Orientation of Temporal Interference for Non-invasive Deep Brain Stimulation in Epilepsy

Abstract

In patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on non-penetrating surface electrodes, namely an orientation-tunable form of temporally interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of Pulse-width-modulation of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally invasive temporally interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue and overcoming several limitations of other non-invasive stimulation methods in epilepsy, such as transcranial magnetic stimulation (TMS).

Responses of Model Cortical Neurons to Temporal Interference Stimulation and Related Transcranial Alternating Current Stimulation Modalities

“…For example, Grossman et al (2017) used c-Fos immunochemistry to demonstrate activation of the hippocampus without activating superficial cortical areas, with strong c-Fos immunoreactivity in the entire region of granule cells within the dentate gyrus. This expression was much stronger than observed anywhere for LFS or elsewhere in TIS, suggesting that TIS achieved strong synchronous activation of the local circuitry in the dentate gyrus, consistent with a seizure-like event evoked by TIS in awake rat (Missey et al, 2021). Furthermore, the area of activation indirectly inferred based on immunohistochemistry does not correlate with the distribution of the simulated E-field modulation envelope amplitude (Grossman et al, 2017, fig.…”

Focal Non-invasive Deep-brain Stimulation with Temporal Interference for the Suppression of Epileptic Biomarkers

“…In a previous study, we showed that it was possible to evoke seizures like events with PMW-TI (45) , the same wave was used here to perform the current study. To analyze the non-invasive DBS like effect of stimulation with TI at 130Hz (TI HFS), we compared its impact with a cortical, TCS-like, high frequency stimulation (CT HFS) and a non-treatment group (Sham) on hippocampal electrophysiological biomarkers.…”

Nonlinearities and Timescales in Temporal Interference Stimulation

“…This heavily influences the electric field lines. With this method, the importance of the direction of the electric field can be shown [26].…”

“…This heavily influences the electric field lines. With this method, the importance of the direction of the electric field can be shown [26]. In the study of the underlying mechanism, it can be considered to investigate more morphologically correct neurons to include propagation of the signal through a neuron.…”