This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2025 Sep 23:2025.05.16.25327804.

doi: 10.1101/2025.05.16.25327804.

Human Applications of Transcranial Temporal Interference Stimulation: A Systematic Review

Ilya Demchenko^{1

2

3}, Ishaan Tailor¹, Sina Chegini¹, Haochen Yu¹, Fatemeh Gholamali Nezhad¹, Alice Rueda^{1

3}, Anne Kever^{4

5}, Sridhar Krishnan^{3

6}, Abhishek Datta^{7

8}, Jed A Meltzer^{2

5

9}, Simon J Graham^{2

10

11}, Tom A Schweizer^{2

12

13

14}, Sumientra Rampersad^{15

16}, Edward S Boyden^{17

18}, Ines R Violante^{19

20}, Robert Chen^{2

21

22

23}, Andres M Lozano^{2

14

21}, Venkat Bhat^{1

2

3

12

13

24}

Affiliations

¹ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON M5B 1M4, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON M5S 3H2, Canada.
³ 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 1×3, Canada.
⁴ BARLO Multiple Sclerosis Centre and Division of Neurology, St. Michael's Hospital - Unity Health Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
⁵ Department of Psychology, Faculty of Arts & Science, University of Toronto, 100 St. George Street, Toronto, ON M5S 3G3, Canada.
⁶ Department of Electrical, Computer, and Biomedical Engineering, Toronto Metropolitan University, Toronto, 350 Victoria Street, ON M5B 2K3, Canada.
⁷ Research and Development, Soterix Medical, Inc., 1480 US-9, Woodbridge, NJ 07095, United States.
⁸ Department of Biomedical Engineering, City College of New York, 160 Convent Avenue, New York, NY 10031, United States.
⁹ Rotman Research Institute, Baycrest Hospital, 3560 Bathurst Street, Toronto, ON M6A 1W1, Canada.
¹⁰ Physical Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
¹¹ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, 101 College Street, Toronto, ON M5G 2C4, Canada.
¹² Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON M5B 1×3, Canada.
¹³ Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON M5B 1×3, Canada.
¹⁴ Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada.
¹⁵ Department of Physics, University of Massachusetts Boston, 100 William T Morrissey Boulevard, Boston, MA 02125, United States.
¹⁶ Department of Electrical and Computer Engineering, Northeastern University, 100 Forsyth Street, Boston, MA 02115, United States.
¹⁷ 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.
¹⁸ Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, United States.
¹⁹ School of Biomedical Engineering & Imaging Sciences, King's College London, Strand, London WC2R 2LS, United Kingdom.
²⁰ School of Psychology, Faculty of Health and Medical Sciences, University of Surrey, 30 Priestley Road, Guildford GU2 7YH, United Kingdom.
²¹ Krembil Brain Institute, Toronto Western Hospital - University Health Network, 135 Nassau Street, Toronto, ON M5T 1M8, Canada.
²² 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.
²³ Division of Neurology, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON M5S 3H2, Canada.
²⁴ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, ON M5T 1R8, Canada.

PMID: 40463528
PMCID: PMC12132165
DOI: 10.1101/2025.05.16.25327804

Human Applications of Transcranial Temporal Interference Stimulation: A Systematic Review

Ilya Demchenko et al. medRxiv. 2025.

[Preprint]. 2025 Sep 23:2025.05.16.25327804.

doi: 10.1101/2025.05.16.25327804.

Authors

Affiliations

¹ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, 193 Yonge Street, Toronto, ON M5B 1M4, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent, Toronto, ON M5S 3H2, Canada.
³ 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 1×3, Canada.
⁴ BARLO Multiple Sclerosis Centre and Division of Neurology, St. Michael's Hospital - Unity Health Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
⁵ Department of Psychology, Faculty of Arts & Science, University of Toronto, 100 St. George Street, Toronto, ON M5S 3G3, Canada.
⁶ Department of Electrical, Computer, and Biomedical Engineering, Toronto Metropolitan University, Toronto, 350 Victoria Street, ON M5B 2K3, Canada.
⁷ Research and Development, Soterix Medical, Inc., 1480 US-9, Woodbridge, NJ 07095, United States.
⁸ Department of Biomedical Engineering, City College of New York, 160 Convent Avenue, New York, NY 10031, United States.
⁹ Rotman Research Institute, Baycrest Hospital, 3560 Bathurst Street, Toronto, ON M6A 1W1, Canada.
¹⁰ Physical Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
¹¹ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, 101 College Street, Toronto, ON M5G 2C4, Canada.
¹² Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON M5B 1×3, Canada.
¹³ Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, 209 Victoria Street, Toronto, ON M5B 1×3, Canada.
¹⁴ Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada.
¹⁵ Department of Physics, University of Massachusetts Boston, 100 William T Morrissey Boulevard, Boston, MA 02125, United States.
¹⁶ Department of Electrical and Computer Engineering, Northeastern University, 100 Forsyth Street, Boston, MA 02115, United States.
¹⁷ 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.
¹⁸ Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, United States.
¹⁹ School of Biomedical Engineering & Imaging Sciences, King's College London, Strand, London WC2R 2LS, United Kingdom.
²⁰ School of Psychology, Faculty of Health and Medical Sciences, University of Surrey, 30 Priestley Road, Guildford GU2 7YH, United Kingdom.
²¹ Krembil Brain Institute, Toronto Western Hospital - University Health Network, 135 Nassau Street, Toronto, ON M5T 1M8, Canada.
²² 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.
²³ Division of Neurology, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON M5S 3H2, Canada.
²⁴ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, ON M5T 1R8, Canada.

PMID: 40463528
PMCID: PMC12132165
DOI: 10.1101/2025.05.16.25327804

Update in

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. PMID: 40835066

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 NIH 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 minutes 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.

PubMed Disclaimer

Figures

**Figure 1.**
PRISMA flow diagram illustrating the study selection process for the systematic review examining tTIS applications in humans.

**Figure 2.. Trends, Study Designs, and Clinical Populations in Human tTIS Research.**
**(A)** Number of published studies and ongoing clinical trials involving human tTIS from 2018 and 2024. (B) Study design types among published human tTIS studies and ongoing clinical trials. (C) Sample size distribution in published human tTIS studies and ongoing clinical trials. (D) Study populations by condition in published human tTIS studies and ongoing clinical trials. **Abbreviations**: AD = Alzheimer’s disease; BD = Bipolar disorder; CP = Cerebral palsy; DoCs = Disorders of consciousness; ET = Essential tremor; MDD = Major depressive disorder; PD = Parkinson’s disease; PPCGD = Pretest-posttest control group design; PPD = Pretest-posttest design; RCT = Randomized controlled trial; TBI = Traumatic brain injury; WSD = Within-subjects design.

**Figure 3.. Status, Allocation, and Blinding Methods of Human tTIS Studies and Ongoing Clinical Trials.**
**(A)** Status of published human tTIS studies (completed) and ongoing clinical trials. **(B)** Distribution of group assignment methods in published human tTIS studies and ongoing clinical trials. **(C)** Distribution of masking methods used in published human tTIS studies and ongoing clinical trials.

**Figure 4.. Global Landscape and Methodological Characteristics of Human tTIS Studies and Ongoing Clinical Trials.**
**(A)** Geographic distribution of published human tTIS studies, highlighting regions actively contributing to the field. *Map lines delineate study areas and do not necessarily depict accepted national boundaries*. **(B)** Geographic distribution of ongoing human tTIS clinical trials, reflecting current global research efforts. *Map lines delineate study areas and do not necessarily depict accepted national boundaries*. **(C)** Outcome measures reported in published human tTIS studies and those being collected in ongoing clinical trials. **(D)** tTIS envelope frequency bands used in published human tTIS studies and ongoing clinical trials, showing variation in stimulation parameters. **Abbreviations:** MRI = Magnetic resonance imaging.

**Figure 5.. Brain Targets in Human tTIS Studies and Ongoing Clinical Trials.**
**(A)** Brain regions targeted in published human tTIS studies, illustrating early applications of the technique. **(B)** Brain regions targeted in ongoing human tTIS clinical trials, reflecting current translational priorities and therapeutic goals. **Abbreviations:** dACC = Dorsal anterior cingulate cortex; dlPFC = Dorsolateral prefrontal cortex; GPi = Globus pallidus internus; IPL = Inferior parietal lobule; M1 = Primary motor cortex; NAc = Nucleus accumbens; PCu = Precuneus; PMC = Posteromedial cortex; Pulv = Pulvinar nuclei; Put = Putamen; S1 = Primary somatosensory cortex; sgACC = Subgenual anterior cingulate cortex; SN = Substantia nigra; STN = Subthalamic nucleus; V1 = Primary visual cortex; vmPFC = Ventromedial prefrontal cortex.

See this image and copyright information in PMC

References

1. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:459–80. 10.1016/S1474-4422(18)30499-X. - DOI - PMC - PubMed
1. GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Psychiatry 2022;9:137–50. 10.1016/S2215-0366(21)00395-3. - DOI - PMC - PubMed
1. Lozano AM, Lipsman N, Bergman H, Brown P, Chabardes S, Chang JW, et al. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol 2019;15:148–60. 10.1038/s41582-018-0128-2. - DOI - PMC - PubMed
1. Fenoy AJ, Simpson RK. Risks of common complications in deep brain stimulation surgery: management and avoidance: Clinical article. JNS 2014;120:132–9. 10.3171/2013.10.JNS131225. - DOI
1. Camacho Conde JA, Gonzalez Bermudez MDR, Carretero Rey M, Khan ZU. Brain stimulation: a therapeutic approach for the treatment of neurological disorders. CNS Neurosci Ther 2022;28:5–18. 10.1111/cns.13769. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

This is a preprint.

Human Applications of Transcranial Temporal Interference Stimulation: A Systematic Review

Affiliations

Human Applications of Transcranial Temporal Interference Stimulation: A Systematic Review

Authors

Affiliations

Update in

Abstract

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources