Noninvasive nanosecond transcranial pulsed electric fields: deep-penetrating, high-field stimulation for suppressing hippocampal amyloid-β and improving cognitive function in an Alzheimer’s disease model_Journal of Biomedical Engineering

Authors：

CHEN Yue ,  YAO Chenguo , YAN Fanping , XIAO Pangxin , LU Xiaoyu

State Key Laboratory of Power Transmission Equipment Technology, School of Electrical Engineering, Chongqing University, Chongqing 401331, P. R. China;

Corresponding?author：

YAO Chenguo, Email: yaochenguo@cqu.edu.cn

Keywords：

Alzheimer's disease; Nanosecond pulsed electric field; Hippocampus; Amyloid-β

DOI：

10.7507/1001-5515.202602022

Video：

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Abnormal deposition of amyloid-β (Aβ) in the deep-brain hippocampus can impair synaptic transmission and disrupt neural network activity, thereby inducing learning and memory deficits and accelerating cognitive decline in Alzheimer’s disease (AD). Therefore, reducing hippocampal Aβ deposition is an important strategy for delaying AD progression. Existing transcranial electrical stimulation methods are limited by safety thresholds and are difficult to achieve effective field strength in deep brain regions under noninvasive conditions, thus failing to effectively intervene in hippocampal Aβ deposition. Nanosecond pulsed electric fields, which contain abundant high-frequency components and exhibit stronger transcranial penetration capability, may overcome this limitation. In this study, nanosecond transcranial pulsed electric field stimulation (ns-tPFS) was applied with parameters of 500 ns band width, 500 V amplitude, and 5 Hz frequency in a five familial AD mutations (5xFAD) mouse model. First, finite element simulation was performed to determine that the electric field strength generated by ns-tPFS in the hippocampal region could reach 3 × 10⁴ V/m. Then, molecular dynamics simulation was used to evaluate the disruptive effect of this field strength on the structural stability of Aβ multimers. Subsequently, Morris water maze and Y-maze behavioral tests, together with immunofluorescence detection, were conducted to assess the intervention effects of ns-tPFS on animal cognitive function and hippocampal Aβ deposition. The results showed that, under the above stimulation parameters, ns-tPFS could disrupt the structure of Aβ multimers, markedly reduce hippocampal Aβ deposition in 5xFAD mice, and effectively improve their cognitive function. In summary, this study demonstrates, from animal simulations and experiments, the feasibility of ns-tPFS for improving AD symptoms and provides a new research perspective and experimental basis for the noninvasive intervention of hippocampal Aβ pathology.

Citation： CHEN Yue, YAO Chenguo, YAN Fanping, XIAO Pangxin, LU Xiaoyu. Noninvasive nanosecond transcranial pulsed electric fields: deep-penetrating, high-field stimulation for suppressing hippocampal amyloid-β and improving cognitive function in an Alzheimer’s disease model. Journal of Biomedical Engineering, 2026, 43(4): 718-728. doi: 10.7507/1001-5515.202602022 Copy

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27.	Sasmita A O, Ong E C, Nazarenko T, et al. Parental origin of transgene modulates amyloid-β plaque burden in the 5xFAD mouse model of Alzheimer's disease[J]. Neuron, 2025, 113(6): 838-846. e4.
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29.	羋金睿, 張帥, 路小超, 等. 基于光纖光度檢測技術對經顱磁聲電刺激影響APP/PS1小鼠海馬CA1區突觸可塑性的研究[J]. 生物醫學工程學雜志, 2026, 42(1): 1-9.
30.	Pádua M S, Guil-Guerrero J L, Lopes P A. Behaviour hallmarks in Alzheimer's disease 5xFAD mouse model[J]. Int J Mol Sci, 2024, 25(12): 6766.
31.	Schneeberger S, Kim S J, Geesdorf M N, et al. Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis[J]. Nat Aging, 2025, 5(4): 622-641.
32.	Kim D W, Tu K J, Wei A, et al. Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes[J]. Mol Neurodegener, 2022, 17(1): 83.
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34.	Liebetanz D, Koch R, Mayenfels S, et al. Safety limits of cathodal transcranial direct current stimulation in rats[J]. Clin Neurophysiol, 2009, 120(6): 1161-1167.
35.	Besio W, Sharma V, Spaulding J. The effects of concentric ring electrode electrical stimulation on rat skin[J]. Ann Biomed Eng, 2010, 38(3): 1111-1118.
36.	Wang Q, Zhang Y, Xue H, et al. Lead-free dual-frequency ultrasound implants for wireless, biphasic deep brain stimulation[J]. Nat Commun, 2024, 15(1): 4017.
37.	Sun Z, Sen P, Hamers J, et al. Optimized conditions for electrical tissue stimulation with biphasic, charge-balanced impulses[J]. Bioengineering, 2025, 12(3): 234.
38.	Rajnicek A M, Casa?-Pastor N. Wireless control of nerve growth using bipolar electrodes: a new paradigm in electrostimulation[J]. Biomater Sci, 2024, 12(9): 2180-2202.
39.	Oishi R, Takeda I, Ode Y, et al. Neuromodulation with transcranial direct current stimulation contributes to motor function recovery via microglia in spinal cord injury[J]. Sci Rep, 2024, 14(1): 18031.
40.	Rathour R K, Kaphzan H. Dendritic effects of tDCS insights from a morphologically realistic model neuron[J]. iScience, 2024, 27(3): 109230.
41.	Rems L, Rainot A, Wiczew D, et al. Cellular excitability and ns-pulsed electric fields: potential involvement of lipid oxidation in the action potential activation[J]. Bioelectrochemistry, 2024, 155: 108588.
42.	Zhang W, Xiao D, Mao Q, et al. Role of neuroinflammation in neurodegeneration development[J]. Signal Transduct Target Ther, 2023, 8(1): 267.

1. Alzheimer's Disease International. World Alzheimer report 2025: reimagining life with dementia-the power of rehabilitation[EB/OL]. (2025-09-18) [2025-12-20]. https://www.alzint.org/resource/world-alzheimer-report-2025/.
2. An J, Kim K, Lim H J, et al. Early onset diagnosis in Alzheimer's disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid[J]. Nat Commun, 2024, 15(1): 1004.
3. Li Z, Sun Y, Li T, et al. The impact of amyloid beta burden on white matter dysfunction and associated transcriptomic signatures in cognitively normal elderly individuals[J]. Alzheimers Dement (Amst), 2025, 17(4): e70192.
4. Alzheimer's Association. 2025 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2025, 21(4): e70235.
5. Gallego-Rudolf J, Wiesman A I, Pichet-Binette A, et al. Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults[J]. Nat Neurosci, 2024, 27(11): 2130-2137.
6. Roemer-Cassiano S N, Wagner F, Evangelista L, et al. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease[J]. Sci Transl Med, 2025, 17(782): eadp2564.
7. 劉素紅, 王龍龍, 李雙燕, 等. 40 Hz光閃爍刺激對阿爾茨海默病大鼠工作記憶及海馬-前額葉神經電活動特性影響的研究[J]. 生物醫學工程學雜志, 2025, 42(6): 1107-1114.
8. Li H, Zhao Z, Fassini A, et al. Impaired hippocampal circuit function underlying memory encoding and consolidation precede robust Aβ deposition in a mouse model of Alzheimer's disease[J]. Sci Rep, 2025, 15(1): 21957.
9. Park G, Kim M S, Lee Y B, et al. Hippocampal-cortical interactions in the consolidation of social memory[J]. Nat Commun, 2025, 16(1): 8430.
10. Ray A, Loghinov I, Ravindranath V, et al. Early hippocampal hyperexcitability and synaptic reorganization in mouse models of amyloidosis[J]. iScience, 2024, 27(9): 110629.
11. 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[J]. 生物醫學工程學雜志, 2023, 40(5): 1005-1011.
12. Pathak H, Suhas S, Sreeraj V S, et al. Home-based transcranial electrical stimulation (tES) for the management of psychiatric disorders: a scoping review[J]. Indian J Psychol Med, 2026, 48(3): 232-250.
13. Borrione L, Cavendish B A, Aparicio L V M, et al. Home-use transcranial direct current stimulation for the treatment of a major depressive episode: a randomized clinical trial[J]. JAMA Psychiatry, 2024, 81(4): 329-337.
14. Huang Y, Liu A A, Lafon B, et al. Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation[J]. eLife, 2017, 6: e18834.
15. Violante I R, Alania K, Cassarà A M, et al. Non-invasive temporal interference electrical stimulation of the human hippocampus[J]. Nat Neurosci, 2023, 26(11): 1994-2004.
16. Vieira P G, Krause M R, Pack C C. Temporal interference stimulation disrupts spike timing in the primate brain[J]. Nat Commun, 2024, 15(1): 4558.
17. Peng J, Du Z, Piao Y, et al. Advances in the application of temporal interference stimulation: a scoping review[J]. Front Hum Neurosci, 2025, 19: 1536906.
18. Opan?ar A, Ondrá?ková P, Rose D S, et al. The same biophysical mechanism is involved in both temporal interference and direct kHz stimulation of peripheral nerves[J]. Nat Commun, 2025, 16(1): 9006.
19. Gul K, Mumtaz S. Nanosecond pulsed electric fields (nsPEFs) for precision intracellular oncotherapy: recent advances and emerging directions[J]. Int J Mol Sci, 2025, 26(23): 11268.
20. Baumgartner C, Hasgall P A, Di-Gennaro F, et al. IT'IS database for thermal and electromagnetic parameters of biological tissues[DS/OL]. version 5.0. IT'IS Foundation (2025-08-21)[2025-12-20]. https://itis.swiss/virtual-population/tissue-properties/database/dielectric-properties.
21. Pr??a J, Cifra M. Molecular dynamics simulation of the nanosecond pulsed electric field effect on kinesin nanomotor[J]. Sci Rep, 2019, 9(1): 19721.
22. Peng W, Zhu Z, Lou J, et al. High-frequency terahertz waves disrupt Alzheimer's β-amyloid fibril formation[J]. eLight, 2023, 3(1): 18.
23. Makhkamov M, Baev A, Kurganov E, et al. Understanding Osaka mutation polymorphic Aβ fibril response to static and oscillating electric fields: insights from computational modeling[J]. Sci Rep, 2024, 14(1): 22246.
24. Vargas-Rosales P A, D'Addio A, Zhang Y, et al. Disrupting dimeric β-amyloid by electric fields[J]. ACS Phys Chem Au, 2023, 3(5): 456-466.
25. Yokoyama M, Kobayashi H, Tatsumi L, et al. Mouse models of Alzheimer's disease[J]. Front Mol Neurosci, 2022, 15: 912995.
26. Kokkali M, Karali K, Thanou E, et al. Multimodal beneficial effects of BNN27, a nerve growth factor synthetic mimetic, in the 5xFAD mouse model of Alzheimer's disease[J]. Mol Psychiatry, 2025, 30(6): 2265-2283.
27. Sasmita A O, Ong E C, Nazarenko T, et al. Parental origin of transgene modulates amyloid-β plaque burden in the 5xFAD mouse model of Alzheimer's disease[J]. Neuron, 2025, 113(6): 838-846. e4.
28. 張儷凡, 耿讀艷, 徐桂芝, 等. 40 Hz脈沖磁場對癡呆小鼠線粒體動力學與心率變異性的影響[J]. 生物醫學工程學雜志, 2025, 42(4): 707-715.
29. 羋金睿, 張帥, 路小超, 等. 基于光纖光度檢測技術對經顱磁聲電刺激影響APP/PS1小鼠海馬CA1區突觸可塑性的研究[J]. 生物醫學工程學雜志, 2026, 42(1): 1-9.
30. Pádua M S, Guil-Guerrero J L, Lopes P A. Behaviour hallmarks in Alzheimer's disease 5xFAD mouse model[J]. Int J Mol Sci, 2024, 25(12): 6766.
31. Schneeberger S, Kim S J, Geesdorf M N, et al. Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis[J]. Nat Aging, 2025, 5(4): 622-641.
32. Kim D W, Tu K J, Wei A, et al. Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes[J]. Mol Neurodegener, 2022, 17(1): 83.
33. Zhu J, Liu X, Liu Z, et al. SOLID: minimizing tissue distortion for brain-wide profiling of diverse architectures[J]. Nat Commun, 2024, 15(1): 8303.
34. Liebetanz D, Koch R, Mayenfels S, et al. Safety limits of cathodal transcranial direct current stimulation in rats[J]. Clin Neurophysiol, 2009, 120(6): 1161-1167.
35. Besio W, Sharma V, Spaulding J. The effects of concentric ring electrode electrical stimulation on rat skin[J]. Ann Biomed Eng, 2010, 38(3): 1111-1118.
36. Wang Q, Zhang Y, Xue H, et al. Lead-free dual-frequency ultrasound implants for wireless, biphasic deep brain stimulation[J]. Nat Commun, 2024, 15(1): 4017.
37. Sun Z, Sen P, Hamers J, et al. Optimized conditions for electrical tissue stimulation with biphasic, charge-balanced impulses[J]. Bioengineering, 2025, 12(3): 234.
38. Rajnicek A M, Casa?-Pastor N. Wireless control of nerve growth using bipolar electrodes: a new paradigm in electrostimulation[J]. Biomater Sci, 2024, 12(9): 2180-2202.
39. Oishi R, Takeda I, Ode Y, et al. Neuromodulation with transcranial direct current stimulation contributes to motor function recovery via microglia in spinal cord injury[J]. Sci Rep, 2024, 14(1): 18031.
40. Rathour R K, Kaphzan H. Dendritic effects of tDCS insights from a morphologically realistic model neuron[J]. iScience, 2024, 27(3): 109230.
41. Rems L, Rainot A, Wiczew D, et al. Cellular excitability and ns-pulsed electric fields: potential involvement of lipid oxidation in the action potential activation[J]. Bioelectrochemistry, 2024, 155: 108588.
42. Zhang W, Xiao D, Mao Q, et al. Role of neuroinflammation in neurodegeneration development[J]. Signal Transduct Target Ther, 2023, 8(1): 267.

Journal of Biomedical Engineering

Noninvasive nanosecond transcranial pulsed electric fields: deep-penetrating, high-field stimulation for suppressing hippocampal amyloid-β and improving cognitive function in an Alzheimer’s disease model

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