Stimulating native seizures with neural resonance: a new approach to localize the seizure onset zone

Abstract

Successful outcomes in epilepsy surgery rely on the accurate localization of the seizure onset zone. Localizing the seizure onset zone is often a costly and time-consuming process wherein a patient undergoes intracranial EEG monitoring, and a team of clinicians wait for seizures to occur. Clinicians then analyse the intracranial EEG before each seizure onset to identify the seizure onset zone and localization accuracy increases when more seizures are captured. In this study, we develop a new approach to guide clinicians to actively elicit seizures with electrical stimulation. We propose that a brain region belongs to the seizure onset zone if a periodic stimulation at a particular frequency produces large amplitude oscillations in the intracranial EEG network that propagate seizure activity. Such responses occur when there is 'resonance' in the intracranial EEG network, and the resonant frequency can be detected by observing a sharp peak in the magnitude versus frequency response curve, called a Bode plot. To test our hypothesis, we analysed single-pulse electrical stimulation response data in 32 epilepsy patients undergoing intracranial EEG monitoring. For each patient and each stimulated brain region, we constructed a Bode plot by estimating a transfer function model from the intracranial EEG 'impulse' or single-pulse electrical stimulation response. The Bode plots were then analysed for evidence of resonance. First, we showed that when Bode plot features were used as a marker of the seizure onset zone, it distinguished successful from failed surgical outcomes with an area under the curve of 0.83, an accuracy that surpassed current methods of analysis with cortico-cortical evoked potential amplitude and cortico-cortical spectral responses. Then, we retrospectively showed that three out of five native seizures accidentally triggered in four patients during routine periodic stimulation at a given frequency corresponded to a resonant peak in the Bode plot. Last, we prospectively stimulated peak resonant frequencies gleaned from the Bode plots to elicit seizures in six patients, and this resulted in an induction of three seizures and three auras in these patients. These findings suggest neural resonance as a new biomarker of the seizure onset zone that can guide clinicians in eliciting native seizures to more quickly and accurately localize the seizure onset zone.

Keywords: cortico-cortical evoked potentials; dynamical network model; seizure induction; single-pulse electrical stimulation; surgical outcome.

Figure 1

SPES evoked potential and pipeline to obtain Bode plots and PW ratios. (A) Stimulation applied in a pseudo-bipolar manner between two adjacent channels. (B) Stimulation elicits a response in remote electrodes. The typical waveform has a sharp negative peak 10–50 ms after the stimulus (N1) and a longer, lower amplitude peak 50–300 ms after the stimulus (N2). (C) In the left panel, a brain region is stimulated. The responses are captured and used to construct a TFM from the input signal. Next, we construct the Bode plot for the system, identify the resonant peaks and calculate the pertinent features (including PW ratio) from the function PW = (a_peak − a_min)/(ω_right − ω_left).

Figure 2

TFMs reconstruct the SPES evoked responses for representative response channels. (A) Representative examples of model reconstructions. The black line is the average evoked response from all trials, the blue line is the model reconstruction and the purple shaded area denotes 1 SD. (B) Box plots representing the fraction of data-points that lie within 1 SD of the mean for each channel and each stimulation pair, separated by patient.

Figure 3

Experimentally derived gains match Bode plots. The system gains were experimentally calculated by computing the ratio of the Frobenius norm of the iEEG responses to the norm of the input pulse (blue circles) for (A) P027, (B) P031 and (C and D) P032. The experimentally derived gains were compared to the TFM-derived Bode plot (black line). The experimental gains (y-axis) were plotted against the theoretical gains (x-axis) along with the Pearson correlation coefficient and P-value associated with the comparison (inset).

Figure 4

Bode plots and PW ratios reflect surgical outcome. (A) Representative patients with successful (P017, top) and failed (P011, bottom) surgical outcomes. The left and middle panels show the Bode plots and PW ratios for all stimulated channel pairs, respectively, and the right panel shows the SOZ location for both patients. (B) ROC analysis finds Bode features superior in discriminating successful and failed outcomes. Best Bode model included PW ratio and the DC gain as features with an AUC of 0.83; the best CCEP model included Z-scores from N2 and N1 amplitudes and had an AUC of 0.76; best CCSR model included theta, alpha and beta frequency bands with an AUC of 0.70. (C) The probability values for individual patients were significantly greater for surgical successes (green box plots, left box for each model) compared with failures (red box plots, right box for each model) in both Bode and CCEP models, but insignificantly greater in the CCSR model.

Figure 5

Bode models are robust to several clinical factors. The probability of success generated by the Bode model (A) was significantly higher if the patient had not had a previous resection. The probability of success was not significantly modulated by (B) a mesial temporal or extratemporal SOZ onset, (C) recording electrode type (ECoG or SEEG), (D) a lesional MRI, (E) patient age or (F) gender.

Figure 6

Seizures are prospectively stimulated in patients with corresponding resonant peaks in Bode plot. The black line shows the Bode plot for each stimulation pair and labelled with the first stimulation channel name for (A) P024, marked a true positive; (B) P027, marked a false negative; (C) P028, a true positive; (D) P030, a false negative and (E) P031, a true positive. The circles indicate the frequency of periodic stimulation that elicited a seizure (red) or aura (green).