A quantitative method for evaluating cortical responses to electrical stimulation

Abstract

Background: Electrical stimulation of the cortex using subdurally implanted electrodes can causally reveal structural connectivity by eliciting cortico-cortical evoked potentials (CCEPs). While many studies have demonstrated the potential value of CCEPs, the methods to evaluate them were often relatively subjective, did not consider potential artifacts, and did not lend themselves to systematic scientific investigations.

New method: We developed an automated and quantitative method called SIGNI (Stimulation-Induced Gamma-based Network Identification) to evaluate cortical population-level responses to electrical stimulation that minimizes the impact of electrical artifacts. We applied SIGNI to electrocorticographic (ECoG) data from eight human subjects who were implanted with a total of 978 subdural electrodes. Across the eight subjects, we delivered 92 trains of approximately 200 discrete electrical stimuli each (amplitude 4-15 mA) to a total of 64 electrode pairs.

Results: We verified SIGNI's efficacy by demonstrating a relationship between the magnitude of evoked cortical activity and stimulation amplitude, as well as between the latency of evoked cortical activity and the distance from the stimulated locations.

Conclusions: SIGNI reveals the timing and amplitude of cortical responses to electrical stimulation as well as the structural connectivity supporting these responses. With these properties, it enables exploration of new and important questions about the neurophysiology of cortical communication and may also be useful for pre-surgical planning.

Keywords: Connectivity; Cortico-cortical evoked potentials; Electrical stimulation; Electrocorticography.

Fig. 1.

Method for automated quantification of neural activity elicited by direct electrical stimulation of the cortex. (A) A cortical stimulator generates electrical stimuli with a specified frequency, pulse duration, current amplitude, and waveform. Red and blue periods indicate alternating anodic and cathodic stimulation. (B) Electrical stimuli are delivered to cortical targets underlying implanted subdural electrodes that are shown in this lateral radiograph. (C) Electrocorticographic (ECoG) signals are recorded from the electrodes with high sampling frequency. (D) Stimulation artifacts, as indicated by the red rectangle, are removed and broadband gamma signals (amplitudes in the 70–170 Hz band) are extracted. (E) The signal-to-noise ratio in a post-stimulus period is calculated with the method described in Schalk et al. (2007). (F) A permutation test is performed to generate a distribution of SNR values that would be expected if no cortical response to stimulation occurred. (G) A p-value is calculated for each channel based on the observed SNR value and the permutation distribution. (H) Resulting p-values are corrected for multiple comparisons and are visualized using NeuralAct software (Kubanek and Schalk, 2015).

Fig. 2.

Demonstration of artifact removal and feature extraction procedure using ECoG from a location that shows a broadband gamma response to cortical stimulation. (A) Averaged ECoG signal with prominent stimulation artifact (± 50 mV). Red and blue traces indicate responses resulting from anodic and cathodic stimulation (alternating monophasic stimulation), respectively. (B) Averaged signals trials after removal of the immediate electrical artifact. (C) Individual trials following subtraction of the corresponding average trial. (D) Band-pass filtered ECoG signals in the broadband gamma (70–170 Hz) range (gray traces) (± 50 μV), and their average envelope (black trace), highlighting a physiological response around 70 ms.

Fig. 3.

Effect of artifact removal on results. (A) Broadband gamma time courses from a single location in subject F. Green/red traces represent signals with/without application of the artifact removal process, respectively. The red trace, but not the green trace, shows a prominent stimulation artifact at the time of stimulation. (B) Relationship between distance between stimulated and responding site, and the onset of the broadband gamma response. Each dot represents results for one combination of stimulated and responding site. The larger dot represents data for the responding site shown in (A). Several data points suggest an onset time close to 0 irrespective of distance to the stimulating site. Relationship between distance and onset time is modest (r² = 0.10). (C) Same data as in (B), except that signals were processed with the artifact removal process. Onset times are at least several ms, and relationship between distance and onset time is greatly improved (r² = 0.42).

Fig. 4.

Higher current amplitude increases stimulus-related cortical activity. (A) Example topography demonstrating stimulation location (yellow), locations responsive to low current amplitude (blue circles), additional locations only responsive to high current amplitude (red circles), and locations with no significant response (black dots). (B) Stimulating six cortical locations at 10 mA (instead of 6 mA) increased cortical response magnitude (paired-sample t-test, p < 0.05). Data for the stimulation site shown in (A) is represented by the blue/red data points.

Fig. 5.

Example of broadband responses at increasing distance from the stimulation site. (A) Cortical model and electrode locations (dots) from subject F. The location of stimulus delivery is marked with a lightning symbol. The locations of three responding sites are marked with colored circles numbered 1–3, respectively. (B) Broadband gamma time courses of these three locations. The peak of the evoked broadband gamma activity occurs later as distance to the stimulation site increases.

Fig. 6.

Latency of broadband responses increases with distance from the stimulation site. Data are from all subjects, and responding electrodes are grouped by increments of 15 mm. Statistical significance (two-sample t-test) between adjacent groups is represented by a single (p < 0.05) or double (p < 0.01) asterisk.

Fig. 7.

Example of systematic study of cortical connectivity in superior temporal gyrus (right hemisphere) of subject H. (A–G) Electrical stimuli were delivered to seven electrode pairs on the depicted electrode array. Stimulated electrodes are shown in yellow, locations that exhibit a statistically significant response evaluated with SIGNI are shown in green. The underlying black lines indicate the approximate location of the superior temporal gyrus (solid lines) and central sulcus (dashed lines). All significant locations are indicated in the final panel.

Fig. 8.

Comparison of traditional evoked potentials (blue traces) and broadband gamma activity measured with SIGNI (red traces) for one stimulation pair (yellow dots) in subject H. (A–C) Locations that show broadband gamma responses to stimulation. Corresponding evoked potentials have complex and differing morphologies. (D–F) Locations that should not be anatomically connected to the sites in superior temporal gyrus, do not have broadband gamma responses, but do still show complex evoked responses.