In normal development there are critical periods during which learning and plasticity are enhanced. We recently found that treatment of a rodent epilepsy model with anti-seizure medication early in life, led to long-term suppression of spike-wave seizures in adulthood even after the medication was stopped. Our previous work in this rodent model demonstrated that spike-wave seizures are associated with abnormal function and structure in specific corticothalamic networks, and that these abnormalities are not present early in life before the development of seizures. Based on this, we now hypothesize that treatment early in development suppresses spike-wave epileptogenesis, and can prevent the long-term abnormalities in brain structure and function in this disorder. To translate this work into the human arena, it will be crucial to identify safe noninvasive methods to monitor biomarkers of epilepsy development in children and its prevention by therapy. Powerful neuroimaging methods now enable the noninvasive assessment of brain function and structure. Our preliminary studies have found abnormally increased resting functional connectivity on fMRI, and abnormally reduced white matter fractional anisotropy on diffusion tensor imaging (DTI) in the rodent spike-wave epilepsy model. Therefore, our aims are now to investigate fMRI resting functional connectivity and DTI as promising biomarker of epileptogenesis and its prevention by therapy. Will performing measurements of fMRI resting functional connectivity at different developmental stages in treated vs. untreated animals. We will also relate these measurements to connectivity evaluated through coherence analysis of electroencephalography. In addition, we will investigate DTI as another promising biomarker by again performing measurements at different ages in treated vs. untreated animals. We will also investigate the anatomical basis of white matter DTI abnormalities through electron microscopy to determine changes in axons and myelin in affected regions. 2.

Public Health Relevance

As the genetic knowledge of epilepsy grows, primary prevention will soon be a realistic goal. Detailed study of a genetic animal model in which epilepsy can be prevented will provide proof-of-principle information to guide human treatment trials. In addition, the use of neuroimaging to track the development of epilepsy will help in understanding the mechanisms of epileptogenesis, and can identify biomarkers for use in monitoring the effectiveness of human therapeutic trials designed to prevent the development of epilepsy. Literature cited ADDIN EN.REFLIST Blumenfeld H, McCormick DA (2000) Corticothalamic inputs control the pattern of activity generated in thalamocortical networks. Journal of Neuroscience 20:5153-5162. Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, Khera DS, Bashyal C, Giblin K, Paul-Laughinghouse CP, Wang F, Phadke A, Mission J, Agarwal RK, Englot DJ, Motelow J, Nersesyan H, Waxman SG, Levin AR (2008) Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 49 (3):400-409. Chahboune H, Mishra AM, DeSalvo MN, Staib LH, Purcaro M, Scheinost D, Papademetris X, Fyson SJ, Lorincz ML, Crunelli V, Hyder F, H. B (2009) DTI abnormalities in anterior corpus callosum of rats with spike-wave epilepsy. Neuroimage 47:459-466. Eriksson SH, Rugg-Gunn FJ, Symms MR, Barker GJ, Duncan JS (2001) Diffusion tensor imaging in patients with epilepsy and malformations of cortical development. Brain 124:617-626. Klein JP, Khera DS, Nersesyan H, Kimchi EY, Waxman SG, Blumenfeld H (2004) Dysregulation of sodium channel expression in cortical neurons in a rodent model of absence epilepsy. Brain Research 1000:102-109. Obenaus A, Jacobs RE (2007) Magnetic resonance imaging of functional anatomy: use for small animal epilepsy models. Epilepsia 48 Suppl 4:11-17. Strauss U, Kole MH, Brauer AU, Pahnke J, Bajorat R, Rolfs A, Nitsch R, Deisz RA (2004) An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy. European Journal of Neuroscience 19:3048-3058. PAGE

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Youngblood, Mark W; Chen, William C; Mishra, Asht M et al. (2015) Rhythmic 3-4Hz discharge is insufficient to produce cortical BOLD fMRI decreases in generalized seizures. Neuroimage 109:368-77
Mishra, Asht Mangal; Bai, Xiaoxiao; Sanganahalli, Basavaraju G et al. (2014) Decreased resting functional connectivity after traumatic brain injury in the rat. PLoS One 9:e95280
Dezsi, Gabi; Ozturk, Ezgi; Stanic, Davor et al. (2013) Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 54:635-43
Bailey, Christopher J; Sanganahalli, Basavaraju G; Herman, Peter et al. (2013) Analysis of time and space invariance of BOLD responses in the rat visual system. Cereb Cortex 23:210-22
Mishra, Asht M; Bai, Xiaoxiao; Motelow, Joshua E et al. (2013) Increased resting functional connectivity in spike-wave epilepsy in WAG/Rij rats. Epilepsia 54:1214-22
van Luijtelaar, Gilles; Mishra, Asht M; Edelbroek, Peter et al. (2013) Anti-epileptogenesis: Electrophysiology, diffusion tensor imaging and behavior in a genetic absence model. Neurobiol Dis 60:126-38
Blumenfeld, Hal (2011) Epilepsy and the consciousness system: transient vegetative state? Neurol Clin 29:801-23
Mishra, Asht Mangal; Ellens, Damien J; Schridde, Ulrich et al. (2011) Where fMRI and electrophysiology agree to disagree: corticothalamic and striatal activity patterns in the WAG/Rij rat. J Neurosci 31:15053-64
Mishra, Asht Mangal; Bai, Harrison; Gribizis, Alexandra et al. (2011) Neuroimaging biomarkers of epileptogenesis. Neurosci Lett 497:194-204
Danielson, Nathan B; Guo, Jennifer N; Blumenfeld, Hal (2011) The default mode network and altered consciousness in epilepsy. Behav Neurol 24:55-65

Showing the most recent 10 out of 34 publications