(222) Interictal Epileptiform Discharges Disrupt Large-Scale Intercortical Networks

Rationale: There is growing evidence of a large-scale cortical network dysfunction from humans and animal models of focal epilepsy. Epileptic activity interferes with large-scale neural networks in the brain that are key to complex information processing, thereby contributing to neurocognitive and behavioral impairments. However, our knowledge of the mechanisms by which epileptic activity disrupts neurophysiological processes and their respective electrophysiological signatures remain sparse. In this study, we investigate the influence of interictal epileptiform discharges (IEDs) on cortical networks to characterize the pathophysiology of an epileptic brain. 

Methods: We studied large-scale intracranial electroencephalography (iEEG) recordings from focal epilepsy patients as well as hippocampal-kindled rodents. IEDs and spindle oscillations were analyzed during non-REM sleep. We performed temporal correlation between these oscillatory events using cross-correlograms. Spatial extent of oscillations was analyzed using cross-correlation as well as wavelet-based coherence. We also investigated the changes in the distribution of widespread versus localized network activity by clustering iEEG electrode locations into cortical regions of interest (ROI). Based on this clustering, we classified IEDs and spindle events as global or local. This approach allowed us to study how IEDs spread to healthy brain regions and affected oscillatory properties of spindles during progression of epilepsy and once it becomes medically refractory.

Results: We determined that IEDs are significantly coupled with spindle oscillations in spatiotemporally distinct patterns across the brain, establishing a pathological connectivity to recruit brain regions outside of the epileptic network. Furthermore, brain regions that exhibit IED-spindle coupling express spindles with broader spatial extent and higher propensity for propagation than spindles occurring in uncoupled regions. Based on these pathological spatiotemporal oscillatory properties, we derived a spindle-based biomarker for predicting brain regions influenced by IEDs independent of IED or seizure detection. 

Conclusions: Our findings suggest that IEDs modulate large-scale cortical networks through establishment of dynamic oscillatory coupling. These IED-induced alterations in the spatiotemporal specificity of brain oscillations could provide a mechanism for distributed network dysfunction in focal epilepsy. Consequently, this coupling may present new opportunities for therapies to address cognitive impairments and disease progression in epileptic patients. 

Funding: Please list any funding that was received in support of this abstract.: This work was supported by a Taking Flight award from CURE (Citizens United for Research in Epilepsy), Finding A Cure for Epilepsy and Seizures (FACES), as well as the Department of Neurology and Institute for Genomic Medicine at Columbia University Irving Medical Center.