The problem: There are fifty million people in the world with epilepsy, and up to 50 cases of new-onset epilepsy per 100,000 people each year. It is estimated that 30% of these cases are patients with drug-resistant epilepsy. For drug-resistant patients most frequently the only remaining option for treatment is resective surgery, an extremely invasive process where a portion of the epileptic brain is surgically removed and the subsequent severity of resulting postoperative neurological deficits (impaired motor function, speech, and memory) is often attributed to inaccurate localization of the surgical target. During presurgical evaluation, patients necessarily require invasive recordings using stereo-electroencephalography (SEEG), involving the implantation of numerous electrodes in different brain regions for the electrophysiological monitoring of seizure onset and the subsequent localization of an epileptogenic zone (EZ). Electrical stimulation from the intracranial electrodes helps define an EZ, with electrophysiological discharges and seizures triggered by different frequencies of stimulation. In general, pathological discharges from the EZ are characterized by several biomarkers, primarily the generation of high-frequency oscillations in the beta/gamma range, classically referred to as rapid-discharges. Although currently performed with invasive SEEG, possibly less-invasive methods capable of evoking such discharges in more regions of brain tissue, namely unimplanted tissue, would be highly interesting as positive surgical outcomes are well-correlated with the removal of tissue regions which generate such high-frequency oscillations. Overall, the limitations for the use of stimulation with SEEG to locate EZs are the electrode interfaces, namely that stimulation can only be performed at the physical location of electrode – with numerous clinically and functionally relevant brain regions unexplored due to the necessary limitation in the number of electrodes which can be implanted or to the inaccessibility of certain brain structures for implant. Therefore, there is an urgent need for simplified, less-invasive methods capable of evoking such discharges and seizures in the localization of EZ tissue, which would have a massive commercial potential.
The solution: Within my ERC Starting Grant Epi-Centrd, I demonstrated that the use of stimulation with intracranial electrodes can be extended beyond the current application, leading me to propose an additional use of the electrode interfaces to stimulate using Temporal Interference (TI) of electric fields to non-invasively explore previously inaccessible brain regions. Points of very focal electrical stimulation at significant distances from the fixed electrode interfaces can be created with interacting envelopes of electric fields provided from pairs of the already-implanted intracranial clinical electrodes or from transcutaneous electrodes. The value proposition of CONECTIF was to demonstrate preliminary efficacy of TI to dramatically address the limitations in the identification of epileptic zones in the brain of patients by providing a simplified, less-invasive method capable of localizing epileptic tissue, including the ability to non-invasively investigate previously inaccessibility and surgically-complicated brain regions. The new method utilizing temporally interfering electric fields could have a massive commercial potential. In CONECTIF we demonstrated the dramatically effective method of using non-invasive skin electrode to target deep nerve and brain targets. 3 human studies have been performed in both epilepsy and related-peripheral nerve diseases. The technologies developed in CONECTIF can return to the core ERC StG project EPI-Centrd and be further utilized in my new ERC Consolidator project EMUNITI for the identification of epileptic zones in other forms of epilepsy, not only in drug-resistant patients. The CONECTIF project delivered 6 publications, a patent (Patent EP 21306447), a startup company (VBTech), and licensing of the patent. My TI technology has achieved therapeutic DBS in epileptic rodents and I have scaled-up to the dimensions of the human brain to achieve the same results in epileptic patients and other related diseases. Although an excellent result, standard TI stimulates subcortically but the focality is limited. By contrast, multipolar TI (mTI) provides a point of focal stimulation better than a standard clinically implanted stimulation electrode, with full spatial and temporal control (topic of Patent EP 21306447).
