Human applications of transcranial temporal interference stimulation: A systematic review

Ilya Demchenko¹, Ishaan Tailor², Sina Chegini³, Haochen Yu⁴, Fatemeh Gholamali Nezhad⁵, Alice Rueda⁶, Anne Kever⁷, Sridhar Krishnan⁸, Abhishek Datta⁹, Jed A Meltzer¹⁰, Simon J Graham¹¹, Tom A Schweizer¹², Sumientra Rampersad¹³, Edward S Boyden¹⁴, Ines R Violante¹⁵, Robert Chen¹⁶, Andres M Lozano¹⁷, Venkat Bhat¹⁸

Affiliations

¹ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada. Electronic address: ilya.demchenko@unityhealth.to.
² Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: ishaan.tailor@rutgers.edu.
³ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: schegin@uwo.ca.
⁴ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: Haochen.Yu@unityhealth.to.
⁵ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: Fatemeh.Gholamalinezhad@unityhealth.to.
⁶ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada. Electronic address: Alice.Rueda@unityhealth.to.
⁷ BARLO Multiple Sclerosis Centre and Division of Neurology, St. Michael's Hospital - Unity Health Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada; Department of Psychology, Faculty of Arts & Science, University of Toronto, 100 St. George Street, Toronto, ON, M5S 3G3, Canada. Electronic address: Anne.Kever@unityhealth.to.
⁸ Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Department of Electrical, Computer, and Biomedical Engineering, Toronto Metropolitan University, 350 Victoria Street, ON, Toronto, M5B 2K3, Canada. Electronic address: krishnan@torontomu.ca.
⁹ Research and Development, Soterix Medical, Inc., 1480 U.S. Highway 9 North, Woodbridge, NJ, 07095, United States; Department of Biomedical Engineering, City College of New York, 160 Convent Avenue, New York, NY, 10031, United States. Electronic address: adatta@soterixmedical.com.
¹⁰ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Department of Psychology, Faculty of Arts & Science, University of Toronto, 100 St. George Street, Toronto, ON, M5S 3G3, Canada; Rotman Research Institute, Baycrest Hospital, 3560 Bathurst Street, Toronto, ON, M6A 1W1, Canada. Electronic address: jmeltzer@research.baycrest.org.
¹¹ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Physical Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, 101 College Street, Toronto, ON, M5G 2C4, Canada. Electronic address: sgraham@sri.utoronto.ca.
¹² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON, M5T 1P5, Canada. Electronic address: Tom.Schweizer@unityhealth.to.
¹³ Department of Physics, University of Massachusetts Boston, 100 William T Morrissey Boulevard, Boston, MA, 02125, United States; Department of Electrical and Computer Engineering, Northeastern University, 100 Forsyth Street, Boston, MA, 02115, United States. Electronic address: s.rampersad@northeastern.edu.
¹⁴ Department of Brain and Cognitive Sciences, Media Arts and Sciences, and Biological Engineering, McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, United States; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD, 20815, United States. Electronic address: edboyden@mit.edu.
¹⁵ School of Biomedical Engineering & Imaging Sciences, King's College London, Strand, London, WC2R 2LS, United Kingdom; School of Psychology, Faculty of Health and Medical Sciences, University of Surrey, 30 Priestley Road, Guildford, GU2 7YH, United Kingdom. Electronic address: ines.violante@kcl.ac.uk.
¹⁶ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Krembil Brain Institute, Toronto Western Hospital - University Health Network, 135 Nassau Street, Toronto, ON, M5T 1M8, Canada; Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital - University Health Network, 399 Bathurst Street, Toronto, ON, M5T 2S6, Canada; Division of Neurology, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, M5S 3H2, Canada. Electronic address: robert.chen@uhn.ca.
¹⁷ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON, M5T 1P5, Canada; Krembil Brain Institute, Toronto Western Hospital - University Health Network, 135 Nassau Street, Toronto, ON, M5T 1M8, Canada. Electronic address: Andres.Lozano@uhn.ca.
¹⁸ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, ON M5T 1R8, Canada. Electronic address: venkat.bhat@utoronto.ca.

PMID: 41167554
DOI: 10.1016/j.brs.2025.10.023

Review

Human applications of transcranial temporal interference stimulation: A systematic review

Ilya Demchenko et al. Brain Stimul. 2025.

. 2025 Oct 28;18(6):2054-2066.

doi: 10.1016/j.brs.2025.10.023. Online ahead of print.

Authors

Affiliations

¹ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada. Electronic address: ilya.demchenko@unityhealth.to.
² Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: ishaan.tailor@rutgers.edu.
³ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: schegin@uwo.ca.
⁴ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: Haochen.Yu@unityhealth.to.
⁵ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada. Electronic address: Fatemeh.Gholamalinezhad@unityhealth.to.
⁶ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada. Electronic address: Alice.Rueda@unityhealth.to.
⁷ BARLO Multiple Sclerosis Centre and Division of Neurology, St. Michael's Hospital - Unity Health Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada; Department of Psychology, Faculty of Arts & Science, University of Toronto, 100 St. George Street, Toronto, ON, M5S 3G3, Canada. Electronic address: Anne.Kever@unityhealth.to.
⁸ Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Department of Electrical, Computer, and Biomedical Engineering, Toronto Metropolitan University, 350 Victoria Street, ON, Toronto, M5B 2K3, Canada. Electronic address: krishnan@torontomu.ca.
⁹ Research and Development, Soterix Medical, Inc., 1480 U.S. Highway 9 North, Woodbridge, NJ, 07095, United States; Department of Biomedical Engineering, City College of New York, 160 Convent Avenue, New York, NY, 10031, United States. Electronic address: adatta@soterixmedical.com.
¹⁰ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Department of Psychology, Faculty of Arts & Science, University of Toronto, 100 St. George Street, Toronto, ON, M5S 3G3, Canada; Rotman Research Institute, Baycrest Hospital, 3560 Bathurst Street, Toronto, ON, M6A 1W1, Canada. Electronic address: jmeltzer@research.baycrest.org.
¹¹ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Physical Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, 101 College Street, Toronto, ON, M5G 2C4, Canada. Electronic address: sgraham@sri.utoronto.ca.
¹² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON, M5T 1P5, Canada. Electronic address: Tom.Schweizer@unityhealth.to.
¹³ Department of Physics, University of Massachusetts Boston, 100 William T Morrissey Boulevard, Boston, MA, 02125, United States; Department of Electrical and Computer Engineering, Northeastern University, 100 Forsyth Street, Boston, MA, 02115, United States. Electronic address: s.rampersad@northeastern.edu.
¹⁴ Department of Brain and Cognitive Sciences, Media Arts and Sciences, and Biological Engineering, McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, United States; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD, 20815, United States. Electronic address: edboyden@mit.edu.
¹⁵ School of Biomedical Engineering & Imaging Sciences, King's College London, Strand, London, WC2R 2LS, United Kingdom; School of Psychology, Faculty of Health and Medical Sciences, University of Surrey, 30 Priestley Road, Guildford, GU2 7YH, United Kingdom. Electronic address: ines.violante@kcl.ac.uk.
¹⁶ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Krembil Brain Institute, Toronto Western Hospital - University Health Network, 135 Nassau Street, Toronto, ON, M5T 1M8, Canada; Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital - University Health Network, 399 Bathurst Street, Toronto, ON, M5T 2S6, Canada; Division of Neurology, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, M5S 3H2, Canada. Electronic address: robert.chen@uhn.ca.
¹⁷ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON, M5T 1P5, Canada; Krembil Brain Institute, Toronto Western Hospital - University Health Network, 135 Nassau Street, Toronto, ON, M5T 1M8, Canada. Electronic address: Andres.Lozano@uhn.ca.
¹⁸ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON, M5B 1M4, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON, M5S 3H2, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON, M5B 1X3, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, ON M5T 1R8, Canada. Electronic address: venkat.bhat@utoronto.ca.

PMID: 41167554
DOI: 10.1016/j.brs.2025.10.023

Abstract

Background: Many neurological and psychiatric disorders involve dysregulation of subcortical structures. Transcranial temporal interference stimulation (tTIS) is a novel, non-invasive method developed to selectively modulate deep brain regions and associated neural circuits.

Methods: A systematic review was conducted to evaluate human applications of tTIS (PROSPERO ID: CRD42024559678). MEDLINE, Embase, APA PsycINFO, CENTRAL, ClinicalTrials.gov, and WHO ICTRP were searched up to December 12, 2024. Studies involving human applications of tTIS were eligible. Methodological quality was appraised using the National Institutes of Health and modified Oxford Centre for Evidence-Based Medicine tools.

Results: Forty-eight records were reviewed (20 published studies, 28 ongoing trials). Of published studies, 16 single-session and 4 multi-session studies assessed safety, mechanistic outcomes, or therapeutic effects of tTIS in 820 participants. Stimulation was most commonly delivered at beta (20 Hz) or gamma (30-130 Hz) envelope frequencies. Neuroimaging studies support target engagement of the motor cortex, basal ganglia, and hippocampus in humans, particularly when stimulation is paired with behavioural tasks. Preliminary clinical findings in small samples demonstrated acute symptom improvements in bradykinesia and tremor within 60 min following a single tTIS session in Parkinson's disease and essential tremor. Reported adverse events across studies were mild (e.g., tingling, itching). Emerging trials increasingly utilize multi-session protocols (2-40 sessions) and are extending tTIS to patients with neurological and psychiatric disorders, particularly epilepsy and depression.

Conclusions: Phase 1 studies demonstrate that tTIS is safe, well-tolerated, and capable of engaging deep brain targets in humans. Well-controlled Phase 2 trials are needed to assess its therapeutic potential in patient populations.

Keywords: Brain; Clinical study; Deep brain stimulation; Electric stimulation; Humans; Systematic review; Temporal interference.

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Conflict of interest statement

Declaration of competing interest IT, SC, HY, FG, AR, AK, SK, JAM, SJG, TAS, and SR report no conflicts of interest. ID is a Vanier Scholar supported by the Canadian Institutes of Health Research (award number 513715). AD is an employee of Soterix Medical, Inc. and is supported by the National Institutes of Health (grant numbers 1UG3NS139014–01 and R01EB035129), the National Aeronautics and Space Administration (grant number 80NSSC22CA071), and the United States Department of Defense (grant number W81XWH22C0111). ESB is an inventor on the Temporal Interference (TI) Stimulation patent and a co-founder of TI Solutions GmbH, a for-profit company. IRV is supported by the Biotechnology and Biological Sciences Research Council (grant number BB/S008314/1). RC has received research funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Parkinson Foundation, the National Organization for Rare Disorders, and the Dystonia Medical Research Foundation. He has served as a consultant for AbbVie, Ipsen, and Merz, and participated in a research study sponsored by AbbVie. AML holds the Hudson Chair in Neurosurgery and is a consultant for Abbott, Boston Scientific, and Functional Neuromodulation Inc. VB is supported by an Academic Scholar Award from the Department of Psychiatry at the University of Toronto and has received research support from the Canadian Institutes of Health Research, the Brain & Behavior Research Foundation, the Ontario Ministry of Health Innovation Funds, the Royal College of Physicians and Surgeons of Canada, the Department of National Defence (Government of Canada), the New Frontiers in Research Fund, the American Foundation for Suicide Prevention, the University of Toronto Connaught Fund, the University of Toronto Excellence in Mental Health Seed Fund, and investigator-initiated trials supported by Roche Canada, Eisai Canada, Novartis, Associated Medical Services Inc. Healthcare, and the National Research Council of Canada.

Update of

WITHDRAWN: Human Applications of Transcranial Temporal Interference Stimulation: A Systematic Review.
Demchenko I, Tailor I, Chegini S, Yu H, Nezhad FG, Rueda A, Kever A, Krishnan S, Datta A, Meltzer JA, Graham SJ, Schweizer TA, Rampersad S, Boyden ES, Violante IR, Chen R, Lozano AM, Bhat V. Demchenko I, et al. Brain Stimul. 2025 Aug 18:S1935-861X(25)00303-1. doi: 10.1016/j.brs.2025.08.010. Online ahead of print. Brain Stimul. 2025. Update in: Brain Stimul. 2025 Oct 28;18(6):2054-2066. doi: 10.1016/j.brs.2025.10.023. PMID: 40835066 Updated.

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Human applications of transcranial temporal interference stimulation: A systematic review

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Human applications of transcranial temporal interference stimulation: A systematic review

Authors

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Abstract

Conflict of interest statement

Update of

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