Non-invasive Temporal Interference Stimulation of the Hippocampus Suppresses Epileptic Biomarkers in Patients with Epilepsy: Biophysical Differences between Kilohertz and Amplitude Modulated Stimulation.

Medication refractory focal epilepsy creates a significant challenge, with approximately 30% of patients ineligible for surgery due to the involvement of eloquent cortex in the epileptogenic network. For such patients with limited surgical options, electrical neuromodulation represents a promising alternative therapy. In this study, we investigate the potential of non-invasive temporal interference (TI) electrical stimulation to reduce epileptic biomarkers in patients with epilepsy by comparing intracerebral recordings obtained before, during, and after TI stimulation, to recordings during low and high kHz frequency (HF) sham stimulation. Thirteen patients with symptoms of mesiotemporal epilepsy (MTLE) and implanted with stereoelectroencephalography (sEEG) depth electrodes received TI stimulation with an amplitude modulation (AM) frequency of 130Hz (df), where the AM was delivered with lower frequency kHz carriers (1kHz + 1.13kHz), or higher frequency carriers (9kHz + 9.13kHz), targeting the hippocampus, a common epileptic focus and consequently stimulation target in MTLE. Our results show that TI stimulation yields a statistically significant decrease in interictal epileptiform discharges (IEDs) and pathological high-frequency oscillations (HFOs) specifically fast ripples (FR), where the suppression is apparent in the hippocampal focus and propagation from the focus is reduced brain-wide. HF sham stimulation at 1kHz frequency also impacted the IED rate in the cortex, but without reaching the hippocampal focus. The HF sham effect diminished with increasing frequencies (2, 5, and 9kHz, respectively), specifically as a function of depth into the cortex. This depth dependence was not observed with the TI, independent of the employed carrier frequency (low or high kHz). Furthermore, a strong carry-over effect, i.e., suppression of epileptic biomarkers for a period of time after the end of stimulation, was observed for TI but not for kHz. Our findings underscore the possible application of TI in epilepsy, as an additional non-invasive brain stimulation tool, potentially offering opportunities to assess brain region response to electrical neuromodulation before committing to a deep brain stimulation (DBS) or responsive neurostimulation (RNS) implants. Our results further demonstrate distinct biophysical differences between kHz and focal AM stimulation.