Focal non-invasive deep-brain stimulation with temporal interference for the suppression of epileptic biomarkers

Abstract

Introduction: Neurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 and 165 Hz, to various deep-seated targets, such as the Mesio-temporal lobe (MTL), which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely an increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs).

Materials and methods: In the current study, we use Temporal Interference (TI) stimulation to provide a non-invasive DBS (130 Hz) of the MTL, specifically the hippocampus, in both mouse models of epilepsy, and scale the method using human cadavers to demonstrate the potential efficacy in human patients. Simulations for both mice and human heads were performed to calculate the best coordinates to reach the hippocampus.

Results: This non-invasive DBS increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. We therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs. TCS in human cadavers. Results show a better penetration of TI fields into the human hippocampus as compared with TCS.

Significance: These results constitute the first proof of the feasibility and efficiency of TI to stimulate at depth an area without impacting the surrounding tissue. The data tend to show the sufficiently focal character of the induced effects and suggest promising therapeutic applications in epilepsy.

Keywords: deep brain stimulation; epilepsy; mouse model; non-invasive stimulation; temporal interference.

FIGURE 1

Forms of temporal interference and ability to scale to larger subjects. (A) Classically, TI has been created via a combination of 2 kHz sine waves (f1:1,300 Hz f2:1,430 Hz, envelope = 130 Hz). We investigated the impact of TI by mixing square waves (PWM-TI). (B) To provide TI stimulation, cortical electrodes (2 pairs) were placed on the cortex of mice and human skin. In both cases, the aim was to focally reach one side of the hippocampus and provide stimulation at depth. (C) Simulated TI envelope modulation amplitude distributions (along the direction of maximal modulation) and peak carrier field magnitude (bottom; TCS) and their corresponding surface field views. Arrows: hippocampus.

FIGURE 2

Focal hippocampal stimulation induces SPW-Rs. (A) Mice are implanted with depth-electrode to induce epileptiform activity. Finite element model of TI-HFS and CT-HFS. It shows the creation of a hot spot of stimulation in the hippocampus via TI compared to the cortical stimulation with HFS. (B) Raw recording and time-frequency plot of activity in the hippocampus showing the identification of SPW-Rs in the frequency band [150–250 Hz]. (C) Example SPW-Rs and the averaged autocorrelation from Sham and TI-HFS. The distance in time of the first and second peaks of the average autocorrelation shows SPW-Rs’ frequency. (D) Analysis of the power spectral density to get the frequency of the recorded SPW-Rs (^**p-value < 0.01). (E) Frequency and occurrence of SPW-Rs for TI-HFS (green), Sham (blue), and CT-HFS (gray) (^***p-value < 0.001).

FIGURE 3

Suppression of IEDs and FRs with a non-invasive DBS via TI-HFS. (A) Pathological IEDs and their properties: rate, duration amplitude, and area of the wave. (B) Occurrence of pathological IEDs in mice hippocampus. Baseline (yellow) grouped all mice before kindling induction (*p-value < 0.05). (C) Analysis of IEDs properties. area, duration, and amplitude were calculated for detected IEDs. (D) Raw and filtered [250–500] Hz signal with detected FRs. Time-frequency plot showing activation in FRs band. (E) Pathological FRs occurrence. A ratio for each mouse was calculated to compare pre- and after-treatment. ***p-value < 0.001 and **p -value < 0.01.

FIGURE 4

Scaling the effect of TI-HFS at 130 Hz in the human head. (A). Placement of electrodes on the skin of the human cadaver. About 10 SEEGs were implanted in the brain for MTLE patients to record the stimulation potentials inside the brain. (B) Co-registration with the scanner and a template MRI show the amplitude of the envelope recorded during the TI-HFS session. It gives an indication on where the focus of stimulation is and the amplitude of the envelope of stimulation. Here, 1 and 3 mA were chosen to better target the anterior hippocampus in this specific cadaver and the field modulation envelope can reach an amplitude of 7 mV. (C) Electrode f is used to show the depth of the focal stimulation of TI-HFS in both square and sine waves. For TCS-like 130 Hz, it shows stronger stimulating fields in the cortex, which is primarily activated, compared to the deep structures, unlike for TI with sine waves or square waves (PWM TI).