Abstracts

Rationale:
Focal epilepsy is an unpredictable disease – some patients experience worsening seizures and new seizure types, whereas others have a relatively stable course. This variability impedes establishment of accurate prognoses and limits initiation of appropriately timed and anatomically targeted therapeutics. We aim to identify large-scale patterns associated with a spreading epileptic network in an animal model, and prime subsequent investigation for similar patterns in the brain activity of patients with epilepsy. Pathologic activity in the form of interictal epileptiform discharges (IEDs) is associated with epileptic tissue and contributes to cognitive dysfunction. Because the mechanisms by which IEDs spread from epileptic to healthy brain regions are unclear, targets for new therapies are limited.
Method:
We use a hippocampal kindling rodent model of mesial temporal lobe epilepsy. We combine the chronic intracranial implantation of silicon probes or wire arrays in hippocampus and mPFC with a novel non-invasive conducting polymer-based conformable microelectrode array (NeuroGrid) covering the dorsal cortical surface (Khodagholy et al., Nat Neurosci 2015; 18(2):310-5). This experimental approach enables us to record local field potential and individual neuronal activity from chronically implanted freely moving rats during the progression of kindling. Results IEDs were first observed in the hippocampus, and developed co-occurrence in the mPFC and dorsal cortical areas within 5-10 days. Independent populations of IEDs were subsequently observed in these regions. IED occurrence increased non-linearly during the progression of the kindling, exhibiting a transient peak at the onset of bilateral convulsive seizures. Late stages of kindling were characterized by a transition from globally synchronized IEDs to locally expressed IEDs. Coupling of IEDs with spindles in different cortical regions was observed prior to development of independent IED populations.
Conclusion:
The progression of focal hippocampal epilepsy results in specific patterns of epileptic activity spread throughout the brain. This spread is associated with spatiotemporally differentiated alterations in hippocampal-cortical coupling. These results have the potential to facilitate development of sensitive and specific biomarkers for brain regions that are at risk of being recruited into the focal epileptic network, providing targets for novel therapeutics that could prevent deterioration in seizure control and associated neuropsychiatric comorbidities.
Funding:
:-Taking Flight award fromCURE (Citizens United for Research in Epilepsy). -Finding A Cure for Epilepsy and Seizures (FACES) . -Department of Neurology and Institute for Genomic Medicine at Columbia University Irving Medical Center.