P136 Computational Modeling of Ca2+ Blocker Effect in the Thalamocortical Network of Epilepsy: A Dynamic Causal Modeling Study
Euisun Kim1, Jiyoung Kang2, Jinseok Eo3, Hae-Jeong Park*1,3,4,5
¹Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
²Department of Scientific Computing, Pukyong National University, Busan, Republic of Korea
³Center for Systems and Translational Brain Sciences, Institute of Human Complexity and Systems Science, Yonsei University, Seoul, Republic of Korea
4Department of Cognitive Science, Yonsei University, Seoul, Republic of Korea
5Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
*1,2 are equally contributed.
*Email: parkhj@yonsei.ac.kr
Introduction
Childhood Absence Epilepsy (CAE) is characterized by excessive thalamocortical synchronization, leading to recurrent loss of consciousness [1]. This phenomenon is linked to T-type calcium channel hyperactivity, a key driver of seizure generation [2]. Ethosuximide (ETX), a T-type Ca²⁺ blocker and first-line CAE treatment, is expected to influence both intrinsic neural property and interregional connectivity, but its mechanism on thalamocortical network hierarchy remain unclear. This study employs Dynamic Causal Modeling (DCM) to analyze ETX-induced network changes from a neuropharmacological perspective [3].
Methods
To examine ETX-induced changes in thalamocortical dynamics, we incorporated voltage dependent calcium channels to a thalamocortical model (TCM) [4]. The model included six cortical populations (pyramidal, interneuron, and stellate cells) and two thalamic populations (reticular and relay neurons) for a thalamocortical system. Their temporal evolution is governed by coupled differential equations, describing membrane potential and conductance changes mediated by AMPA, NMDA, GABA-A receptors, and T-type calcium channels —the latter capturing ETX effects. Resting-state EEG data were collected before and after ETX administration in CAE patients. Using DCM of longitudinal EEG, we analyzed hierarchical thalamocortical connectivity changes and modeled nonlinear interactions influencing EEG cross-spectral density (CSD) within the Default Mode Network (DMN), including the mPFC, Precuneus, and lateral parietal cortices —which is often aberrantly deactivated during CAE seizures, potentially due to subcortical inhibition [5].
Results
ETX significantly altered both thalamocortical and cortical network dynamics. We observed changes in intrinsic neural properties as well as interregional connectivity when comparing pre- and post-ETX conditions. These findings indicate that ETX modulates local neural excitability and large-scale network interactions, thereby contributing to seizure suppression in CAE.
Discussion
By incorporating voltage-dependent Ca²⁺ channels into a thalamocortical model, this study provides a preliminary computational evidence that calcium channel blockers help restore large-scale network stability in CAE. The results underscore the therapeutic mechanism by which these agents modify pathological thalamocortical interactions. Further validation and refinement of the computational model may enhance clinical approaches to treating CAE and related epileptic disorders.
Acknowledgements
This research was supported by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2024-00401794).
References
● https://doi.org/10.1016/j.nbd.2023.106094
● https://doi.org/10.1111/epi.13962
● https://doi.org/10.1016/j.neuroimage.2023.120161
● https://doi.org/10.1016/j.neuroimage.2020.117189
● 10.3233/BEN-2011-0310
