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.

Public Health Relevance

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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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
Cepeda, Carlos; Chen, Jane Y; Wu, Joyce Y et al. (2014) Pacemaker GABA synaptic activity may contribute to network synchronization in pediatric cortical dysplasia. Neurobiol Dis 62:208-17
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
Owens, Geoffrey C; Huynh, My N; Chang, Julia W et al. (2013) Differential expression of interferon-ýý and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. J Neuroinflammation 10:56
Hauptman, Jason S; Dadour, Andrew; Oh, Taemin et al. (2013) Time to pediatric epilepsy surgery is longer and developmental outcomes lower for government compared with private insurance. Neurosurgery 73:152-7
Baca, Christine B; Vickrey, Barbara G; Vassar, Stefanie et al. (2013) Time to pediatric epilepsy surgery is related to disease severity and nonclinical factors. Neurology 80:1231-9
Baek, Seung Tae; Gibbs, Elizabeth M; Gleeson, Joseph G et al. (2013) Hemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disorders. Curr Opin Neurol 26:122-7
Phung, Jennifer; Krogstad, Paul; Mathern, Gary W (2013) Etiology associated with developing posthemispherectomy hydrocephalus after resection-disconnection procedures. J Neurosurg Pediatr 12:469-75
Hauptman, Jason S; Dadour, Andrew; Oh, Taemin et al. (2013) Sociodemographic changes over 25 years of pediatric epilepsy surgery at UCLA. J Neurosurg Pediatr 11:250-5
Cepeda, Carlos; Andre, Veronique M; Hauptman, Jason S et al. (2012) Enhanced GABAergic network and receptor function in pediatric cortical dysplasia Type IIB compared with Tuberous Sclerosis Complex. Neurobiol Dis 45:310-21

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