BRIEF RESEARCH REPORT article
Front. Neurosci.
Sec. Neural Technology
Safety assessment of temporal interference non-invasive intracranial stimulation
Richard Hou
Emma ACERBO
Ryohei Yoshimoto
Nealen Gordon Laxpati
Ken Berglund
Claire-Anne Gutekunst
Emory University, Atlanta, United States
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Abstract
Temporal interference (TI) stimulation is a promising non-invasive neuromodulation strategy that uses two high-frequency electric fields to generate a low-frequency amplitude-modulated envelope at their intersection, enabling targeting of deep brain regions. However, in vivo safety concerns remain regarding the impact of the low-frequency envelope applied to the brain. Therefore, the objective of this study was to systematically evaluate the acute thermal and cellular safety profile of TI using an invasive in vivo mouse model, and to compare its thermal effects with those of direct low-frequency stimulation using an in vitro egg-white model. In the egg-white model, no protein coagulation was observed with TI stimulation (10 mA at 1,000 Hz and 1,005 Hz for 20 min), which generated a 5 Hz envelope. In contrast, conventional 5 Hz alternating current stimulation (tACS) at 10 mA induced localized coagulation. In the mouse model, intracranial TI stimulation (2 mA at 1,000 Hz and 1,005 Hz for 20 min) targeting the hippocampus resulted in a mild and stable temperature increase of ~0.7°C. Histological analysis revealed a localized increase in astrocyte activation (GFAP) in the stratum lacunosum-moleculare (SLM) compared to other hippocampal subfields. No significant expression difference was observed in the hippocampus for the heat stress marker (HSP70) or the inflammatory marker (iNOS). These findings suggest that TI has a favorable short-term safety profile, with minimal thermal effects and no widespread inflammatory response.
Summary
Keywords
Astrogliosis, Neural safety, Neuroinflammation, Neuromodulation, Thermal injury
Received
21 November 2025
Accepted
15 January 2026
Copyright
© 2026 Hou, ACERBO, Yoshimoto, Laxpati, Berglund and Gutekunst. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ken Berglund; Claire-Anne Gutekunst
Disclaimer
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