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Large-scale electrophysiology at single-spike resolution

Nature Reviews Neuroscience (2026)Cite this article

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Abstract

Recent advances in electrode technology — including the development of Neuropixels and SiNAPS probes — have made it possible to routinely capture spike trains from thousands of neurons distributed across the brain. Widespread dissemination of these tools has not only yielded new discoveries but also changed the way in which neuroscientific questions are asked and answered. In this article, we describe the motivations for collecting electrophysiological recordings on this scale, review the basic physical principles underlying these measurements and discuss key considerations for generating optimally useful datasets. We compare the latest devices for large-scale recordings and address challenges and opportunities in data analysis, rigour, reproducibility and data sharing. Finally, we provide a roadmap for future advances in this space. We argue that widely available hardware, software and protocols are now empowering scientists to perform experiments matched to the scale and complexity of the neural circuits that underlie complex mammalian behaviours.

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Fig. 1: Comparing the spatial and temporal scale of neural recording techniques.
The alternative text for this image may have been generated using AI.
Fig. 2: Principles of extracellular potential recordings.
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Fig. 3: Example devices for large-scale electrophysiology.
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Fig. 4: Reproducibility of large-scale electrophysiological measurements.
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Fig. 5: Large-scale, open datasets available for studying distributed spiking activity.
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Data availability

The data used to generate the images in Fig. 5 are available at public, open repositories: https://doi.org/10.6084/m9.figshare.9598406 (Steinmetz et al.12), https://doi.org/10.48324/dandi.000021/0.251116.2246 and https://doi.org/10.48324/dandi.000022/0.251116.2247 (Siegle et al.15), https://doi.org/10.6084/m9.figshare.21365598 (Ottenheimer et al.309), https://doi.org/10.48324/dandi.000363/0.231012.2129 (Chen et al.13), https://doi.org/10.48324/dandi.001260/0.250911.0744 (Le Merre et al.18), https://doi.org/10.48324/dandi.001326/0.250528.1957 (Kauvar et al.310), https://doi.org/10.6084/m9.figshare.19493588 (Ye et al.55), https://www.internationalbrainlab.com/brainwide-map (International Brain Laboratory (IBL)19) and https://doi.org/10.48324/dandi.000713/0.240702.1725 (Bennett et al.311).

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Acknowledgements

The authors thank A. Li, C. Schoonover and C. Mora Lopez for helpful suggestions and feedback on this manuscript. They thank A. Li for help in preparing the publicly available data replotted in Fig. 5. This work was supported by The Pew Biomedical Scholars Program (N.A.S.), a Klingenstein–Simons Fellowship in Neuroscience (N.A.S.) and the National Institutes of Health (NIH) (U01NS113252 to N.A.S.). Additional funding was provided by the Allen Institute.

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  1. Allen Institute/Neural Dynamics, Seattle, WA, USA

    Joshua H. Siegle

  2. Department of Neurobiology & Biophysics, University of Washington, Seattle, WA, USA

    Nicholas A. Steinmetz

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The authors contributed equally to all aspects of the article.

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Related links

Blackrock Neurotech: https://blackrockneurotech.com/

NeuroNexus: https://www.neuronexus.com/

Neuropixels: https://www.neuropixels.org/

Plexon: https://plexon.com/

Glossary

Calcium imaging

An optical imaging technique that uses fluorescent calcium indicators to detect neural activity, typically using two-photon imaging for neuronal or sub-neuronal spatial resolution but with temporal resolution limited by indicator kinetics and imaging rate.

Complementary metal-oxide semiconductor

(CMOS). A semiconductor fabrication technology that enables the monolithic integration of high-density recording sites with on-chip amplification, digitization and multiplexing circuitry, as used in Neuropixels probes.

Dimensionality reduction

A set of computational techniques that compress high-dimensional neural data (such as activity across many channels or neurons) into a smaller number of variables, used both within spike sorting algorithms and in analyses of population activity.

Dipole

A simplified model of a neural current source in which current flows between two spatially separated poles, producing an extracellular electric field whose voltage falls off with distance from the source.

Ground truth

Data in which the true spike times and identities of neurons are independently verified (for example, via simultaneous extracellular and intracellular recording), used as a benchmark to evaluate the accuracy of spike sorting algorithms.

International Brain Laboratory

(IBL). A consortium of neuroscience laboratories that uses standardized protocols across multiple sites to collect large-scale electrophysiology datasets spanning the mouse brain.

Manifold

A low-dimensional geometric structure embedded within the high-dimensional space of neural population activity, whose discovery can require simultaneous recordings from large numbers of neurons.

Microwire

A thin, insulated metal wire (typically less than 100 µm in diameter) used as an implanted neural electrode, often arranged in bundles to record extracellular activity from populations of neurons.

Optotagging

A technique in which light-sensitive opsins are expressed in a genetically defined neuronal population, such that these neurons can be identified in extracellular recordings on the basis of their low-latency spikes when illuminated.

Recording sites

The individual electrode contacts on a probe that sense the extracellular potential; their size affects the trade-off between spatial averaging of the signal and thermal noise from impedance.

Shanks

Thin, elongated structural elements of a multielectrode probe that penetrate neural tissue and carry an array of recording sites along their lengths.

Spike sorting

A computational procedure that detects extracellular voltage deflections caused by action potentials and assigns them to putative individual neural sources (units) on the basis of the consistency of their spatiotemporal waveform profiles across channels.

Spike trains

Discrete sequences of action potential times attributed to individual neurons, forming the primary data representation used in analyses of neural coding, decoding and reproducibility across laboratories.

Spike waveform

The characteristic spatiotemporal pattern of extracellular voltage deflections produced by a neuron’s action potential, which can vary with cell morphology and transcriptomic type.

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Siegle, J.H., Steinmetz, N.A. Large-scale electrophysiology at single-spike resolution. Nat. Rev. Neurosci. (2026). https://doi.org/10.1038/s41583-026-01042-4

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