We have taken a functional genomic approach to ask what is different between nearby regions of electrically-mapped human neocortex removed surgically for the treatment of medically refractory epilepsy. We identified a small group of genes that are significantly induced at epileptic foci in almost all patients examined, regardless of underlying lesion. For the first time now, we have highly reliable molecular markers of epileptic neocortex that point to a specific signaling pathways and populations of neurons that characterize neocortical epileptic foci. While it is still not clear whether the induction of these genes are a consequence or a driving force of abnormally firing neurons, we found that the induction of many of these genes correlate precisely with the degree interictal spiking suggesting that the molecular pathways identified and interictal spiking are closely related. In this proposal, we will measure a group of quantitative parameters of interictal spiking from the neocortex of patients undergoing epilepsy surgery and relate these to the generation of seizures and the underlying gene expression and signaling pathways. These will be placed within the 3-dimensional structure of the human brain to ask further questions about the human brain's infoldings on human epilepsy. One long-term goal for this project is to develop an understanding of the clinical significance of interictal spiking to help guide future clinical decisions. Another goal is to understand the relationships between electrical activity with molecular and cellular pathways that will help us develop new, biologically-driven, diagnostics and therapeutics for human epilepsy. Relevance: Epilepsy is a common neurological disorder affecting up to 1% of the world's population. It is one of the least understood disorders that can develop after a wide range of brain insults. At present, there are no treatments to prevent epilepsy, and while existing medications reduce seizure frequency, they do not "cure" the disorder. It is possible to "cure" epilepsy by removing electrically-defined epileptic foci. Removal of these focal brain regions also presents an opportunity to discover the molecular and cellular basis of human epilepsy in a way that cannot be achieved in animal models. The improved methods we develop to measure spiking and the molecular and clinical correlates of interictal spiking will have great utility both for clinical management of patients with epilepsy and for the development of novel, targeted treatment and diagnostic strategies. Epilepsy is a common neurological disorder affecting up to 1% of the world's population. At present, there are no treatments to prevent epilepsy, and while existing medications reduce seizure frequency, they do not "cure" the disorder. In this proposal we take advantage of electrically-defined human epileptic brain areas to discover the molecular and cellular basis of human epilepsy in a way that cannot be achieved in animal models. We will develop improved methods to measure spiking and determine the underlying molecular and cellular basis of epileptic spiking placed into the 3-dimensional context of the human brain in order to develop novel, targeted treatment and diagnostic strategies. Epilepsy is a common neurological disorder affecting up to 1% of the world's population. At present, there are no treatments to prevent epilepsy, and while existing medications reduce seizure frequency, they do not ?cure? the disorder. In this proposal we take advantage of electrically-defined human epileptic brain areas to discover the molecular and cellular basis of human epilepsy in a way that cannot be achieved in animal models. We will develop improved methods to measure spiking and determine the underlying molecular and cellular basis of epileptic spiking placed into the 3-dimensional context of the human brain in order to develop novel, targeted treatment and diagnostic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058802-05
Application #
8318221
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Fureman, Brandy E
Project Start
2008-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$332,145
Indirect Cost
$104,028
Name
Wayne State University
Department
Neurology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Rossignol, Elsa; Kobow, Katja; Simonato, Michele et al. (2014) WONOEP appraisal: new genetic approaches to study epilepsy. Epilepsia 55:1170-86
Wang, Jieqiong; Li, Wenjing; Miao, Wen et al. (2014) Age estimation using cortical surface pattern combining thickness with curvatures. Med Biol Eng Comput 52:331-41
Galanopoulou, Aristea S; Kokaia, Merab; Loeb, Jeffrey A et al. (2013) Epilepsy therapy development: technical and methodologic issues in studies with animal models. Epilepsia 54 Suppl 4:13-23
Taimouri, Vahid; Hua, Jing (2013) Visualization of shape motions in shape space. IEEE Trans Vis Comput Graph 19:2644-52
Chen, X; He, H; Zou, G et al. (2013) Ricci Flow-based Spherical Parameterization and Surface Registration. Comput Vis Image Underst 117:1107-1118
Yadav, R; Shah, A K; Loeb, J A et al. (2012) Morphology-based automatic seizure detector for intracerebral EEG recordings. IEEE Trans Biomed Eng 59:1871-81
Barkmeier, Daniel T; Shah, Aashit K; Flanagan, Danny et al. (2012) High inter-reviewer variability of spike detection on intracranial EEG addressed by an automated multi-channel algorithm. Clin Neurophysiol 123:1088-95
Barkmeier, Daniel T; Senador, Danielle; Leclercq, Karine et al. (2012) Electrical, molecular and behavioral effects of interictal spiking in the rat. Neurobiol Dis 47:92-101
Zou, Guangyu; Hu, Jiaxi; Gu, Xianfeng et al. (2011) Authalic parameterization of general surfaces using Lie advection. IEEE Trans Vis Comput Graph 17:2005-14
Taimouri, Vahid; Liu, Xin; Lai, Zhaoqiang et al. (2011) Colon segmentation for prepless virtual colonoscopy. IEEE Trans Inf Technol Biomed 15:709-15

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