Between seizures, irritative network generates frequent brief synchronous activity, which manifests on the EEG as interictal epileptiform discharges (IEDs). Recent insights into the mechanism of IEDs at the microscopic level have demonstrated a high variance in the recruitment of neuronal populations generating IEDs and a high variability in the trajectories through which IEDs propagate across the brain. These phenomena represent one of the major constraints for precise characterization of network organization and for the utilization of IEDs during presurgical evaluations. We have developed a new approach to dissect human neocortical irritative networks and quantify their properties. We have demonstrated that irritative network has modular nature and it is composed of multiple independent sub-regions, each with specific IED propagation trajectories and differing in the extent of IED activity generated. The global activity of the irritative network is determined by long-term and circadian fluctuations in sub-region spatiotemporal properties. Also, the most active sub-region co-localizes with the seizure onset zone in 12/14 cases. This study demonstrates that principles of recruitment variability and propagation are conserved at the macroscopic level and that they determine irritative network properties in humans. Functional stratification of the irritative network increases the diagnostic yield of intracranial investigations with the potential to improve the outcomes of surgical treatment of neocortical epilepsy.

Department of Circuit Theory Faculty of Electrical Engineering Czech Technical University Prague Prague Czechia

Department of Developmental Epileptology Institute of Physiology The Czech Academy of Sciences Prague Czechia

Department of Neurology 2nd Faculty of Medicine Charles University Motol University Hospital Prague Czechia

Department of Pediatric Neurology 2nd Faculty of Medicine Charles University Motol University Hospital Prague Czechia

Front Neurol. 2019 Jun 14;10:631. doi: 10.3389/fneur.2019.00631. PubMed

See more in PubMed

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. PubMed

Rosenow F, Lüders H. Presurgical evaluation of epilepsy. Brain (2001) 124:1683–700.10.1093/brain/124.9.1683 PubMed DOI

Asano E, Muzik O, Shah A, Juhász C, Chugani DC, Sood S, et al. Quantitative interictal subdural EEG analyses in children with neocortical epilepsy. Epilepsia (2003) 44:425–34.10.1046/j.1528-1157.2003.38902.x PubMed DOI

Goncharova II, Spencer SS, Duckrow RB, Hirsch LJ, Spencer DD, Zaveri HP. Intracranially recorded interictal spikes: relation to seizure onset area and effect of medication and time of day. Clin Neurophysiol (2013) 124:2119–28.10.1016/j.clinph.2013.05.027 PubMed DOI

Hamer HM, Najm I, Mohamed A, Wyllie E. Interictal epileptiform discharges in temporal lobe epilepsy due to hippocampal sclerosis versus medial temporal lobe tumors. Epilepsia (1999) 40:1261–8.10.1111/j.1528-1157.1999.tb00856.x PubMed DOI

Thornton R, Vulliemoz S, Rodionov R, Carmichael DW, Chaudhary UJ, Diehl B, et al. Epileptic networks in focal cortical dysplasia revealed using electroencephalography-functional magnetic resonance imaging. Ann Neurol (2011) 70:822–37.10.1002/ana.22535 PubMed DOI PMC

Bautista RED, Cobbs MA, Spencer DD, Spencer SS. Prediction of surgical outcome by interictal epileptiform abnormalities during intracranial EEG monitoring in patients with extrahippocampal seizures. Epilepsia (1999) 40:880–90.10.1111/j.1528-1157.1999.tb00794.x PubMed DOI

Hufnagel A, Dumpelmann M, Zentner J, Schijns O, Elger CE. Clinical relevance of quantified intracranial interictal spike activity in presurgical evaluation of epilepsy. Epilepsia (2000) 41:467–78.10.1111/j.1528-1157.2000.tb00191.x PubMed DOI

Muldoon SF, Villette V, Tressard T, Malvache A, Reichinnek S, Bartolomei F, et al. GABAergic inhibition shapes interictal dynamics in awake epileptic mice. Brain (2015) 138:2875–90.10.1093/brain/awv227 PubMed DOI

Sabolek HR, Swiercz WB, Lillis KP, Cash SS, Huberfeld G, Zhao G, et al. A candidate mechanism underlying the variance of interictal spike propagation. J Neurosci (2012) 32:3009–21.10.1523/JNEUROSCI.5853-11.2012 PubMed DOI PMC

Bautista RED. On the nature of interictal epileptiform discharges. Clin Neurophysiol (2013) 124:2073–4.10.1016/j.clinph.2013.06.009 PubMed DOI

Kramer MA, Eden UT, Kolaczyk ED, Zepeda R, Eskandar EN, Cash SS. Coalescence and fragmentation of cortical networks during focal seizures. J Neurosci (2010) 30:10076–85.10.1523/JNEUROSCI.6309-09.2010 PubMed DOI PMC

van Diessen E, Hanemaaijer JI, Otte WM, Zelmann R, Jacobs J, Jansen FE, et al. Are high frequency oscillations associated with altered network topology in partial epilepsy? Neuroimage (2013) 82:564–73.10.1016/J.NEUROIMAGE.2013.06.031 PubMed DOI

Zubler F, Steimer A, Gast H, Schindler KA. Seizure termination. Int Rev Neurobiol (2014) 114:187–207.10.1016/B978-0-12-418693-4.00008-X PubMed DOI

Engel J. Surgical Treatment of the Epilepsies. New York: Raven Press; (1993).

Litt B, Esteller R, Echauz J, D’Alessandro M, Shor R, Henry T, et al. Epileptic seizures may begin hours in advance of clinical onset: a report of five patients. Neuron (2001) 30:51–64.10.1016/S0896-6273(01)00262-8 PubMed DOI

Marsh ED, Peltzer B, Brown MW, Wusthoff C, Storm PB, Litt B, et al. Interictal EEG spikes identify the region of electrographic seizure onset in some, but not all, pediatric epilepsy patients. Epilepsia (2010) 51:592–601.10.1111/j.1528-1167.2009.02306.x PubMed DOI PMC

Janca R, Jezdik P, Cmejla R, Tomasek M, Worrell GA, Stead M, et al. Detection of interictal epileptiform discharges using signal envelope distribution modelling: application to epileptic and non-epileptic intracranial recordings. Brain Topogr (2014) 28:172–83.10.1007/s10548-014-0379-1 PubMed DOI

Peres-Neto PR, Jackson DA, Somers KM. How many principal components? Stopping rules for determining the number of non-trivial axes revisited. Comput Stat Data Anal (2005) 49:974–97.10.1016/j.csda.2004.06.015 DOI

Janca R, Jezdik P, Cmejla R, Krsek P, Jefferys JGR, Marusic P, et al. Automatic detection and spatial clustering of interictal discharges in invasive recordings. 2013 IEEE International Symposium on Medical Measurements and Applications Proceedings (MeMeA). Gatineau, QC, Canada: (2013).

Jung T-P, Humphries C, Lee T-W, Makeig S, McKeown MJ, Iragui V, et al. Removing electroencephalographic artifacts: comparison between ICA and PCA. Neural Networks for Signal Processing VIII. Proceedings of the 1998 IEEE Signal Processing Society Workshop (Cat. No.98TH8378) Cambridge, UK: IEEE (1998). p. 63–72.

Lee HW, Youngblood MW, Farooque P, Han X, Jhun S, Chen WC, et al. Seizure localization using three-dimensional surface projections of intracranial EEG power. Neuroimage (2013) 83:616–26.10.1016/j.neuroimage.2013.07.010 PubMed DOI PMC

Alarcon G, Garcia Seoane JJ, Binnie CD, Martin Miguel MC, Juler J, Polkey CE, et al. Origin and propagation of interictal discharges in the acute electrocorticogram. Implications for pathophysiology and surgical treatment of temporal lobe epilepsy. Brain (1997) 120:2259–82.10.1093/brain/120.12.2259 PubMed DOI

Bourien J, Bartolomei F, Bellanger JJ, Gavaret M, Chauvel P, Wendling F. A method to identify reproducible subsets of co-activated structures during interictal spikes. Application to intracerebral EEG in temporal lobe epilepsy. Clin Neurophysiol (2005) 116:443–55.10.1016/j.clinph.2004.08.010 PubMed DOI

Bertram EH. Temporal lobe epilepsy: where do the seizures really begin? Epilepsy Behav (2009) 14(Suppl 1):32–7.10.1016/j.yebeh.2008.09.017 PubMed DOI PMC

Thom M, Mathern GW, Cross JH, Bertram EH. Mesial temporal lobe epilepsy: how do we improve surgical outcome? Ann Neurol (2010) 68:424–34.10.1002/ana.22142 PubMed DOI PMC

Oishi M, Kameyama S, Masuda H, Tohyama J, Kanazawa O, Sasagawa M, et al. Single and multiple clusters of magnetoencephalographic dipoles in neocortical epilepsy: significance in characterizing the epileptogenic zone. Epilepsia (2006) 47:355–64.10.1111/j.1528-1167.2006.00428.x PubMed DOI

Pittau F, Mégevand P, Sheybani L, Abela E, Grouiller F, Spinelli L, et al. Mapping epileptic activity: sources or networks for the clinicians? Front Neurol (2014) 5:218.10.3389/fneur.2014.00218 PubMed DOI PMC

Fahoum F, Lopes R, Pittau F, Dubeau F, Gotman J. Widespread epileptic networks in focal epilepsies: EEG-fMRI study. Epilepsia (2012) 53:1618–27.10.1111/j.1528-1167.2012.03533.x PubMed DOI PMC

Kobayashi E, Bagshaw AP, Grova C, Gotman J, Dubeau F. Grey matter heterotopia: what EEG-fMRI can tell us about epileptogenicity of neuronal migration disorders. Brain (2006) 129:366–74.10.1093/brain/awh710 PubMed DOI

Pittau F, Grouiller F, Spinelli L, Seeck M, Michel CM, Vulliemoz S. The role of functional neuroimaging in pre-surgical epilepsy evaluation. Front Neurol (2014) 5:31.10.3389/fneur.2014.00031 PubMed DOI PMC

van Houdt PJ, Ossenblok PPW, Colon AJ, Boon PAJM, de Munck JC. A framework to integrate EEG-correlated fMRI and intracerebral recordings. Neuroimage (2012) 60:2042–53.10.1016/j.neuroimage.2012.02.023 PubMed DOI

Zijlmans M, Huiskamp G, Hersevoort M, Seppenwoolde JH, Van Huffelen AC, Leijten FSS. EEG-fMRI in the preoperative work-up for epilepsy surgery. Brain (2007) 130:2343–53.10.1093/brain/awm141 PubMed DOI

Khoo HM, Hao Y, von Ellenrieder N, Zazubovits N, Hall J, Olivier A, et al. The hemodynamic response to interictal epileptic discharges localizes the seizure-onset zone. Epilepsia (2017) 58:811–23.10.1111/epi.13717 PubMed DOI

Tyvaert L, Hawco C, Kobayashi E, LeVan P, Dubeau F, Gotman J. Different structures involved during ictal and interictal epileptic activity in malformations of cortical development: an EEG-fMRI study. Brain (2008) 131:2042–60.10.1093/brain/awn145 PubMed DOI PMC

Whiting S, Duchowny M. Topical review: clinical spectrum of cortical dysplasia in childhood: diagnosis and treatment issues. J Child Neurol (1999) 14:759–71.10.1177/088307389901401201 PubMed DOI

Chassoux F, Devaux B, Landré E, Turak B, Nataf F, Varlet P, et al. Stereoelectroencephalography in focal cortical dysplasia: a 3D approach to delineating the dysplastic cortex. Brain (2000) 123:1733–51.10.1093/brain/123.8.1733 PubMed DOI

Avoli M, De Curtis M, Köhling R. Does interictal synchronization influence ictogenesis? Neuropharmacology (2013) 69:37–44.10.1016/j.neuropharm.2012.06.044 PubMed DOI PMC

de Curtis M, Gnatkovsky V. Reevaluating the mechanisms of focal ictogenesis: the role of low-voltage fast activity. Epilepsia (2009) 50:2514–25.10.1111/j.1528-1167.2009.02249.x PubMed DOI

Derry CP, Duncan S. Epilepsy & behavior sleep and epilepsy. Epilepsy Behav (2013) 26:394–404.10.1016/j.yebeh.2012.10.033 PubMed DOI

Foldvary-Schaefer N, Grigg-Damberger M. Sleep and epilepsy: what we know, don’t know, and need to know. J Clin Neurophysiol (2006) 23:4–20.10.1097/01.wnp.0000206877.90232.cb PubMed DOI

Herman ST, Walczak TS, Bazil CW. Distribution of partial seizures during the sleep-wake cycle: differences by seizure onset site. Neurology (2001) 56:1453–9.10.1212/WNL.56.11.1453 PubMed DOI

Del Felice A, Storti SF, Manganotti P. Sleep affects cortical source modularity in temporal lobe epilepsy: a high-density EEG study. Clin Neurophysiol (2015) 126:1677–83.10.1016/j.clinph.2014.12.003 PubMed DOI

Rocamora R, Andrzejak RG, Jiménez-Conde J, Elger CE. Sleep modulation of epileptic activity in mesial and neocortical temporal lobe epilepsy: a study with depth and subdural electrodes. Epilepsy Behav (2013) 28:185–90.10.1016/j.yebeh.2013.04.010 PubMed DOI

A new perspective on drug-resistant epilepsy in children with focal cortical dysplasia type 1: From challenge to favorable outcome

Epilepsy surgery in children with operculoinsular epilepsy: Results of a large unicentric cohort

Epilepsy Research in the Institute of Physiology of the Czech Academy of Sciences in Prague