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  • Protocol
  • Published:

Modified Neuropixels probes for recording human neurophysiology in the operating room

Nature Protocols volume 18, pages 2927–2953 (2023)Cite this article

Subjects

Abstract

Neuropixels are silicon-based electrophysiology-recording probes with high channel count and recording-site density. These probes offer a turnkey platform for measuring neural activity with single-cell resolution and at a scale that is beyond the capabilities of current clinically approved devices. Our team demonstrated the first-in-human use of these probes during resection surgery for epilepsy or tumors and deep brain stimulation electrode placement in patients with Parkinson’s disease. Here, we provide a better understanding of the capabilities and challenges of using Neuropixels as a research tool to study human neurophysiology, with the hope that this information may inform future efforts toward regulatory approval of Neuropixels probes as research devices. In perioperative procedures, the major concerns are the initial sterility of the device, maintaining a sterile field during surgery, having multiple referencing and grounding schemes available to de-noise recordings (if necessary), protecting the silicon probe from accidental contact before insertion and obtaining high-quality action potential and local field potential recordings. The research team ensures that the device is fully operational while coordinating with the surgical team to remove sources of electrical noise that could otherwise substantially affect the signals recorded by the sensitive hardware. Prior preparation using the equipment and training in human clinical research and working in operating rooms maximize effective communication within and between the teams, ensuring high recording quality and minimizing the time added to the surgery. The perioperative procedure requires ~4 h, and the entire protocol requires multiple weeks.

Key points

  • This Protocol describes the structural reinforcement of Neuropixels 1.0-S, ensuring their correct insertion into the human cortex; the extensive perioperative procedures required to maintain sterile conditions; and coordination with the surgical team.

  • Neuropixels 1.0-S enables the recording of spiking activity from up to hundreds of cortical neurons, a feat currently not possible with single-neuron resolution devices such as microwire bundles, laminar microelectrode arrays, microelectrode contacts and the Utah array.

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Fig. 1: Recording human brain activity with the Neuropixels probe in the operating room.
Fig. 2: Neuropixels 1.0-S probe differences compared to the Neuropixels 1.0 probe (Box 1).
Fig. 3: Overall timeline of events required for the setup and data acquisition.
Fig. 4: Neuropixels probe and the materials and tools used for sterile preparation of the probe for recording and setup.
Fig. 5: Sequence of events for probe preparation.
Fig. 6: Preparation for holding the Neuropixels probe in two different OR settings.
Fig. 7: Electrode localization and DREDge motion registration for eventual spike sorting and mapping to cortical layers.

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Data availability

The main data discussed in this protocol are available for download at Dryad (https://doi.org/10.5061/dryad.d2547d840). Further datasets that were used in the study were neural reconstructions of human neurons from NeuroMorpho.Org 61–65 relative to the Neuropixels array and 1.5-mm Utah array. Neural reconstructions were from Neuromorpho.Org ID: NMO_86955, NMO_86997, NMO_109433, NMO_61420 and NMO_61421.

Code availability

Custom code described in this paper has been made available at https://github.com/Center-For-Neurotechnology/HumanNeuropixelsPipeline (currently without a license), which includes links to other useful repositories not maintained by the authors of this paper, with the exceptions of https://github.com/evarol/dredge (available under the Creative Commons Zero v1.0 Universal license) and https://github.com/williamunoz/InterpolationAfterDREDge (available under the MIT license).

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Acknowledgements

We thank Y. Chou, A. Tripp, F. Minidio, A. Zhang and A. O’Donnell for help in data collection, and we thank S. Shah and S. Sheth for manuscript input. We especially thank the patients for their willingness to participate in this research. This research was supported by the ECOR and K24-NS088568 (to S.S.C.), the Tiny Blue Dot Foundation (to S.S.C. and A.C.P.) and NIH grant U01NS121616 (to Z.M.W.). This research was also supported by NIH NINDS BRAIN R01NS11662301 (to K.V.S.), NIH NIDCD R01DC01403406 (to K.V.S.), the Simons Foundation (543045 to K.V.S. and 872146SPI to S.D.S.) the Howard Hughes Medical Institute at Stanford University (to K.V.S. and E.M.T.) and NIH/NINDS Neuroscience Resident Research Program R25NS065743 (to W.M.). S.D.S. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. E.M.T. is additionally funded by the Brain and Behavior Research Foundation and the Grossman Institute. E.V. is funded by NIH NIMH 1K99MH128772-01A1. The views and conclusions contained in this document are those of the authors and do not represent the official policies, either expressed or implied, of the funding sources. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Brian Coughlin, William Muñoz, Yoav Kfir.

Authors and Affiliations

  1. Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Brian Coughlin, Michael J. Young, Domokos Meszéna, Richard Hardstone, Dan J. Soper, Leigh R. Hochberg, Sydney S. Cash & Angelique C. Paulk

  2. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Brian Coughlin, Michael J. Young, Domokos Meszéna, Richard Hardstone, Dan J. Soper, Leigh R. Hochberg, Sydney S. Cash & Angelique C. Paulk

  3. Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA

    William Muñoz, Yoav Kfir, Mohsen Jamali, Irene Caprara, Arjun Khanna, R. Mark Richardson & Ziv M. Williams

  4. Department of Neurosurgery, Harvard Medical School and Brigham & Women’s Hospital, Boston, MA, USA

    Martina L. Mustroph

  5. Department of Neuroscience, Columbia University Medical Center, New York, NY, USA

    Eric M. Trautmann

  6. Zuckerman Institute, Columbia University, New York, NY, USA

    Eric M. Trautmann

  7. Grossman Center for the Statistics of Mind, Columbia University Medical Center, New York, NY, USA

    Eric M. Trautmann

  8. Department of Statistics, Zuckerman Institute, Columbia University, New York, NY, USA

    Charlie Windolf & Erdem Varol

  9. Department of Computer Science and Engineering, Zuckerman Institute, Columbia University, New York, NY, USA

    Erdem Varol

  10. Department of Neurological Surgery, University of California Davis, Davis, CA, USA

    Sergey D. Stavisky

  11. Department of Neurosurgery, Stanford University, Stanford, CA, USA

    Sergey D. Stavisky & Krishna V. Shenoy

  12. Wu Tsai Neurosciences Institute and Bio-X Institute, Stanford University, Stanford, CA, USA

    Sergey D. Stavisky & Krishna V. Shenoy

  13. Howard Hughes Medical Institute at Stanford University, Stanford, CA, USA

    Sergey D. Stavisky & Krishna V. Shenoy

  14. imec, Leuven, Belgium

    Marleen Welkenhuysen & Barundeb Dutta

  15. Department of Electrical Engineering, Stanford University, Stanford, CA, USA

    Krishna V. Shenoy

  16. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Krishna V. Shenoy

  17. Department of Neurobiology, Stanford University, Stanford, CA, USA

    Krishna V. Shenoy

  18. VA RR&D Center for Neurorestoration and Neurotechnology, Rehabilitation R&D Service, Providence VA Medical Center, Providence, RI, USA

    Leigh R. Hochberg

  19. School of Engineering and Carney Institute for Brain Science, Brown University, Providence, RI, USA

    Leigh R. Hochberg

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  1. Brian Coughlin
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Contributions

The experiment was conceived by S.S.C., Y.K., A.C.P., Z.M.W., K.V.S., L.R.H., E.M.T., W.M., I.C., M.J., D.M., B.C. and S.D.S. Z.M.W. and R.M.R. performed the surgeries and placed the arrays, while A.C.P., D.J.S., B.C., M.L.M., A.K., W.M., I.C., M.J., D.M., C.W., E.V. and Y.K. collected the data or did a first-pass analysis. A.C.P., B.C. and S.S.C. prepared the first manuscript draft. A.C.P., W.M., R.H., C.W. and Y.K. analyzed all the data for the final results, and A.C.P. and B.C. prepared all the figures. E.V. and C.W. developed software for analysis. All authors edited and revised the manuscript. B.D., M.W. and E.M.T. conceived of and advanced the production of the thicker custom Neuropixels probes with sharpened tips used in the study. The imec employees (B.D. and M.W.) are authors because of their technological development of the probe hardware and software and were not involved in these human pilot studies.

Corresponding authors

Correspondence to Ziv M. Williams, Sydney S. Cash or Angelique C. Paulk.

Ethics declarations

Competing interests

K.V.S. is a consultant to Neuralink Corp. and CTRL-Labs Inc. (now a part of the Meta Reality Labs division of Meta) and is on the Scientific Advisory Boards of Mind-X Inc., Inscopix Inc. and Heal Inc. The MGH Translational Research Center has clinical research support agreements with Neuralink, Paradromics and Synchron, for which S.S.C. and L.R.H. provide consultative input. None of these entities listed are involved with this research or the Neuropixels device. B.D. and M.W. are employees of imec, a non-profit semiconductor research and development organization that manufactures, sells and distributes the Neuropixels probes, at cost, to the research community. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Protocols thanks Anton Arkhipov, Anne Churchland, Daniel Denman, Christoph Koch and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Key references using this protocol

Paulk, A. C. et al. Nat. Neurosci. 25, 252–263 (2022): https://doi.org/10.1038/s41593-021-00997-0

Windolf, C. et al. Presented at ICASSP 2023–2023 IEEE International Conference on Acoustics, Speech and Signal Processing (2023): https://doi.org/10.1109/ICASSP49357.2023.10095487

Windolf, C. et al. Preprint (2022): https://doi.org/10.1101/2022.12.04.519043

Supplementary information

Supplementary Information

Supplementary Discussion, Table 1 and Figs. 1–5

Reporting Summary

Supplementary Video 1

Ongoing human brain neural activity recorded via Neuropixels and SpikeGLX and OpenEphys recording software, as recorded in the OR.

Supplementary Video 2

Demonstration of the additional electrical noise from the wall-powered anesthesia pump through a saline tube while recording in saline and gelatine.

Supplementary Video 3

Setting up the Neuropixels probe in the sterile field to be connected to the recording system.

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Coughlin, B., Muñoz, W., Kfir, Y. et al. Modified Neuropixels probes for recording human neurophysiology in the operating room. Nat Protoc 18, 2927–2953 (2023). https://doi.org/10.1038/s41596-023-00871-2

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