Biophysical mechanisms of temporal interference on epileptic discharges in the human brain from macro- to microscale

About This Grant

PROJECT SUMMARY Surgical interventions for drug-resistant epilepsy have reached a ceiling in efficacy. Neuromodulation, however, provides a potent alternative: by delivering electrical pulses to the epileptic focus or to central hubs like the thalamus, it disrupts pathological synchrony, raises the seizure threshold, and aborts seizures. One important limitation is that all FDA-approved neuromodulation systems currently require surgical implantation, limiting accessibility, and increasing risk. By developing non-invasive neuromodulation technologies, we can offer millions of patients safer, more accessible, and cost-effective treatments. Temporal interference (TI) stimulation is an emerging non-invasive technique in which pairs of scalp electrodes deliver distinct high-frequency electric fields that intersect within targeted brain regions, generating individually tailored neuromodulation in targeted brain structures. While promising, rigorous experiments on biophysical mechanisms and effects of TI on the human epileptic brain remain scarce. More specifically, we do not know HOW TI stimulation works at the neuronal level, WHERE (brain region) it should be applied to be most effective, and WHEN (brain state) it works best. Finally, there is no head-to-head comparison between TI stimulation and direct subthreshold stimulation. In this project, performed at the Comprehensive Epilepsy Center at Duke University, we will leverage on the unique opportunity provided by stereo-electroencephalography (sEEG), a method allowing exact definition of the epileptic network by inserting depth electrodes into the human brain, combined with macroscale scalp EEG and research microwire EEG recordings. We will investigate the biophysical mechanisms of TI, map the spatial and temporal effects of TI on epileptic biomarkers, and compare the effect of TI stimulation to direct electrical stimulation. Our specific aims are: (1) determine the biophysical mechanisms of TI at different spatial scales in 20 consecutive patients implanted with sEEG electrodes and deployable microwires by applying TI stimulation to the epileptic focus and the thalamus as central network hub for seizure propagation (main target for deep brain stimulation); (2) in the same patient cohort, evaluate how TI stimulation influences epileptic biomarkers in both the focus and the thalamus across sleep-wake states (since epileptic activity often intensifies during non-rapid-eye-movement sleep) to guide optimal timing and targeting strategies; and (3) compare the effects of TI on epileptic biomarkers to direct subthreshold electrical stimulation using matched parameters. We anticipate that these studies will reveal how local neuronal activity and network- level biomarkers are modulated by TI, pinpoint optimal targets, and identify the most effective brain states for personalized neuromodulation in epilepsy. The proposed research is innovative in that it leverages a unique set- up allowing us to investigate the mechanisms and effects of TI in the human epileptic brain from cell assemblies to networks. This project has the huge potential to lay the foundation for a future clinical trial exploring non- invasive personalized treatments for the many millions of people with uncontrolled seizures.