are available in the Zenodo repository (https://doi.org/10.5281/zenodo.6477861).

References

  1. Camporeze, B. et al. Optogenetics: the new molecular approach to control functions of neural cells in epilepsy, depression and tumors of the central nervous system. Am. J. Cancer Res. 8, 1900–1918 (2018).

    CAS  Google Scholar 

  2. Grosenick, L., Marshel, J. H. & Deisseroth, K. Closed-loop and activity-guided optogenetic control. Neuron 86, 106–139 (2015).

    Article  CAS  Google Scholar 

  3. Segev, E. et al. Patterned photostimulation via visible-wavelength photonic probes for deep brain optogenetics. Neurophotonics 4, 11002 (2016).

    Article  Google Scholar 

  4. Zorzos, A. N., Boyden, E. S. & Fonstad, C. G. Multiwaveguide implantable probe for light delivery to sets of distributed brain targets. Opt. Lett. 35, 4133–4135 (2010).

    Article  Google Scholar 

  5. Wu, F. et al. An implantable neural probe with monolithically integrated dielectric waveguide and recording electrodes for optogenetics applications. J. Neural Eng. 10, 56012 (2013).

    Article  Google Scholar 

  6. Deubner, J., Coulon, P. & Diester, I. Optogenetic approaches to study the mammalian brain. Curr. Opin. Struct. Biol. 57, 157–163 (2019).

    Article  CAS  Google Scholar 

  7. Nakamura, T. et al. Increased intracellular Ca2+ concentration in the hippocampal CA1 area during global ischemia and reperfusion in the rat: a possible cause of delayed neuronal death. Neuroscience 88, 57–67 (1999).

    Article  CAS  Google Scholar 

  8. Bradley, P. M. J., Murphy, D., Kasparov, S., Croker, J. & Paton, J. F. R. A micro-optrode for simultaneous extracellular electrical and intracellular optical recording from neurons in an intact oscillatory neuronal network. J. Neurosci. Methods 168, 383–395 (2008).

    Article  CAS  Google Scholar 

  9. 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 

  10. 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 

  11. Kim, E. G. R. et al. 3D silicon neural probe with integrated optical fibers for optogenetic modulation. Lab Chip 15, 2939–2949 (2015).

    Article  CAS  Google Scholar 

  12. Sileo, L. et al. Tapered fibers combined with a multi-electrode array for optogenetics in mouse medial prefrontal cortex. Front. Neurosci. https://doi.org/10.3389/fnins.2018.00771 (2018).

  13. Kozai, T. D. Y. & Vazquez, A. L. Photoelectric artefact from optogenetics and imaging on microelectrodes and bioelectronics: new challenges and opportunities. J. Mater. Chem. B 3, 4965–4978 (2015).

    Article  CAS  Google Scholar 

  14. Kampasi, K. et al. Dual color optogenetic control of neural populations using low-noise, multishank optoelectrodes. Microsyst. Nanoeng. 4, 10 (2018).

  15. Park, S. et al. One-step optogenetics with multifunctional flexible polymer fibers. Nat. Neurosci. 20, 612–619 (2017).

    Article  CAS  Google Scholar 

  16. Lee, J., Ozden, I., Song, Y.-K. & Nurmikko, A. V. Transparent intracortical microprobe array for simultaneous spatiotemporal optical stimulation and multichannel electrical recording. Nat. Methods 12, 1157–1162 (2015).

    Article  CAS  Google Scholar 

  17. Aravanis, A. M. et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J. Neural Eng. 4, S143 (2007).

    Article  Google Scholar 

  18. 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 

  19. Mohanty, A. et al. Reconfigurable nanophotonic silicon probes for sub-millisecond deep-brain optical stimulation. Nat. Biomed. Eng. 4, 223–231 (2020).

    Article  CAS  Google Scholar 

  20. Klein, E., Gossler, C., Paul, O. & Ruther, P. High-density μLED-based optical cochlear implant with improved thermomechanical behavior. Front. Neurosci. https://doi.org/10.3389/fnins.2018.00659 (2018).

  21. Wu, F. et al. Monolithically integrated μLEDs on silicon neural probes for high-resolution optogenetic studies in behaving animals. Neuron 88, 1136–1148 (2015).

    Article  CAS  Google Scholar 

  22. Kim, K. et al. Artifact-free and high-temporal-resolution in vivo opto-electrophysiology with microLED optoelectrodes. Nat. Commun. 11, 2063 (2020).

    Article  CAS  Google Scholar 

  23. McAlinden, N. et al. Thermal and optical characterization of micro-LED probes for in vivo optogenetic neural stimulation. Opt. Lett. 38, 992–994 (2013).

    Article  CAS  Google Scholar 

  24. Scharf, R. et al. Depth-specific optogenetic control in vivo with a scalable, high-density μLED neural probe. Sci. Rep. 6, 28381 (2016).

    Article  Google Scholar 

  25. Pisanello, F. et al. Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber. Nat. Neurosci. 20, 1180–1188 (2017).

  26. Pisanello, M. et al. Tailoring light delivery for optogenetics by modal demultiplexing in tapered optical fibers. Sci. Rep. 8, 4467 (2018).

  27. Pisano, F. et al. Depth-resolved optical monitoring of neural activity in freely moving animals. In 22nd International Conference on Transparent Optical Networks (ICTON 2020), Publisher: IEEE, Page number Tu.D7.4, https://doi.org/10.1109/ICTON51198.2020.9203401

  28. Pisanello, M., Pisanello, F., Sileo, L. and De Vittorio, M. Photonic technologies for optogenetics. In 16th International Conference on Transparent Optical Networks (ICTON 2014). Publisher: IEEE, Page number Mo.C5.3, https://doi.org/10.1109/ICTON.2014.6876293

  29. Warden, M. R., Cardin, J. A. & Deisseroth, K. Optical neural interfaces. Annu. Rev. Biomed. Eng. 16, 103–129 (2014).

    Article  CAS  Google Scholar 

  30. Dufour, S. & De Koninck, Y. Optrodes for combined optogenetics and electrophysiology in live animals. Neurophotonics 2, 031205 (2015).

    Article  Google Scholar 

  31. Kostovski, G., Stoddart, P. R. & Mitchell, A. The optical fiber tip: an inherently light‐coupled microscopic platform for micro‐and nanotechnologies. Adv. Mater. 26, 3798–3820 (2014).

    Article  CAS  Google Scholar 

  32. Pisanello, M. et al. Modal demultiplexing properties of tapered and nanostructured optical fibers for in vivo optogenetic control of neural activity. Biomed. Opt. Express 6, 4014–4026 (2015).

    Article  CAS  Google Scholar 

  33. Pisanello, F. et al. Multipoint-emitting optical fibers for spatially addressable in vivo optogenetics. Neuron 82, 1245–1254 (2014).

    Article  CAS  Google Scholar 

  34. Sileo, L. et al. Fabrication of multipoint light emitting optical fibers for optogenetics. Proc. SPIE https://doi.org/10.1117/12.2075819 (2015).

  35. Song, J. S., Lee, S., Jung, S. H., Cha, G. C. & Mun, M. S. Improved biocompatibility of parylene‐C films prepared by chemical vapor deposition and the subsequent plasma treatment. J. Appl. Polym. Sci. 112, 3677–3685 (2009).

    Article  CAS  Google Scholar 

  36. Pisano, F. et al. Focused ion beam nanomachining of tapered optical fibers for patterned light delivery. Microelectron. Eng. 195, 41–49 (2018).

    Article  CAS  Google Scholar 

  37. Abouzari, M. R. S., Berkemeier, F., Schmitz, G. & Wilmer, D. On the physical interpretation of constant phase elements. Solid State Ion. 180, 922–927 (2009).

    Article  Google Scholar 

  38. Rocha, P. R. F. et al. Electrochemical noise and impedance of Au electrode/electrolyte interfaces enabling extracellular detection of glioma cell populations. Sci. Rep. 6, 34843 (2016).

    Article  CAS  Google Scholar 

  39. Hazubski, S., Soekadar, S. R., Hoppe, H. & Otte, A. Neuroprosthetics 2.0. EBioMedicine 48, 22 (2019).

    Article  Google Scholar 

  40. Stujenske, J. M., Spellman, T. & Gordon, J. A. Modeling the spatiotemporal dynamics of light and heat propagation for in vivo optogenetics. Cell Rep. 12, 525–534 (2015).

    Article  CAS  Google Scholar 

  41. Maglie, E. et al. Ray tracing models for estimating light collection properties of microstructured tapered optical fibers for optical neural interfaces. Opt. Lett. 45, 3856–3859 (2020).

    Article  Google Scholar 

  42. Steenland, H. W. & McNaughton, B. L. in Analysis and Modeling of Coordinated Multi-neuronal Activity (ed. Tatsuno, M.) 41–61 (Springer, 2015).

  43. Saleh, B. E. A. & Teich, M. C. Fundamentals of Photonics (John Wiley & Sons, 2019).

  44. Baldacchini, T. Three-Dimensional Microfabrication Using Two-Photon Polymerization: Fundamentals, Technology, and Applications (William Andrew, 2015).

  45. Nieh, E. H. et al. Decoding neural circuits that control compulsive sucrose seeking. Cell 160, 528–541 (2015).

    Article  CAS  Google Scholar 

  46. Brown, J. et al. Expanding the optogenetics toolkit by topological inversion of rhodopsins. Cell 175, 1131–1140 (2018).

    Article  CAS  Google Scholar 

  47. Stark, E. et al. Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations. Neuron 83, 467–480 (2014).

    Article  CAS  Google Scholar 

  48. Pisanello, F., Sileo, L. & De Vittorio, M. Micro- and nanotechnologies for optical neural interfaces. Front. Neurosci. https://doi.org/10.3389/fnins.2016.00070 (2016).

  49. Sigurdsson, T., Stark, K. L., Karayiorgou, M., Gogos, J. A. & Gordon, J. A. Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010).

    Article  CAS  Google Scholar 

  50. Schmitzer-Torbert, N. 1, 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 

  51. Dhawale, A. K. et al. Automated long-term recording and analysis of neural activity in behaving animals. Elife 6, e27702 (2017).

    Article  Google Scholar 

Download references

Acknowledgements

B.S., A.B., M.B., F. Pisano and F. Pisanello acknowledge funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (no. 677683); M.P. and M.D.V. acknowledge funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (no. 692943). M.B., M.D.V. and F.Pisanello acknowledge funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (no. 966674). F. Pisano, M.D.V. and F. Pisanello acknowledge funding from the European Union’s Horizon 2020 research and innovation programme (no. 101016787). L.S., M.D.V. and B.L.S. are funded by the US National Institutes of Health (U01NS094190). M.P., L.S., F. Pisanello, M.D.V. and B.L.S. are funded by the US National Institutes of Health (1UF1NS108177-01). A.B., F. Pisanello and M.D.V. also acknowledge funding from the European Union’s Horizon 2020 research and innovation programme (no. 828972). We also acknowledge J. Lee for help setting up the optrode fibre launch system.

Author information

Author notes

  1. These authors contributed equally: Barbara Spagnolo, Antonio Balena, Rui T. Peixoto, Marco Pisanello.

  2. These authors jointly supervised this work: Massimo De Vittorio, Ferruccio Pisanello.

Authors and Affiliations

  1. Istituto Italiano di Tecnologia, CBN, Lecce, Italy

    Barbara Spagnolo, Antonio Balena, Marco Pisanello, Leonardo Sileo, Marco Bianco, Alessandro Rizzo, Filippo Pisano, Antonio Qualtieri, Massimo De Vittorio & Ferruccio Pisanello

  2. Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Rui T. Peixoto, John A. Assad & Bernardo L. Sabatini

  3. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Rui T. Peixoto

  4. Dipartimento di Ingegneria dell’Innovazione, Università del Salento, Lecce, Italy

    Marco Bianco, Alessandro Rizzo & Massimo De Vittorio

  5. DiSTeBA - Department of Biological and Environmental Sciences and Technologies, Università del Salento, Lecce, Italy

    Dario Domenico Lofrumento & Francesco De Nuccio

  6. Istituto Italiano di Tecnologia, Genova, Italy

    John A. Assad

Authors
  1. Barbara Spagnolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Balena
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui T. Peixoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco Pisanello
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leonardo Sileo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marco Bianco
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alessandro Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Filippo Pisano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antonio Qualtieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dario Domenico Lofrumento
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Francesco De Nuccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John A. Assad
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bernardo L. Sabatini
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Massimo De Vittorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ferruccio Pisanello
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.B., B.S., M.P. and R.T.P. equally contributed to this work. A.B., M.P., M.B., A.R., M.D.V., F. Pisano and F. Pisanello developed the 2PP system and the related fibertrode. L.S., B.S., M.P., A.Q., F. Pisano, M.D.V. and F. Pisanello developed the FIB fabrication protocol and the related fibertrode. B.S., A.B., M.P., M.B. and F. Pisanello performed the optoelectrical characterization of the probes. B.S. and R.T.P. performed the in vivo experiments. B.S., A.B., M.P., F. Pisano, F. Pisanello, R.T.P., B.L.S., J.A.A. and M.D.V. analysed and discussed the in vivo data. B.L.S., R.T.P., B.S., D.D.L., F.D.N. and F. Pisanello developed the in vivo experiment protocols. A.B., B.S., L.S., F. Pisanello, M.D.V., B.L.S. and J.A.A. wrote the manuscript and prepared the figures with contributions from all authors. M.D.V., B.L.S., J.A.A. and F. Pisanello conceived the study and jointly supervised the work.

Corresponding authors

Correspondence to Barbara Spagnolo, Antonio Balena, Massimo De Vittorio or Ferruccio Pisanello.

Ethics declarations

Competing interests

L.S., B.L.S., M.D.V. and F. Pisanello are founders of and hold private equity in Optogenix, a company that develops, produces and sells technologies to deliver light into the brain. Tapered fibres commercially available from Optogenix were used as tools in the research. The remaining authors declare no competing interests. F. Pisano and M.P. have been employed by OptogeniX. OptogeniX did not fund the research described in this work.

Peer review

Peer review information

Nature Materials thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–9 and Table 1.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Spagnolo, B., Balena, A., Peixoto, R.T. et al. Tapered fibertrodes for optoelectrical neural interfacing in small brain volumes with reduced artefacts. Nat. Mater. 21, 826–835 (2022). https://doi.org/10.1038/s41563-022-01272-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41563-022-01272-8

This article is cited by

Search

Advanced 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