Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy (TLE) is a common and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including the hippocampus. Interestingly, partial temporal lobe seizures often cause functional deficits such as impaired consciousness, which is not expected from local hippocampal impairment alone. Human focal temporal lobe seizures in which consciousness is impaired are associated with slow waves on electro- encephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex, distant from the hippocampus. The mechanisms by which focal seizures in the hippocampus cause depressed function in the neocortex are not known. Based on our preliminary studies, we propose that ictal neocortical slow activity reflects a distinct state of depressed cortical function, more closely resembling deep anesthesia or sleep than seizure activity. In support of this, we recently found in a rat model that spontaneous and induced limbic seizures exhibit high frequency discharges in the hippocampus, but slow 1-3 Hz activity in the orbital frontal cortex. Ictal neocortical slow activity was characterized by decreased neuronal firing, CBF, blood oxygen level dependent functional MRI (BOLD fMRI), cerebral blood volume, and metabolism, while at the same time the hippocampus showed increases in all of these measures. We also found that ictal neocortical slow activity could be prevented by disrupting the fornix (a main connection between the hippocampus and subcortical nuclei important for arousal) and by introducing a replacement for acetycholine (a major neurotransmitter of subcortical arousal nuclei). Therefore, our central hypothesis is that focal limbic seizures inhibit subcortical arousal systems (including acetylcholine) leading to depressed function in the neocortex resembling sleep. We plan to investigate this hypothesis at the level of networks, neurotransmitters, and neurons in a rodent model.
Our aims are to first define the network of cortical and subcortical structures which cause ictal neocortical slow activity in partial limbic seizures using fMRI, local field and multiunit recordings, local stimulation, disconnection and inactivation experiments. Second, we will investigate the neurotransmitters producing neocortical slow activity through application of neurotransmitter agonists/antagonists, and neurotransmitter measurements using in vivo biosensor probes. Third, we will determine the changes in firing patterns and synaptic activity of identified neurons in the cortex and subcortical structures involved in ictal neocortical slow activity using juxtacellular and intracellular recordings. The integration of information across these levels will increase our understanding of abnormal long-range network changes in TLE, potentially leading to new therapeutic options in the treatment of this disorder.

Public Health Relevance

Impaired function of the cerebral cortex and cognitive deficits have a large impact on quality of life in patients with temporal lobe epilepsy. Understanding the fundamental mechanisms of remote network impairment in focal epilepsy may lead to novel surgical, neurostimulation, or pharmacologic therapies for this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066974-03
Application #
8415578
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2011-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$351,032
Indirect Cost
$139,938
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Furman, Moran; Zhan, Qiong; McCafferty, Cian et al. (2015) Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology. Epilepsia 56:e198-202
Blumenfeld, Hal; Meador, Kimford; Jackson, Graeme D (2015) Commentary: The return of consciousness to epilepsy seizure classification. Epilepsia 56:345-7

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