Space–time network connectivity and cortical activations preceding spike wave discharges in human absence epilepsy: a MEG study

  • Disha Gupta
  • Pauly OssenblokEmail author
  • Gilles van Luijtelaar
Special Issue - Original Article


To describe the spatial and temporal profiles of connectivity networks and sources preceding generalized spike-and-wave discharges (SWDs) in human absence epilepsy. Nonlinear associations of MEG signals and cluster indices obtained within the framework of graph theory were determined, while source localization in the frequency domain was performed in the low frequency bands with dynamic imaging of coherent sources. The results were projected on a three-dimensional surface rendering of the brain using a semi-realistic head model and MRI images obtained for each of the five patients studied. An increase in clustering and a decrease in path length preceding SWD onset and a rhythmic pattern of increasing and decreasing connectivity were seen during SWDs. Beamforming showed a consistent appearance of a low frequency frontal cortical source prior to the first generalized spikes. This source was preceded by a low frequency occipital source. The changes in the connectivity networks with the onset of SWDs suggest a pathologically predisposed state towards synchronous seizure networks with increasing connectivity from interictal to preictal and ictal state, while the occipital and frontal low frequency early preictal sources demonstrate that SWDs are not suddenly arising but gradually build up in a dynamic network.


Spike wave discharge Absence epilepsy Nonlinear association analysis Beamforming Magnetoencephalography Connectivity Small world networks 



This study was funded by the Netherlands Organization for Scientific Research (NWO), Grant number 400-04-483 to GvL and PO. We would like to thank Prof. Dr. P. Fries and co-workers for their hospitality at the Donders Center for Neuroimaging, Nijmegen, the Netherlands.


  1. 1.
    Amor F, Rudrauf D, Navarro V, N’diaye K, Garnero L, Martinerie J, Le Van Quyen M (2005) Imaging brain synchrony at high spatio-temporal resolution: application to MEG signals during absence seizures. Signal Process 85:2101–2111CrossRefGoogle Scholar
  2. 2.
    Amor F, Baillet S, Navarro V, Adam C, Martinerie J, Le Van Quyen M (2009) Cortical local and long-range synchronization interplay in human absence seizure initiation. NeuroImage 45:950–962PubMedCrossRefGoogle Scholar
  3. 3.
    Andrezejak RG, Laehnertz K, Mormann F, Rieke C, David P, Elger CE (2001) Indications of nonlinear deterministic and finite-dimensional structure in time series of brain electrical activity: dependence on recording region and brain state. Phys Rev E 64:061907CrossRefGoogle Scholar
  4. 4.
    Bassett DS, Bullmore E (2006) Small-world brain networks. Neuroscientist 12:512–523PubMedCrossRefGoogle Scholar
  5. 5.
    Breakspear M (2004) Dynamic connectivity in neural systems. NeuroInformatics 2:205–224PubMedCrossRefGoogle Scholar
  6. 6.
    Breakspear M, Roberts JA, Terry JR, Rodrigues S, Mahant N, Robinson PA (2006) A unifying explanation of primary generalized seizures through nonlinear brain modeling and bifurcation analysis. Cereb Cortex 16:1296–1313PubMedCrossRefGoogle Scholar
  7. 7.
    Canolty RT, Edwards E, Dalal SS, Soltani M, Nagarajan SS, Kirsch HE, Berger MS, Barbaro NM, Knight RT (2006) High gamma power is phase-locked to theta oscillations in human neocortex. Science 313:1626–1628PubMedCrossRefGoogle Scholar
  8. 8.
    Dalal SS, Guggisberg AG, Edwards E, Sekihara K, Findlay AM, Canolty RT, Berger MS, Knight RT, Barbaro NM, Kirsch HE, Nagarajan SS (2008) Five-dimensional neuroimaging: localization of the time–frequency dynamics of cortical activity. Neuroimage 40:1686–1700PubMedCrossRefGoogle Scholar
  9. 9.
    de Jongh A, de Munck JC, Gonçalves SI, Ossenblok P (2005) Differences in MEG/EEG epileptic spike yields explained by regional differences in signal-to-noise ratios. J Clin Neurophysiol 22:153–158PubMedCrossRefGoogle Scholar
  10. 10.
    Depaulis A, van Luijtelaar G (2006) Genetic models of absence epilepsy in the rat. In: Pitkänen A, Schwartzkroin F, Moshe S (eds) Models of seizures and epilepsy. Elsevier, Amsterdam, pp 233–248CrossRefGoogle Scholar
  11. 11.
    Dominguez LG, Wennberg RA, Gaetz W, Cheyne D, Snead OC, Velazquez JLP (2005) Enhanced synchrony in epileptiform activity? Local versus distant phase synchronization in generalized seizures. J Neurosci 25:8077–8084CrossRefGoogle Scholar
  12. 12.
    Fieldtrip open source toolbox for Neuroimaging: Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, the Netherlands
  13. 13.
    Gross J, Kujala J, Hämäläinen M, Timmermann L, Schnitzler A, Salmelin R (2001) Dynamic imaging of coherent sources: Studying neural interactions in the human brain. Proc Natl Acad Sci USA 98:694–699PubMedCrossRefGoogle Scholar
  14. 14.
    Gurbanova AA, Aker R, Sirvanci S, Demiralp T, Onat FY (2008) Intra-amygdaloid injection of kainic acid in rats with genetic absence epilepsy: the relationship of typical absence epilepsy and temporal lobe epilepsy. J Neurosci 28:7828–7836PubMedCrossRefGoogle Scholar
  15. 15.
    Hadjipapas A, Hillebrand A, Holliday IE, Singh KD, Barnes GR (2005) Assessing intersections of linear and non-linear neuronal sources using MEG beamformers: a proof of concept. Clin Neurophysiol 116:1300–1313PubMedCrossRefGoogle Scholar
  16. 16.
    Hamalainen MS, Ilmoniemi RJ (1984) Interpreting measured magnetic fields of the brain: estimates of current distributions, Helsinki Univ. of Tech., Finland, TReport TKKK-F-A599Google Scholar
  17. 17.
    Holmes M, Brown M, Tucker D (2004) Are ‘generalized’ seizures truly generalized? Evidence of localized medial frontal and frontopolar discharges in absence. Epilepsia 45:1568–1579PubMedCrossRefGoogle Scholar
  18. 18.
    Iasemidis LD, Sackellare JC (1996) Review: chaos theory and epilepsy. Neuroscientist 2:118–126CrossRefGoogle Scholar
  19. 19.
    Inouye T, Sakamoto H, Shinosaki K, Toi S, Ukai S (1990) Analysis of rapidly changing EEGs before generalized spike and wave complexes. Electroencephalogr Clin Neurophysiol 76:205–221PubMedCrossRefGoogle Scholar
  20. 20.
    Jasper HH, Kershman J (1941) Electroencephalographic classification of the epilepsies. Arch Neurol Psychiatry 45:903–943Google Scholar
  21. 21.
    Kapucu LO, Serdaroglu A, Okuyaz C, Kose G, Gucuyener K (2003) Brain single photon emission computed tomographic evaluation of patients with childhood absence epilepsy. J Child Neurol 18:542–548PubMedCrossRefGoogle Scholar
  22. 22.
    Kujala J (2008) Study of cortical rhythmic activity and connectivity with magnetoencephalography. PhD thesis, Helsinki University of TechnologyGoogle Scholar
  23. 23.
    Kujala J, Gross J, Salmelin R (2008) Localization of correlated network activity at the cortical level with MEG. NeuroImage 39:1706–1720PubMedCrossRefGoogle Scholar
  24. 24.
    Le Van Quyen M (2005) Anticipating epileptic seizures: from mathematics to clinical applications. C R Biol 328:187–198PubMedCrossRefGoogle Scholar
  25. 25.
    Lehnertz K, Elger CE (1995) Spatio-temporal dynamics of the primary epileptogenic area in temporal lobe epilepsy characterized by neuronal complexity loss. Electroencephalogr Clin Neurophysiol 95:108–117PubMedCrossRefGoogle Scholar
  26. 26.
    Lehnertz K, Mormann F, Kreuz T, Andrzejak RG, Rieke C, David P, Elger CE (2003) Seizure prediction by nonlinear EEG analysis. IEEE Eng Med Biol 22:57–63CrossRefGoogle Scholar
  27. 27.
    Litvak V, Eusebio A, Jha A, Oostenveld R, Barnes GR, Penny WD, Zrinzo L, Hariz MI, Limousin P, Friston KJ, Brown P (2010) Optimized beamforming for simultaneous MEG and intracranial local field potential recordings in deep brain stimulation patients. Neuroimage 50:1578–1588PubMedCrossRefGoogle Scholar
  28. 28.
    Meeren HKM, Pijn JPM, van Luijtelaar ELJM, Coenen AML, Lopes da Silva FH (2002) Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J Neurosci 22:1480–1495PubMedGoogle Scholar
  29. 29.
    Meeren H, van Luijtelaar G, Lopes da Silva F, Coenen A (2005) Evolving concepts on the pathophysiology of absence seizures the cortical focus theory. Arch Neurol 62:25–37CrossRefGoogle Scholar
  30. 30.
    Mitra PP, Pesaran B (1999) Analysis of dynamic brain imaging data. Biophys J 76:691–708PubMedCrossRefGoogle Scholar
  31. 31.
    Mormann F, Andrzejak RG, Kreuz T, Rieke C, David P, Elger CE, Lehnertz K (2003) Automated preictal state detection based on a decrease in synchronization in intracranial electroencephalography recordings from epilepsy patients. Phys Rev E 67:021912CrossRefGoogle Scholar
  32. 32.
    Mormann F, Kreuz T, Andrzejak RG, David P, Lehnertz K, Elger CE (2003) Epileptic seizures are preceded by a decrease in synchronization. Epilepsy Res 53:173–185PubMedCrossRefGoogle Scholar
  33. 33.
    Nolte G (2003) The magnetic lead field theorem in the quasi-static approximation and its use for magnetoencephalography forward calculation in realistic volume conductors. Phys Med Biol 48:3637–3652PubMedCrossRefGoogle Scholar
  34. 34.
    Ossenblok P, de Munck JC, Colon A, Drolsbach W, Boon P (2007) Magnetoencephalography is more successful for screening and localizing frontal lobe epilepsy than electroencephalography. Epilepsia 48:2139–2149PubMedCrossRefGoogle Scholar
  35. 35.
    Palva JM, Palva S, Kaila K (2005) Phase synchrony among neuronal oscillations in the human cortex. J Neurosci 25:3962–3972PubMedCrossRefGoogle Scholar
  36. 36.
    Pascal-Marqui RD, Michel CM, Lehmann D (1994) Low resolution electromagnetic tomography, a new method for localizing electrical activity in the brain. Int J Psychophysiol 18:49–65CrossRefGoogle Scholar
  37. 37.
    Pijn JPM (1990) Quantitative evaluation of EEG signals in epilepsy: nonlinear associations time delays and nonlinear dynamics. University of Amsterdam, NetherlandsGoogle Scholar
  38. 38.
    Polack PO, Guillemain I, Hu E, Deransart C, Depaulis A, Charpier S (2007) Deep layer somatosensory cortical neurons initiate spike-and-wave discharges in a genetic model of absence seizures. J Neurosci 27:6590–6599PubMedCrossRefGoogle Scholar
  39. 39.
    Quraan MA, Moses SN, Hung Y, Mills T, Taylor MJ (2010) Detection and localization of hippocampal activity using beamformers with MEG: a detailed investigation using simulations and empirical data. Human Brain Mapping, n/a. doi: 10.1002/hbm.21068
  40. 40.
    Rodin E, Rodin M, Thompson J (1994) Source analysis of generalized spike–wave complexes. Brain Topogr 7:113–119PubMedCrossRefGoogle Scholar
  41. 41.
    Rubinov M, Knock SA, Stam CJ, Micheloyannis S, Harris AW, Williams LM, Breakspear M (2009) Small-world properties of nonlinear brain activity in schizophrenia. Hum Brain Mapp 30:403–416PubMedCrossRefGoogle Scholar
  42. 42.
    Sekihara K, Nagarajan SS, Peoppel D, Marantz A, Miyashita Y (2001) Reconstructing spatio-temporal activities of neural sources using an MEG vector beamformer technique. IEEE Trans Biomed Eng 48:760–771PubMedCrossRefGoogle Scholar
  43. 43.
    Sitnikova E, van Luijtelaar G (2009) Electroencephalographic precursors of spike-wave discharges in a genetic rat model of absence epilepsy: power spectrum and coherence EEG analyses. Epilepsy Res 84:159–171PubMedCrossRefGoogle Scholar
  44. 44.
    Soffer SN, Vázquez A (2005) Network clustering coefficient without degree-correlation biases. Phys Rev E Stat Nonlin Soft Matter Phys 71(5 Pt 2):057101Google Scholar
  45. 45.
    Stam CJ (2004) Functional connectivity patterns of human magnetoencephalographic recordings: a ‘small-world’ network? Neurosci Lett 355:25–28PubMedCrossRefGoogle Scholar
  46. 46.
    Stam C, van Dijk B (2002) Synchronization likelihood: an unbiased measure of generalized synchronization in multivariate data sets. Phys D: Nonlinear Phenom 163:236–251CrossRefGoogle Scholar
  47. 47.
    Stam CJ, Jones BF, Nolte G, Breakspear M, Scheltens P (2007) Small-world networks and functional connectivity in Alzheimer’s disease. Cereb Cortex 17:92–99PubMedCrossRefGoogle Scholar
  48. 48.
    Tucker D, Brown M, Luu P, Holmes M (2007) Discharges in ventromedial frontal cortex during absence spells. Epilepsy Behav 11:546–557PubMedCrossRefGoogle Scholar
  49. 49.
    van Luijtelaar G, Sitnikova E (2006) Global and focal aspects of absence epilepsy: the contribution of genetic models. Neurosci Biobehav Rev 30:983–1003PubMedCrossRefGoogle Scholar
  50. 50.
    van Luijtelaar G, Hramov A, Sitnikova E, Koronovskii AA (2011) Spike-wave discharges in WAG/Rij rats are preceded by delta and theta precursor activity in cortex and thalamus. Clin Neurophysiol 122:687–695PubMedCrossRefGoogle Scholar
  51. 51.
    van Veen BD, van Drongelen W, Yuchtman M, Suzuki A (1997) Localization of brain electrical activity visa linearly constrained minimum variance spatial filtering. IEEE Trans Biomed Eng 44:867–880PubMedCrossRefGoogle Scholar
  52. 52.
    Vuilleumier P, Assal F, Blanke O, Jallon P (2000) Distinct behavioral and EEG topographic correlates of loss of consciousness in absences. Epilepsia 41:687–693PubMedCrossRefGoogle Scholar
  53. 53.
    Westmijse I, Ossenblok P, Gunning B, van Luijtelaar G (2009) Onset and propagation of spike and slow wave discharges in human absence epilepsy: a MEG study. Epilepsia 50:2538–2548PubMedCrossRefGoogle Scholar

Copyright information

© International Federation for Medical and Biological Engineering 2011

Authors and Affiliations

  • Disha Gupta
    • 1
  • Pauly Ossenblok
    • 2
    Email author
  • Gilles van Luijtelaar
    • 1
  1. 1.Donders Centre for Cognition, Institute for Brain Cognition and BehaviourRadboud University NijmegenNijmegenThe Netherlands
  2. 2.Department of Clinical PhysicsEpilepsy Center KempenhaegheHeezeThe Netherlands

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