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

Abstract

IntroductionNeurostimulation 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 methodsIn 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.ResultsThis 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.SignificanceThese 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.

Focal control of non-invasive deep brain stimulation using multipolar temporal interference

“…As illustrated in Figure 1A, standard TI creates deep subcortical stimulation by a combination of two kHz frequencies applied through two pairs of electrodes, where the field from the first pair (red) and the field from the second pair (light red) overlap to create a region with strong envelope modulation (yellow). The frequency of the envelope is equal to the difference between the two kHz frequencies and is set to a value equal to a frequency from traditional deep brain stimulation to be non-invasively replicated – for example in the hippocampus 50Hz for excitation or 130Hz for inhibition in accordance with our previous publications on TI stimulation in epilepsy 13 . Neural activity can only be influenced in the region of overlap, where a significant low-frequency envelope results, as the minimally modulated kHz exposure outside that region does not efficiently drive neuronal activity.…”

“…The method simultaneously applies two high frequency electric fields -too high to activate neurons individually -with slightly differing frequencies, thus allowing the fields to constructively and destructively interfere in time, resulting in an amplitude-modulated field. Neurons have been shown by us and by others to respond to the amplitude modulated field [8][9][10] . As a result, it is possible to restrict neurostimulation to the region where the two fields overlap.…”

“…For that, tuning the size of the stimulation region and the intensity of the stimulation independently would be immensely useful, for both medical (therapeutic and diagnostic) and research applications – certainly if the size of the stimulated region could be as focal as that of implanted DBS electrodes. In the clinic, it could replace the use of certain invasive procedures such as brain mapping to identify epileptogenic region of an epileptic brain 12 , or permit investigation of whether a patient will benefit from DBS prior to the implantation 13 . When coupled with non-invasive imaging techniques such as f-MRI or MEG, a non-invasive and focal stimulation technique would be an ideal way to gather data in order to build tailored, patient-specific brain models, e.g.…”

Advanced Temporally‐Spatially Precise Technologies for On‐Demand Neurological Disorder Intervention

“…For instance, the group of Williamson reported that TI stimulation with envelop frequency around 130 Hz effectively suppressed the epileptic seizure in the hippocampus of rat models, while transcranial current stimulation in the same frequency failed to reach such deep brain tissue (Figure 5B,C). [48] Furthermore, the group of Williamson was devoted to combining TI Figure 6. Genetics-based neuromodulation.…”

Obstructive Sleep Apnea Improves with Non-invasive Hypoglossal Nerve Stimulation using Temporal Interference

“…applications(Missey et al, 2021;Missey et al, 2022;Acerbo et al, 2022). However, peripheral nerve stimulation using TI is not common(Botzanowski et al, 2021), especially for targeting facial nerves.…”