Imaging the effective networks associated with cortical function through intracranial high-frequency stimulation

Abstract

Direct electrical stimulation (DES) is considered to be the gold standard for mapping cortical function. A careful mapping of the eloquent cortex is key to successful resective or ablative surgeries, with a minimal postoperative deficit, for treatment of drug-resistant epilepsy. There is accumulating evidence suggesting that not only local, but also remote activations play an equally important role in evoking clinical effects. By introducing a new intracranial stimulation paradigm and signal analysis methodology allowing to disambiguate EEG responses from stimulation artifacts we highlight the spatial extent of the networks associated with clinical effects. Our study includes 26 patients that underwent stereoelectroencephalographic investigations for drug-resistant epilepsy, having 337 depth electrodes with 4,351 contacts sampling most brain structures. The routine high-frequency electrical stimulation protocol for eloquent cortex mapping was altered in a subtle way, by alternating the polarity of the biphasic pulses in a train, causing the splitting the spectral lines of the artifactual components, exposing the underlying tissue response. By performing a frequency-domain analysis of the EEG responses during DES we were able to capture remote activations and highlight the effect's network. By using standard intersubject averaging and a fine granularity HCP-MMP parcellation, we were able to create local and distant connectivity maps for 614 stimulations evoking specific clinical effects. The clinical value of such maps is not only for a better understanding of the extent of the effects' networks guiding the invasive exploration, but also for understanding the spatial patterns of seizure propagation given the timeline of the seizure semiology.

Keywords: clinical effects; direct electrical stimulation; effective connectivity; spectral analysis; stereoelectroencephalography.

FIGURE 1

Analysis workflow that describes the process of creating per‐symptom activation maps from HFS stimulation‐evoked EEG responses and clinical effects

FIGURE 2

(a) The regular biphasic stimulation waveform $y\left(t\right)$, the modulating function $y_m\left(t\right)$ and the alternating polarity waveform $y_{\mathit{ap}}\left(t\right)=y_m\left(t\right)*y\left(t\right)$; (b) the Fourier spectrum of the waveforms $y\left(t\right)$ and $y_m\left(t\right)$, where $\left|c_n\right|$ and $\left|d_k\right|$ are the absolute values of the Fourier coefficients; (c) the Fourier spectrum of the modulated waveform that has null components (Fourier coefficients $b_m$) at the frequency of the original biphasic train and its harmonics

FIGURE 3

Numerical analysis of simulated signals and a comparison between time‐domain (TDA) and frequency‐domain analysis (FDA). (a) alternating polarity biphasic stimulation train; (b) calculated frequency spectrum of the stimulation train (red) and of a rectified derivative of it (green); (c) illustration of how the modulation theorem applied to first harmonic of signals explains the splitting of the spectral lines of the artifactual components, opening up a window for detecting the underlying tissue response; (d) simulated signals obtained by differentiating Gaussians having an amplitude of 1/10 of the stimulus artifact, $\sigma$ in the range $[T_0/10$, $5T_0/10$] and latencies in the range $[0.3T_0$, $0.8T_0$], where $T_0=1/f_0$, $T_0\approx 23$ ms; the shaded area indicates the blanking interval containing the residual signal artifact excluded from the TDA analysis; (e) time‐frequency decomposition of a 5 s stimulation train based on the dark‐green waveform in (d) plus the artifact; (f) time‐frequency decomposition of a train where only the artifact is present; (g) comparison of the TDA and FDA performance, for various $\sigma$ values of a gaussian having a latency of 12.7 ms; (h) comparison of the TDA and FDA performance for various latencies of a Gaussian having a $\sigma =4.6$ ms; (i) scatterplot of FDA versus TDA responses for the points in G and H

FIGURE 4

(a) Recorded EEG traces (n = 112) using a bipolar montage when stimulating the pair X'11‐X'12 located in the left Rolandic cortex of patient 12, with the baseline (green) and cortical responses to direct electrical stimulation (red) obtained by comb‐filtering the raw signals (gray), as described in 2.6; the filtered signals are represented with a magnification factor of 10 compared to raw signal; (b) magnitude of the responses on the 112 recorded channels; (c) 3D view of all SEEG electrode contacts locations (12 electrodes, 168 contacts) in patient 12, with the 128 recording contacts highlighted in green; (d) time‐domain analysis of waveforms by averaging responses to opposite pulse polarities (red, blue), illustrating incomplete artifact cancelation (green); (e) time‐amplitude map of the interpulse responses, illustrating fast onset and sustained evoked responses; (f) time‐frequency map of the signal recorded on pair M'05–M'06, illustrating spectral properties in agreement with simulation in Figure 3b; (g) same as (f), but for X'01‐X'02 pair where only artifactual components are visible; (h) same as (f), but for N′05–N′06 pair, where a 50 Hz line noise component is present, distinct from the 43.2 Hz stimulation frequency

FIGURE 5

Example of the connectivity analysis for 13 stimulation sites that evoked elementary somatosensory effects in patient 12. (a) Connectivity matrix. Connections not sampled are shown in dark gray; (b) circular diagram of the third quartile of the significant connections (Z‐score >3, p <.05); (c) 3D representation of the connections in (b)

FIGURE 6

(a) Histogram of the number of responses recorded on all implanted contacts, and of the number of significant responses (Z‐score >3, p <.05) as a function of the Euclidean distance from the stimulated site; (b) histogram of the ratio between significant nonsignificant responses shown in a; (c,d) histogram of the significant responses as a function of the distance from the stimulated site for L1 (c) and L2 (d) effect classification. Only top 5 effects in terms of number of evoked symptoms have been represented

FIGURE 7

Current threshold (a) for evoking clinical effects and response maps (b–d) for all 614 stimulations in 26 patients. Sites evoking clinical effects were shown using green circles (a–d), while the others were shown using empty circles (a); (b) response maps for all stimulations and all distances between stimulation site and recorded site; (c) response maps for short‐range connections (Euclidean distance from stimulated site <30 mm); and (d) for long‐range connections (≥30 mm)

FIGURE 8

The thresholds for the 42 stimulated sites evoking auditory effects (a); All evoked activations are shown in b, whereas local (Euclidean distance from stimulated site d <30 mm) and distant (d ≥30 mm) ones are shown in c and d, respectively

FIGURE 9

The mean normalized outdegree for stimulations evoking effects according to the L1 classification. The number of stimulations evoking each class of effects is shown on the bars