Connectivity and Centrality Characteristics of the Epileptogenic Focus Using Directed Network Analysis.

Accurate epileptogenic focus localization is required prior to surgical resection of brain tissue for the treatment of patients with antiepileptic drug-resistant (intractable) epilepsy. This clinical need is only partially fulfilled through a subjective, and at times inconclusive, the evaluation of the recorded electroencephalogram (EEG) at seizures' onset (the so-called gold standard for focus localization in epilepsy). We herein present a novel method of multivariate analysis of the EEG that appears to be very promising for an objective and robust localization of the epileptogenic focus at seizures' onset. Using the measure of generalized partial directed coherence, combined with surrogate data analysis, we first estimated from multichannel intracranial EEG the statistically significant causal interactions between brain regions at the onset of 92 clinical seizures from nine patients with temporal lobe intractable epilepsy. From the networks that were formed based on the thus derived interactions, a set of centrality metrics was estimated per network node (brain site). Brain sites located anatomically within the epileptogenic focus were shown to be associated with greater inward centrality values than non-focal brain regions at high frequencies ( γ band), and particular inward centrality metrics accurately localized the focus in all nine patients. In addition to focus localization from seizure (ictal) onset, the developed novel framework for analysis of EEG could be employed to identify the changes of the focal network over time, peri-ictally and interictally, and thus shed light onto the dynamics of ictogenesis, which could then have a significant impact on automated prediction and closed-loop control of seizures by neuromodulation.

Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP).

People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/-) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1-/-) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1-/- mice with partial genetic ablation of Nav1.2 channels (i.e. Scn2a+/-; Kcna1-/-) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/-; Kcna1-/- mice compared with Kcna1-/- mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1-/- mice compared with wild types, which was partially restored in Scn2a+/-; Kcna1-/- mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility.