Spike propagation mapping reveals effective connectivity and predicts surgical outcome in epilepsy

: Neurosurgical intervention is the best available treatment for selected patients with drug resistant epilepsy. For these patients, surgical planning requires biomarkers that delineate the epileptogenic zone, the brain area that is indispensable for the generation of seizures. Interictal spikes recorded with electrophysiological techniques are considered key biomarkers of epilepsy. Yet, they lack specificity mostly because they propagate across brain areas forming networks. Understanding the relationship between interictal spike propagation and functional connections among the involved brain areas may help develop novel biomarkers that can delineate the epileptogenic zone with high precision. Here, we reveal the relationship between spike propagation and effective connectivity among onset and areas of spread and assess the prognostic value of resecting these areas. We analyzed intracranial electroencephalography data from 43 children with drug resistant epilepsy who underwent invasive monitoring for neurosurgical planning. Using electric source imaging, we mapped spike propagation in the source domain and identified three zones: onset, early-spread, and late-spread. For each zone, we calculated the overlap and distance from surgical resection. We then estimated a virtual sensor for each zone and, the direction of information flow among them via Granger Causality. Finally, we compared the prognostic value of resecting these zones, the clinically-defined seizure onset zone, and the spike-onset on intracranial electroencephalography channels, by estimating their overlap with resection. We observed a spike propagation in source space for 37 patients with a median duration of 95 ms (IQR: 34-206), a spatial displacement of 14 cm (7.5-22), and a velocity of 0.5 m/s (0.3-0.8). In patients with good surgical outcome (25 patients, Engel I), the onset had higher overlap with resection [96% (40-100%)] than early-spread [86% (34-100%), P = 0.01] and late-spread [59% (12-100%), P = 0.002], and it was also closer to resection than late-spread [5 vs. 9 mm, P = 0.007]. We found an information flow from onset to early-spread in 66% of patients with good outcomes, and from early-spread to onset in 50% of patients with poor outcome. Finally, resection of spike-onset, but not area of spike-spread or the seizure onset zone, predicted outcome with positive predictive value of 79% and negative predictive value of 56% (P = 0.04). Spatiotemporal mapping of spike propagation reveals information flow from onset to areas of spread in epilepsy brain. Surgical resection of the spike-onset disrupts the epileptogenic network and may render patients with drug resistant epilepsy seizure-free without having to wait for a seizure to occur during intracranial monitoring.