Dynamical Mechanisms of Interictal Resting-State Functional Connectivity in Epilepsy

Drug-resistant focal epilepsy is a large-scale brain networks disorder characterized by altered spatiotemporal patterns of functional connectivity (FC), even during interictal resting state (RS). Although RS-FC-based metrics can detect these changes, results from RS functional magnetic resonance imaging (RS-fMRI) studies are unclear and difficult to interpret, and the underlying dynamical mechanisms are still largely unknown. To better capture the RS dynamics, we phenomenologically extended the neural mass model of partial seizures, the Epileptor, by including two neuron subpopulations of epileptogenic and nonepileptogenic type, making it capable of producing physiological oscillations in addition to the epileptiform activity. Using the neuroinformatics platform The Virtual Brain, we reconstructed 14 epileptic and 5 healthy human (of either sex) brain network models (BNMs), based on individual anatomical connectivity and clinically defined epileptogenic heatmaps. Through systematic parameter exploration and fitting to neuroimaging data, we demonstrated that epileptic brains during interictal RS are associated with lower global excitability induced by a shift in the working point of the model, indicating that epileptic brains operate closer to a stable equilibrium point than healthy brains. Moreover, we showed that functional networks are unaffected by interictal spikes, corroborating previous experimental findings; additionally, we observed higher excitability in epileptogenic regions, in agreement with the data. We shed light on new dynamical mechanisms responsible for altered RS-FC in epilepsy, involving the following two key factors: (1) a shift of excitability of the whole brain leading to increased stability; and (2) a locally increased excitability in the epileptogenic regions supporting the mixture of hyperconnectivity and hypoconnectivity in these areas.