Spontaneous HFO Sequences Reveal Propagation Pathways for Precise Delineation of Epileptogenic Networks.

Epilepsy, a neurological disorder affecting millions worldwide, poses great challenges in precisely delineating the epileptogenic zone - the brain region generating seizures - for effective treatment. High-frequency oscillations (HFOs) are emerging as promising biomarkers; however, the clinical utility is hindered by the difficulties in distinguishing pathological HFOs from non- epileptiform activities at single electrode and single patient resolution and understanding their dynamic role in epileptic networks. Here, we introduce an HFO-sequencing approach to analyze spontaneous HFOs traversing cortical regions in 40 drug-resistant epilepsy patients. This data- driven method automatically detected over 8.9 million HFOs, pinpointing pathological HFO- networks, and unveiled intricate millisecond-scale spatiotemporal dynamics, stability, and functional connectivity of HFOs in prolonged intracranial EEG recordings. These HFO sequences demonstrated a significant improvement in localization of epileptic tissue, with an 818.47% increase in concordance with seizure-onset zone (mean error: 2.92 mm), compared to conventional benchmarks. They also accurately predicted seizure outcomes for 90% AUC based on pre-surgical information using generalized linear models. Importantly, this mapping remained reliable even with short recordings (mean standard deviation: 3.23 mm for 30-minute segments). Furthermore, HFO sequences exhibited distinct yet highly repetitive spatiotemporal patterns, characterized by pronounced synchrony and predominant inward information flow from periphery towards areas involved in propagation, suggesting a crucial role for excitation-inhibition balance in HFO initiation and progression. Together, these findings shed light on the intricate organization of epileptic network and highlight the potential of HFO-sequencing as a translational tool for improved diagnosis, surgical targeting, and ultimately, better outcomes for vulnerable patients with drug-resistant epilepsy. One Sentence Summary: Pathological fast brain oscillations travel like traffic along varied routes, outlining recurrently visited neural sites emerging as critical hotspots in epilepsy network.

Noninvasive high-frequency oscillations riding spikes delineates epileptogenic sources.

High-frequency oscillations (HFOs) are a promising biomarker for localizing epileptogenic brain and guiding successful neurosurgery. However, the utility and translation of noninvasive HFOs, although highly desirable, is impeded by the difficulty in differentiating pathological HFOs from nonepileptiform high-frequency activities and localizing the epileptic tissue using noninvasive scalp recordings, which are typically contaminated with high noise levels. Here, we show that the consistent concurrence of HFOs with epileptiform spikes (pHFOs) provides a tractable means to identify pathological HFOs automatically, and this in turn demarks an epileptiform spike subgroup with higher epileptic relevance than the other spikes in a cohort of 25 temporal epilepsy patients (including a total of 2,967 interictal spikes and 1,477 HFO events). We found significant morphological distinctions of HFOs and spikes in the presence/absence of this concurrent status. We also demonstrated that the proposed pHFO source imaging enhanced localization of epileptogenic tissue by 162% (∼5.36 mm) for concordance with surgical resection and by 186% (∼12.48 mm) with seizure-onset zone determined by invasive studies, compared to conventional spike imaging, and demonstrated superior congruence with the surgical outcomes. Strikingly, the performance of spike imaging was selectively boosted by the presence of spikes with pHFOs, especially in patients with multitype spikes. Our findings suggest that concurrent HFOs and spikes reciprocally discriminate pathological activities, providing a translational tool for noninvasive presurgical diagnosis and postsurgical evaluation in vulnerable patients.

Noninvasive electromagnetic source imaging of spatiotemporally distributed epileptogenic brain sources.

Brain networks are spatiotemporal phenomena that dynamically vary over time. Functional imaging approaches strive to noninvasively estimate these underlying processes. Here, we propose a novel source imaging approach that uses high-density EEG recordings to map brain networks. This approach objectively addresses the long-standing limitations of conventional source imaging techniques, namely, difficulty in objectively estimating the spatial extent, as well as the temporal evolution of underlying brain sources. We validate our approach by directly comparing source imaging results with the intracranial EEG (iEEG) findings and surgical resection outcomes in a cohort of 36 patients with focal epilepsy. To this end, we analyzed a total of 1,027 spikes and 86 seizures. We demonstrate the capability of our approach in imaging both the location and spatial extent of brain networks from noninvasive electrophysiological measurements, specifically for ictal and interictal brain networks. Our approach is a powerful tool for noninvasively investigating large-scale dynamic brain networks.

Multiple Oscillatory Push-Pull Antagonisms Constrain Seizure Propagation.

OBJECTIVE: Drug-resistant focal epilepsy is widely recognized as a network disease in which epileptic seizure propagation is likely coordinated by different neuronal oscillations such as low-frequency activity (LFA), high-frequency activity (HFA), or low-to-high cross-frequency coupling. However, the mechanism by which different oscillatory networks constrain the propagation of focal seizures remains unclear. METHODS: We studied focal epilepsy patients with invasive electrocorticography (ECoG) recordings and compared multilayer directional network interactions between focal seizures either with or without secondary generalization. Within-frequency and cross-frequency directional connectivity were estimated by an adaptive directed transfer function and cross-frequency directionality, respectively. RESULTS: In the within-frequency epileptic network, we found that the seizure onset zone (SOZ) always sent stronger information flow to the surrounding regions, and secondary generalization was accompanied by weaker information flow in the LFA from the surrounding regions to SOZ. In the cross-frequency epileptic network, secondary generalization was associated with either decreased information flow from surrounding regions' HFA to SOZ's LFA or increased information flow from SOZ's LFA to surrounding regions' HFA. INTERPRETATION: Our results suggest that the secondary generalization of focal seizures is regulated by numerous within- and cross-frequency push-pull dynamics, potentially reflecting impaired excitation-inhibition interactions of the epileptic network. ANN NEUROL 2019;86:683-694.