Single-cell and population-level neuromodulation dynamics in dual-electrode intracortical microstimulation

Intracortical microstimulation (ICMS) is widely used to activate cortical networks and evoke sensory percepts. Despite its successful clinical outcomes, how individual neurons respond to adjacent multi-electrode ICMS remains unclear. In this study, we combined two-photon calcium imaging with dual-electrode in mouse visual cortex, allowing us to directly observe how neurons behave converging electrical stimulation inputs.

This specific setting revealed that at low stimulation levels (5–7 µA), neural activity changed only modestly during dual-electrode stimulation input compared to single-electrode stimulation. As stimulation increased to intermediate levels (10–15 µA), neurons exhibited diverse nonlinear interactions—yet the overall population response shifted toward enhancement. At stronger stimulation (15–18 µA), the proportion of modulated neurons increased in both enhancement and attenuation directions, however, the net effect at the population level was neutral.

Neurons that responded strongly to single-electrode ICMS tended to be attenuated during dual-electrode stimulation, whereas weaker responders were often enhanced. The most pronounced modulatory effects occur at intermediate distances between the two electrodes. Together, our results indicate nonlinear neuromodulatory effects from dual-electrode, reflecting complex circuit-level interactions.

This data provides better understanding of single-cell modulation demonstrating how cortical networks integrate multiple ICMS inputs, informing necessary strategies to optimize neuroprosthetic performance. This study was supported by the Lundbeck Foundation (R402-2022-1530, R345-2020-1440, R436-2023-1125, R518-2025-934, and R392-2018-2266), the Independent Research Fund Denmark (#1133-00016B, #1030-00374B, and #1030-00374A), the Novo Nordisk Foundation (0064289, 0092323, 117272, 14CC0001, NNF26OC0112875, NNF24OC0092323, NNF20OC0064289, and NNF24OC0095407), Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Legat, Dagmar Marshalls Fond, Familien Hede Nielsens Fond and Hørslev fonden, and Oda og Hans Svenningsens Fond, the cNational Eye Institute (R01-EY-035437), the National Institute on Deafness and Other Communication Disorders (R01-DC-019916), and the U.S. Department of Veterans Affairs (1I01 BX-005959).

An animal image was created using Biorender under a license. Department of Neuroscience, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen N, Denmark Kayeon Kim, Victor Sonego, Beck Strohmer, Xiyuan Liu, Alexandra Katherine Isis Yonza, Krzysztof Kucharz, Antonios Asiminas, Barbara Lind, Lechan Tao, Xiao Zhang & Changsi Cai Department of Civil and Mechanical Engineering, Technical University of Denmark, Lyngby, Denmark Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Boston VA Healthcare System, Boston, MA, USA Correspondence to Kayeon Kim or Changsi Cai. The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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.