Epilepsy is a devastating illness affecting 3 million Americans. Unfortunately, we currently have only a rudimentary understanding of the intertwined issues of how to define the cortical areas which generate seizures and how those seizures start and spread. Based on preliminary data we posit that within the seizure onset zone epileptiform activity arises from deep cortical layers and then spreads via cortico-cortical connections to superficial layers. There is, consequently, a discernable physiological signature of the seizure focus and events leading to seizure initiation and propagation. We will test this hypothesis by recording synaptic activity, intrinsic currents, and action potential firing from all layers of human cortex during and between seizures using unique microelectrode arrays. Specifically, we aim to: 1. Demonstrate that the intracolumnar dynamics of interictal discharges depend on the location of that column in the epileptogenic network. We hypothesize that interictal discharges in the epileptogenic focus are generated by current sinks and increased neuronal firing in deep cortical layers, whereas propagated epileptiform discharges will show initial sinks and activation in middle and upper cortical layers. Such results are consistent with epileptiform activity arising from recurrent excitatory activity in deep cortical layers augmented by rebound intrinsic currents and delineate a microphysiological signature of ictogenic cortex. 2. Determine the role of different cortical layers and neuronal firing during seizure initiation. We expect that action potential firing in deep cortical layers within the seizure focus precedes overt seizure initiation. Further, we expect that these same layers are the site of current sinks during discharges that occur at seizure initiation. These features further define the seizure focus, shed light on how seizures start, and may provide a novel method for seizure prediction. 3. Examine the role of neuronal group dynamics during seizure spread. Finally, we hypothesize that from the focus, seizures spread by direct recruitment via projections to upper cortical layers. Further, for certain regions there will be increased involvement of deeper cortical layers as the seizure progresses correlated with an ability of that region to independently generate epileptiform discharges. Consistent with this evolution from direct recruitment to multi-focal autonomous event generation, analysis of functional coupling between cortical regions will show progression from tight to loose association. This description may further differentiate the seizure focus and suggest new strategies for interrupting seizure propagation.
These aims address essential aspects of the neurophysiology of human seizures at an unprecedented level of detail and breadth. The results will lead to a clear mechanistic understanding of what constitutes the seizure focus in humans. This can lead to increased effectiveness of surgical management of medically refractory epilepsy, as well as innovative approaches to seizure prediction, detection and termination.

Public Health Relevance

Epilepsy remains a devastating and poorly understood illness. The experiments proposed in this project utilize novel techniques to record detailed neuronal activity directly from human cortex before and during seizures. We hope to use these techniques to better appreciate the differences between cortical tissue that will and will not generate seizures and what happens in those different areas as seizures start and spread. The information obtained will allow us to understand the neuronal dynamics underlying epilepsy at an unprecedented level of resolution. This will foster the development of new approaches to seizure prediction, detection and termination as well as more effective surgical management of medically refractory focal epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS062092-04S1
Application #
8795271
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2014-01-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$15,723
Indirect Cost
$6,687
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Chu, C J; Leahy, J; Pathmanathan, J et al. (2014) The maturation of cortical sleep rhythms and networks over early development. Clin Neurophysiol 125:1360-70
Truccolo, Wilson; Ahmed, Omar J; Harrison, Matthew T et al. (2014) Neuronal ensemble synchrony during human focal seizures. J Neurosci 34:9927-44
Williamson, Craig A; Wahlster, Sarah; Shafi, Mouhsin M et al. (2014) Sensitivity of compressed spectral arrays for detecting seizures in acutely ill adults. Neurocrit Care 20:32-9
Karakis, Ioannis; Pathmanathan, Jay S; Chang, Richard et al. (2014) Prognostic value of EEG asymmetries for development of drug-resistance in drug-naive patients with genetic generalized epilepsies. Clin Neurophysiol 125:263-9
Shafi, Mouhsin M; Brandon Westover, M; Oberman, Lindsay et al. (2014) Modulation of EEG functional connectivity networks in subjects undergoing repetitive transcranial magnetic stimulation. Brain Topogr 27:172-91
Cash, Sydney S (2013) Status epilepticus as a system disturbance: is status epilepticus due to synchronization or desynchronization? Epilepsia 54 Suppl 6:37-9
Ferguson, Matthew; Bianchi, Matt T; Sutter, Raoul et al. (2013) Calculating the risk benefit equation for aggressive treatment of non-convulsive status epilepticus. Neurocrit Care 18:216-27
Westover, M Brandon; Bianchi, Matt T; Shafi, Mouhsin et al. (2013) Inferring seizure frequency from brief EEG recordings. J Clin Neurophysiol 30:174-7
Brandon Westover, M; Shafi, Mouhsin M; Ching, Shinung et al. (2013) Real-time segmentation of burst suppression patterns in critical care EEG monitoring. J Neurosci Methods 219:131-41
Chu, Catherine J; Kramer, Mark A; Pathmanathan, Jay et al. (2012) Emergence of stable functional networks in long-term human electroencephalography. J Neurosci 32:2703-13

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