William D Gaillard - US grants

[unreadable] DESCRIPTION (provided by applicant): This study will examine the effects of seizures on the functional anatomy of language skills in children with both early onset and chronic epilepsy. This population provides an opportunity to gain insight into the effect of chronic neuronal dysfunction on the development of human language abilities and their brain representation. We hypothesize that seizures cause neuronal injury and force reorganization of the representation of essential cognitive skills, such as language. Patients with early epilepsy onset are expected to have greater variation in fMRI language activation patterns than those with later onset; these changes are expected to occur only after several years of epilepsy. Children will be evaluated with high resolution structural 1.5 Tesla MR.1, and functional MRI. Image data will also be transformed into a standard brain atlas to facilitate intra-subject regional comparison, as well as to account for inter-subject variability of language activation patterns. Three groups will be compared: 1) children within one year after localization related seizure onset 2) children with chronic localization related epilepsy (>3 years duration) 3) a normal control population. As a result of this study a greater understanding of the anatomic organization of language during critical periods of cognitive development and neuronal plasticity will be gained. We will determine whether seizures themselves or a common brain pathology is the driving force behind brain plasticity. Such information is important to plan intervention strategies to mitigate the sequelae of epilepsy at disease onset and in the most vulnerable children to its effects. Unlike acute and limited neuronal insults, such as head trauma and stroke, epilepsy is a chronic process with continuing but paroxysmal neuronal sequelae. Furthermore, patients may be identified and evaluated at the outset of the disease process so that the neuronal response and degree of plasticity may be assessed and monitored.

Project Summary The long-term objectives of the proposed research are to deepen our understanding of the epidemiology of pediatric epilepsy in a geographic area with a racially and economically diverse population. Children in DC are among the most racially and socioeconomically diverse populations in the country, with approximately 66% Black, 18% white, 11% Hispanic and 5% some other race. A total of 29% of all DC children live below the poverty level, and almost 50% of families are run by a single head of household. DC presents a rich population for study to formulate policies and programs to address the needs of a vulnerable and potentially underserved population. To meet our objectives, the following specific aims will be addressed: (1) determine utilization of healthcare resources, responsiveness of health systems and obstacles to care experienced by children with epilepsy and their families, (2) characterize risk factors, outcomes and comorbidities related to prevalent and new onset pediatric epilepsy, and (3) reassess population-based estimates of epilepsy incidence and prevalence over a 2-year period among children living in DC. In support of Aims 1 and 2, we propose creating a cohort of at least 500 DC children with epilepsy. We will use a self-administered questionnaire to obtain data from the parents of the pediatric cases. This questionnaire will ask questions about personal history of epilepsy, types of care sought and received, comorbidities such as cardiac disease and sleep disorders, family history of epilepsy, and the family and social environment. To supplement these data, medical records will be abstracted for treatment schedules, medication use, epilepsy phenotype, and other health measures. Follow- up data collection is expected to occur every 6 months. In support of Aim 3, we will determine whether previously obtained prevalence and incidence estimates for pediatric epilepsy are accurate and stable over time. This will be performed by using an existing health screening tool, the Behavioral Risk Factor Surveillance Survey, used to obtain data on public health in DC and across the country. We will also examine DC-mandated public school immunization records, maintained by CNMC, that also include an indicator for epilepsy, to compare estimates of epilepsy in school-age children with that found in the telephone survey. Children with epilepsy are a socially and educationally vulnerable group. Characterizing epilepsy in the DC school age population will play a role in better defining the resources needed to provide essential health and educational services to an underserved population. As a community with such rich diversity, DC is an ideal geographical area to implement population-based studies of epilepsy. Results from our study may contribute to recommendations for changes in health policy and guidelines used by primary care providers and neurologists for treatment of children with epilepsy.

CORE E ? HUMAN AND ANIMAL IMAGING CORE William D. Gaillard, MD Core Director Associate Director, DC-IDDRC Chief of the Divisions of Child Neurology, Epilepsy, Neurophysiology, and Critical Care Neurology Children's National Health System Professor of Pediatrics and Neurology, George Washington University School of Medicine and Health Sciences Professor of Neurology, Georgetown University Paul Wang, PhD Core Co-Director Site Director, Howard University Director of Molecular Imaging Laboratory, Howard University John VanMeter, PhD Site Director, Georgetown University Director, Center for the Functional and Molecular Imaging Georgetown University L. Gilbert Vézina, MD Site Director, Children's National Health System Director of Neuroradiology Children's National Health System Stanley Thomas Fricke, Nucl Eng, PhD MR-Physicist, Children's National Health System Professor, Diagnostic Imaging and Radiology George Washington University School of Medicine and Health Sciences Adjunct Associate Professor, Georgetown University The Human and Animal Imaging Core (HAIC) provides access to state-of-the-art in vivo whole brain imaging technologies to DC-IDDRC investigators in order to support, facilitate, and enhance IDD-targeted research in humans and in animal models. To achieve the Core's aims we have established advanced imaging facilities at three collaborating DC-IDDRC institutions [Howard University (HU), Georgetown University (GU), and Children's National Health System (CNHS)] that provide structural and functional imaging of animal models and human populations. The HAIC provides access to a wide array of imaging tools to investigate mechanisms of disease, establish biomarkers, examine effects of disease, and monitor outcomes of interventions. We have made significant institutional investments in 3T human MRI scanners at CNHS that provide researchers with state-of-the-art imaging instrumentation and expand our imaging capacity in neonates and ill children. Furthermore, we now extend our capabilities with the addition of the preclinical animal imaging facilities, including 7.4 and 9T MRI scanners, at HU. To support this growth in the HAIC, a Co-Director with extensive animal imaging experience joins HAIC leadership. HAIC personnel provide technical expertise in imaging strategy design and essential imaging services, acquisition and innovative analysis methods across all sites and institutions. Core faculty and staff also help educate, train, and support investigators in the use of advanced neuroimaging methods, applications, and analysis software. The HAIC works synergistically, and fosters collaborations with other DC-IDDRC cores including the Neurobehavioral Evaluation, Genomics and Proteomics, Cell and Tissue Microscopy, and Clinical Translational Cores. Our administrative structure provides the quality control necessary for the integrity of a smoothly functioning core to achieve the DC-IDDRC mission.

ABSTRACT This study aims to demonstrate the feasibility of early recruitment of children immediately following resolution of febrile status epilepticus and the successful acquisition of EEG and MRI studies within 6 hours of FSE cessation. These achievements are a necessary prerequisite to antiepileptogenesis trials designed to interrupt the acute cascade of events following FSE and thus prevent a common cause of temporal lobe epilepsy. This study builds on findings from the previous FEBSTAT clinical investigation trial and seeks to translate and validate novel imaging biomarkers of epileptogenesis identified in rodent febrile status models. We aim to identify altered T2* and T2 signal in hippocampus and amygdala within 6 hours of febrile status that may then be employed as biomarkers which can be used as targets for future clinical trials to prevent the adverse outcomes of FSE. The study also seeks to investigate neurological mechanisms underlying T2* signal and of hippocampal injury which can be evaluated by advanced multimodal imaging. This project will identify and remove the barriers to future intervention trials. The ultimate, long-term, goal of this project is to identify potential therapeutic targets, necessary for the prevention of hippocampal injury, and for the design and properly powered future interventions to prevent mesial temporal sclerosis caused by febrile status epilepticus, a common cause of pharmaco-resistant temporal lobe epilepsy.

Abstract The Human and Animal Imaging Core (HAIC) provides access to state-of-the-art in vivo whole brain imaging technologies to DC-IDDRC investigators in order to support, facilitate, and enhance IDD-targeted research in humans and in animal models. To achieve the Core?s aims we have established advanced imaging facilities at three collaborating DC-IDDRC institutions - Howard University (HU), Georgetown University (GU), and Children?s National Hospital (CNH) - that provide structural and functional imaging of animal models and human populations. The HAIC provides access to a wide array of imaging tools to investigate mechanisms of disease, establish biomarkers, examine effects of disease, and monitor outcomes of interventions. We have made significant institutional investments in 3T human MRI scanners at CNH, and GU that provide researchers with state-of-the-art imaging instrumentation and expand our imaging capacity in neonates and ill children. Furthermore, we have also invested in MRI scanner/software upgrades and added PET, SPECT, and CT to the preclinical animal imaging facilities at HU. HAIC personnel provide technical expertise in imaging strategy design, essential imaging services, acquisition and innovative imaging sequences and analysis methods across all sites and institutions. Core faculty and staff also help educate, train, and support investigators in the use of advanced neuroimaging methods, applications, and analysis software as well as foster innovation. The HAIC works synergistically, and fosters collaborations, with other DC-IDDRC cores including the Neurobehavioral Evaluation, the Cell and Tissue Microscopy Core, the Genomics and Bioinformatics Core, and Clinical Translational Cores, and supports the P50 Research Project. Our administrative structure provides the quality control necessary for the integrity of a smoothly functioning core to achieve the DC-IDDRC mission.