Abstracts

Rationale:
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 nonpenetrating 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.
Method:
We show a method of orientation-tunable Electrical stimulation was performed using two pairs of surface electrodes with frequencies 1200 Hz and 1250 Hz and biphasic, bipolar pulses of 500 μs with the overall stimulation time of 10s, varied over a range of currents and associated voltages. Points of focal stimulation at significant distances below the cortex surface are created by envelopes of interacting electric fields applied by the surface electrodes to evoke SLEs in the hippocampus. The orientation of the electric field, as defined by the orientation of the surface electrodes (see Figure) determines the effectiveness and the threshold of stimulation necessary to evoke the SLE.
Results:
Our target was the CA3-CA1 border structure where the Schaffer collaterals are a well-known target for evoking seizures in vivo and in vitro with penetrating electrodes. In our alternative technique relying exclusively on nonpenetrating surface electrodes and ot-TI electric fields, we have shown that the SLEs generated are indeed focally evoked in the hippocampus and identical to focally evoked SLEs generated with classically implanted electrodes. We additionally demonstrated the use of square-waves with TI stimulation, as clinically, square-waves are most often used in stimulation. As we have shown, the orientation of the electric field plays a key role in evoking events, and if carefully controlled, optimal orientation dramatically lowers thresholds for both implantable electrodes and correspondingly the minimally-invasive ot-TI, replicating the implantable stimulation without the need of penetrating the cortex.
Conclusion:
The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. 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. This method has promise to significantly advance our capacity of probing the organization of spatiotemporal brain activity and could dramatically increase the explorable tissue for clinical definition of the EZ. The technique undoubtedly holds great promises with potential applications in epilepsy, but also for a wide range of other brain disorders currently managed by electrical brain stimulation.
Funding:
:A.W. acknowledges funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC Starting Grant, agreement No 716867) and acknowledges support from the Knut and Alice Wallenberg Foundation.