Reproducibility of interictal spike propagation in children with refractory epilepsy

Abstract

Objective: Interictal spikes are a characteristic feature of invasive electroencephalography (EEG) recordings in children with refractory epilepsy. Spikes frequently co-occur across multiple brain regions with discernable latencies, suggesting that spikes can propagate through distributed neural networks. The purpose of this study was to examine the long-term reproducibility of spike propagation patterns over hours to days of interictal recording.

Methods: Twelve children (mean age 13.1 years) were retrospectively studied. A mean ± standard deviation (SD) of 47.2 ± 40.1 hours of interictal EEG recordings were examined per patient (range 17.5-166.5 hours). Interictal recordings were divided into 30-minute segments. Networks were extracted based on the frequency of spike coactivation between pairs of electrodes. For each 30-minute segment, electrodes were assigned a "Degree Preference (DP)" based on the tendency to appear upstream or downstream within propagation sequences. The consistency of DPs across segments ("DP-Stability") was quantified using the Spearman rank correlation.

Results: Regions exhibited highly stable preferences to appear upstream, intermediate, or downstream in spike propagation sequences. Across networks, the mean ± SD DP-Stability was 0.88 ± 0.07, indicating that propagation patterns observed in 30-minute segments were representative of the patterns observed in the full interictal window. At the group level, regions involved in seizure generation appeared more upstream in spike propagation sequences.

Significance: Interictal spike propagation is a highly reproducible output of epileptic networks. These findings shed new light on the spatiotemporal dynamics that may constrain the network mechanisms of refractory epilepsy.

Keywords: epilepsy surgery; interictal spike; invasive EEG; network; propagation.

Figure 1.. Interictal segment selection and spike co-activation.

A) For each patient, the longest window of interictal activity without an interruption ≥2 hours in duration was selected and divided into non-overlapping 30-minute segments. Segments overlapping with file breaks, peri-ictal intervals, and artifact were excluded. In this example (Patient #10), 83/102 possible interictal segments (41.5 hours) were preserved. B) Left: Intraoperative photograph and schematic of subdural electrode implant. Right: Representative 10-second epoch containing spike discharges that co-occur across multiple electrodes in the frontal and temporal regions. C) Co-activation matrix (C) quantifying the tendency for regions to co-activate during spike discharges (i.e., spike peaks separated by <150 ms). Dotted boxes indicate clustering of matrix C to reveal two co-activation networks, which are represented in the electrode schematic in (D).

Figure 2.. Examination of regional propagation tendencies over time.

A) Left: Co-activation network encompassing 14 electrodes over the left temporal/parasylvian regions (Patient #12). Colors denote three Upstream electrodes (Overall DP ≥+20; red), four Intermediate electrodes (gray), and seven Downstream electrodes (Overall DP <−20; blue). Right: Three representative spike co-activation discharges (500-ms waveforms) revealing millisecond-scale latencies between Upstream electrodes (anterior temporal lobe) and Downstream electrodes (posterior temporal/parasylvian). Dotted lines represent the peak time of the earliest spike in the sequence. B) Rasters from 8 representative co-activation discharges marking peak times at each electrode. The Overall DP for each electrode (right) reflects the tendency to appear upstream or downstream within sequences. C) Heat map encoding Segment DPs within each 30-minute segment. Warmer colors reflect a preference to appear more upstream. The heat map is sorted top to bottom according to rank order of Overall DPs. The number of sequences captured per segment is shown in gray. The first 13 segments (6.5 hours) are sparse compared to the rest of the analysis window. D) The rank correlation between each Segment DP vector and the Overall DP vector is shown. The median of correlation values is the ‘DP-Stability.’

Figure 3.. Sequence-by-sequence reproducibility of network activation.

A) The rank order of Overall DPs constituted the ‘expected’ sequence of network activation. B) Three hypothetical sequences with peak times marked by dotted lines. From left to right, observed sequences exhibit decreasing concordance with the ‘expected’ sequence order. C) Calculation of the Sequence Similarity (S) value for each observed sequence. A point is awarded for each pairwise interaction that adheres to the expected order (e.g., for Observed (1), +1 point is awarded for the Electrode 1 → Electrode 2 interaction because Electrode 1 appears more upstream, consistent with the expected order. Zero points are awarded for ties, and −1 point is awarded when the interaction violates the expected order (e.g., Electrode 8 → 9). For each sequence (i), S_i is the sum of points divided by the maximum possible score, which is given by: N*(N-1)/2, where N is the number of sequence spikes. D) Histogram of S_i values for all sequences (collapsed across segments). The Reproducibility Index (R_orig) is the median S_i value.

Figure 4.. Temporal stability of Degree Preferences.

Upper Left Panel: A) Two co-activation networks for Patient #2 involving the left frontal and parietal regions. B) Heat map encoding Segment DPs within each segment. Electrodes exhibit stable tendencies to appear at upstream (red), intermediate (green), or downstream (blue) positions in sequences. C) Each dot represents the correlation between the Segment DP vector and the Overall DP vector for each segment. The solid black line represents the median correlation value across segments (‘DP-Stability’). In both networks, propagation tendencies were highly stable over time (DP-Stability, IQR): Network #1: 0.92 (0.85–0.94), Network #2: 0.92 (0.81–0.95). Upper Right Panel: The same figure components are presented for Patient #10. Network #2 exhibited the lowest DP-Stability in the study: 0.77 (0.16–0.94). D) Upstream (n = 59) and Downstream (n = 75) electrodes were defined based on Overall DPs. On average, Upstream electrodes exhibited an upstream Segment DP in 77.6 ± 19.8% of segments and almost never exhibited a downstream Segment DP (2.1 ± 3.5% of segments). The same pattern was seen for Downstream electrodes. Two circled Downstream electrodes are from Patient #10, Network 2 (see asterisks in B’ showing these two electrodes, with inversion of upstream and downstream tendencies).