This project aims to achieve a major conceptual advance in the interpretation of EEG, the cornerstone of epilepsy diagnostic evaluation and the basis for therapies whose effectiveness relies on targeting relevant brain areas. The use of EEG recordings to identify cortical sites that are active during a seizure relies heavily on the assumption that high amplitude EEG waveforms reflect intense, synchronous neural firing at the same site. Data from in vitro studies, however, suggest that during the extreme pathological conditions that exist during a seizure, two regional neuronal activity patterns dominate: a sharply demarcated ictal focus marked by hypersynchronous burst firing, and a surrounding ictal penumbra characterized by large synaptic conductances but minimal, desynchronized firing, attributed to a rapidly activated feedforward inhibitory restraint. Thus, neural activity in the penumbra does not actively propagate the seizure, but rather takes the role of an innocent bystander. Because EEG signals in the visual range readily reflect synaptic conductances but are less sensitive to neural activity, brain regions clinically identified as the seizure onset zoe and targeted for resection or focused treatment include both the ictal focus and penumbra. The goal of this proposal is to establish the degree to which the penumbra distorts the view of epileptic brain regions provided by EEG. We will obtain targeted microelectrode array recordings of seizures in patients undergoing invasive long term monitoring as part of surgical treatment for pharmacoresistant epilepsy, to assess the contribution to EEG of neuronal activity both in the ictal focus and in penumbral regions. The focus/penumbra dischotomy also provides a clear, mechanistic explanation for the role of high frequency oscillations (HFOs), due to the well- known relationship between high gamma activity and multiunit firing. By using the neural firing data to establish criteria for ictal HFOs that are specific for the seizure focus, we will ceate a useful method of identifying the temporal and spatial trajectory of the ictal focus across the entire region sampled by clinical electrodes. We expect that these studies will lead to a new clinical methodology for ictal EEG interpretation. This would be a fundamental advance that will affect all epilepsy treatments targeting seizures where they arise.

Public Health Relevance

The ability to pinpoint seizure onset and propagation with a high degree of accuracy can potentially reduce the size of neocortical resections that are considered necessary to control seizures, while improving surgical outcomes and making surgical options available to patients who would otherwise have been considered poor candidates. Additionally, our studies will help to characterize basic mechanisms of seizure spread in human neocortical partial epilepsy syndromes, a key requisite for achieving new therapeutic advances.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS084142-05
Application #
9288237
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Whittemore, Vicky R
Project Start
2013-09-01
Project End
2018-09-29
Budget Start
2017-07-01
Budget End
2018-09-29
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Liou, Jyun-You; Ma, Hongtao; Wenzel, Michael et al. (2018) Role of inhibitory control in modulating focal seizure spread. Brain 141:2083-2097
Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146
Sklar, Samuel; Walmer, Matthew; Sacre, Pierre et al. (2017) Neuronal activity in human anterior cingulate cortex modulates with internal cognitive state during multi-source interference task. Conf Proc IEEE Eng Med Biol Soc 2017:962-965
Hernan, Amanda E; Schevon, Catherine A; Worrell, Gregory A et al. (2017) Methodological standards and functional correlates of depth in vivo electrophysiological recordings in control rodents. A TASK1-WG3 report of the AES/ILAE Translational Task Force of the ILAE. Epilepsia 58 Suppl 4:28-39
Rosenberg, Evan C; Louik, Jay; Conway, Erin et al. (2017) Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia 58:e96-e100
Liou, Jyun-You; Smith, Elliot H; Bateman, Lisa M et al. (2017) Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings. J Neural Eng 14:044001
Eissa, Tahra L; Schevon, Catherine A (2017) The role of computational modelling in seizure localization. Brain 140:254-256
Eissa, Tahra L; Dijkstra, Koen; Brune, Christoph et al. (2017) Cross-scale effects of neural interactions during human neocortical seizure activity. Proc Natl Acad Sci U S A 114:10761-10766
Smith, Elliot H; Schevon, Catherine A (2016) Toward a Mechanistic Understanding of Epileptic Networks. Curr Neurol Neurosci Rep 16:97
Cowan, Jack D; Neuman, Jeremy; van Drongelen, Wim (2016) Wilson-Cowan Equations for Neocortical Dynamics. J Math Neurosci 6:1

Showing the most recent 10 out of 20 publications