The electrophysiological EEG features such as high frequency oscillations, spikes and functional connectivity are often used for delineation of epileptogenic tissue and study of the normal function of the brain. The epileptogenic activity is also known to be suppressed by cognitive processing. However, differences between epileptic and healthy brain behavior during rest and task were not studied in detail. In this study we investigate the impact of cognitive processing on epileptogenic and non-epileptogenic hippocampus and the intracranial EEG features representing the underlying electrophysiological processes. We investigated intracranial EEG in 24 epileptic and 24 non-epileptic hippocampi in patients with intractable focal epilepsy during a resting state period and during performance of various cognitive tasks. We evaluated the behavior of features derived from high frequency oscillations, interictal epileptiform discharges and functional connectivity and their changes in relation to cognitive processing. Subsequently, we performed an analysis whether cognitive processing can contribute to classification of epileptic and non-epileptic hippocampus using a machine learning approach. The results show that cognitive processing suppresses epileptogenic activity in epileptic hippocampus while it causes a shift toward higher frequencies in non-epileptic hippocampus. Statistical analysis reveals significantly different electrophysiological reactions of epileptic and non-epileptic hippocampus during cognitive processing, which can be measured by high frequency oscillations, interictal epileptiform discharges and functional connectivity. The calculated features showed high classification potential for epileptic hippocampus (AUC = 0.93). In conclusion, the differences between epileptic and non-epileptic hippocampus during cognitive processing bring new insight in delineation between pathological and physiological processes. Analysis of computed iEEG features in rest and task condition can improve the functional mapping during pre-surgical evaluation and provide additional guidance for distinguishing between epileptic and non-epileptic structure which is absolutely crucial for achieving the best possible outcome with as little side effects as possible.

Behavioral and Social Neuroscience Research Group CEITEC Central European Institute of Technology Masaryk University Brno Czechia

Department of Neurology Faculty of Medicine Brno Epilepsy Center St Anne's University Hospital Masaryk University Brno Czechia

Department of Sports Medicine and Rehabilitation Faculty of Medicine St Anne's University Hospital Masaryk University Brno Czechia

Institute of Scientific Instruments The Czech Academy of Sciences Brno Czechia

International Clinical Research Center St Anne's University Hospital Brno Czechia

Zobrazit více v PubMed

Leonardi M, Ustun TB. The global burden of epilepsy. Epilepsia. (2002) 43 (Suppl. 6):21–5. 10.1046/j.1528-1157.43.s.6.11.x PubMed DOI

Jefferys JGR. Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence? Brain. (1999) 122:1007–8. 10.1093/brain/122.6.1007 PubMed DOI

Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. (2001) 345:311–8. 10.1056/NEJM200108023450501 PubMed DOI

Buzsaki G, Horvath Z, Urioste R, Hetke J, Wise K. High-frequency network oscillation in the hippocampus. Science. (1992) 256:1025–7. 10.1126/science.1589772 PubMed DOI

Bragin A, Engel J, Jr, Wilson CL, Fried I, Mathern GW. Hippocampal and entorhinal cortex high-frequency oscillations (100–500 Hz) in human epileptic brain and in kainic acid–treated rats with chronic seizures. Epilepsia. (1999) 40:127–37. 10.1111/j.1528-1157.1999.tb02065.x PubMed DOI

Jacobs J, LeVan P, Chander R, Hall J, Dubeau F, Gotman J. Interictal high-frequency oscillations (80-500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain. Epilepsia. (2008) 49:1893–907. 10.1111/j.1528-1167.2008.01656.x PubMed DOI PMC

Worrell G, Gotman J. High-frequency oscillations and other electrophysiological biomarkers of epilepsy: clinical studies. Biomark Med. (2011) 5:557–66. 10.2217/bmm.11.74 PubMed DOI PMC

Zijlmans M, Jacobs J, Kahn YU, Zelmann R, Dubeau F, Gotman J. Ictal and interictal high frequency oscillations in patients with focal epilepsy. Clin Neurophysiol. (2011) 122:664–71. 10.1016/j.clinph.2010.09.021 PubMed DOI PMC

Engel J, Jr, da Silva FL. High-frequency oscillations - where we are and where we need to go. Prog Neurobiol. (2012) 98:316–8. 10.1016/j.pneurobio.2012.02.001 PubMed DOI PMC

Fedele T, Burnos S, Boran E, Krayenbühl N, Hilfiker P, Grunwald T, et al. . Resection of high frequency oscillations predicts seizure outcome in the individual patient. Sci Rep. (2017) 7:13836. 10.1038/s41598-017-13064-1 PubMed DOI PMC

Frauscher B, Bartolomei F, Kobayashi K, Cimbalnik J, van't Klooster MA, Rampp S, et al. . High-frequency oscillations: the state of clinical research. Epilepsia. (2017) 58:1316–29. 10.1111/epi.13829 PubMed DOI PMC

Matsumoto A, Brinkmann BH, Matthew Stead S, Matsumoto J, Kucewicz MT, Marsh WR, et al. . Pathological and physiological high-frequency oscillations in focal human epilepsy. J Neurophysiol. (2013) 110:1958–64. 10.1152/jn.00341.2013 PubMed DOI PMC

Cimbalnik J, Brinkmann B, Kremen V, Jurak P, Berry B, Van Gompel J, et al. . Physiological and pathological high frequency oscillations in focal epilepsy. Ann Clin Transl Neurol. (2018) 5:1062–76. 10.1002/acn3.618 PubMed DOI PMC

Buzsáki G, da Silva FL. High frequency oscillations in the intact brain. Prog Neurobiol. (2012) 98:241–9. 10.1016/j.pneurobio.2012.02.004 PubMed DOI PMC

Bragin A, Engel J, Staba RJ. High-frequency oscillations in epileptic brain. Curr Opin Neurol. (2010) 23:151–6. 10.1097/WCO.0b013e3283373ac8 PubMed DOI PMC

Jacobs J, Zijlmans M, Zelmann R, Chatillon C-É, Hall J, Olivier A, et al. High-frequency electroencephalographic oscillations correlate with outcome of epilepsy surgery. Ann Neurol. (2010) 67:209–20. 10.1002/ana.21847 PubMed DOI PMC

Serafini R. Similarities and differences between the interictal epileptiform discharges of green-spikes and red-spikes zones of human neocortex. Clin Neurophysiol. (2019) 130:396–405. 10.1016/j.clinph.2018.12.011 PubMed DOI

Klimes P, Duque JJ, Brinkmann B, Van Gompel J, Stead M, St Louis EK, et al. . The functional organization of human epileptic hippocampus. J Neurophysiol. (2016) 115:3140–5. 10.1152/jn.00089.2016 PubMed DOI PMC

Zweiphenning WJEM, van't Klooster MA, van Diessen E, van Klink NEC, Huiskamp GJM, Gebbink TA, et al. . High frequency oscillations and high frequency functional network characteristics in the intraoperative electrocorticogram in epilepsy. Neuroimage Clin. (2016) 12:928–39. 10.1016/j.nicl.2016.09.014 PubMed DOI PMC

Chen D, Wan S, Bao FS. Epileptic focus localization using discrete wavelet transform based on interictal intracranial EEG. IEEE Trans Neural Syst Rehabil Eng. (2017) 25:413–25. 10.1109/TNSRE.2016.2604393 PubMed DOI

Varatharajah Y, Berry B, Cimbalnik J, Kremen V, Van Gompel J, Stead M, et al. . Integrating artificial intelligence with real-time intracranial EEG monitoring to automate interictal identification of seizure onset zones in focal epilepsy. J Neural Eng. (2018) 15:046035. 10.1088/1741-2552/aac960 PubMed DOI PMC

Cimbalnik J, Klimes P, Sladky V, Nejedly P, Jurak P, Pail M, et al. . Multi-feature localization of epileptic foci from interictal, intracranial EEG. Clin Neurophysiol. (2019) 130:1945–53. 10.1016/j.clinph.2019.07.024 PubMed DOI PMC

Klimes P, Cimbalnik J, Brazdil M, Hall J, Dubeau F, Gotman J, et al. . NREM sleep is the state of vigilance that best identifies the epileptogenic zone in the interictal electroencephalogram. Epilepsia. (2019) 60:2404–15. 10.1111/epi.16377 PubMed DOI

Polich J. Updating P300: an integrative theory of P3a and P3b. Clin Neurophysiol. (2007) 118:2128–48. 10.1016/j.clinph.2007.04.019 PubMed DOI PMC

Albares M, Lio G, Criaud M, Anton JL, Desmurget M, Boulinguez P. The dorsal medial frontal cortex mediates automatic motor inhibition in uncertain contexts: evidence from combined fMRI and EEG studies. Hum Brain Mapp. (2014) 35:5517–31. 10.1002/hbm.22567 PubMed DOI PMC

Shaw DJ, Czekóová K, Staněk R, Mareček R, Urbánek T, Špalek J, et al. . A dual-fMRI investigation of the iterated Ultimatum Game reveals that reciprocal behaviour is associated with neural alignment. Sci Rep. (2018) 8:10896. 10.1038/s41598-018-29233-9 PubMed DOI PMC

Näätänen R, Paavilainen P, Rinne T, Alho K. The mismatch negativity (MMN) in basic research of central auditory processing: a review. Clin Neurophysiol. (2007) 118:2544–90. 10.1016/j.clinph.2007.04.026 PubMed DOI

Duncan CC, Barry RJ, Connolly JF, Fischer C, Michie PT, Näätänen R, et al. . Event-related potentials in clinical research: guidelines for eliciting, recording, and quantifying mismatch negativity, P300, and N400. Clin Neurophysiol. (2009) 120:1883–908. 10.1016/j.clinph.2009.07.045 PubMed DOI

Higuchi Y, Seo T, Miyanishi T, Kawasaki Y, Suzuki M, Sumiyoshi T. Mismatch negativity and p3a/reorienting complex in subjects with schizophrenia or at-risk mental state. Front Behav Neurosci. (2014) 8:172 10.3389/fnbeh.2014.00172 PubMed DOI PMC

Kucewicz MT, Cimbalnik J, Matsumoto JY, Brinkmann BH, Bower MR, Vasoli V, et al. High frequency oscillations are associated with cognitive processing in human recognition memory. Brain. (2014) 137:2231–44. 10.1093/brain/awu149 PubMed DOI PMC

Rehulka P, Cimbálník J, Pail M, Chrastina J, Hermanová M, Brázdil M. Hippocampal high frequency oscillations in unilateral and bilateral mesial temporal lobe epilepsy. Clin Neurophysiol. (2019) 130:1151–9. 10.1016/j.clinph.2019.03.026 PubMed DOI

Barkmeier DT, Shah AK, Flanagan D, Atkinson MD, Agarwal R, Fuerst DR, et al. . High inter-reviewer variability of spike detection on intracranial EEG addressed by an automated multi-channel algorithm. Clin Neurophysiol. (2012) 123:1088–95. 10.1016/j.clinph.2011.09.023 PubMed DOI PMC

Urrestarazu E, Chander R, Dubeau F, Gotman J. Interictal high-frequency oscillations (100-500 Hz) in the intracerebral EEG of epileptic patients. Brain. (2007) 130:2354–66. 10.1093/brain/awm149 PubMed DOI

Jacobs J, Levan P, Châtillon C-E, Olivier A, Dubeau F, Gotman J. High frequency oscillations in intracranial EEGs mark epileptogenicity rather than lesion type. Brain. (2009) 132:1022–37. 10.1093/brain/awn351 PubMed DOI PMC

Nagasawa T, Juhász C, Rothermel R, Hoechstetter K, Sood S, Asano E. Spontaneous and visually driven high-frequency oscillations in the occipital cortex: intracranial recording in epileptic patients. Hum Brain Mapp. (2012) 33:569–83. 10.1002/hbm.21233 PubMed DOI PMC

Pail M, Rehulka P, Cimbálník J, DoleŽalová I, Chrastina J, Brázdil M. Frequency-independent characteristics of high-frequency oscillations in epileptic and non-epileptic regions. Clin Neurophysiol. (2017) 128:106–14. 10.1016/j.clinph.2016.10.011 PubMed DOI

Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG? Lancet Neurol. (2003) 2:725–30. 10.1016/S1474-4422(03)00584-2 PubMed DOI

Brázdil M, Cimbálník J, Roman R, Shaw DJ, Stead MM, Daniel P, et al. . Impact of cognitive stimulation on ripples within human epileptic and non-epileptic hippocampus. BMC Neurosci. (2015) 16:47. 10.1186/s12868-015-0184-0 PubMed DOI PMC

Warren CP, Hu S, Stead M, Brinkmann BH, Bower MR, Worrell GA. Synchrony in normal and focal epileptic brain: the seizure onset zone is functionally disconnected. J Neurophysiol. (2010) 104:3530–9. 10.1152/jn.00368.2010 PubMed DOI PMC

High frequency oscillations in human memory and cognition: a neurophysiological substrate of engrams?

Weak coupling of neurons enables very high-frequency and ultra-fast oscillations through the interplay of synchronized phase shifts

Leveraging electrophysiologic correlates of word encoding to map seizure onset zone in focal epilepsy: Task-dependent changes in epileptiform activity, spectral features, and functional connectivity