Interhemispheric Functional Hypoconnectivity Is an Early Marker of Cortical Epileptogenesis

Background: Epilepsy is a network disorder, and network-based approaches to its diagnostics and therapies attract growing attention. Identification of prognostic markers of epileptogenesis and long-term risk for developing epilepsy after brain insults is an urgent, unresolved problem. We examined whether intracortical connectivity patterns reflect early epileptogenic changes in the cortex. Methods: We used the 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 during interictal and immediate postictal periods in awake rats. 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 several models of epileptogenesis, was used as an electrographic marker of the 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 elicited mild postictal depression of cortical gamma oscillations without changes in interhemispheric functional connectivity. Early in kindling, seizures produced wideband postictal depression of cortical activity and a striking drop in hemispheric connectivity. Conclusions: Primary network alterations during epileptogenesis involve hemispheric decoupling and reduced synchronization, both sustained (between seizures) and transient (postictal). Breakdown of long-range intracortical communication may reflect homeostatic plasticity and an active attempt to restrict epileptogenic reorganization of neural networks. We think that resting-state hemispheric hypocoupling could be an early marker of epileptogenesis. Seizure-induced SD contributes to the generation of postictal events.