Abstracts

Rationale: Neuromodulation by electrical stimulation is a new therapy that is increasingly being utilized for patients with intractable epilepsy. However, little is known about the influences of the external stimuli on the epileptic network. We have been focusing on the early responses (cortico-cortical evoked potentials: CCEPs) to a single-pulse electrical stimulation (SPES), which traces cortico-cortical networks involved in brain functions and seizure propagation. We reported that the early and late negative components of CCEP (N1 and N2) can be regarded as dynamic measures of cortical excitation and inhibition, respectively (Matsumoto et al. 2005; Usami et al. 2015; Kobayashi et al. 2017). Herein, by utilizing the excellent time resolution of SPES, we recorded the CCEPs time-locked to the phase of spike (reflecting excitation) and post-spike slow (PSS, reflecting inhibition) in interictal epileptiform discharges (IEDs) at the epileptic focus, and clarified the dynamics of epileptic network. Methods: We recruited 14 patients with intractable partial epilepsy who underwent invasive presurgical evaluation with chronic implantation of subdural electrodes (IRB #443/C1212). By analyzing CCEPs evoked by SPES to the seizure onset zone (SOZ) and averaging IEDs in SOZ, we identified the 1) IED propagation network (CCEP+/IED+) and 2) IED non-propagation network (CCEP+/IED-). We applied SPES to individual IEDs using the auto trigger at the timing of spike and PSS, based on the averaged IEDs in one electrode of the SOZ adjacent to the stimulus sites. We compared the amplitudes of CCEP N1 and N2 in the following 3 conditions to investigate the differences in excitability of epileptic network affected by internal excitability at the timing of SPES: 1) control CCEPs (C-CCEPs), 2) CCEPs by SPES time-locked to the spikes (SP-CCEPs), and 3) CCEPs by SPES time-locked to the PSS (PSS-CCEPs). CCEPs were recorded by off-line averaging time-locked to the stimulus onset, and the averaged activity of IEDs was subtracted for SP-CCEPs and PSS-CCEPs from the original waveforms. Results: In total, 83 electrodes in the IED propagation network and 62 in the IED non-propagation network were analyzed across 14 patients. The N1 amplitude of SP-CCEPs was significantly smaller than that of PSS-CCEPs, especially in the IED propagation network. With regard to the N2 amplitude, it was significantly larger in PSS-CCEPs than that in SP-CCEPs, especially in the IED non-propagation network. The distribution of SP-CCEP and PSS-CCEP did not differ from that of C-CCEP. Conclusions: Regarding CCEP N1 and N2 as an index of excitation and inhibition, respectively, the excitability of epileptic network is hard to get more excited by external stimulation at the timing of spike, namely, when it is already internally excited. On the other hand, the inhibition of the epileptic network was increased by the external stimuli at the timing of PSS, internally suppressed state. The connectivity of the epileptic network was modulated dynamically according to the degree of underlying internal cortical excitability. These findings indicate the importance of the timing of electrical stimulation for neuromodulation therapy. Funding: JSPS KAKENHI [grant numbers 26560465, 26282218, 26293209, 15H05874 (Non-linear Neuro-oscillology), 17H05907, 17K16120, 18H02709]The Research Grant from the Japan Epilepsy Research Foundation