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

Nature Biotechnology volume 33, pages 277284 (2015) | Download Citation

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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.

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References

  1. 1.

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

  2. 2.

    , , , & Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).

  3. 3.

    , , , & Circuit-breakers: optical technologies for probing neural signals and systems. Nat. Rev. Neurosci. 8, 577–581 (2007).

  4. 4.

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

  5. 5.

    & Corticostriatal neurons in auditory cortex drive decisions during auditory discrimination. Nature 497, 482–485 (2013).

  6. 6.

    , & Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat. Neurosci. 15, 816–818 (2012).

  7. 7.

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

  8. 8.

    , , , & A polymer-based neural microimplant for optogenetic applications: design and first in vivo study. Lab Chip 13, 579–588 (2013).

  9. 9.

    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).

  10. 10.

    , , , & A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array. IEEE Trans. Biomed. Eng. 38, 758–768 (1991).

  11. 11.

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

  12. 12.

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

  13. 13.

    , & 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).

  14. 14.

    , , & Novel multi-sided, microelectrode arrays for implantable neural applications. Biomed. Microdevices 13, 441–451 (2011).

  15. 15.

    , , & Mechanical properties of acellular peripheral nerve. J. Surg. Res. 114, 133–139 (2003).

  16. 16.

    , & In vivo brain viscoelastic properties measured by magnetic resonance elastography. NMR Biomed. 21, 755–764 (2008).

  17. 17.

    , , & Toward a comparison of microelectrodes for acute and chronic recordings. Brain Res. 1282, 183–200 (2009).

  18. 18.

    , & Response of brain tissue to chronically implanted neural electrodes. J. Neurosci. Methods 148, 1–18 (2005).

  19. 19.

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

  20. 20.

    & Neural probe design for reduced tissue encapsulation in CNS. Biomaterials 28, 3594–3607 (2007).

  21. 21.

    , , & Biomechanical analysis of silicon microelectrode-induced strain in the brain. J. Neural Eng. 2, 81–89 (2005).

  22. 22.

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

  23. 23.

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

  24. 24.

    , , & Interaction of glia with a compliant, microstructured silicone surface. Acta Biomater. 9, 6936–6942 (2013).

  25. 25.

    , , & 3D flexible multichannel neural probe array. J. Micromech. Microeng. 14, 104–107 (2004).

  26. 26.

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

  27. 27.

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

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

    , , , & Polycarbonate intraocular lenses. J. Cataract Refract. Surg. 14, 393–395 (1988).

  32. 32.

    & Optical properties of cyclic olefin copolymers. Opt. Eng. 40, 1024–1029 (2001).

  33. 33.

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

  34. 34.

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

  35. 35.

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

  36. 36.

    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).

  37. 37.

    , , , & Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience 131, 1–11 (2005).

  38. 38.

    , & Endogenous glutamatergic control of rhythmically active mammalian respiratory motoneurons in vivo. J. Neurosci. 28, 6826–6835 (2008).

  39. 39.

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

  40. 40.

    , & Creating low-impedance tetrodes by electroplating with additives. Sens. Actuators A Phys. 156, 388–393 (2009).

  41. 41.

    , , , & Complex impedance spectroscopy for monitoring tissue responses to inserted neural implants. J. Neural Eng. 4, 410–423 (2007).

  42. 42.

    , & The density difference between tissue and neural probes is a key factor for glial scarring. Sci. Rep. 3, 2942 (2013).

  43. 43.

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

  44. 44.

    , & Chronic intracortical microelectrode arrays induce non-uniform, depth-related tissue responses. J. Neural Eng. 10, 026007 (2013).

  45. 45.

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

  46. 46.

    , , , & Optogenetics in neural systems. Neuron 71, 9–34 (2011).

  47. 47.

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

  48. 48.

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

  49. 49.

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

  50. 50.

    , & Unsupervised spike detection and sorting with wavelets and superparamagnetic clustering. Neural Comput. 16, 1661–1687 (2004).

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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

Author notes

    • Andres Canales
    • , Xiaoting Jia
    • , Ulrich P Froriep
    •  & Ryan A Koppes

    These authors contributed equally to this work.

Affiliations

  1. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Andres Canales
    • , Christina M Tringides
    • , Jennifer Selvidge
    • , Chi Lu
    • , Chong Hou
    • , Yoel Fink
    •  & Polina Anikeeva
  2. Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Xiaoting Jia
    • , Ulrich P Froriep
    • , Ryan A Koppes
    • , Lei Wei
    • , Yoel Fink
    •  & Polina Anikeeva
  3. Simons Center for the Social Brain, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Ulrich P Froriep

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Polina Anikeeva.

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DOI

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

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