Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy is a common and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including the hippocampus. Interestingly, focal 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 with impaired consciousness show slow waves on electro-encephalography (EEG) and decreased cerebral blood flow 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. We established a rat model with focal limbic seizures exhibiting high frequency discharges in the hippocampus, but slow 1-3 Hz activity in the neocortex, decreased cortical blood flow and metabolism, as well as decreased behavioral responsiveness resembling the human disorder. In this model we found that important subcortical arousal systems including brainstem and basal forebrain cholinergic neurons are depressed. These finding suggest that sleep-like cortical slow waves may occur in focal limbic seizures because of decreased subcortical arousal. In addition we found that putative descending GABAergic systems including the lateral septum and anterior hypothalamus are strongly activated by focal limbic seizures. Based on these findings, our central hypothesis is that focal limbic seizures activate inhibitory systems which depress subcortical arousal leading to sleep-like cortical slow waves and impaired consciousness. We plan to investigate this hypothesis at the level of neurons, networks, and behavior in a rodent model. Recent work has also raised the exciting prospect of restoring subcortical arousal to improve cortical function during seizures. Therefore, our aims are to first investigate the inputs to subcortical arousal systems using whole-cell electrophysiology to determine incoming synaptic activity; and using optogenetics to selectively activate or inhibit input pathways. Second, we will determine which subcortical arousal systems are critical for depressed cortical function by electrically or optogenetically restoring outputs from these systems during focal limbic seizures, and measure effects on the cortex through electrophysiology recordings and high-field functional magnetic resonance imaging (fMRI). Third, we will examine the effects of focal limbic seizures on attention and decision-making tasks and investigate the ability of restored subcortical arousal to improve behavioral responsiveness during seizures. The integration of information across these levels will increase our understanding of abnormal long-range network changes in epilepsy, 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 #
5R01NS066974-06
Application #
9343048
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Stewart, Randall R
Project Start
2011-02-01
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kundishora, Adam J; Gummadavelli, Abhijeet; Ma, Chanthia et al. (2017) Restoring Conscious Arousal During Focal Limbic Seizures with Deep Brain Stimulation. Cereb Cortex 27:1964-1975
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Zhan, Qiong; Buchanan, Gordon F; Motelow, Joshua E et al. (2016) Impaired Serotonergic Brainstem Function during and after Seizures. J Neurosci 36:2711-22
Gummadavelli, Abhijeet; Kundishora, Adam J; Willie, Jon T et al. (2015) Neurostimulation to improve level of consciousness in patients with epilepsy. Neurosurg Focus 38:E10
Li, Wei; Motelow, Joshua E; Zhan, Qiong et al. (2015) Cortical network switching: possible role of the lateral septum and cholinergic arousal. Brain Stimul 8:36-41
Sedigh-Sarvestani, Madineh; Blumenfeld, Hal; Loddenkemper, Tobias et al. (2015) Seizures and brain regulatory systems: consciousness, sleep, and autonomic systems. J Clin Neurophysiol 32:188-93
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
Gummadavelli, Abhijeet; Motelow, Joshua E; Smith, Nicholas et al. (2015) Thalamic stimulation to improve level of consciousness after seizures: evaluation of electrophysiology and behavior. Epilepsia 56:114-24
Faingold, Carl L; Blumenfeld, Hal (2015) Targeting Neuronal Networks with Combined Drug and Stimulation Paradigms Guided by Neuroimaging to Treat Brain Disorders. Neuroscientist 21:460-74
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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