Epilepsy is a common neurological disorder, with one third of patients not responding to currently available antiepileptic drugs. The proportion of pharmacoresistant epilepsies has remained unchanged for many decades. To cure epilepsy and control seizures requires a paradigm shift in the development of new approaches to epilepsy diagnosis and treatment. Contemporary medicine has benefited from the exponential growth of computational modeling, and the application of network dynamics theory to understanding and treating human brain disorders. In epilepsy, the introduction of these approaches has led to personalized epileptic network modeling that can explore the patient's seizure genesis and predict the functional impact of resection on its individual network's propensity to seize. The application of the dynamic systems approach to neurostimulation therapy of epilepsy allows designing stimulation strategies that consider the patient's seizure dynamics and long-term fluctuations in the stability of their epileptic networks. In this article, we review, in a nontechnical fashion suitable for a broad neuroscientific audience, recent progress in personalized dynamic brain network modeling that is shaping the future approach to the diagnosis and treatment of epilepsy.

Department of Complex Systems Institute of Computer Science Czech Academy of Sciences Prague Czech Republic

Department of Physiology 2nd Faculty of Medicine Charles University Prague Czech Republic

National Institute of Mental Health Klecany Czech Republic

Zobrazit více v PubMed

World Health Organization. WHO, “Epilepsy”. 2019 [cited 2019]. Available from: https://www.who.int/news-room/fact-sheets/detail/epilepsy

Rocha L, Cavalheiro EA. Pharmacoresistance in epilepsy: from genes and molecules to promising therapies. New York: Springer; 2013. p. 329.

Rosenow F, van Alphen N, Becker A, Chiocchetti A, Deichmann R, Deller T, et al. Personalized translational epilepsy research - novel approaches and future perspectives. Epilepsy Behav. 2017;76:13-8.

Engel J. The current place of epilepsy surgery. Curr Opin Neurol. 2018;31(2):192-7.

Thomschewski A, Hincapié A-S, Frauscher B. Localization of the epileptogenic zone using high frequency oscillations. Front Neurol. 2019;10:94.

Fisher RS, Velasco AL. Electrical brain stimulation for epilepsy. Nat Rev Neurol. 2014;10(5):261-70.

Billakota S, Devinsky O, Kim K-W. Why we urgently need improved epilepsy therapies for adult patients. Neuropharmacology. 2020;170:107855.

Duffy DJ. Problems, challenges and promises: perspectives on precision medicine. Brief Bioinform. 2016;17(3):494-504.

Falcon MI, Jirsa VK, Solodkin A. A new neuroinformatics approach to personalized medicine in neurology: the virtual brain. Curr Opin Neurol. 2016;29(4):429-36.

Stam CJ. Modern network science of neurological disorders. Nat Rev Neurosci. 2014;15(10):683-95.

Bassett DS, Sporns O. Network neuroscience. Nat Neurosci. 2017;20(3):353-64.

Laufs H. Functional imaging of seizures and epilepsy: evolution from zones to networks. Curr Opin Neurol. 2012;25(2):194-200.

Spencer S. Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia. 2002;43(3):219-27.

Engel J, Stern JM, Bragin A, Mody I. Connectomics and epilepsy. Curr Opin Neurol. 2013;26(2):186-94.

Gleichgerrcht E, Kocher M, Bonilha L. Connectomics and graph theory analyses: novel insights into network abnormalities in epilepsy. Epilepsia. 2015;56(11):1660-8.

Englot DJ, Konrad PE, Morgan VL. Regional and global connectivity disturbances in focal epilepsy, related neurocognitive sequelae, and potential mechanistic underpinnings. Epilepsia. 2016;57(10):1546-57.

Jiruska P, de Curtis M, Jefferys JGR. Modern concepts of focal epileptic networks. Int Rev Neurobiol. 2014;114:1-7.

Avanzini G, Manganotti P, Meletti S, Moshé SL, Panzica F, Wolf P, et al. The system epilepsies: a pathophysiological hypothesis: system epilepsies. Epilepsia. 2012;53(5):771-8.

Lopes Da Silva FH, Blanes W, Kalitzin SN, Parra J, Suffczynski P, Velis DN. Epilepsies as dynamical diseases of brain systems: basic models of the transition between Normal and epileptic activity. Epilepsia. 2003;44(s12):72-83.

Kalitzin S, Petkov G, Suffczynski P, Grigorovsky V, Bardakjian BL, Lopes da Silva F, et al. Epilepsy as a manifestation of a multistate network of oscillatory systems. Neurobiol Dis. 2019;130:104488.

Jirsa VK, Proix T, Perdikis D, Woodman MM, Wang H, Gonzalez-Martinez J, et al. The virtual epileptic patient: individualized whole-brain models of epilepsy spread. Neuroimage. 2017;145:377-88.

Jirsa VK, Stacey WC, Quilichini PP, Ivanov AI, Bernard C. On the nature of seizure dynamics. Brain. 2014;137(8):2210-30.

Baud MO, Rao VR. Gauging seizure risk. Neurology. 2018;91(21):967-73.

Baud MO, Kleen JK, Mirro EA, Andrechak JC, King-Stephens D, Chang EF, et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun. 2018;9(1):88.

Maturana MI, Meisel C, Dell K, Karoly PJ, D'Souza W, Grayden DB, et al. Critical slowing down as a biomarker for seizure susceptibility. Nat Commun. 2020;11(1):2172.

Saggio ML, Crisp D, Scott JM, Karoly P, Kuhlmann L, Nakatani M, et al. A taxonomy of seizure dynamotypes. eLife. 2020;9:e55632.

Holt AB, Netoff TI. Computational modeling of epilepsy for an experimental neurologist. Exp Neurol. 2013;244:75-86.

Lytton WW. Computer modelling of epilepsy. Nat Rev Neurosci. 2008;9(8):626-37.

Richardson MP. Large scale brain models of epilepsy: dynamics meets connectomics. J Neurol Neurosurg Psychiatry. 2012;83(12):1238-48.

Stefanescu RA, Shivakeshavan RG, Talathi SS. Computational models of epilepsy. Seizure. 2012;21(10):748-59.

Wendling F, Benquet P, Bartolomei F, Jirsa VK. Computational models of epileptiform activity. J Neurosci Methods. 2016;260:233-51.

An S, Kang C, Lee HW. Artificial intelligence and computational approaches for epilepsy. J Epilepsy Res. 2020;10(1):8-17.

Bansal K, Nakuci J, Muldoon SF. Personalized brain network models for assessing structure-function relationships. Curr Opin Neurobiol. 2018;52:42-7.

Sun R, Sohrabpour A, Worrell GA, He B. Deep neural networks constrained by neural mass models improve electrophysiological source imaging of spatiotemporal brain dynamics. Proc Natl Acad Sci USA. 2022;119(31):e2201128119.

Saggio ML, Jirsa VK. Phenomenological mesoscopic for seizure activity models. Complex System Approach Epilepsy Concept Pract Ther 2022 41.

Taylor PN, Kaiser M, Dauwels J. Structural connectivity based whole brain modelling in epilepsy. J Neurosci Methods. 2014;236:51-7.

Engel J, Wiebe S, French J, Sperling M, Williamson P, Spencer D, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the quality standards Subcommittee of the American Academy of neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology. 2003;60(4):538-47.

Englot DJ, Birk H, Chang EF. Seizure outcomes in nonresective epilepsy surgery: an update. Neurosurg Rev. 2017;40(2):181-94.

Labiner DM, Bagic AI, Herman ST, Fountain NB, Walczak TS, Gumnit RJ, et al. Essential services, personnel, and facilities in specialized epilepsy centers-revised 2010 guidelines: guidelines for specialized epilepsy centers. Epilepsia. 2010;51(11):2322-33.

Englot DJ, Chang EF. Rates and predictors of seizure freedom in resective epilepsy surgery: an update. Neurosurg Rev. 2014;37(3):389-405.

Spencer S, Huh L. Outcomes of epilepsy surgery in adults and children. Lancet Neurol. 2008;7(6):525-37.

Téllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain. 2005;128(5):1188-98.

Jehi L. The epileptogenic zone: concept and definition. Epilepsy Curr. 2018;18(1):12-6.

Kahane P, Landré E, Minotti L, Francione S, Ryvlin P. The Bancaud and Talairach view on the epileptogenic zone: a working hypothesis. Epileptic Disord. 2006;8(Suppl 2):S16-26.

Rosenow F. Presurgical evaluation of epilepsy. Brain. 2001;124(9):1683-700.

Zijlmans M, Zweiphenning W, van Klink N. Changing concepts in presurgical assessment for epilepsy surgery. Nat Rev Neurol. 2019;15(10):594-606.

Grigsby J, Kramer RE, Schneiders JL, Gates JR, Brewster SW. Predicting outcome of anterior temporal lobectomy using simulated neural networks. Epilepsia. 1998;39(1):61-6.

Bartolomei F, Lagarde S, Wendling F, McGonigal A, Jirsa V, Guye M, et al. Defining epileptogenic networks: contribution of SEEG and signal analysis. Epilepsia. 2017;58(7):1131-47.

Stacey W, Kramer M, Gunnarsdottir K, Gonzalez-Martinez J, Zaghloul K, Inati S, et al. Emerging roles of network analysis for epilepsy. Epilepsy Res. 2020;159:106255.

Taylor PN, Sinha N, Wang Y, Vos SB, de Tisi J, Miserocchi A, et al. The impact of epilepsy surgery on the structural connectome and its relation to outcome. NeuroImage Clin. 2018;18:202-14.

Tracy JI, Doucet GE. Resting-state functional connectivity in epilepsy: growing relevance for clinical decision making. Curr Opin Neurol. 2015;28(2):158-65.

Janca R, Jahodova A, Hlinka J, Jezdik P, Svobodova L, Kudr M, et al. Ictal gamma-band interactions localize ictogenic nodes of the epileptic network in focal cortical dysplasia. Clin Neurophysiol. 2021;132(8):1927-36.

Wilke C, Worrell G, He B. Graph analysis of epileptogenic networks in human partial epilepsy: graph analysis of epileptogenic networks. Epilepsia. 2011;52(1):84-93.

Zubler F, Gast H, Abela E, Rummel C, Hauf M, Wiest R, et al. Detecting functional hubs of Ictogenic networks. Brain Topogr. 2015;28(2):305-17.

Moraes MFD, De Castro Medeiros D, Mourao FAG, Cancado SAV, Cota VR. Epilepsy as a dynamical system, a most needed paradigm shift in epileptology. Epilepsy Behav. 2021;121:106838.

Terry JR, Benjamin O, Richardson MP. Seizure generation: the role of nodes and networks: networks and seizure generation. Epilepsia. 2012;53(9):e166-9.

Scheffer M, Bascompte J, Brock WA, Brovkin V, Carpenter SR, Dakos V, et al. Early-warning signals for critical transitions. Nature. 2009;461(7260):53-9.

Chang W-C, Kudlacek J, Hlinka J, Chvojka J, Hadrava M, Kumpost V, et al. Loss of neuronal network resilience precedes seizures and determines the ictogenic nature of interictal synaptic perturbations. Nat Neurosci. 2018;21(12):1742-52.

Wilkat T, Rings T, Lehnertz K. No evidence for critical slowing down prior to human epileptic seizures. Chaos. 2019;29(9):91104.

Pérez-Cervera A, Hlinka J. Perturbations both trigger and delay seizures due to generic properties of slow-fast relaxation oscillators. PLOS Comput Biol. 2021;17(3):e1008521.

Wendling F, Bartolomei F, Bellanger JJ, Chauvel P. Epileptic fast activity can be explained by a model of impaired GABAergic dendritic inhibition: epileptic activity explained by dendritic dis-inhibition. Eur J Neurosci. 2002;15(9):1499-508.

Kalitzin SN, Velis DN, Lopes Da Silva FH. Stimulation-based anticipation and control of state transitions in the epileptic brain. Epilepsy Behav. 2010;17(3):310-23.

Amari S. Dynamics of pattern formation in lateral-inhibition type neural fields. Biol Cybern. 1977;27(2):77-87.

Suffczynski P, Kalitzin S, Lopes Da Silva FH. Dynamics of non-convulsive epileptic phenomena modeled by a bistable neuronal network. Neuroscience. 2004;126(2):467-84.

Ashourvan A, Pequito S, Khambhati AN, Mikhail F, Baldassano SN, Davis KA, et al. Model-based design for seizure control by stimulation. J Neural Eng. 2020;17(2):026009.

Gunnarsdottir KM, Li A, Smith RJ, Kang J-Y, Korzeniewska A, Crone NE, et al. Source-sink connectivity: a novel interictal EEG marker for seizure localization. Brain. 2022;145(11):3901-15.

Kini LG, Bernabei JM, Mikhail F, Hadar P, Shah P, Khambhati AN, et al. Virtual resection predicts surgical outcome for drug-resistant epilepsy. Brain. 2019;142(12):3892-905.

Petkov G, Goodfellow M, Richardson MP, Terry JR. A critical role for network structure in seizure onset: a computational modeling approach. Front Neurol. 2014;5:261.

Lopes MA, Richardson MP, Abela E, Rummel C, Schindler K, Goodfellow M, et al. Elevated ictal brain network Ictogenicity enables prediction of optimal seizure control. Front Neurol. 2018;9:98.

Goodfellow M, Rummel C, Abela E, Richardson MP, Schindler K, Terry JR. Estimation of brain network ictogenicity predicts outcome from epilepsy surgery. Sci Rep. 2016;6(1):29215.

Proix T, Bartolomei F, Guye M, Jirsa VK. Individual brain structure and modelling predict seizure propagation. Brain. 2017;140(3):641-54.

Cao M, Vogrin SJ, Peterson ADH, Woods W, Cook MJ, Plummer C. Dynamical network models from EEG and MEG for epilepsy surgery-a quantitative approach. Front Neurol. 2022;13:837893.

Cao M, Galvis D, Vogrin SJ, Woods WP, Vogrin S, Wang F, et al. Virtual intracranial EEG signals reconstructed from MEG with potential for epilepsy surgery. Nat Commun. 2022;13(1):994.

Hutchings F, Han CE, Keller SS, Weber B, Taylor PN, Kaiser M. Predicting surgery targets in temporal lobe epilepsy through structural connectome based simulations. PLOS Comput Biol. 2015;11(12):e1004642.

Laiou P, Avramidis E, Lopes MA, Abela E, Müller M, Akman OE, et al. Quantification and selection of Ictogenic zones in epilepsy surgery. Front Neurol. 2019;10:1045.

Sinha N, Dauwels J, Kaiser M, Cash SS, Brandon Westover M, Wang Y, et al. Predicting neurosurgical outcomes in focal epilepsy patients using computational modelling. Brain. 2017;140(2):319-32.

Sip V, Hashemi M, Vattikonda AN, Woodman MM, Wang H, Scholly J, et al. Data-driven method to infer the seizure propagation patterns in an epileptic brain from intracranial electroencephalography. PLOS Comput Biol. 2021;17(2):e1008689.

Makhalova J, Medina Villalon S, Wang H, Giusiano B, Woodman M, Bénar C, et al. Virtual epileptic patient brain modeling: relationships with seizure onset and surgical outcome. Epilepsia. 2022;63(8):1942-55.

Liu Y, Li C. Localizing targets for neuromodulation in drug-resistant epilepsy using intracranial EEG and computational model. Front Physiol. 2022;13:1015838.

Yang C, Luan G, Wang Q, Liu Z, Zhai F, Wang Q. Localization of epileptogenic zone with the correction of pathological networks. Front Neurol. 2018;9:143.

Gerster M, Taher H, Škoch A, Hlinka J, Guye M, Bartolomei F, et al. Patient-specific network connectivity combined with a next generation neural mass model to test clinical hypothesis of seizure propagation. Front Syst Neurosci. 2021;15:675272.

Millán AP, van Straaten ECW, Stam CJ, Nissen IA, Idema S, Baayen JC, et al. Epidemic models characterize seizure propagation and the effects of epilepsy surgery in individualized brain networks based on MEG and invasive EEG recordings. Sci Rep. 2022;12(1):4086.

Lopes MA, Junges L, Tait L, Terry JR, Abela E, Richardson MP, et al. Computational modelling in source space from scalp EEG to inform presurgical evaluation of epilepsy. Clin Neurophysiol. 2020;131(1):225-34.

Gadhoumi K, Lina J-M, Mormann F, Gotman J. Seizure prediction for therapeutic devices: a review. J Neurosci Methods. 2016;260:270-82.

An S, Bartolomei F, Guye M, Jirsa V. Optimization of surgical intervention outside the epileptogenic zone in the virtual epileptic patient (VEP). PLOS Comput Biol. 2019;15(6):e1007051.

Olmi S, Petkoski S, Guye M, Bartolomei F, Jirsa VK. Controlling seizure propagation in large-scale brain networks. PLOS Comput Biol. 2019;15(2):e1006805.

Wang Y, Hutchings F, Kaiser M. Computational modeling of neurostimulation in brain diseases. Prog Brain Res. 2015;222:191-228.

Orlandi JG, Soriano J, Alvarez-Lacalle E, Teller S, Casademunt J. Noise focusing and the emergence of coherent activity in neuronal cultures. Nat Phys. 2013;9(9):582-90.

Bourdillon P, Rheims S, Catenoix H, Montavont A, Ostrowsky-Coste K, Isnard J, et al. Surgical techniques: Stereoelectroencephalography-guided radiofrequency-thermocoagulation (SEEG-guided RF-TC). Seizure. 2019;77:64-8.

Vakharia VN, Sparks R, Rodionov R, Vos SB, Dorfer C, Miller J, et al. Computer-assisted planning for the insertion of stereoelectroencephalography electrodes for the investigation of drug-resistant focal epilepsy: an external validation study. J Neurosurg. 2019;130(2):601-10.

Famm K, Litt B, Tracey KJ, Boyden ES, Slaoui M. A jump-start for electroceuticals. Nature. 2013;496(7444):159-61.

Lin Y, Wang Y. Neurostimulation as a promising epilepsy therapy. Epilepsia Open. 2017;2(4):371-87.

Nagaraj V, Lee ST, Krook-Magnuson E, Soltesz I, Benquet P, Irazoqui PP, et al. Future of seizure prediction and intervention: closing the loop. J Clin Neurophysiol. 2015;32(3):194-206.

Parastarfeizabadi M, Kouzani AZ. Advances in closed-loop deep brain stimulation devices. J Neuroengineering Rehabil. 2017;14(1):79.

Walker LE, Janigro D, Heinemann U, Riikonen R, Bernard C, Patel M. WONOEP appraisal: molecular and cellular biomarkers for epilepsy. Epilepsia. 2016;57(9):1354-62.

Baumgartner C, Koren JP, Rothmayer M. Automatic computer-based detection of epileptic seizures. Front Neurol. 2018;9:639.

Kudlacek J, Chvojka J, Kumpost V, Hermanovska B, Posusta A, Jefferys JGR, et al. Long-term seizure dynamics are determined by the nature of seizures and the mutual interactions between them. Neurobiol Dis. 2021;154:105347.

Schroeder GM, Diehl B, Chowdhury FA, Duncan JS, de Tisi J, Trevelyan AJ, et al. Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy. Proc Natl Acad Sci USA. 2020;117(20):11048-58.

Karoly PJ, Goldenholz DM, Freestone DR, Moss RE, Grayden DB, Theodore WH, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018;17(11):977-85.

Cook MJ, Varsavsky A, Himes D, Leyde K, Berkovic SF, O'Brien T, et al. The dynamics of the epileptic brain reveal long-memory processes. Front Neurol. 2014;5:217.

Jiruska P, Powell AD, Deans JK, Jefferys JGR. Effects of direct brain stimulation depend on seizure dynamics: brain stimulation depends on seizure dynamics. Epilepsia. 2010;51:93-7.

Bikson M, Hahn PJ, Fox JE, Jefferys JGR. Depolarization block of neurons during maintenance of electrographic seizures. J Neurophysiol. 2003;90(4):2402-8.

Bikson M, Inoue M, Akiyama H, Deans JK, Fox JE, Miyakawa H, et al. Effects of uniform extracellular DC electric fields on excitability in rat hippocampal slices in vitro: modulation of neuronal function by electric fields. J Physiol. 2004;557(1):175-90.

Bikson M, Lian J, Hahn PJ, Stacey WC, Sciortino C, Durand DM. Suppression of epileptiform activity by high frequency sinusoidal fields in rat hippocampal slices. J Physiol. 2001;531(1):181-91.

Barbarosie M, Avoli M. CA3-driven hippocampal-entorhinal loop controls rather than sustains In vitro limbic seizures. J Neurosci. 1997;17(23):9308-14.

Jensen MS, Yaari Y. The relationship between interictal and ictal paroxysms in an in vitro model of focal hippocampal epilepsy. Ann Neurol. 1988;24(5):591-8.

Librizzi L, de Curtis M. Epileptiform ictal discharges are prevented by periodic interictal spiking in the olfactory cortex. Ann Neurol. 2003;53(3):382-9.

Krook-Magnuson E, Gelinas JN, Soltesz I, Buzsáki G. Neuroelectronics and biooptics: closed-loop technologies in neurological disorders. JAMA Neurol. 2015;72(7):823-9.

Mina F, Benquet P, Pasnicu A, Biraben A, Wendling F. Modulation of epileptic activity by deep brain stimulation: a model-based study of frequency-dependent effects. Front Comput Neurosci. 2013;7:94.

Sunderam S, Gluckman B, Reato D, Bikson M. Toward rational design of electrical stimulation strategies for epilepsy control. Epilepsy Behav. 2010;17(1):6-22.

Basu I, Crocker B, Farnes K, Robertson MM, Paulk AC, Vallejo DI, et al. A neural mass model to predict electrical stimulation evoked responses in human and non-human primate brain. J Neural Eng. 2018;15(6):066012.

Giannakakis E, Hutchings F, Papasavvas CA, Han CE, Weber B, Zhang C, et al. Computational modelling of the long-term effects of brain stimulation on the local and global structural connectivity of epileptic patients. Wennekers T, editor. PLOS One. 2020;15(2):e0221380.

Stamoulis C, Chang BS. Modeling noninvasive neurostimulation in epilepsy as stochastic interference in brain networks. IEEE Trans Neural Syst Rehabil Eng. 2013;21(3):354-63.

Chang S, Wang J, Liu C, Yi G, Lu M, Che Y, et al. A data driven experimental system for individualized brain stimulation design and validation. IEEE Trans Neural Syst Rehabil Eng. 2021;29:1848-57.

Taylor PN, Thomas J, Sinha N, Dauwels J, Kaiser M, Thesen T, et al. Optimal control based seizure abatement using patient derived connectivity. Front Neurosci. 2015;9:202.

Stanslaski S, Farooqi H, Sanabria DE, Netoff TI. Fully closed loop test environment for adaptive implantable neural stimulators using computational models. J Med Device. 2022;16(3):34501.

Scheid BH, Ashourvan A, Stiso J, Davis KA, Mikhail F, Pasqualetti F, et al. Time-evolving controllability of effective connectivity networks during seizure progression. Proc Natl Acad Sci USA. 2021;118(5):e2006436118.

Sandler RA, Geng K, Song D, Hampson RE, Witcher MR, Deadwyler SA, et al. Designing patient-specific optimal neurostimulation patterns for seizure suppression. Neural Comput. 2018;30(5):1180-208.

Bernabei JM, Arnold TC, Shah P, Revell A, Ong IZ, Kini LG, et al. Electrocorticography and stereo EEG provide distinct measures of brain connectivity: implications for network models. Brain Commun. 2021;3(3):fcab156.

Junges L, Woldman W, Benjamin OJ, Terry JR. Epilepsy surgery: evaluating robustness using dynamic network models. Chaos. 2020;30(11):113106.

Zaveri HP, Schelter B, Schevon CA, Jiruska P, Jefferys JGR, Worrell G, et al. Controversies on the network theory of epilepsy: debates held during the ICTALS 2019 conference. Seizure. 2020;78:78-85.

Tamilia E, Madsen JR, Grant PE, Pearl PL, Papadelis C. Current and emerging potential of magnetoencephalography in the detection and localization of high-frequency oscillations in epilepsy. Front Neurol. 2017;8:14.

Computational modeling allows unsupervised classification of epileptic brain states across species