Epilepsy is a frequent neurological condition, and approximately 25% of children have medically refractory seizures. In children with pharmacoresistant epilepsy undergoing neurosurgery, cortical dysplasia (CD) is the most frequent etiology. This proposal focuses on identifying mechanisms of epileptogenesis in pediatric epilepsy surgery patients with CD. The use of human surgical tissue is important because animal models of CD do not fully replicate the histopathology seen in humans, especially abnormal cytomegalic neurons and balloon cells. Furthermore, this proposal has a translational aim that will develop new treatments for children with CD. Our previous studies identified the characteristics of normal and abnormal cells in the cerebral cortex of patients with CD. These studies found changes in MRI volumes, neuronal densities, and electrophysiological properties that resembled immature developing cortex. Based on these findings we introduced the Dysmature Cerebral Developmental Hypothesis, that proposes that the histopathology of CD represents tissue in which normal developmental processes, such as apoptosis of cells in the molecular layer and subplate and synaptic maturation are slowed or stopped in association with increased numbers of late born pyramidal neurons in the intermediate layers of the gray matter. We propose that with delayed development, CD cells in ectopic locations, such as the molecular layer and the subcortical transition zone (STZ), participate in seizure generation. In addition, some of the normal and abnormal cells in CD tissue have immature synaptic features that are pro-epileptic. These hypotheses will be tested by: 1) Examining the morphological and electrophysiological properties of neurons in the molecular layer and STZ;2) Examining synaptic interactions between pairs of normal and abnormal neurons using dual patch recordings and;3) Examining the acute effects of drug combinations that affect GABAA receptors and chloride transporters, GABAB receptors, and the mTOR pathway (rapamycin) on synaptic activity and induced epileptiform discharges in CD cases. These studies are significant because they elucidate operational mechanisms of pathogenesis and epileptogenesis in patients with CD to better define causes of the seizures and to develop treatments.

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The most common cause of epilepsy in children undergoing neurosurgery is cortical malformations of the brain. We propose that malformed brains do not fully develop and retain immature features. We will test this hypothesis by using clinical, anatomical and electrophysiological approaches to examine brain tissue removed at surgery to understand the causes of epilepsy and alleviate seizures in children.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Fureman, Brandy E
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Hussain, Shaun A; Mathern, Gary W; Hung, Phoebe et al. (2017) Intraoperative fast ripples independently predict postsurgical epilepsy outcome: Comparison with other electrocorticographic phenomena. Epilepsy Res 135:79-86
D'Gama, Alissa M; Woodworth, Mollie B; Hossain, Amer A et al. (2017) Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias. Cell Rep 21:3754-3766
Jehi, Lara; Mathern, Gary W (2015) Who's responsible to refer for epilepsy surgery? We all are! Neurology 84:112-3
de Bode, Stella; Smets, Lieselotte; Mathern, Gary W et al. (2015) Complex syntax in the isolated right hemisphere: Receptive grammatical abilities after cerebral hemispherectomy. Epilepsy Behav 51:33-9
Cepeda, Carlos; Chang, Julia W; Owens, Geoffrey C et al. (2015) In Rasmussen encephalitis, hemichannels associated with microglial activation are linked to cortical pyramidal neuron coupling: a possible mechanism for cellular hyperexcitability. CNS Neurosci Ther 21:152-63
D'Gama, Alissa M; Geng, Ying; Couto, Javier A et al. (2015) Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 77:720-5
Baca, Christine B; Pieters, Huibrie C; Iwaki, Tomoko J et al. (2015) ""A journey around the world"": Parent narratives of the journey to pediatric resective epilepsy surgery and beyond. Epilepsia 56:822-32
Abdijadid, Sara; Mathern, Gary W; Levine, Michael S et al. (2015) Basic mechanisms of epileptogenesis in pediatric cortical dysplasia. CNS Neurosci Ther 21:92-103
de Bode, Stella; Chanturidze, Marine; Mathern, Gary W et al. (2015) Literacy after cerebral hemispherectomy: Can the isolated right hemisphere read? Epilepsy Behav 45:248-53
Varadkar, Sophia; Bien, Christian G; Kruse, Carol A et al. (2014) Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 13:195-205

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