The long-range objectives of this research include establishment of more universal criteria for neocortical epilepsy surgery in children, with the assistance of quantitative analysis of intracranial EEG and neuroimaging data, as well as understanding of the mechanisms of ictal epileptic discharges seen on EEG in pediatric neocortical epilepsy using in vivo quantitative multimodality analyses. The training aspects of this proposal focus on progression to independence as a researcher. The educational plan include supervised research in quantitative analyses of intracranial EEG and neuroimaging as well as formal training and experience in applied biostatistics, data management, and the ethical conduct of research. One-fifth of epilepsy in children is medically intractable. A subset of children with intractable neocortical epilepsy have benefited from respective surgery of the presumed epileptogenic zone. Yet, the chance of long-term seizure-free outcome by respective brain surgery is reported as low as 50% in children with extra temporal lobe epilepsy. Objective delineation of abnormalities on positron emission tomography (PET) imaging has recently yielded better surgical outcomes (-80% seizure-free) in our institute, but even this is not optimum. The applicant hypothesizes that an epileptic brain has a spatial gradient of epileptogenicity and that some of the failed surgery may have been due to the incomplete resection of epileptogenic cortex, which is missed by imaging studies and optimal EEG analysis. The concept of a gradient of epileptogenicity is supported by observations that 1) some patients experience seizure recurrence several years after resection of the presumed epileptogenic zone, including neuroimaging abnormalities and 2) discontinuation of antiepileptic drugs after apparently successful epilepsy surgery induce seizure recurrence in one-third of patients. Since EEG parameters retain continuous values among intracranial electrodes, we will determine whether surgical outcome is correlated with the degree of neurophysiological abnormalities in the cortex not respected by surgery, and establish the cutoff threshold resulting in the best surgical outcome in children with neocortical epilepsy (including epileptic spasms). Epileptic seizures are represented as sustained rhythmic ictal discharges on EEG, of which underlying mechanisms are unknown. Since ictal discharges typically show synchronization and propagation to other brain regions, in vitro analysis of isolated human brain tissues may not be representative of the entire epileptic circuitry. In contrast, in vivo quantitative analyses of ictal electrographic changes in children with neocortical partial seizures, using intracranial EEG and functional neuroimaging data will provide a different perspective regarding the mechanism and clinical significance of ictal discharges on the EEG. Ultimately, such knowledge may lead to better surgical and pharmaco-therapies for seizure disorders. If funded, the applicant will achieve the necessary training in an excellent environment to develop into an independent investigator. ? ?
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