The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures

Abstract

The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area.

Figures

Figure 1. Progression of seizure activity recorded from a microelectrode array in the ictal core.

Colours indicate the different epochs in the seizure: light blue is the pre-recruitment epoch, orange is the ictal wavefront epoch, purple is the post-recruitment epoch and pink is the pre-termination epoch. Seizure termination is labelled with a dark blue dotted line. (a) Cartoon of hypothesized spatial organization of seizure activity relative to the microelectrode array (MEA) location. (b) Raw LFP traces recorded from a single microelectrode during a seizure. (c) Averaged firing rate over electrodes on the array during the seizure in b. (d) Multiunit raster plot over MEA channels during the seizure in b. (e) Inter-discharge intervals (IDIs) for each discharge through the duration of the same seizure. The abrupt transition from regular to irregular IDIs at 36 s after seizure onset marks the transition from post-recruitment (period following passage of the ictal wavefront) to the pre-termination epoch. In both b and c, the abrupt cessation of discharges in both LFP and MUA, which is the defining event marking seizure termination, is evident.

Figure 2. Ictal discharges form travelling waves across the microelectrode array.

(a) Example, low-frequency LFP recorded from each microelectrode during three ictal (EEG) discharges, one from each seizure epoch as indicated by the coloured asterisks in the seizure traces, colour coded by when the maximally negative slope of the travelling wave occurs on each microelectrode. Seizures from two patients (patient 3 and 5) are shown. (b) The footprint of the microelectrode array corresponding to the three ictal discharges in a, with electrode positions colour coded the same way as the LFP in a. Vectors indicating travelling wave direction are superimposed on the microelectrode array footprint in white. (c) Histograms of delays between the first and last discharges on array microelectrodes during each epoch (pre-recruitment in light blue, post-recruitment in purple and pre-termination in pink). (d) Measures of discharge speed across all patients, during the three epochs shown in a. Post hoc Tukey's range test determined that pre-recruitment bursts (N=273) were significantly slower than both post-recruitment (N=315) and pre-termination (N=282) bursts (P=9.5 × 10−10 and P=9.5 × 10−10). Post-recruitment and pre-termination bursts did not exhibit significantly different speeds (P=0.82). Error bars indicate s.e.

Figure 3. Travelling wave directions during seizure epochs are dependent on the location of the ictal wavefront.

(a) Example velocity vectors for one seizure before and after recruitment. The black line indicates the direction of ictal wavefront passage across the MEA. The shift in direction between pre-recruitment and post-recruitment discharges that occurs precisely at the time of ictal wavefront passage is apparent. In each case, the ictal wavefront's location relative to the MEA site is opposite to the predominant travelling wave direction. (b–d) Distributions of travelling wave directions across all seizures, relative to the direction of the ictal wavefront (black line), coloured by epoch (b: pre-recruitment, c: post-recruitment, d: pre-termination).

Figure 4. Travelling waves propagating across the microelectrode array correspond to those propagating across the ECoG grid.

(a) Examples of ictal discharges recorded across ECoG electrodes in two patients colour coded by when the maximally decreasing slope occurs, with cyan indicating earlier electrodes and magenta later electrodes. Colour-coded circles above the discharges indicate a spatial representation of delays over the ECoG grid, with the same colour code as the voltage traces. (b) Reconstructions of ECoG grid and MEA locations for the same patients in a. Average delays across ECoG electrodes are colour coded as in a. Black arrows indicate MEA locations. (c) Distributions of MEA pre-recruitment travelling waves (black) and travelling waves ECoG (orange). (d) Three channels of LFP recorded from ECoG electrodes during one seizure (patient 3) and a representative increase in variance explained by the first-principal component, across all ECoG electrodes on the grid shown in b (lower), during the pre-termination epoch. The black dotted line shows linear regression used to determine the slope of the variance explained during the pre-termination epoch for the example seizure.

Figure 5. Decreasing input to a network of simulated neurons recreates mean-field dynamics observed in the data.

(a) Mean firing rate of the simulated ictal network progresses from tonic firing, to rhythmic discharging, to self-termination, with decreasing extra-network input. The colours correspond to the epochs labelled in Fig. 1 as apparent in the model's firing rate. (b) Firing rate from all microelectrode channels during one spontaneous human seizure, showing the progression from tonic firing during ictal wavefront passage, to rhythmic discharging, to seizure termination. The coloured bars above the seizures correspond to the epochs labelled in Fig. 1. (c) Peak mean firing rate during each discharge in the pre-termination period for the simulated neurons (green) and the seizure shown in b (purple). (d) Inter-discharge intervals during the pre-termination period, for the simulated neurons (green) and the seizure shown in b (purple). (e) Discharge width during the pre-termination period, for the simulated neurons (green) and the seizure shown in b (purple).

Figure 6. High-γ activity in the seizure core decreases in amplitude and frequency before seizure termination.

(a) High-γ instantaneous amplitude and multiunit firing recorded from an example microelectrode through the duration of the same seizure shown in Fig. 5b. The blue dotted line indicates linear regression of the peak high-γ amplitude for each discharge during the pre-termination epoch, and the orange dotted line similarly indicates peak firing rate. (b) Spectrogram of the same seizure in a. The white dotted line indicates peak high-γ frequency through the duration of the seizure, and the blue dotted line indicates linear regression of the peak high-γ frequency during the pre-termination epoch. c and d show the same seizure as in a and b recorded on the ECoG electrode adjacent to the microelectrode array. Dotted lines indicate the same linear regression measurements as in a and b.

Figure 7. Local desynchronization in the ictal core precedes seizure termination.

(a) Examples of filtered data for two sample discharges during the pre-termination epoch. Low-frequency filtered data (0.3–50 Hz) are shown in grey and filtered data for multiunit activity detection (500–3000 Hz) are shown in teal. The threshold for multiunit event detection is indicated with a blue line. Bursts are indicated on the seizure in grey using black arrows. (b) Examples of high-γ (orange), firing rate (blue) and Gaussian fit (black dotted lines) for burst width superimposed on the multiunit activity raster plot (teal) for two bursts in one seizure: one at the beginning of the pre-termination epoch (early) and one at the end of the pre-termination epoch (late). Maximum mutual information values for each discharge are shown in boxes. (c) Relationship between peak multiunit firing rate and peak high-γ amplitude for each discharge. (d) Relationship between high-γ amplitude and multiunit discharge width for each discharge. (e) Relationship between peak high-γ amplitude and multiunit synchrony in each discharge. Colours in c, d, and e represent when each discharge occurred during the pre-termination epoch, with black dots occurring earlier and copper dots occurring later.

Figure 8. Summary model of spatial dynamics of seizure evolution and termination.

(a) Schematic showing snapshots of seizure progression through the four seizure epochs. Colours represent the spatial organization of the epochs shown in time series data of Fig. 1. Dashed-line squares represent the MEA footprint, and dashed-line circles represent ECoG electrodes. Yellow ECoG electrodes represent those exhibiting hypersynchronous ictal activity in the low-frequency (0.3–50 Hz) LFP. As the recruited region (seizure core) gradually expands to envelope the MEA site, the ictal wavefront approaches the site, passes through it and then continues to move away from the site. (b) Schematic depictions of travelling wave activity across the MEA microelectrodes during each of the four seizure epochs. Rapidly moving travelling waves across the MEA change direction based on the MEAs location relative to the slowly moving ictal wavefront.