Abstract
Brain–computer interfaces—which allow direct communication between the brain and external computers—have potential applications in neuroscience, medicine and virtual reality. Current approaches are, however, based on conventional rigid electronics and are limited by their intrinsic mechanical and geometrical mismatch with brain tissue. Flexible electronics, which can have mechanical properties compatible with the brain, could address these limitations and be used to create the next generation of brain–computer interfaces. Here we explore the use of flexible electronics in the development of brain–computer interfaces. We examine the unique advantages of flexible, stretchable and soft electronics in such interfaces and consider the potential impact of the technology on neuroscience, neuroprosthetic control, bioelectronic medicine, and brain and machine intelligence integration. We also explore the challenges in materials, device fabrication and system integration that need to be addressed to develop flexible brain–computer interfaces of general applicability.
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References
Thakor, N. V. Translating the brain–machine interface. Sci. Transl. Med. 5, 210ps17 (2013).
Stanley, G. B. Reading and writing the neural code. Nat. Neurosci. 16, 259–263 (2013).
Hochberg, L. R. et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature 485, 372–375 (2012).
Patel, S. R. & Lieber, C. M. Precision electronic medicine in the brain. Nat. Biotechnol. 37, 1007–1012 (2019).
Makin, T. R., Micera, S. & Miller, L. E. Neurocognitive and motor-control challenges for the realization of bionic augmentation. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-022-00930-1 (2022).
Nicolas-Alonso, L. F. & Gomez-Gil, J. Brain computer interfaces, a review. Sensors 12, 1211–1279 (2012).
Pochay, P., Wise, K. D., Allard, L. F. & Rutledge, L. T. A multichannel depth probe fabricated using electron-beam lithography. IEEE Trans. Biomed. Eng. BME-26, 199–206 (1979).
Schwartz, A. B. Cortical neural prosthetics. Annu. Rev. Neurosci. 27, 487–507 (2004).
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., 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).
Kleinfeld, D. et al. Can one concurrently record electrical spikes from every neuron in a mammalian brain? Neuron 103, 1005–1015 (2019).
Abbott, J. et al. A nanoelectrode array for obtaining intracellular recordings from thousands of connected neurons. Nat. Biomed. Eng. 4, 232–241 (2020).
Jun, J. J. et al. Fully integrated silicon probes for high-density recording of neural activity. Nature 551, 232–236 (2017).
Steinmetz, N. A. et al. Neuropixels 2.0: a miniaturized high-density probe for stable, long-term brain recordings. Science 372, eabf4588 (2021).
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).
Obaid, A. et al. Massively parallel microwire arrays integrated with CMOS chips for neural recording. Sci. Adv. 6, eaay2789 (2020).
Zeng, H. & Sanes, J. R. Neuronal cell-type classification: challenges, opportunities and the path forward. Nat. Rev. Neurosci. 18, 530–546 (2017).
Chung, J. E. et al. High-density, long-lasting, and multi-region electrophysiological recordings using polymer electrode arrays. Neuron 101, 21–31.e5 (2019).
Musk, E. & Neuralink An integrated brain-machine interface platform with thousands of channels. J. Med. Internet Res. 21, e16194 (2019).
Xie, C. et al. Three-dimensional macroporous nanoelectronic networks as minimally invasive brain probes. Nat. Mater. 14, 1286–1292 (2015).
Fu, T.-M. et al. Stable long-term chronic brain mapping at the single-neuron level. Nat. Methods 13, 875–882 (2016).
Yang, X. et al. Bioinspired neuron-like electronics. Nat. Mater. 18, 510–517 (2019).
Lacour, S. P., Courtine, G. & Guck, J. Materials and technologies for soft implantable neuroprostheses. Nat. Rev. Mater. 1, 16063 (2016).
Liu, J. et al. Syringe-injectable electronics. Nat. Nanotechnol. 10, 629–636 (2015).
Kim, T. et al. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 340, 211–216 (2013).
Degenhart, A. D. et al. Stabilization of a brain–computer interface via the alignment of low-dimensional spaces of neural activity. Nat. Biomed. Eng. 4, 672–685 (2020).
Salatino, J. W., Ludwig, K. A., Kozai, T. D. Y. & Purcell, E. K. Glial responses to implanted electrodes in the brain. Nat. Biomed. Eng. 1, 862–877 (2017).
Khodagholy, D. et al. NeuroGrid: recording action potentials from the surface of the brain. Nat. Neurosci. 18, 310–315 (2015).
Viventi, J. et al. Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo. Nat. Neurosci. 14, 1599–1605 (2011).
Minev, I. R. et al. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).
Tian, B. et al. Macroporous nanowire nanoelectronic scaffolds for synthetic tissues. Nat. Mater. 11, 986–994 (2012).
Zhao, S. et al. Tracking neural activity from the same cells during the entire adult life of mice. Preprint at bioRxiv https://doi.org/10.1101/2021.10.29.466524 (2021).
Rogers, J. A., Someya, T. & Huang, Y. Materials and mechanics for stretchable electronics. Science 327, 1603–1607 (2010).
Le Floch, P. et al. Stretchable mesh nanoelectronics for 3D single-cell chronic electrophysiology from developing brain organoids. Adv. Mater. 34, 2106829 (2022).
Tringides, C. M. et al. Viscoelastic surface electrode arrays to interface with viscoelastic tissues. Nat. Nanotechnol. 16, 1019–1029 (2021).
Liu, Y. et al. Morphing electronics enable neuromodulation in growing tissue. Nat. Biotechnol. 38, 1031–1036 (2020).
Guan, S. et al. Elastocapillary self-assembled neurotassels for stable neural activity recordings. Sci. Adv. 5, eaav2842 (2019).
Zhao, Z. et al. Ultraflexible electrode arrays for months-long high-density electrophysiological mapping of thousands of neurons in rodents. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-022-00941-y (2022).
Fu, T.-M., Hong, G., Viveros, R. D., Zhou, T. & Lieber, C. M. Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology. Proc. Natl Acad. Sci. USA 114, E10046–E10055 (2017).
Chiang, C.-H. et al. Development of a neural interface for high-definition, long-term recording in rodents and nonhuman primates. Sci. Transl. Med. 12, eaay4682 (2020).
Luan, L. et al. Ultraflexible nanoelectronic probes form reliable, glial scar-free neural integration. Sci. Adv. 3, e1601966 (2017).
Liu, Y. et al. Soft and elastic hydrogel-based microelectronics for localized low-voltage neuromodulation. Nat. Biomed. Eng. 3, 58–68 (2019).
Zheng, Y.-Q. et al. Monolithic optical microlithography of high-density elastic circuits. Science 373, 88–94 (2021).
Wang, S. et al. Skin electronics from scalable fabrication of an intrinsically stretchable transistor array. Nature 555, 83–88 (2018).
Le Floch, P. et al. Fundamental limits to the electrochemical impedance stability of dielectric elastomers in bioelectronics. Nano Lett. 20, 224–233 (2020).
Liu, J. et al. Genetically targeted chemical assembly of functional materials in living cells, tissues, and animals. Science 367, 1372–1376 (2020).
Li, Q. et al. In situ electro-sequencing in three-dimensional tissues. Preprint at bioRxiv https://doi.org/10.1101/2021.04.22.440941 (2021).
Marin, C. & Fernández, E. Biocompatibility of intracortical microelectrodes: current status and future prospects. Front. Neuroeng. 3, 8 (2010).
Kozai, T. D. Y. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nat. Mater. 11, 1065–1073 (2012).
Cui, Y. et al. A stretchable and transparent electrode based on PEGylated silk fibroin for in vivo dual-modal neural-vascular activity probing. Adv. Mater. 33, 2100221 (2021).
Adewole, D. O. et al. Development of optically controlled ‘living electrodes’ with long-projecting axon tracts for a synaptic brain–machine interface. Sci. Adv. 7, eaay5347 (2021).
Won, C. et al. Mechanically tissue-like and highly conductive Au nanoparticles embedded elastomeric fiber electrodes of brain–machine interfaces for chronic in vivo brain neural recording. Adv. Funct. Mater. 32, 2205145 (2022).
Natraj, N., Silversmith, D. B., Chang, E. F. & Ganguly, K. Compartmentalized dynamics within a common multi-area mesoscale manifold represent a repertoire of human hand movements. Neuron 110, 154–174.e12 (2022).
Schoonover, C. E., Ohashi, S. N., Axel, R. & Fink, A. J. P. Representational drift in primary olfactory cortex. Nature 594, 541–546 (2021).
Tang, X. et al. Multi-task learning for single-cell multi-modality biology. Preprint at bioRxiv https://doi.org/10.1101/2022.06.03.494730 (2022).
Anumanchipalli, G. K., Chartier, J. & Chang, E. F. Speech synthesis from neural decoding of spoken sentences. Nature 568, 493–498 (2019).
Jazayeri, M. & Ostojic, S. Interpreting neural computations by examining intrinsic and embedding dimensionality of neural activity. Curr. Opin. Neurobiol. 70, 113–120 (2021).
Panzeri, S., Moroni, M., Safaai, H. & Harvey, C. D. The structures and functions of correlations in neural population codes. Nat. Rev. Neurosci. 23, 551–567 (2022).
Chaudhuri, R., Gerçek, B., Pandey, B., Peyrache, A. & Fiete, I. The intrinsic attractor manifold and population dynamics of a canonical cognitive circuit across waking and sleep. Nat. Neurosci. 22, 1512–1520 (2019).
Yamins, D. L. K. et al. Performance-optimized hierarchical models predict neural responses in higher visual cortex. Proc. Natl Acad. Sci. USA 111, 8619–8624 (2014).
Yang, G. R., Joglekar, M. R., Song, H. F., Newsome, W. T. & Wang, X.-J. Task representations in neural networks trained to perform many cognitive tasks. Nat. Neurosci. 22, 297–306 (2019).
Zidan, M. A., Strachan, J. P. & Lu, W. D. The future of electronics based on memristive systems. Nat. Electron. 1, 22–29 (2018).
Liu, J. et al. Fully stretchable active-matrix organic light-emitting electrochemical cell array. Nat. Commun. 11, 3362 (2020).
Jiang, Y. et al. Topological supramolecular network enabled high-conductivity, stretchable organic bioelectronics. Science 375, 1411–1417 (2022).
Dong, R. et al. Printed stretchable liquid metal electrode arrays for in vivo neural recording. Small 17, 2006612 (2021).
Afanasenkau, D. et al. Rapid prototyping of soft bioelectronic implants for use as neuromuscular interfaces. Nat. Biomed. Eng. 4, 1010–1022 (2020).
Opie, N. L. et al. Focal stimulation of the sheep motor cortex with a chronically implanted minimally invasive electrode array mounted on an endovascular stent. Nat. Biomed. Eng. 2, 907–914 (2018).
Even-Chen, N. et al. Power-saving design opportunities for wireless intracortical brain–computer interfaces. Nat. Biomed. Eng. 4, 984–996 (2020).
Jeong, J.-W. et al. Wireless optofluidic systems for programmable in vivo pharmacology and optogenetics. Cell 162, 662–674 (2015).
Park, S. I. et al. Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Nat. Biotechnol. 33, 1280–1286 (2015).
Huo, Q. et al. A computing-in-memory macro based on three-dimensional resistive random-access memory. Nat. Electron. 5, 469–477 (2022).
Lein, E., Borm, L. E. & Linnarsson, S. The promise of spatial transcriptomics for neuroscience in the era of molecular cell typing. Science 358, 64–69 (2017).
Lichtman, J. W., Pfister, H. & Shavit, N. The big data challenges of connectomics. Nat. Neurosci. 17, 1448–1454 (2014).
Dorrah, A. H. & Capasso, F. Tunable structured light with flat optics. Science 376, eabi6860 (2022).
Acknowledgements
This work is supported by the Harvard School of Engineering and Applied Sciences Faculty Start Up Fund and Harvard University Dean’s Competitive Fund for Promising Scholarship. Elements in Figs. 1–4 created with BioRender.com.
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J.L., X.T. and H.S. conceived this Perspective. All authors wrote the manuscript.
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J.L. is co-founder of Axoft, Inc.
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Tang, X., Shen, H., Zhao, S. et al. Flexible brain–computer interfaces. Nat Electron 6, 109–118 (2023). https://doi.org/10.1038/s41928-022-00913-9
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DOI: https://doi.org/10.1038/s41928-022-00913-9