A Proposed Mechanism of Epileptic Spasms
Abstract number :
2.071
Submission category :
3. Neurophysiology / 3G. Computational Analysis & Modeling of EEG
Year :
2021
Submission ID :
1826565
Source :
www.aesnet.org
Presentation date :
12/5/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:55 AM
Authors :
Dillon Scott, BS - University of Wisconsin Madison; Tom Bugnon - University of Wisconsin Madison; Giulio Tononi - Professor, Psychiatry, University of Wisconsin Madison; Andrew Knox - Assistant Professor, Neurology, University of Wisconsin Madison
Rationale: West Syndrome is a unique epileptic encephalopathy with pathophysiology that is not yet fully understood. While several animal models have been developed to reproduce the phenotypic features of West Syndrome, the physiological basis of patterns of epileptic spams (ES), its hallmark seizure type, is not completely understood. Here we hypothesize that diffuse elevation of the GABAA (chloride) reversal potential resulting in excitatory GABAA currents could play an important role in generating epileptic spasms.
Methods: In order to study changes in GABAA reversal potential, we utilized a computational thalamocortical loop model with biophysical correlates developed by Hill and Tononi for the study of slow wave sleep [Hill 2005]. We employed a parameter search of network variables corresponding to ligand gated ion channels (GABAA, AMPA, and NMDA conductance), firing thresholds for cortical pyramidal cells and basket cells, and GABAA reversal potential under network states of both sleep and wake. A total of 582 simulations of four seconds each were run to assess for the emergence of epileptiform features.
Results: A parameter search of different values for the GABAA reversal potential generated simulated local field potentials that resembled EEG patterns seen in clusters of epileptic spasms. We observed that values of chloride reversal potential below the resting membrane potential of pyramidal cells generated normal behavior, and values substantially above the resting membrane potential of pyramidal neurons generated sustained low voltage fast activity seen in tonic seizures. When the reversal potential of GABAA was close to the resting membrane potential, prolonged bursts of chaotic firing were seen. These were sustained by excitatory GABAA currents which were ultimately terminated by a combination of accumulating GABAB currents and synaptic depletion.
Conclusions: These results suggest that elevation of the GABAA reversal potential could play a key role in the generation of ES. Understanding the mechanisms underlying ES may contribute to novel and effective treatments for catastrophic epilepsies such as West Syndrome.
Funding: Please list any funding that was received in support of this abstract.: Tiny Blue Dot Foundation; Departmental Start-Up Grant, Department of Neurology, University of Wisconsin.
Neurophysiology