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Peer-reviewedCC BYCell Systems

Multipair phase-modulated temporal interference electrical stimulation combined with fMRI

  • Iurii Savvateev1,2
  • Florian Missey3
  • Valeriia Beliaeva1,2
  • Sofia Peressotti4,5
  • Marija Markicevic6,7,8
  • Diana Kindler9,7,8
  • Fabrice Chaudun10,11
  • Giulia Casarotto10,11,3
  • Camilla Bellone10,2
  • Christian Lüscher10,12,13
  • Daniel Razansky9
  • Viktor Jirsa14
3 more authors
  • Adam Williamson15
  • Rafael Hernán Polanía16
  • Valerio Zerbi17
17 affiliations
  1. 1Decision Neuroscience Lab, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
  2. 2Decision Neuroscience lab, Department of Health Sciences and Technology, ETH Zurich, Switzerland
  3. 3International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
  4. 4Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  5. 5Department of Radiology and Biomedical Imaging, Yale School of Medicine, United States
  6. 6Department of Neurology, Insel University Hospital Bern and University of Bern, Bern, Switzerland
  7. 7Institute for Biomedical Engineering, Department of Information Technology and Electrical Engineering, ETH Zurich, Switzerland
  8. 8Institute of Pharmacology and Toxicology and Institute for Biomedical Engineering, Faculty of Medicine, University of Zurich, Switzerland
  9. 9Institute of Pharmacology and Toxicology, Institute for Biomedical Engineering, Faculty of Medicine, University of Zurich, Zurich, Switzerland; Institute for Biomedical Engineering, Department of Information Technology and Electrical Engineering, ETH Zurich, Zurich, Switzerland
  10. 10Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  11. 11Aix-Marseille Université, Inserm, Institut de Neurosciences des Systèmes (INS) UMR_S 110, Marseille, France
  12. 12CIBM Centre for Biomedical Imaging, Lausanne, Switzerland
  13. 13Neuro-X Institute, School of Engineering (STI), EPFL, Lausanne, Switzerland
  14. 14Aix-Marseille Université, Inserm, Institut de Neurosciences des Systèmes (INS) UMR_S, 1106 Marseille, France
  15. 15International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic; Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
  16. 16Decision Neuroscience Lab, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland; Centre for Brain, Mind and Markets, Faculty of Business and Economics, The University of Melbourne, Melbourne, VIC, Australia
  17. 17Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: [email protected]
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Abstract

Temporal interference stimulation (TIS) is a non-invasive brain stimulation technique that exploits frequency-shifted kHz fields to modulate oscillatory neural activity. While human studies suggest TIS efficacy in targeting relatively deep brain structures, recent computational modeling and animal studies indicate potential off-target stimulations via standard TIS protocols. Here, we computationally optimized TIS targeting for the medial prefrontal cortex (mPFC) in mice. Combining in vivo electrophysiological recordings, intracellular calcium dynamics with fiber photometry, and functional MRI, we confirmed TIS-induced amplitude modulation, neuronal entrainment, and hemodynamic responses in the mPFC, while also identifying off-target modulations. To mitigate off-target effects, we introduced a configuration with three electrode pairs, one of which is actively phase-shifted by 180°. This canceling field enhanced TIS focality, thereby reducing off-target effects without compromising TIS efficacy in the target area. This work effectively addresses one of TIS's most critical shortcomings and opens new avenues for research and clinical applications. A record of this paper's transparent peer review process is included in the supplemental information.

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Cite

BibTeXRIS
BibTeX
@article{savvateev2026multipair,
  title = {{Multipair phase-modulated temporal interference electrical stimulation combined with fMRI}},
  author = {Iurii Savvateev and Florian Missey and Valeriia Beliaeva and Sofia Peressotti and Marija Markicevic and Diana Kindler and Fabrice Chaudun and Giulia Casarotto and Camilla Bellone and Christian Lüscher and Daniel Razansky and Viktor Jirsa and Adam Williamson and Rafael Hernán Polanía and Valerio Zerbi},
  journal = {Cell Systems},
  year = {2026},
  month = may,
  doi = {10.1016/j.cels.2026.101610},
  url = {https://doi.org/10.1016/j.cels.2026.101610},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Multipair phase-modulated temporal interference electrical stimulation combined with fMRI
AU  - Iurii Savvateev
AU  - Florian Missey
AU  - Valeriia Beliaeva
AU  - Sofia Peressotti
AU  - Marija Markicevic
AU  - Diana Kindler
AU  - Fabrice Chaudun
AU  - Giulia Casarotto
AU  - Camilla Bellone
AU  - Christian Lüscher
AU  - Daniel Razansky
AU  - Viktor Jirsa
AU  - Adam Williamson
AU  - Rafael Hernán Polanía
AU  - Valerio Zerbi
PY  - 2026
DA  - 2026/05/14
JO  - Cell Systems
DO  - 10.1016/j.cels.2026.101610
UR  - https://doi.org/10.1016/j.cels.2026.101610
AB  - Temporal interference stimulation (TIS) is a non-invasive brain stimulation technique that exploits frequency-shifted kHz fields to modulate oscillatory neural activity. While human studies suggest TIS efficacy in targeting relatively deep brain structures, recent computational modeling and animal studies indicate potential off-target stimulations via standard TIS protocols. Here, we computationally optimized TIS targeting for the medial prefrontal cortex (mPFC) in mice. Combining in vivo electrophysiological recordings, intracellular calcium dynamics with fiber photometry, and functional MRI, we confirmed TIS-induced amplitude modulation, neuronal entrainment, and hemodynamic responses in the mPFC, while also identifying off-target modulations. To mitigate off-target effects, we introduced a configuration with three electrode pairs, one of which is actively phase-shifted by 180°. This canceling field enhanced TIS focality, thereby reducing off-target effects without compromising TIS efficacy in the target area. This work effectively addresses one of TIS's most critical shortcomings and opens new avenues for research and clinical applications. A record of this paper's transparent peer review process is included in the supplemental information.
SN  - 2405-4712
SN  - 2405-4720
SN  - 2639-5460
ER  -