Epilepsy is one of the most prevalent neurological disorders. Patients with epilepsy experience recurrent seizures that can cause a variety of symptoms ranging from muscle stiffness to loss of consciousness. Partial epilepsy is the most common syndrome in adult epilepsy patients and mesial temporal lobe epilepsy (MTLE) is the most common form of partial epilepsy. Epilepsy is characterized by the abnormal synchronization of large numbers of neurons. Current therapeutic agents cannot control seizures in 25% of all epileptic patients. Although electrical stimulation of the brain has been very effective to suppress some symptoms of Parkinson's disease, the level of seizure suppression by brain stimulation has been limited. The reason for this low therapeutic outcome could be attributed to an inadequate target for stimulation, lack of understanding of the mechanisms and non-optimum stimulation parameters. During the previous grant period, we have developed a novel method to suppress seizures by activating a fiber tract target at low frequency that has been tested in several animal models and in patients with mesial temporal lobe epilepsy. We now propose to study the mechanisms underlying this powerful suppression method in order to improve the suppression and guide the clinical implementation. Specifically, we propose to 1) unravel the cellular mechanisms of the suppression and the after effects, 2) study the specific role of inhibitory neurons using optogenetics methodology and 3) determine the axonal pathways involved in the suppression. The results of this neuro-technology project should provide valuable insights into the mechanisms underlying seizure suppression as well as capitalizing on the previous grant period to develop a novel therapeutic method for the control of seizures in patients with mesial temporal lobe epilepsy.

Public Health Relevance

Recent research has shown that it is possible to stimulate the brain in specific areas and to generate significant seizure reduction in animals and in patients. In this project, we propose to study the mechanisms of this effect and to develop new methods to prevent seizure generation and propagation. The goal of this project is to develop novel methods to control seizures in patients with mesial temporal lobe epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060757-06
Application #
8711567
Study Section
Special Emphasis Panel (BNVT)
Program Officer
Fureman, Brandy E
Project Start
2007-12-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$343,252
Indirect Cost
$126,689
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Zhang, Mingming; Shivacharan, Rajat S; Chiang, Chia-Chu et al. (2016) Propagating Neural Source Revealed by Doppler Shift of Population Spiking Frequency. J Neurosci 36:3495-505
Qiu, Chen; Shivacharan, Rajat S; Zhang, Mingming et al. (2015) Can Neural Activity Propagate by Endogenous Electrical Field? J Neurosci 35:15800-11
Zhang, Mingming; Kibler, Andrew B; Gonzales-Reyes, Luis E et al. (2015) Neural activity propagation in an unfolded hippocampal preparation with a penetrating micro-electrode array. J Vis Exp :
Ladas, Thomas P; Chiang, Chia-Chu; Gonzalez-Reyes, Luis E et al. (2015) Seizure reduction through interneuron-mediated entrainment using low frequency optical stimulation. Exp Neurol 269:120-32
Tang, Y; Wodlinger, B; Durand, D M (2014) Bayesian spatial filters for source signal extraction: a study in the peripheral nerve. IEEE Trans Neural Syst Rehabil Eng 22:302-11
Wang, Y; Toprani, S; Tang, Y et al. (2014) Mechanism of highly synchronized bilateral hippocampal activity. Exp Neurol 251:101-11
Zhang, Mingming; Ladas, Thomas P; Qiu, Chen et al. (2014) Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions, or diffusion and is consistent with electrical field transmission. J Neurosci 34:1409-19
Feng, Zhouyan; Yu, Ying; Guo, Zheshan et al. (2014) High frequency stimulation extends the refractory period and generates axonal block in the rat hippocampus. Brain Stimul 7:680-9
Toprani, Sheela; Durand, Dominique M (2013) Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation. J Physiol 591:5765-90
Toprani, Sheela; Durand, Dominique M (2013) Fiber tract stimulation can reduce epileptiform activity in an in-vitro bilateral hippocampal slice preparation. Exp Neurol 240:28-43

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