Quantifying trial‐by‐trial variability during cortico‐cortical evoked potential mapping of epileptogenic tissue

Abstract Objective Measuring cortico‐cortical evoked potentials (CCEPs) is a promising tool for mapping epileptic networks, but it is not known how variability in brain state and stimulation technique might impact the use of CCEPs for epilepsy localization. We test the hypotheses that (1) CCEPs demonstrate systematic variability across trials and (2) CCEP amplitudes depend on the timing of stimulation with respect to endogenous, low‐frequency oscillations. Methods We studied 11 patients who underwent CCEP mapping after stereo‐electroencephalography electrode implantation for surgical evaluation of drug‐resistant epilepsy. Evoked potentials were measured from all electrodes after each pulse of a 30 s, 1 Hz bipolar stimulation train. We quantified monotonic trends, phase dependence, and standard deviation (SD) of N1 (15–50 ms post‐stimulation) and N2 (50–300 ms post‐stimulation) amplitudes across the 30 stimulation trials for each patient. We used linear regression to quantify the relationship between measures of CCEP variability and the clinical seizure‐onset zone (SOZ) or interictal spike rates. Results We found that N1 and N2 waveforms exhibited both positive and negative monotonic trends in amplitude across trials. SOZ electrodes and electrodes with high interictal spike rates had lower N1 and N2 amplitudes with higher SD across trials. Monotonic trends of N1 and N2 amplitude were more positive when stimulating from an area with higher interictal spike rate. We also found intermittent synchronization of trial‐level N1 amplitude with low‐frequency phase in the hippocampus, which did not localize the SOZ. Significance These findings suggest that standard approaches for CCEP mapping, which involve computing a trial‐averaged response over a .2–1 Hz stimulation train, may be masking inter‐trial variability that localizes to epileptogenic tissue. We also found that CCEP N1 amplitudes synchronize with ongoing low‐frequency oscillations in the hippocampus. Further targeted experiments are needed to determine whether phase‐locked stimulation could have a role in localizing epileptogenic tissue.