Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity

Abstract

Purpose: Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment.

Methods: Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared.

Results: Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03).

Conclusions: Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal.

Figure 1.. Local propagation within a seizure hub

(A) Schematic model of multi-site seizure propagation with recruited territory distinguished from non-recruited territory by the presence of high frequency (HF) activity phase-locked to the low frequency (LF) ictal EEG rhythm. (B-E) Representative example of local contiguous recruitment. Seizure onset (B) in standard EEG (top trace, black arrowhead) precedes the activation of phase-locked ictal HGA (bottom trace, green arrowhead). Sequential activation of ictal HGA occurs from deep to superficial contacts along the depth array (C). Standard EEG reveals early activity across multiple contacts (D), compared to the ordered recruitment demonstrated by ictal HGA activation (E). Artifact (gray bars) is characterized by identical high frequency events in all channels.

Figure 2.. Remote propagation between seizure hubs

(A-E) Representative example of multi-site recruitment. In a bilateral implant (A), ictal HGA occurs in three distinct clusters (green, blue, maroon), representing a minority of the contacts with standard ictal EEG rhythms (gray). Standard EEG (1–70 Hz) demonstrates asynchronous ictal rhythms leading to asynchronous terminations in compressed (B) and expanded (C) views. Ictal HGA reveals delayed activation (D) with an ordered pattern of recruitment across clusters. Non-sustained HGA is seen in Channel #2 prior to development of sustained activity, and distinct from artifact (gray bar). Localization of ictal HGA reveals a recruited cluster in entorhinal cortex followed by parahippocampal gyrus and then contralateral temporal neocortex.

Figure 3.. Ictal high gamma clustering and seizure termination

(A) Inter-cluster activation delay versus distance. Euclidean distances are measured between the first-to-second activated clusters (blue), and in later clusters from the most proximally located earlier cluster (yellow). Dashed lines indicate estimated propagation speed, including nearly simultaneous activation between distant clusters (**). (B) Ictal HGA clusters plotted against asynchronous seizure termination groups, stratified by seizure type, and showing lack of asynchronous terminations in FAS. (C) Correlation between total number of seizure hubs and termination groups per patient. Gray shaded area represents the 95% confidence interval.

Figure 4.. Association between interictal ripples and seizure hubs

Overlap of interictal ripples (80–250 Hz) in cases with at least one seizure hub defined by ictal HGA. All interictal ripples overlap with ictal HGA in cases with a single seizure hub, whereas in cases with multiple seizure hubs, ripples are found in 8/19 (42%) of seizure hubs, and 29% of ripple channels are located outside of all hubs.