Non-invasive temporal interference stimulation of the hippocampus suppresses epileptic biomarkers in patients with Epilepsy: biophysical differences between kilohertz and amplitude modulated stimulation

INTRODUCTION: Medication-refractory focal epilepsy creates a significant clinical challenge, with approximately 30 % of patients deemed ineligible for surgery due to involvement of eloquent cortical regions within the epileptogenic network. For these patients, electrical neuromodulation represents a promising alternative therapy. We investigated the potential of non-invasive temporal interference (TI) electrical stimulation in reducing epileptic biomarkers in patients with mesiotemporal epilepsy (MTLE) MATERIAL AND METHOD: Thirteen patients implanted with stereoelectroencephalography (sEEG) depth electrodes received TI stimulation with an amplitude modulation (AM) frequency of 130 Hz (Δf), delivered through either low-frequency (1 kHz + 1.13 kHz) or high-frequency (9 kHz + 9.13 kHz) carrier waves, specifically targeting the hippocampus-a common epileptic focus in MTLE. Intracerebral recordings before, during, and after TI stimulation were compared to recordings during sham stimulation at varying high-frequency (HF) carrier frequencies (1, 2, 5, and 9 kHz). RESULTS: TI stimulation resulted in a statistically significant decrease in interictal epileptiform discharges (IEDs) and pathological high-frequency oscillations (HFOs), particularly fast-ripples (FR), with prominent suppression observed in the hippocampal focus and reduced propagation brain-wide. In contrast, HF sham stimulation at 1 kHz frequency partially reduced cortical IED rates without effectively reaching the hippocampal focus. This cortical impact diminished progressively at higher sham frequencies (2, 5, and 9 kHz), exhibiting depth-dependent attenuation-a phenomenon not observed with TI stimulation, irrespective of carrier frequency. Additionally, TI stimulation demonstrated a significant carry-over effect, suppressing epileptic biomarkers beyond the stimulation period, which was not evident following kHz sham stimulation. CONCLUSION: Our findings underscore the therapeutic potential of TI as a non-invasive brain stimulation modality for epilepsy, offering significant suppression of epileptic biomarkers through subthreshold modulation of the epileptogenic zone. Furthermore, this study highlights distinct biophysical differences between kilohertz-frequency stimulation and focal amplitude-modulated stimulation, supporting TI's unique utility in neuromodulation research.