Functional Connectivity of Oscillatory Neural Networks in Children with Medically-intractable Localization-related Epilepsy

Epilepsy is the most common serious neurological condition affecting children. Currently, a fraction of children who may be eligible for epilepsy surgery are referred for presurgical evaluation. This lack of access to epilepsy surgery is partially due to an incomplete understanding of the ways in which epilepsy interferes with childhood development and uncertainty in the mapping of epileptogenic cortex. Since neuronal oscillations within the human brain facilitate inter-regional communication and subserve a host of cognitive functions, the study of networks measuring direct (electroencephalographic and electromagnetic signals) and indirect (blood oxygen-dependent neurovascular signals) oscillating neuronal populations in the brain may prove valuable in understanding epilepsy and developing improved strategies for the treatment of affected children. The first segment of the dissertation explores putative mechanisms by which localization-related epilepsy interferes with typical childhood development. First, intrinsic connectivity networks (ICNs), formed by coherence in spontaneous fluctuations of blood oxygen level dependent signal were measured using resting-state fMRI. The development and functional organization of ICNs in children with epilepsy were compared to matched controls. Clinical heterogeneity in the patient population was also modeled against neuroimaging data to identify patient phenotypes that are associated with specific network impairments. Second, ICNs were reconstructed by measuring phase-locking synchrony in neuromagnetic recordings using magnetoencephalography. The resilience and vulnerability of ICNs to interictal epileptiform discharges (IEDs) was correlated with neurocognitive outcomes. Finally the effects of seizures on the organization of functional networks were tested using electrocorticography (ECoG) data obtained during invasive monitoring from subdural electrodes. This segment provides evidence that epilepsy disrupts the developmental trajectory of functional networks in affected children and that these effects may be mediated both by ongoing IEDs as well as recurrent seizure activity. The second segment examines ECoG recordings from children undergoing invasive monitoring for surgical candidacy to study the extent to which normative patterns of connectivity are disrupted during seizure activity. One emerging marker of epileptogenic networks is the expression of pathological high frequency oscillations (pHFOs; >80 Hz). Since the hierarchical coupling of high frequency amplitudes to the phase of slower oscillations is described as a mechanism to regulate neural communication within networks across different spatiotemporal scales, the cross-frequency coupling (CFC) of pHFOs to the phase of slower cortical rhythms was studied. Topographic concentrations of CFC were evaluated as a marker of epileptogenic cortex and breakdowns in the expected normative relations between pHFOs and slower oscillations were identified during seizure initiation and propagation. During these epochs, frequency-specific inter-regional phase synchrony in ECoG recordings was also found to be disturbed, suggesting that aberrant functional interactions within epileptogenic cortex are inextricably related to impaired inter-regional communication during seizures. These findings highlight dynamic changes in neural communication within epileptogenic networks that are associated with seizure activity, and supply novel avenues for seizure mapping and treatment.Ph.D.2016-11-16 00:00:0