Interhemispheric Functional Hypoconnectivity Is an Early Marker of Cortical Epileptogenesis

Background: Epilepsy is network disorder and network-based approaches to its diagnostics and therapies attract growing attention. Identification of prognostic markers of epilepsy, allowing selecting patients with risk of epilepsy development, is urgent unresolved problem. We examined whether intracortical connectivity patterns reflect early epileptogenic changes in the cortex. Methods: We used audiogenic kindling model, in which cortical epileptogenesis is initiated by repetition of reflex subcortically-driven seizures. Two measures of functional connectivity - mutual information and mean phase coherence – were applied to electrocorticographic recordings obtained from homotopical sites of parietal cortex in awake rats during interictal and immediate postictal periods. Interhemispheric connectivity and synchrony in non-kindled and slightly kindled rats were compared. Cortical spreading depolarization (SD), the first manifestation of growing cortical excitability in the model, was used as electrographic marker of earliest kindling stage. Results: In kindled animals, baseline levels of hemispheric connectivity and gamma band synchrony were significantly lower compared to seizure-naive rats. Before kindling, subcortical seizures were followed by mild postictal depression of cortical gamma oscillations without changes in interhemispheric functional connectivity. Early in kindling, seizures produced wideband depression of cortical activity and striking drop of hemispheric connectivity. Conclusion: Thus, primary network alterations during epileptogenesis are reduced synchronization and decoupling of hemispheres, both sustained (between seizures) and transient (postictal). Breakdown of long-range communication may reflect homeostatic plastic changes and active attempt to restrict epileptogenic reorganization of neural networks early in epileptogenesis. We think that resting-state hemispheric disconnection may be used as an early marker of epileptogenesis. Seizure-induced SD contributes to generation of postictal events.