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Computational modeling of epileptiform activities in medial temporal lobe epilepsy combined with in vitro experiments

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Abstract

In this paper, we propose a comprehensive computational model that is able to reproduce three epileptiform activities. The model targets a hippocampal formation that is known to be an important lesion in medial temporal lobe epilepsy. It consists of four sub-networks consisting of excitatory and inhibitory neurons and well-known signal pathways, with consideration of propagation delay. The three epileptiform activities involve fast and slow interictal discharge and ictal discharge, and those activities can be induced in vitro by application of 4-Aminopyridine in entorhinal cortex combined hippocampal slices. We model the three epileptiform activities upon previously reported biological mechanisms and verify the simulation results by comparing them with in vitro experimental data obtained using a microelectrode array. We use the results of Granger causality analysis of recorded data to set input gains of signal pathways in the model, so that the compatibility between the computational and experimental models can be improved. The proposed model can be expanded to evaluate the suppression effect of epileptiform activities due to new treatment methods.

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References

  • Avoli, M., Barbarosie, M., Lücke, A., Nagao, T., Lopantsev, V., & Köhling, R. (1996). Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro. The Journal of Neuroscience, 16(12), 3912–3924.

    CAS  PubMed  Google Scholar 

  • Avoli, M., D’Antuono, M., Louvel, J., Köhling, R., Biagini, G., Pumain, R., et al. (2002). Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Progress in Neurobiology, 68(3), 167–207.

    Article  CAS  PubMed  Google Scholar 

  • Bazhenov, M., Timofeev, I., Fröhlich, F., & Sejnowski, T. J. (2008). Cellular and network mechanisms of electrographic seizures. Drug Discovery Today: Disease Models, 5(1), 45–57.

    PubMed  PubMed Central  Google Scholar 

  • Bischofberger, J., Engel, D., Li, L., Geiger, J. R., & Jonas, P. (2006). Patch-clamp recording from mossy fiber terminals in hippocampal slices. Nature Protocols, 1(4), 2075–2081.

    Article  CAS  PubMed  Google Scholar 

  • Cadotte, A. J., DeMarse, T. B., Mareci, T. H., Parekh, M. B., Talathi, S. S., Hwang, D.-U.,. .. Carney, P. R. (2010). Granger causality relationships between local field potentials in an animal model of temporal lobe epilepsy. Journal of Neuroscience Methods, 189(1), 121–129.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chiang, C.-C., Lin, C.-C. K., Ju, M.-S., & Durand, D. M. (2013). High frequency stimulation can suppress globally seizures induced by 4-AP in the rat hippocampus: An acute in vivo study. Brain Stimulation, 6(2), 180–189.

    Article  PubMed  Google Scholar 

  • Cosandier-Rimélé, D., Merlet, I., Badier, J.-M., Chauvel, P., & Wendling, F. (2008). The neuronal sources of EEG: modeling of simultaneous scalp and intracerebral recordings in epilepsy. Neuro Image, 42(1), 135–146.

    PubMed  Google Scholar 

  • Cossart, R., Bernard, C., & Ben-Ari, Y. (2005). Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies. Trends in Neurosciences, 28(2), 108–115.

    Article  CAS  PubMed  Google Scholar 

  • Cressman Jr, J. R., Ullah, G., Ziburkus, J., Schiff, S. J., & Barreto, E. (2009). The influence of sodium and potassium dynamics on excitability, seizures, and the stability of persistent states: I. Single neuron dynamics. Journal of Computational Neuroscience, 26(2), 159–170.

    Article  PubMed  PubMed Central  Google Scholar 

  • De Deyn, P. P., D'Hooge, R., Marescau, B., & Pei, Y.-Q. (1992). Chemical models of epilepsy with some reference to their applicability in the development of anticonvulsants. Epilepsy Research, 12(2), 87–110.

    Article  PubMed  Google Scholar 

  • Debanne, D., Guerineau, N. C., Gähwiler, B., & Thompson, S. M. (1996). Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release. The Journal of Physiology, 491(1), 163–176.

    Article  CAS  PubMed  Google Scholar 

  • Fröhlich, F., Sejnowski, T. J., & Bazhenov, M. (2010). Network bistability mediates spontaneous transitions between normal and pathological brain states. The Journal of Neuroscience, 30(32), 10734–10743.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Sulser, A., Wang, J., Motamedi, G. K., Avoli, M., Vicini, S., & Dzakpasu, R. (2011). The 4-aminopyridine in vitro epilepsy model analyzed with a perforated multi-electrode array. Neuropharmacology, 60(7), 1142–1153.

    Article  CAS  PubMed  Google Scholar 

  • Granger, C. W. (1969). Investigating causal relations by econometric models and cross-spectral methods. Econometrica:. Journal of the Econometric Society, 424–438.

  • Gupta, A., Wang, Y., & Markram, H. (2000). Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science, 287(5451), 273–278.

    Article  CAS  PubMed  Google Scholar 

  • Hall, D., & Kuhlmann, L. (2013). Mechanisms of seizure propagation in 2-dimensional Centre-surround recurrent networks. PloS One, 8(8), e71369.

    Article  CAS  PubMed Central  Google Scholar 

  • Hamzei-Sichani, F., Davidson, K. G., Yasumura, T., Janssen, W. G., Wearne, S. L., Hof, P. R., et al. (2012). Mixed electrical–chemical synapses in adult rat hippocampus are primarily glutamatergic and coupled by connexin-36. Frontiers in Neuroanatomy, 6(13), 1–26.

    Google Scholar 

  • Henze, D. A., Borhegyi, Z., Csicsvari, J., Mamiya, A., Harris, K. D., & Buzsáki, G. (2000). Intracellular features predicted by extracellular recordings in the hippocampus in vivo. Journal of Neurophysiology, 84(1), 390–400.

    CAS  PubMed  Google Scholar 

  • Holt, A. B., & Netoff, T. I. (2013). Computational modeling of epilepsy for an experimental neurologist. Experimental Neurology, 244, 75–86.

    Article  PubMed  Google Scholar 

  • Huang, C. W., Huang, C. C., Cheng, J. T., Tsai, J. J., & Wu, S. N. (2007). Glucose and hippocampal neuronal excitability: role of ATP-sensitive potassium channels. Journal of Neuroscience Research, 85(7), 1468–1477.

    Article  CAS  PubMed  Google Scholar 

  • Izhikevich, E. M. (2003). Simple model of spiking neurons. IEEE Transactions on Neural Networks, 14(6), 1569–1572.

    Article  CAS  PubMed  Google Scholar 

  • Izhikevich, E. M. (2004). Which model to use for cortical spiking neurons? IEEE Transactions on Neural Networks, 15(5), 1063–1070.

    Article  PubMed  Google Scholar 

  • Izhikevich, E. M., Gally, J. A., & Edelman, G. M. (2004). Spike-timing dynamics of neuronal groups. Cerebral Cortex, 14(8), 933–944.

    Article  PubMed  Google Scholar 

  • Jirsa, V. K., Stacey, W. C., Quilichini, P. P., Ivanov, A. I., & Bernard, C. (2014). On the nature of seizure dynamics. Brain, 137(8), 2210–2230.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiruska, P., de Curtis, M., Jefferys, J. G., Schevon, C. A., Schiff, S. J., & Schindler, K. (2013). Synchronization and desynchronization in epilepsy: controversies and hypotheses. The Journal of Physiology, 591(4), 787–797.

    Article  CAS  PubMed  Google Scholar 

  • Kamiński, M., Ding, M., Truccolo, W. A., & Bressler, S. L. (2001). Evaluating causal relations in neural systems: granger causality, directed transfer function and statistical assessment of significance. Biological Cybernetics, 85(2), 145–157.

    Article  PubMed  Google Scholar 

  • Khalilov, I., Khazipov, R., Esclapez, M., & Ben-Ari, Y. (1997). Bicuculline induces ictal seizures in the intact hippocampus recorded in vitro. European Journal of Pharmacology, 319(2), R5–R6.

    Article  CAS  PubMed  Google Scholar 

  • Kim, S., Putrino, D., Ghosh, S., & Brown, E. N. (2011). A granger causality measure for point process models of ensemble neural spiking activity. PLoS Computational Biology, 7(3), e1001110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kramer, M. A., Kirsch, H. E., & Szeri, A. J. (2005). Pathological pattern formation and cortical propagation of epileptic seizures. Journal of the Royal Society Interface, 2(2), 113–127.

    Article  PubMed Central  Google Scholar 

  • Lado, F. A., & Moshé, S. L. (2008). How do seizures stop? Epilepsia, 49(10), 1651–1664.

    Article  PubMed  PubMed Central  Google Scholar 

  • Markram, H., Wang, Y., & Tsodyks, M. (1998). Differential signaling via the same axon of neocortical pyramidal neurons. Proceedings of the National Academy of Sciences, 95(9), 5323–5328.

    Article  CAS  Google Scholar 

  • McIntyre, C. C., Savasta, M., Kerkerian-Le Goff, L., & Vitek, J. L. (2004). Uncovering the mechanism (s) of action of deep brain stimulation: activation, inhibition, or both. Clinical Neurophysiology, 115(6), 1239–1248.

    Article  PubMed  Google Scholar 

  • Netoff, T. I., Clewley, R., Arno, S., Keck, T., & White, J. A. (2004). Epilepsy in small-world networks. The Journal of Neuroscience, 24(37), 8075–8083.

    Article  CAS  PubMed  Google Scholar 

  • Perucca, E., French, J., & Bialer, M. (2007). Development of new antiepileptic drugs: challenges, incentives, and recent advances. The Lancet Neurology, 6(9), 793–804.

    Article  CAS  PubMed  Google Scholar 

  • Regehr, W. G. (2012). Short-term presynaptic plasticity. Cold Spring Harbor Perspectives in Biology, 4(7), a005702.

  • Sato, J. R., Junior, E. A., Takahashi, D. Y., de Maria Felix, M., Brammer, M. J., & Morettin, P. A. (2006). A method to produce evolving functional connectivity maps during the course of an fMRI experiment using wavelet-based time-varying granger causality. NeuroImage, 31(1), 187–196.

    Article  PubMed  Google Scholar 

  • Schiller, Y., & Bankirer, Y. (2007). Cellular mechanisms underlying antiepileptic effects of low-and high-frequency electrical stimulation in acute epilepsy in neocortical brain slices in vitro. Journal of Neurophysiology, 97(3), 1887–1902.

    Article  PubMed  Google Scholar 

  • Seth, A. (2007). Granger causality. Scholarpedia, 2(7), 1667.

  • Seth, A. K. (2010). A MATLAB toolbox for granger causal connectivity analysis. Journal of Neuroscience Methods, 186(2), 262–273.

    Article  PubMed  Google Scholar 

  • Staley, K. J., Soldo, B. L., & Proctor, W. R. (1995). Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science, 269(5226), 977.

  • Stepan, J. (2015). Real-time imaging of hippocampal network dynamics reveals trisynaptic induction of CA1 LTP and" circuit-level" effects of chronic stress and antidepressants. der Ludwig-Maximilians-Universität.

  • Toprani, S., & Durand, D. M. (2013). Fiber tract stimulation can reduce epileptiform activity in an in-vitro bilateral hippocampal slice preparation. Experimental Neurology, 240, 28–43.

    Article  PubMed  Google Scholar 

  • van Drongelen, W., Koch, H., Marcuccilli, C., Pena, F., & Ramirez, J.-M. (2003). Synchrony levels during evoked seizure-like bursts in mouse neocortical slices. Journal of Neurophysiology, 90(3), 1571–1580.

    Article  PubMed  Google Scholar 

  • Volman, V., Perc, M., & Bazhenov, M. (2011). Gap junctions and epileptic seizures-two sides of the same coin. PloS One, 6(5), e20572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Volman, V., Bazhenov, M., & Sejnowski, T. J. (2012). Computational models of neuron-astrocyte interaction in epilepsy. Frontiers in Computational Neuroscience, 6(58), 6–15.

    Google Scholar 

  • Watts, D. J., & Strogatz, S. H. (1998). Collective dynamics of ‘small-world’networks. Nature, 393(6684), 440–442.

    Article  CAS  PubMed  Google Scholar 

  • Wendling, F., Hernandez, A., Bellanger, J.-J., Chauvel, P., & Bartolomei, F. (2005). Interictal to ictal transition in human temporal lobe epilepsy: insights from a computational model of intracerebral EEG. Journal of Clinical Neurophysiology, 22(5), 343.

    PubMed  PubMed Central  Google Scholar 

  • Wendling, F., Benquet, P., Bartolomei, F., & Jirsa, V. (2016). Computational models of epileptiform activity. Journal of Neuroscience Methods, 260, 233–251.

    Article  PubMed  Google Scholar 

  • Yamada, K., Ji, J. J., Yuan, H., Miki, T., Sato, S., Horimoto, N., et al. (2001). Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science, 292(5521), 1543–1546.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Z. J. (2010). Transition to Seizure in the CA3 Hippocampal Network: Predominant Preictal GABAergic Potentials, followed by Predominant Ictal Glutamatergic Potentials. University of Toronto.

  • Zhang, M., Ladas, T. P., Qiu, C., Shivacharan, R. S., Gonzalez-Reyes, L. E., & Durand, D. M. (2014). Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions, or diffusion and is consistent with electrical field transmission. The Journal of Neuroscience, 34(4), 1409–1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ziburkus, J., Cressman, J. R., Barreto, E., & Schiff, S. J. (2006). Interneuron and pyramidal cell interplay during in vitro seizure-like events. Journal of Neurophysiology, 95(6), 3948–3954.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the National Research Foundation of Korea (No. 2014R1A2A1A11052763).

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Authors and Affiliations

  1. Department of Electronics Engineering, Ewha Womans University, Seoul, 120-750, South Korea

    Sora Ahn, Sang Beom Jun & Seungjun Lee

  2. Department of Neurology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, 158-710, South Korea

    Hyang Woon Lee

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  1. Sora Ahn
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  2. Sang Beom Jun
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Correspondence to Seungjun Lee.

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Ahn, S., Jun, S.B., Lee, H.W. et al. Computational modeling of epileptiform activities in medial temporal lobe epilepsy combined with in vitro experiments. J Comput Neurosci 41, 207–223 (2016). https://doi.org/10.1007/s10827-016-0614-8

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