Abstract
Monitoring neural population activity at single-cell resolution is essential for fundamental research and clinical innovation. However, translating advanced recording techniques from animal models to humans remains a challenge. Flexible neural electrodes have emerged as powerful tools for large-scale single-unit recordings due to their biocompatibility and high recording density. Here, we demonstrate reliable, high-density single-unit recordings during intraoperative procedures in human patients using ultra-Flexible Implantable Neural Electrode (uFINE) arrays. The uFINE array exhibited sufficient mechanical robustness to maintain structural integrity throughout surgical operations. We successfully recorded 719 single units from 11 patients, with up to 135 single units simultaneously recorded. The flexibility of uFINE array minimized signal disturbances from brain pulsations, enabling stable and continuous single-unit detection. Stimulus and response tuning were observed at the level of individual neurons in awake patients.
Similar content being viewed by others
Data availability
All data supporting the findings of this study are available within the article and its supplementary files.
The raw datasets generated in this study are protected and are not publicly available due to data privacy laws and ethical restrictions regarding personally identifiable patient information. The anonymized data are available under restricted access for protecting patient privacy.
Data access and any additional requests can be obtained by submitting a specific research proposal and signing a Data Transfer Agreement with the lead contact (xli@ion.ac.cn). Data sharing is restricted to academic researchers for non-commercial purposes. We will respond to requests within two weeks, and access is granted for a 2-year authorization period.
Code availability
The custom code used for data processing, spike sorting, and statistical analysis in this study has been deposited in the Zenodo repository, https://doi.org/10.5281/zenodo.18774630. The code is publicly available under the MIT License.
References
Engel, A. K., Moll, C. K. E., Fried, I. & Ojemann, G. A. Invasive recordings from the human brain: clinical insights and beyond. Nat. Rev. Neurosci. 6, 35–47 (2005).
Rutishauser, U., Reddy, L., Mormann, F. & Sarnthein, J. The Architecture of Human Memory: Insights from Human Single-Neuron Recordings. J. Neurosci. 41, 883–890 (2021).
Hutchison, W. D. et al. Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann. Neurol. 44, 622–628 (1998).
Williams, Z. M., Bush, G., Rauch, S. L., Cosgrove, G. R. & Eskandar, E. N. Human anterior cingulate neurons and the integration of monetary reward with motor responses. Nat. Neurosci. 7, 1370–1375 (2004).
Verzeano, M., Crandall, P. H. & Dymond, A. Neuronal activity of the amygdala in patients with psychomotor epilepsy. Neuropsychologia 9, 331–344 (1971).
Fried, I., MacDonald, K. A. & Wilson, C. L. Single neuron activity in human hippocampus and amygdala during recognition of faces and objects. Neuron 18, 753–765 (1997).
Quiroga, R. Q., Reddy, L., Kreiman, G., Koch, C. & Fried, I. Invariant visual representation by single neurons in the human brain. Nature 435, 1102–1107 (2005).
Daume, J. et al. Control of working memory by phase-amplitude coupling of human hippocampal neurons. Nature 629, 393–401 (2024).
Misra, A. et al. Methods for implantation of micro-wire bundles and optimization of single/multi-unit recordings from human mesial temporal lobe. J. Neural Eng. 11, 026013 (2014).
Lehongre, K. et al. Long-term deep intracerebral microelectrode recordings in patients with drug-resistant epilepsy: Proposed guidelines based on 10-year experience. Neuroimage 254, 119116 (2022).
Kehl, M. S. et al. Single-neuron representations of odours in the human brain. Nature 634, 626–634 (2024).
Guan, C. et al. Decoding and geometry of ten finger movements in human posterior parietal cortex and motor cortex. J. Neural Eng. 20, 036020 (2023).
Aflalo, T. et al. Decoding motor imagery from the posterior parietal cortex of a tetraplegic human. Science 348, 906–910 (2015).
Willett, F. R., Avansino, D. T., Hochberg, L. R., Henderson, J. M. & Shenoy, K. V. High-performance brain-to-text communication via handwriting. Nature 593, 249–254 (2021).
Flesher, S. N. et al. A brain-computer interface that evokes tactile sensations improves robotic arm control. Science 372, 831–836 (2021).
Willett, F. R. et al. A high-performance speech neuroprosthesis. Nature 620, 1031–1036 (2023).
Card, N. S. et al. An Accurate and Rapidly Calibrating Speech Neuroprosthesis. N. Engl. J. Med. 391, 609–618 (2024).
Fernández, E. et al. Acute human brain responses to intracortical microelectrode arrays: challenges and future prospects. Front. Neuroeng. 7, 24 (2014).
Eisenkolb, V. M. et al. Human acute microelectrode array recordings with broad cortical access, single-unit resolution, and parallel behavioral monitoring. Cell Rep. 42, 112467 (2023).
Chung, J. E. et al. High-density single-unit human cortical recordings using the Neuropixels probe. Neuron 110, 2409–2421.e3 (2022).
Paulk, A. C. et al. Large-scale neural recordings with single neuron resolution using Neuropixels probes in human cortex. Nat. Neurosci. 25, 252–263 (2022).
Leonard, M. K. et al. Large-scale single-neuron speech sound encoding across the depth of human cortex. Nature 626, 593–602 (2023).
Khanna, A. R. et al. Single-neuronal elements of speech production in humans. Nature 626, 603–610 (2024).
Jamali, M. et al. Semantic encoding during language comprehension at single-cell resolution. Nature 631, 610–616 (2024).
Coughlin, B. et al. Modified Neuropixels probes for recording human neurophysiology in the operating room. Nat. Protoc. 18, 2927–2953 (2023).
Chung, J. E. et al. High-Density, Long-Lasting, and Multi-region Electrophysiological Recordings Using Polymer Electrode Arrays. Neuron 101, 21–31.e5 (2019).
Luan, L. et al. Ultraflexible nanoelectronic probes form reliable, glial scar–free neural integration. Sci. Adv. 3, e1601966 (2017).
Seo, K. J. et al. A soft, high-density neuroelectronic array. npj Flex. Electron 7, 1–8 (2023).
Zhao, Z. et al. Ultraflexible electrode arrays for months-long high-density electrophysiological mapping of thousands of neurons in rodents. Nat. Biomed. Eng. 7, 520–532 (2023).
Tian, Y. et al. An Ultraflexible Electrode Array for Large-Scale Chronic Recording in the Nonhuman Primate Brain. Adv. Sci. (Weinh.) 10, 2302333 (2023).
Zhao, S. et al. Tracking neural activity from the same cells during the entire adult life of mice. Nat. Neurosci. 26, 696–710 (2023).
He, F., Lycke, R., Ganji, M., Xie, C. & Luan, L. Ultraflexible Neural Electrodes for Long-Lasting Intracortical Recording. iScience 23, 101387 (2020).
Tang, X., Shen, H., Zhao, S., Li, N. & Liu, J. Flexible brain–computer interfaces. Nat. Electron 6, 109–118 (2023).
Yasar, T. B. et al. Months-long tracking of neuronal ensembles spanning multiple brain areas with Ultra-Flexible Tentacle Electrodes. Nat. Commun. 15, 4822 (2024).
Musk, E. & Neuralink An Integrated Brain-Machine Interface Platform With Thousands of Channels. J. Med. Internet Res. 21, e16194 (2019).
Lee, K. et al. Flexible, scalable, high channel count stereo-electrode for recording in the human brain. Nat. Commun. 15, 218 (2024).
Merken, L., Schelles, M., Ceyssens, F., Kraft, M. & Janssen, P. Thin flexible arrays for long-term multi-electrode recordings in macaque primary visual cortex. J. Neural Eng. 19, 1741–2552 (2022).
Pothof, F. et al. Chronic neural probe for simultaneous recording of single-unit, multi-unit, and local field potential activity from multiple brain sites. J. Neural Eng. 13, 046006 (2016).
Buzsáki, G., Anastassiou, C. A. & Koch, C. The origin of extracellular fields and currents — EEG, ECoG, LFP and spikes. Nat. Rev. Neurosci. 13, 407–420 (2012).
Pachitariu, M., Sridhar, S., Pennington, J. & Stringer, C. Spike sorting with Kilosort4. Nat. Methods 21, 914–921 (2024).
Ye, Z. et al. Ultra-high-density Neuropixels probes improve detection and identification in neuronal recordings. Neuron 113, 3966–3982.e12 (2025).
Edler, M. K. et al. Neuron loss associated with age but not Alzheimer’s disease pathology in the chimpanzee brain. Philos. Trans. R. Soc. Lond. B Biol. Sci. 375, 20190619 (2020).
Wang, Y. et al. Flexible multichannel electrodes for acute recording in nonhuman primates. Microsyst. Nanoeng. 9, 93 (2023).
Sun, S. H. et al. Analysis of extracellular spike waveforms and associated receptive fields of neurons in cat primary visual cortex. J. Physiol. 599, 2211–2238 (2021).
Boussard, J., Varol, E., Lee, H. D., Dethe, N. & Paninski, L. Three-dimensional spike localization and improved motion correction for Neuropixels recordings. in Advances in Neural Information Processing Systems (eds. Ranzato, M., Beygelzimer, A., Dauphin, Y., Liang, P. S. & Vaughan, J. W.) vol. 34 22095–22105 (Curran Associates, Inc., 2021).
Windolf, C. et al. DREDge: robust motion correction for high-density extracellular recordings across species. Nat. Methods 22, 788–800 (2025).
Barbey, A. K., Koenigs, M. & Grafman, J. Dorsolateral prefrontal contributions to human working memory. Cortex 49, 1195–1205 (2013).
Arnsten, A. F. T. Stress signalling pathways that impair prefrontal cortex structure and function. Nat. Rev. Neurosci. 10, 410–422 (2009).
Uddin, L. Q. Cognitive and behavioural flexibility: neural mechanisms and clinical considerations. Nat. Rev. Neurosci. 22, 167–179 (2021).
Kaller, C. P., Rahm, B., Spreer, J., Weiller, C. & Unterrainer, J. M. Dissociable Contributions of Left and Right Dorsolateral Prefrontal Cortex in Planning. Cereb. Cortex 21, 307–317 (2011).
Xiao, Y. et al. Deep brain stimulation induces sparse distributions of locally modulated neuronal activity. Sci. Rep. 8, 2062 (2018).
Pettersen, K. H., Devor, A., Ulbert, I., Dale, A. M. & Einevoll, G. T. Current-source density estimation based on inversion of electrostatic forward solution: Effects of finite extent of neuronal activity and conductivity discontinuities. J. Neurosci. Methods 154, 116–133 (2006).
Chen, X., Zirnsak, M. & Moore, T. Dissonant Representations of Visual Space in Prefrontal Cortex during Eye Movements. Cell Rep. 22, 2039–2052 (2018).
Redinbaugh, M. J. et al. Thalamus Modulates Consciousness via Layer-Specific Control of Cortex. Neuron 106, 66–75.e12 (2020).
Hill, D. N., Mehta, S. B. & Kleinfeld, D. Quality metrics to accompany spike sorting of extracellular signals. J. Neurosci. 31, 8699–8705 (2011).
Wu, Y. et al. Ultraflexible electrodes for recording neural activity in the mouse spinal cord during motor behavior. Cell Rep. 43, 114199 (2024).
Liu, Y. et al. A high-density 1,024-channel probe for brain-wide recordings in non-human primates. Nat. Neurosci. 27, 1620–1631 (2024).
Lee, E. K. et al. Non-linear dimensionality reduction on extracellular waveforms reveals cell type diversity in premotor cortex. Elife 10, e67490 (2021).
Schoonover, C. E., Ohashi, S. N., Axel, R. & Fink, A. J. P. Representational drift in primary olfactory cortex. Nature 594, 541–546 (2021).
Acknowledgements
We thank Xiaocheng Li and Nanofabrication Facility for Advanced Brain Science at CEBSIT for supporting electrode fabrication; Xingyu Liu for discussing paradigm design and optimization; Bingbing Li for refining visual representations; Xing Shao for designing the implantable casing and the micro-drive system; Guangyao Zhang for “Word-repeating” task coding; Zexing Zhao for his work in data acquisition; Zhuo Chen for processing and analyzing the collected data; Zeyu Wang for assisting with electrical impedance spectroscopy (EIS) characterization; Shun Bai, Kang Meng and all members in our lab for recommendations on electrophysiological recording techniques; Shanghai Stairmed Technology Co.,Ltd. for supporting electrode fabrication, hardware & software support and medical communication; and the clinical teams for their invaluable collaboration and support. We are deeply grateful to the patients who participated in this study, whose contributions were essential for this research. Z.Z. (Zhengtuo Zhao) is supported by National Science and Technology Innovation 2030 Major Program grant 2022ZD0210300, Shanghai Municipal Science and Technology Major Project grant 2018SHZDZX05, and Shanghai Municipal Science and Technology Major Project grant 2021SHZDZX. X.L. (Xue Li) is supported by National Science and Technology Innovation 2030 Major Program grant 2021ZD0202202 and Shanghai Municipal Science and Technology Major Project grant 2021SHZDZX. X.L. (Xia Li) is supported by the Shaanxi Health Research and Innovation Capacity Enhancement Program: Precision Prevention and Treatment of Cerebrovascular Diseases Research Innovation Team (Grant No. 2025TD-03).
Author information
Authors and Affiliations
Contributions
Conceptualization, X.L, Z.Z; Methodology, X.L, Z.Z, S.W, Z.Y, X.L, J.L; Investigation, S.W, X.L, Z.Y, X.L, Y.Q, J.L, Q.D, C.K, G.C, B.C, Z.Z; Data curation, S.W, C.K; Visualization, C.K, S.W; Writing—original draft, C.R, S.W, C.K; Writing—review & editing, Z.Z, S.W, J.L, X.L, X.L, X.J; Supervision, X.L, Z.Z, C.R; Project administration, X.L, Z.Z, C.R, S.W; Funding acquisition, X.L, Z.Z.
Corresponding authors
Ethics declarations
Competing interests
Z.Z. and X.L are the founders of Shanghai Stairmed Technology Co., Ltd. Z.Z., X.L are co-inventors on a patent (CN202210689990.9, 2022) on the electrode related to this study. The other authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks Ueli Rutishauser, Richárd Fiáth, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Wu, S., Yan, Z., Kong, C. et al. Large-scale single-neuron recording in the human cortex using an ultra-flexible electrode array. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71443-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-71443-7
