Effects of stimulation intensity on intracranial cortico-cortical evoked potentials: A titration study

Abstract

Objective: The aim of the present study was to investigate the optimal stimulation parameters for eliciting cortico-cortical evoked potentials (CCEPs) for mapping functional and epileptogenic networks.

Methods: We studied 13 patients with refractory epilepsy undergoing intracranial EEG monitoring. We systematically titrated the intensity of single-pulse electrical stimulation at multiple sites to assess the effect of increasing current on salient features of CCEPs such as N1 potential magnitude, signal to noise ratio, waveform similarity, and spatial distribution of responses. Responses at each incremental stimulation setting were compared to each other and to a final set of responses at the maximum intensity used in each patient (3.5-10 mA, median 6 mA).

Results: We found that with a biphasic 0.15 ms/phase pulse at least 2-4 mA is needed to differentiate between non-responsive and responsive sites, and that stimulation currents of 6-7 mA are needed to maximize amplitude and spatial distribution of N1 responses and stabilize waveform morphology.

Conclusions: We determined a minimum stimulation threshold necessary for eliciting CCEPs, as well as a point at which the current-dependent relationship of several response metrics all saturate.

Significance: This titration study provides practical, immediate guidance on optimal stimulation parameters to study specific features of CCEPs, which have been increasingly used to map both functional and epileptic brain networks in humans.

Keywords: Cortico-cortical evoked potential; Effective connectivity; Intracranial EEG; Single-pulse electrical stimulation.

Figure 1.

Experimental Methods. (A) Single-pulse electrical stimulation (SPES) was applied in a bipolar manner to adjacent electrodes at 0.4 or 0.5 Hz. At each stimulation site, SPES consisted of titration blocks at incrementally increasing current intensities for 10 trials each and a full block at the maximum current intensity for 40 or 50 trials. (B) Example response traces at the same site to SPES of increasing current intensity. Trials at each current intensity were centered using the baseline mean (−500 to −10 ms) and averaged to obtain average responses of each stimulation-response pair at each current intensity. (C) The amplitude, latency, and polarity of the N1 peak within 10 to 50 ms post-stimulus was identified in each average response trace. (D) The amplitude of the N1 peak normalized by the pre-stimulus baseline was used to quantify the Z-score. Responses with Z-score greater than 6 were considered significant evoked potentials, representing an electrophysiological relationship between stimulation and response site. Example significant responses from a full block are mapped here, as circles located at the response site colored according to the magnitude of the Z-score with lines coming from the red stimulation site. Three response electrodes are highlighted to show how the average response waveform varied with current intensity at different locations.

Figure 2.

Dynamic time warping (DTW) and DTW barycenter averaging (DBA) k-Means Analysis. (A) Average responses of the same stimulation-response pair to each titrating current intensity were normalized and clustered using DBA k-Means. (B) The DTW distance from the normalized average response to the center of the cluster at greater current intensities was computed. Example traces for the responses to 1, 3, and 5 mA are shown.

Figure 3.

N1 voltage comparisons across current intensity. The N1 peak voltages of stimulation-response pairs at each titration current intensity were compared using Kruskal-Wallis tests separately for stimulation-response pairs classified as significantly responsive or non-responsive in the full block. There was a significant effect of current intensity in each patient, and post-hoc Dunn’s test pairwise comparisons showed significant differences between median N1 voltages at low current intensities. At higher current intensities pairwise differences between N1 voltages of significantly responsive stimulation-response pairs were no longer significant, indicated by the bar labeled n.s. (non-significant) on each plot. Error bars represent 95% confidence interval of the median.

Figure 4.

Early response signal to noise ratio (SNR) comparisons across current intensity. (A) The observed SNR at each titration current intensity was compared separately for stimulation-response pairs classified as significantly responsive or non-responsive in the full block. Post-hoc Dunn’s test pairwise comparisons show significant differences between observed SNR at low current intensities. At higher current intensities pairwise differences between median observed SNR of significantly responsive stimulation-response pairs were no longer significant, indicated by the bar labeled n.s. on each plot. Error bars represent 95% confidence interval of the median. (B) Box plots indicating the distribution of the current intensities above which the observed SNR stayed significant, for each patient.

Figure 5.

Comparisons of evoked potential waveforms across current intensity using dynamic time warping (DTW) distance. (A) The DTW distance of stimulation-response pairs at each titration current intensity were compared using Kruskal-Wallis tests separately for stimulation-response pairs classified as significantly responsive or non-responsive in the full block. There was a significant effect of current intensity in each patient, and post-hoc Dunn’s test pairwise comparisons show significant differences between median DTW distance at low current intensities. At higher current intensities pairwise differences between DTW distance of significantly responsive stimulation-response pairs were no longer significant, indicated by the bar labeled n.s. on each plot. Error bars represent 95% confidence interval of the median. (B) Box plots indicating the distribution of the current intensities above which the cluster assignment of each stimulation-response pair remained constant, for each patient.

Figure 6.

Comparisons of spatial distributions across current intensity. (A) Correlation of N1 Z-scores of responses at maximum current intensity in full block with N1 Z-scores of responses at each titration block shows increasing similarity of response distribution with current intensity. Error bars represent 95% confidence interval of the median. (B) Receiver operating characteristic (ROC) curves were generated by varying the threshold of titration block Z-scores to predict significance of responses in the full block (Z-score > 6). High accuracy (area under the curve [AUC] > 0.80) was achieved from responses to stimulations at 2.5–5 mA, depending on the patient, and accuracy generally increased and plateaued at greater current intensities.