Progresses on temporal interference electromagnetic stimulation for non-invasive deep brain function modulation_Journal of Biomedical Engineering

Authors：

ZHOU Ting ^1,2 , YU Peng ² ,  XU Yajie ²

1. School of Biomedical Engineering, School of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, P. R. China;
2. Medical Imaging Laboratory, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, P. R. China;

Corresponding?author：

Keywords：

Temporal interference electromagnetic stimulation; Deep brain function modulation; Electric field focusing; Artificial intelligence optimization

DOI：

10.7507/1001-5515.202502016

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

This article presents a systematic review of the research progress on temporal interference (TI) electromagnetic stimulation for deep brain function modulation. It first analyzes the fundamental principle of generating low-frequency envelopes through the interference of dual-frequency electric or magnetic fields. Combined with simulation studies, this analysis reveals that TI offers superior focal specificity in deep brain regions compared with traditional transcranial electric or magnetic stimulation. The reviewed studies indicate that multi-electrode or multi-coil configurations can substantially enhance the focality and penetration of electric fields in deep brain areas. In clinical applications, TI has shown potential advantages in improving motor symptoms in Parkinson’s disease, enhancing working memory, and localizing epileptic foci, though careful evaluation on TI’s safety and ethical considerations remains essential. Finally, this review highlights that integrating artificial intelligence-based parameter optimization with personalized brain network modeling represents a key pathway toward overcoming current technical limitations, hoping to lay a theoretical foundation for developing closed-loop precise neuromodulation systems.

1.	Davidson B, Bhattacharya A, Sarica C, et al. Neuromodulation techniques–from non-invasive brain stimulation to deep brain stimulation. Neurotherapeutics, 2024, 21(3): e00330.
2.	Denison T, Morrell M J. Neuromodulation in 2035: the neurology future forecasting series. Neurology, 2022, 98(2): 65-72.
3.	胡燦芳, 鐘傳鈺, 曹立. 神經調控技術在帕金森病治療中的應用研究進展. 上海交通大學學報(醫學版), 2024, 44(2): 258-263.
4.	任偉, 卜楊瑩, 朱文禮, 等. 神經調控技術在精神分裂癥中的應用進展. 臨床精神醫學雜志, 2024, 34(5): 415-417.
5.	Oehrn C R, Cernera S, Hammer L H, et al. Chronic adaptive deep brain stimulation versus conventional stimulation in Parkinson’s disease: a blinded randomized feasibility trial. Nature Medicine, 2024, 30(11): 3345-3356.
6.	Meyer G M, Hollunder B, Li N, et al. Deep brain stimulation for obsessive-compulsive disorder: optimal stimulation sites. Biological Psychiatry, 2024, 96(2): 101-113.
7.	Violante I R, Alania K, Cassarà A M, et al. Non-invasive temporal interference electrical stimulation of the human hippocampus. Nature Neuroscience, 2023, 26(11): 1994-2004.
8.	Guo W, He Y, Zhang W, et al. A novel non-invasive brain stimulation technique: “temporally interfering electrical stimulation”. Front Neurosci, 2023, 17: 1092539.
9.	Deng Z D, Lisanby S H, Peterchev A V. Electric field depth-focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul, 2013, 6(1): 1-13.
10.	Khalifa A, Abrishami S M, Zaeimbashi M, et al. Magnetic temporal interference for noninvasive and focal brain stimulation. J Neural Eng, 2023, 20(1): 016002.
11.	Grossman N, Bono D, Dedic N, et al. Noninvasive deep brain stimulation via temporally interfering electric fields. Cell, 2017, 169(6): 1029-1041.
12.	Karimi F, Attarpour A, Amirfattahi R, et al. Computational analysis of non-invasive deep brain stimulation based on interfering electric fields. Phys Med Biol, 2019, 64(23): 235010.
13.	Mirzakhalili E, Barra B, Capogrosso M, et al. Biophysics of temporal interference stimulation. Cell Syst, 2020, 11(6): 557-572.
14.	Howell B, McIntyre C C. Feasibility of interferential and pulsed transcranial electrical stimulation for neuromodulation at the human scale. Neuromodulation, 2021, 24(5): 843-853.
15.	Cao J, Doiron B, Goswami C, et al. The mechanics of temporal interference stimulation. arXiv preprint, 2020, arXiv: 2020.04.23.051870.
16.	Caldas-Martinez S, Goswami C, Forssell M, et al. Cell-specific effects of temporal interference stimulation on cortical function. Commun Biol, 2024, 7(1): 1076.
17.	Qi S, Liu X, Yu J, et al. Temporally interfering electric fields brain stimulation in primary motor cortex of mice promotes motor skill through enhancing neuroplasticity. Brain Stimul, 2024, 17(2): 245-257.
18.	Gomez-Tames J, Asai A, Hirata A. Multiscale computational model reveals nerve response in a mouse model for temporal interference brain stimulation. Front Neurosci, 2021, 15: 684465.
19.	Ahsan F, Chi T, Cho R, et al. EMvelop stimulation: minimally invasive deep brain stimulation using temporally interfering electromagnetic waves. J Neural Eng, 2022, 19(4): 046005.
20.	Xin Z, Kuwahata A, Liu S, et al. Magnetically induced temporal interference for focal and deep-brain stimulation. Front Hum Neurosci, 2021, 15: 693207.
21.	Luff C E, Dzialecka P, Acerbo E, et al. Pulse-width modulated temporal interference (PWM-TI) brain stimulation. Brain Stimul, 2024, 17(1): 92-103.
22.	Mojiri Z, Akhavan A, Rouhani E, et al. Quantitative analysis of noninvasive deep temporal interference stimulation: a simulation and experimental study. Heliyon, 2024, 10(8): e29482.
23.	Wang T, Yan L, Yang X, et al. Optimal design of array coils for multi-target adjustable electromagnetic brain stimulation system. Bioengineering, 2023, 10(5): 568.
24.	Zibandepour M, Shojaei A, Larki A A, et al. Preliminary guidelines for electrode positioning in noninvasive deep brain stimulation via temporally interfering electric fields//2023 11th RSI International Conference on Robotics and Mechatronics (ICRoM), Qom: IEEE, 2023: 739-744.
25.	Membrilla J A V, Pantoja M F, Puerta A P V, et al. Design of transcranial magnetic stimulation coils with optimized stimulation depth. IEEE Access, 2023, 12: 1330-1340.
26.	Khatoun A, Asamoah B, Mc Laughlin M. A computational modeling study to investigate the use of epicranial electrodes to deliver interferential stimulation to subcortical regions. Front Neurosci, 2021, 15: 779271.
27.	Lee S, Park J, Choi D S, et al. Multipair transcranial temporal interference stimulation for improved focalized stimulation of deep brain regions: a simulation study. Computers in Biology and Medicine, 2022, 143: 105337.
28.	Song X, Zhao X, Li X, et al. Multi-channel transcranial temporally interfering stimulation (tTIS): application to living mice brain. J Neural Eng, 2021, 18(3): 036003.
29.	Sorkhabi M M, Wendt K, Denison T. Temporally interfering TMS: focal and dynamic stimulation location//2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Montreal: IEEE, 2020: 3537-3543.
30.	Botzanowski B, Acerbo E, Lehmann S, et al. Focal control of non-invasive deep brain stimulation using multipolar temporal interference. Bioelectron Med, 2025, 11(1): 7.
31.	Bahn S, Lee C, Kang B Y. A computational study on the optimization of transcranial temporal interfering stimulation with high-definition electrodes using unsupervised neural networks. Hum Brain Mapp, 2023, 44(5): 1829-1845.
32.	Stoupis D, Samaras T. Non-invasive stimulation with temporal interference: optimization of the electric field deep in the brain with the use of a genetic algorithm. J Neural Eng, 2022, 19(5): 056018.
33.	Liu X, Qi S, Hou L, et al. Noninvasive deep brain stimulation via temporal interference electric fields enhanced motor performance of mice and its neuroplasticity mechanisms. Mol Neurobiol, 2024, 61(6): 3314-3329.
34.	Ma R, Xia X, Zhang W, et al. High gamma and beta temporal interference stimulation in the human motor cortex improves motor functions. Front Neurosci, 2022, 15: 800436.
35.	Wessel M J, Beanato E, Popa T, et al. Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning. Nature Neurosci, 2023, 26(11): 2005-2016.
36.	Zhang Y, Zhou Z, Zhou J, et al. Temporal interference stimulation targeting right frontoparietal areas enhances working memory in healthy individuals. Front Hum Neurosci, 2022, 16: 918470.
37.	Liu R, Zhu G, Wu Z, et al. Temporal interference stimulation targets deep primate brain. NeuroImage, 2024, 291: 120581.
38.	Acerbo E, Botzanowski B, Dellavale D, et al. Improved temporal and spatial focality of non-invasive deep-brain stimulation using multipolar single-pulse temporal interference with applications in epilepsy. arXiv preprint, 2024, arXiv: 2024.01. 11.575301.
39.	Kim E, Ye E, Lee J, et al. Optimization framework for temporal interference current tibial nerve stimulation in tibial nerves based on in-silico studies. Applied Sciences, 2023, 13(4): 2430.
40.	Sunshine M D, Cassarà A M, Neufeld E, et al. Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation. Commun Biol, 2021, 4(1): 107.
41.	孟緯鈺, 張丞, 吳昌哲, 等. 經顱電刺激用于深腦刺激的研究進展. 生物醫學工程學雜志, 2023, 40(5): 1005-1011.
42.	Balzan P, Tattersall C, Palmer R. Non-invasive brain stimulation for treating neurogenic dysarthria: a systematic review. Ann Phys Rehabil Med, 2022, 65(5): 101580.
43.	Zhu Z, Yin L. A mini-review: recent advancements in temporal interference stimulation in modulating brain function and behavior. Front Hum Neurosci, 2023, 17: 1266753.
44.	Nasr K, Haslacher D, Soekadar S. Towards adaptive deep brain neuromodulation using temporal interference magnetic stimulation. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 2023, 16(1): 262.
45.	Zhang S, Qin Y, Wang J, et al. Noninvasive electrical stimulation neuromodulation and digital brain technology: a review. Biomedicines, 2023, 11(6): 1513.

1. Davidson B, Bhattacharya A, Sarica C, et al. Neuromodulation techniques–from non-invasive brain stimulation to deep brain stimulation. Neurotherapeutics, 2024, 21(3): e00330.
2. Denison T, Morrell M J. Neuromodulation in 2035: the neurology future forecasting series. Neurology, 2022, 98(2): 65-72.
3. 胡燦芳, 鐘傳鈺, 曹立. 神經調控技術在帕金森病治療中的應用研究進展. 上海交通大學學報(醫學版), 2024, 44(2): 258-263.
4. 任偉, 卜楊瑩, 朱文禮, 等. 神經調控技術在精神分裂癥中的應用進展. 臨床精神醫學雜志, 2024, 34(5): 415-417.
5. Oehrn C R, Cernera S, Hammer L H, et al. Chronic adaptive deep brain stimulation versus conventional stimulation in Parkinson’s disease: a blinded randomized feasibility trial. Nature Medicine, 2024, 30(11): 3345-3356.
6. Meyer G M, Hollunder B, Li N, et al. Deep brain stimulation for obsessive-compulsive disorder: optimal stimulation sites. Biological Psychiatry, 2024, 96(2): 101-113.
7. Violante I R, Alania K, Cassarà A M, et al. Non-invasive temporal interference electrical stimulation of the human hippocampus. Nature Neuroscience, 2023, 26(11): 1994-2004.
8. Guo W, He Y, Zhang W, et al. A novel non-invasive brain stimulation technique: “temporally interfering electrical stimulation”. Front Neurosci, 2023, 17: 1092539.
9. Deng Z D, Lisanby S H, Peterchev A V. Electric field depth-focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul, 2013, 6(1): 1-13.
10. Khalifa A, Abrishami S M, Zaeimbashi M, et al. Magnetic temporal interference for noninvasive and focal brain stimulation. J Neural Eng, 2023, 20(1): 016002.
11. Grossman N, Bono D, Dedic N, et al. Noninvasive deep brain stimulation via temporally interfering electric fields. Cell, 2017, 169(6): 1029-1041.
12. Karimi F, Attarpour A, Amirfattahi R, et al. Computational analysis of non-invasive deep brain stimulation based on interfering electric fields. Phys Med Biol, 2019, 64(23): 235010.
13. Mirzakhalili E, Barra B, Capogrosso M, et al. Biophysics of temporal interference stimulation. Cell Syst, 2020, 11(6): 557-572.
14. Howell B, McIntyre C C. Feasibility of interferential and pulsed transcranial electrical stimulation for neuromodulation at the human scale. Neuromodulation, 2021, 24(5): 843-853.
15. Cao J, Doiron B, Goswami C, et al. The mechanics of temporal interference stimulation. arXiv preprint, 2020, arXiv: 2020.04.23.051870.
16. Caldas-Martinez S, Goswami C, Forssell M, et al. Cell-specific effects of temporal interference stimulation on cortical function. Commun Biol, 2024, 7(1): 1076.
17. Qi S, Liu X, Yu J, et al. Temporally interfering electric fields brain stimulation in primary motor cortex of mice promotes motor skill through enhancing neuroplasticity. Brain Stimul, 2024, 17(2): 245-257.
18. Gomez-Tames J, Asai A, Hirata A. Multiscale computational model reveals nerve response in a mouse model for temporal interference brain stimulation. Front Neurosci, 2021, 15: 684465.
19. Ahsan F, Chi T, Cho R, et al. EMvelop stimulation: minimally invasive deep brain stimulation using temporally interfering electromagnetic waves. J Neural Eng, 2022, 19(4): 046005.
20. Xin Z, Kuwahata A, Liu S, et al. Magnetically induced temporal interference for focal and deep-brain stimulation. Front Hum Neurosci, 2021, 15: 693207.
21. Luff C E, Dzialecka P, Acerbo E, et al. Pulse-width modulated temporal interference (PWM-TI) brain stimulation. Brain Stimul, 2024, 17(1): 92-103.
22. Mojiri Z, Akhavan A, Rouhani E, et al. Quantitative analysis of noninvasive deep temporal interference stimulation: a simulation and experimental study. Heliyon, 2024, 10(8): e29482.
23. Wang T, Yan L, Yang X, et al. Optimal design of array coils for multi-target adjustable electromagnetic brain stimulation system. Bioengineering, 2023, 10(5): 568.
24. Zibandepour M, Shojaei A, Larki A A, et al. Preliminary guidelines for electrode positioning in noninvasive deep brain stimulation via temporally interfering electric fields//2023 11th RSI International Conference on Robotics and Mechatronics (ICRoM), Qom: IEEE, 2023: 739-744.
25. Membrilla J A V, Pantoja M F, Puerta A P V, et al. Design of transcranial magnetic stimulation coils with optimized stimulation depth. IEEE Access, 2023, 12: 1330-1340.
26. Khatoun A, Asamoah B, Mc Laughlin M. A computational modeling study to investigate the use of epicranial electrodes to deliver interferential stimulation to subcortical regions. Front Neurosci, 2021, 15: 779271.
27. Lee S, Park J, Choi D S, et al. Multipair transcranial temporal interference stimulation for improved focalized stimulation of deep brain regions: a simulation study. Computers in Biology and Medicine, 2022, 143: 105337.
28. Song X, Zhao X, Li X, et al. Multi-channel transcranial temporally interfering stimulation (tTIS): application to living mice brain. J Neural Eng, 2021, 18(3): 036003.
29. Sorkhabi M M, Wendt K, Denison T. Temporally interfering TMS: focal and dynamic stimulation location//2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Montreal: IEEE, 2020: 3537-3543.
30. Botzanowski B, Acerbo E, Lehmann S, et al. Focal control of non-invasive deep brain stimulation using multipolar temporal interference. Bioelectron Med, 2025, 11(1): 7.
31. Bahn S, Lee C, Kang B Y. A computational study on the optimization of transcranial temporal interfering stimulation with high-definition electrodes using unsupervised neural networks. Hum Brain Mapp, 2023, 44(5): 1829-1845.
32. Stoupis D, Samaras T. Non-invasive stimulation with temporal interference: optimization of the electric field deep in the brain with the use of a genetic algorithm. J Neural Eng, 2022, 19(5): 056018.
33. Liu X, Qi S, Hou L, et al. Noninvasive deep brain stimulation via temporal interference electric fields enhanced motor performance of mice and its neuroplasticity mechanisms. Mol Neurobiol, 2024, 61(6): 3314-3329.
34. Ma R, Xia X, Zhang W, et al. High gamma and beta temporal interference stimulation in the human motor cortex improves motor functions. Front Neurosci, 2022, 15: 800436.
35. Wessel M J, Beanato E, Popa T, et al. Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning. Nature Neurosci, 2023, 26(11): 2005-2016.
36. Zhang Y, Zhou Z, Zhou J, et al. Temporal interference stimulation targeting right frontoparietal areas enhances working memory in healthy individuals. Front Hum Neurosci, 2022, 16: 918470.
37. Liu R, Zhu G, Wu Z, et al. Temporal interference stimulation targets deep primate brain. NeuroImage, 2024, 291: 120581.
38. Acerbo E, Botzanowski B, Dellavale D, et al. Improved temporal and spatial focality of non-invasive deep-brain stimulation using multipolar single-pulse temporal interference with applications in epilepsy. arXiv preprint, 2024, arXiv: 2024.01. 11.575301.
39. Kim E, Ye E, Lee J, et al. Optimization framework for temporal interference current tibial nerve stimulation in tibial nerves based on in-silico studies. Applied Sciences, 2023, 13(4): 2430.
40. Sunshine M D, Cassarà A M, Neufeld E, et al. Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation. Commun Biol, 2021, 4(1): 107.
41. 孟緯鈺, 張丞, 吳昌哲, 等. 經顱電刺激用于深腦刺激的研究進展. 生物醫學工程學雜志, 2023, 40(5): 1005-1011.
42. Balzan P, Tattersall C, Palmer R. Non-invasive brain stimulation for treating neurogenic dysarthria: a systematic review. Ann Phys Rehabil Med, 2022, 65(5): 101580.
43. Zhu Z, Yin L. A mini-review: recent advancements in temporal interference stimulation in modulating brain function and behavior. Front Hum Neurosci, 2023, 17: 1266753.
44. Nasr K, Haslacher D, Soekadar S. Towards adaptive deep brain neuromodulation using temporal interference magnetic stimulation. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 2023, 16(1): 262.
45. Zhang S, Qin Y, Wang J, et al. Noninvasive electrical stimulation neuromodulation and digital brain technology: a review. Biomedicines, 2023, 11(6): 1513.

Journal of Biomedical Engineering

Latest ArticlesProgresses on temporal interference electromagnetic stimulation for non-invasive deep brain function modulation

Abstract Full text Figures/Tables Video References Cited by

Format

Content