Epilepsy is a chronic neurological condition that affects about 1% of the population in the United States. Although it is usually readily treatable with medications, about 25-30% of epileptic patients continue to experience recurrent seizures in spite of multiple drug therapy. A very common form of difficult to control human epilepsy is the mesial temporal lope epilepsy syndrome, which involves limbic structures such as the hippocampus, entorhinal cortex and amygdala. Understanding the pathophysiological basis for this condition is essential for the development of improved treatments. Human studies have suggested that the process of seizure initiation may involve multiple sites. In these situations the seizures often begin simultaneously at several of the limbic sites. These observations raise the possibility that seizure onset may be triggered in part through a subcortical mechanism that has input to multiple limbic structures. Testing this idea has not been possible until recently with the development of several new rat models of limbic epilepsy that have similarities to the human condition. These limbic epilepsy models are characterized by spontaneous seizures as well as limbic pathology and seizure physiology on EEG that are morphologically similar to the human condition (mesial temporal lobe epilepsy). Work completed or nearing completion has suggested that all of the limbic sites demonstrated to participate in seizure onset have hyperexcitable responses to stimulation. More importantly, we have recently discovered that the midline thalamic nuclei have significant excitatory input to these areas (amygdala, hippocampus and entorhinal cortex). We have also found that the midline thalamic nuclei participate in, and may regulate, the seizure activity in the limbic system. These observations suggest that these thalamic regions may have an important role in seizure initiation and modulation. In this project we propose to evaluate the role of the midline thalamic nuclei in limbic seizures and epilepsy to answer the following questions: 1) What role does the midline thalamic nuclei play in limbic seizures and epilepsy to answer the following questions: 2) How are the interactions between the midline thalamic nuclei and its limbic targets altered in limbic epilepsy? 3) How is the physiology of the midline thalamic nuclei changed in chronic limbic epilepsy? These experiments will combine in vitro and in vivo physiology of several rat models of limbic seizures, including chronic limbic seizures, to examine these issues, which are the first steps to understanding the role of this region in limbic epilepsy. These results will provide new insights into the network changes and basis for these conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1 (01))
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Fureman, Brandy E
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University of Virginia
Schools of Medicine
United States
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Zhang, De Xing; Bertram, Edward H (2015) Suppressing limbic seizures by stimulating medial dorsal thalamic nucleus: factors for efficacy. Epilepsia 56:479-88
Kendirli, M Tansel; Rose, Dominique T; Bertram, Edward H (2014) A model of posttraumatic epilepsy after penetrating brain injuries: effect of lesion size and metal fragments. Epilepsia 55:1969-77
Bertram, Edward H (2013) Neuronal circuits in epilepsy: do they matter? Exp Neurol 244:67-74
Sloan, David M; Zhang, Dexing; Bertram 3rd, Edward H (2011) Excitatory amplification through divergent-convergent circuits: the role of the midline thalamus in limbic seizures. Neurobiol Dis 43:435-45
Sloan, David M; Zhang, DeXing; Bertram 3rd, Edward H (2011) Increased GABAergic inhibition in the midline thalamus affects signaling and seizure spread in the hippocampus-prefrontal cortex pathway. Epilepsia 52:523-30
Thom, Maria; Mathern, Gary W; Cross, J Helen et al. (2010) Mesial temporal lobe epilepsy: How do we improve surgical outcome? Ann Neurol 68:424-34
Sloan, David M; Bertram 3rd, Edward H (2009) Changes in midline thalamic recruiting responses in the prefrontal cortex of the rat during the development of chronic limbic seizures. Epilepsia 50:556-65
Bertram, Edward H (2009) Temporal lobe epilepsy: where do the seizures really begin? Epilepsy Behav 14 Suppl 1:32-7
Rajasekaran, Karthik; Sun, Chengsan; Bertram, Edward H (2009) Altered pharmacology and GABA-A receptor subunit expression in dorsal midline thalamic neurons in limbic epilepsy. Neurobiol Dis 33:119-32
Bertram, Edward H; Zhang, DeXing; Williamson, John M (2008) Multiple roles of midline dorsal thalamic nuclei in induction and spread of limbic seizures. Epilepsia 49:256-68

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