Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG\u2013fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory\u2013motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG\u2013fMRI coregistration. During the \u201cawake session\u201d, fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory\u2013motor cortex. During the \u201csleep session\u201d, BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical\u2013subcortical network involving the thalamus, basal ganglia, sensory\u2013motor cortex, perisylvian cortex, and cerebellum.

In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical\u2013subcortical network related to CTS. In particular, the involvement of a thalamic\u2013perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication

Avanzini P

Benuzzi F

Cantalupo G

Cossu G

Meletti S

Mirandola L

Nichelli PF

Pisani F

Ruggieri A

Tassinari CA

Vaudano AE

Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG-fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory-motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG-fMRI coregistration. During the "awake session", fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory-motor cortex. During the "sleep session", BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical-subcortical network involving the thalamus, basal ganglia, sensory-motor cortex, perisylvian cortex, and cerebellum.In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical-subcortical network related to CTS. In particular, the involvement of a thalamic-perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication. © 2013 The Authors

Mirandola L.

Cantalupo G.

Vaudano A. E.

Avanzini P.

Ruggieri A.

Pisani F.

Cossu G.

Tassinari C. A.

Nichelli P. F.

Benuzzi F.

Meletti S.

Archivio della ricerca- Università di Roma La Sapienza

Centrotemporal spikes during NREM sleep: The promoting action of thalamus revealed by simultaneous EEG and fMRI coregistration

Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG–fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory–motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG–fMRI coregistration. During the “awake session”, fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory–motor cortex. During the “sleep session”, BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical–subcortical network involving the thalamus, basal ganglia, sensory–motor cortex, perisylvian cortex, and cerebellum.

In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical–subcortical network related to CTS. In particular, the involvement of a thalamic–perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication

CANTALUPO, Gaetano

Catalogo dei prodotti della ricerca

Epilepsy & Behavior Case Reports 1 (2013) 106–109Contents lists available at ScienceDirectEpilepsy & Behavior Case Reportsj ourna l homepage: www.e lsev ie r .com/ locate /ebcrCase ReportCentrotemporal spikes during NREM sleep: The promoting action ofthalamus revealed by simultaneous EEG and fMRI coregistration☆Laura Mirandola a, Gaetano Cantalupo b,c, Anna Elisabetta Vaudano a, Pietro Avanzini a,d, Andrea Ruggieri a,Francesco Pisani b, Giuseppe Cossu b,d, Carlo Alberto Tassinari d, Paolo Frigio Nichelli a,Francesca Benuzzi a, Stefano Meletti a,⁎a Department of Biomedical Sciences, Metabolism, and Neuroscience, University of Modena and Reggio Emilia, Italyb Child Neuropsychiatry Unit, Department of Neuroscience, University-Hospital of Parma, Italyc Department of Life and Reproduction Sciences, University of Verona, Italyd Department of Neuroscience, University of Parma, ItalyAbbreviations: CTS, centrotemporal spikes; BECTS, benispikes; BOLD, blood oxygen level dependent; ESI, EEG sourcepilepticus in sleep.⁎ Corresponding author at: Department of BiomediNeuroscience, University of Modena and Reggio Emilia,1355, 41126 Modena, Italy. Fax: +39 0513961336.E-mail address: stefano.meletti@unimore.it (S. Mele2213-3232 © 2013 The Authors Published by Elsevierhttp://dx.doi.org/10.1016/j.ebcr.2013.06.005a b s t r a c ta r t i c l e i n f oArticle history:Received 31 March 2013Received in revised form 18 June 2013Accepted 21 June 2013Available online 27 July 2013Keywords:EEG–fMRIBECTSESESThalamusSleepBenign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG–fMRIwith the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation ofthe sensory–motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigatedthe brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy withCTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG–fMRIcoregistration. During the “awake session”, fMRI analysis of right-sided CTS showed increments of BOLD sig-nal in the bilateral sensory–motor cortex. During the “sleep session”, BOLD increments related to right-sidedCTS were observed in a widespread bilateral cortical–subcortical network involving the thalamus, basalganglia, sensory–motor cortex, perisylvian cortex, and cerebellum.In this patient, who fulﬁlled neither the diagnostic criteria for BECTS nor that for electrical status epilepticusin sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespreadcortical–subcortical network related to CTS. In particular, the involvement of a thalamic–perisylvian neuralnetwork similar to the one previously observed in patients with ESES suggests a common sleep-relatednetwork dysfunction even in cases with milder phenotypes without seizures. This ﬁnding, if conﬁrmed in alarger cohort of patients, could have relevant therapeutic implication.© 2013 The Authors. Published by Elsevier Inc. Open access under CC BY-NC-ND license.1. IntroductionBenign childhood epilepsy with centrotemporal spikes (BECTS) isan idiopathic focal epilepsy characterized by distinctive interictal EEGparoxysms over rolandic regions, age-dependent onset, and benigncourse [1]. The rolandic or centrotemporal spikes (CTS) show charac-teristic waveform features and are signiﬁcantly enhanced duringNREM sleep [2]. The increase of CTS frequency during slow-wavesleep might cause the worsening in language and executive functions,gnepilepsywith centrotemporale imaging; ESES, electrical statuscal Sciences, Metabolism andNOCSAE Hospital, via Giardinitti)..Inc Open access under CC BY-NC-ND las observed in patients with atypical BECTS and in electrical statusepilepticus during sleep (ESES) [3]. In this respect, the study of thebrain networks involved by CTS while awake and asleep in thesame patient is an intriguing, still open question. It is reasonable tohypothesize that different networks might be triggered by CTS duringsleep, in relation to changes in the patient's level of vigilance. We ex-pect that CTS in sleep may involve extra sensory–motor networks andespecially subcortical, namely thalamic, structures [4].To address these issues, we present the case of a 13-year-old boywith moderate language impairment and CTS who underwent EEG–fMRI coregistration and EEG source imaging (ESI) during bothawake and asleep periods. Notably, the patient came to our attentionbecause he had language disorder/learning difﬁculties, and, at thetime of the study, no overt seizure occurred.2. Patient and methodsA13-year-old right-handed boywas referred to our center for inves-tigating school difﬁculties. His past medical history, including birth anddevelopment milestones, was unremarkable. The patient's familyicense.107L. Mirandola et al. / Epilepsy & Behavior Case Reports 1 (2013) 106–109history shows three paternal cousins affected by a benign form of epi-lepsy not otherwise speciﬁed. At the neuropsychological assessment, adiscrepancy in the linguistic (mildly deﬁcient) and nonlinguistic func-tions (normal) was found, and moderate-learning difﬁculties in read-ing, writing, and calculation emerged.The patient underwent scalp EEG while awake and asleep, demon-strating the presence of CTS occurring independently in the right andleft hemispheres which were signiﬁcantly increased during slow-wave sleep (Fig. 1A–B). A complete overnight video-EEG recording con-ﬁrmed an increase in CTS frequency during non-REM sleep but withoutreaching the criteria for ESES (spike index N 85%).2.1. EEG–fMRI acquisitionCentrotemporal spikes were recorded in the patient, who wassleep-deprived from the previous night, in the late afternoon. ScalpEEG was recorded by means of a 32-channel MRI-compatible EEGrecording system (Micromed, Italy). A simultaneously recorded videoduring the EEG–fMRI acquisition allowed checking patient's behaviorand changes in vigilance states. Functional magnetic resonance imagingdata (200 volumes, 30 axial slices, TR/TE = 3000/50 ms)were acquiredover three 10-min sessions with simultaneous EEG recording using aFig. 1. Patient's EEG trace while awake and asleep and ESI results. Panel A: representative pagright hemispheres are evident. Panel B: representative page of the EEG recorded during sleappear isolated or in brief discharges, synchronous or asynchronous over the two hemisphmontage. Panel C: spike averaging and topographic map related to the left CTS events (topthe left sensory–motor cortex. The electric potential ﬁeld used by the sLORETA software wThe MNI brain volume was scanned at 5-mm resolution obtaining a source space of 6239 co(in [A/m2]) for each of the cortical voxels, indicating the MNI coordinates of the best ﬁt, i.epographic map related to the right CTS events (top image); ESI (bottom image) related toPhilips Intera System 3T. A high-resolution T1-weighted anatomicalimage was obtained for anatomical reference (170 sagittal slices,TR/TE = 9.9/4.6 ms).The Human Ethic Committee of the University of Modena andReggio Emilia approved the study, and written consent was obtained.2.2. EEG and fMRI analysisOff-line analysis of the EEG was performed by means of theBrainVision Analyzer 2.0 software (Brain Products, Munich, Germany).The detection of sleep stages was deﬁned based on the presence ofsleep spindles and K-complexes and conﬁrmed by the video record.Functional magnetic resonance imaging data were preprocessed andanalyzed using SPM8 (http://www.ﬁl.ion.ucl.ac.uk/spm/). Two separateanalyses were performed: the ﬁrst related to CTS during wakefulnessand the second related to CTS during the sleep phase. Centrotemporalspikes were visually marked and served as onsets for a general linearmodel (GLM) convolved with the standard hemodynamic responsefunction (HRF), its temporal (TD) and dispersion derivatives (DD). Forthe sleep-related fMRImaps, K-complex and spindleswere visually iden-tiﬁed andmarked according to the criteria of Rechtschaffen andKales [5].The onset of K-complexes and spindleswas included in the general lineare of the EEG during wakefulness. Rare independently and isolated CTS from the left andep (phase 2 NREM). Note the increase in CTS frequency compared to wakefulness. CTSeres. Sleep spindles and vertex spike are evident. The EEG traces are shown in bipolarimage); ESI (bottom image) related to the left CTS demonstrates a main source overas computed using the boundary element method applied to the MNI152 template.rtical gray matter voxels. The sLORETA algorithm returns the current density measure., the voxel with the maximum current density value. Panel D: Spike averaging and to-the right CTS demonstrates a main source over the right sensory–motor cortex.108 L. Mirandola et al. / Epilepsy & Behavior Case Reports 1 (2013) 106–109model (GLM) as a separate regressor. Functional magnetic resonanceimaging scan time series realignment parameters were used to modelthe nuisance effects of motion. One-tailed t-test was applied to test forregional BOLD increases or decreases in relationship to the CTS. The com-puted SPM{T} was thresholded at P b 0.05 (FWE corrected). Resultswere superimposed onto the individual high-resolution T1-weightedimages normalized into the MNI space.EEG source imaging (ESI) analysis of CTS recorded during scan-ning was performed with 3D sLORETA (standardized low resolutionbrain electromagnetic tomography). The equivalent source currentdensity for each spike was estimated using component topographiesas input data.3. ResultsDuring the ﬁrst 10-min session, the patient was awake and 69 CTS(6.9 spikes/min) were identiﬁed: 47 from the right hemisphere and 22from the left. During the second and third sessions, the patient fell asleep,reaching phase two of NREM sleep, and 249 CTS (12.5 spikes/min) wereobserved: 191 from the right hemisphere and 58 from the left.3.1. EEG source imagingSpike averaging and localization results of CTS during wakefulnessand sleep are displayed in Fig. 1C–D. EEG source imaging analysisshowed the involvement of the sensory–motor cortex ipsilateral toCTS, both during awake and asleep periods.3.2. EEG–fMRI studyDuring the “awake session”, fMRI analysis of right-sided CTS showedincrements of BOLD signal in the bilateral sensory–motor cortex (Fig. 2,Fig. 2. EEG–fMRI results. Left panel.Wakefulness: A color-coded overlay of SPM{T} (red: posimultiple comparison) onto the patient's T1 slice overlay showing BOLD signal increases relatCTS and a decrease in clusters for both right and left CTS were not detected. Right panel. “Sleeresponse)-HRF related (P b 0.05 corrected for multiple comparison) onto the patient's T1 sthalamus, basal ganglia, sensory–motor cortex, perisylvian cortex, paracentral lobule, cingustrate any signiﬁcant hemodynamic changes both in the awake and asleep sessions. No BOleft panel). No BOLD signal changes were detected for left-sided CTS.During the “sleep session”, BOLD increments related to right-sidedCTS were observed in a widespread bilateral cortical–subcortical net-work involving the thalamus, basal ganglia, sensory–motor cortex,perisylvian cortex, paracentral lobule, anterior cingulated cortex, andcerebellum (Fig. 2, right panel). The same results were obtained in rela-tion to the left-sided CTS, although with less statistical power (notshown). No decrements in BOLD signal were detected in both sessions.4. DiscussionThe main ﬁnding of the study is that EEG–fMRI data analysis ofCTS recorded from the same patient while awake and asleep revealeddifferent hemodynamic networks. In particular, sleep-related fMRImaps showed the involvement of a wide network including the thal-amus. Conversely, the hemodynamic changes observed during the“awake state” covered the sensory–motor cortex, concordant withESI results and with previous EEG–fMRI studies. Indeed, fMRI dataanalysis in typical BECTS revealed, in most cases, a cortical activationlimited to the sensory–motor cortex ipsilateral to CTS [6–9].Our data conﬁrm the involvement of thalamocortical neurons inthe promotion of CTS during NREM sleep. These ﬁndings are not sur-prising if we consider that the facilitation of CTS during NREM sleep isdue to two different thalamic mechanisms of synchronization thatlead to the appearance of spindles and delta waves on the EEG [4].The activating properties of these two mechanisms on CTS genera-tions have been demonstrated through animal experimental data[10] and also in humans by means of EEG spectral analysis [11]. Inparticular, a high signiﬁcant correlation between CTS and sigma activ-ity has been observed in BECTS, suggesting that CTS are sensitive tothe promoting action of the spindle-generating mechanisms [4,11].tive BOLD response; blue: negative BOLD response)-HRF related (P b 0.05 corrected fored to right CTS in the bilateral sensory–motor cortex. BOLD signal changes for left-sidedp”: A color-coded overlay of SPM{T} (red: positive BOLD response; blue: negative BOLDlice overlay showing BOLD signal increases related to right CTS involving the bilaterallated cortex, and cerebellum. fMRI data analysis regarding TD and DD did not demon-LD signal decreases were detected.109L. Mirandola et al. / Epilepsy & Behavior Case Reports 1 (2013) 106–109Previous EEG–fMRI studies in patients classiﬁed as having purelyBECTS did not show the cortical–subcortical network observed inour case while asleep [6–9]. On the contrary, in our patient, we ob-served fMRI activation of the thalamus and of the bilateral perisylvianregions, including the ﬁrst temporal gyrus, suggesting that theseareas could be functionally altered. Notably, this ﬁnding could be re-lated to the clinical picture of the patient who could not fulﬁll theclear diagnostic criteria for BECTS or for ESES, falling into the categoryof patients with CTS and a learning/language disorder.Interestingly, these results are similar to the ones observed byEEG–fMRI analysis in patients with ESES [12], supporting the exis-tence of a common sleep-related network dysfunction even in caseswith milder phenotypes.Recently, the term “intermediate epilepsy-aphasia disorder” hasbeen proposed to classify those patients showing a combination ofabnormal cognitive development (predominantly affecting languagefunction), with or without clinical seizures, and sleep activation offocal epileptiform discharges not fulﬁlling the electroclinical criteriafor BECTS, Landau–Kleffner syndrome, or ESES but considered tohave a place within the spectrum [13]. In this context, the possibilityof demonstrating, by means of fMRI, a network dysfunction in pa-tients with CTS and moderate cognitive impairment, like our patient,may represent a chance to identify these patients in early stages. Ourwork hence provides evidence for a potential diagnostic value of theEEG–fMRI studies as a marker of atypical BECTS.Finally, the information obtained by the EEG–fMRI technique addsvalue to the theory that idiopathic focal epilepsies result from a dys-function of distributed neuronal systems extending beyond a focal cor-tical seed but involving thalamic and thalamocortical circuits that showa hyperexcitable condition as a whole [14]. Of course, further studies ona larger cohort of patients are needed to conﬁrm this hypothesis.Acknowledgments and fundingAuthor RA was supported by a PhD bursary from the University ofModena and Reggio Emilia. Author AEV was supported by a researchbursary from the grant “Ricerca Internazionale 2010” of “FondazioneCassa di Risparmio di Modena”.References[1] Commission on Classiﬁcation and Terminology of the International LeagueAgainst Epilepsy. Proposal for classiﬁcation of epilepsies, epileptic syndromesand related disorders. Epilepsia 1989;30:389–99.[2] Baumgartner C, Graf M, Doppelbauer A, Serles W, Lindinger G, Olbrich A, et al. Thefunctional organization of the interictal spike complex in benign rolandic epilepsy.Epilepsia 1996;37:1164–74.[3] Tassinari CA, Cantalupo G, Dalla Bernardina B, Darra F, Bureau M, Cirelli C, et al.Encephalopathy related to status epilepticus during slow sleep (ESES) includingLandau–Kleffner syndrome. In: Bureau M, Genton P, Dravet C, Delgado-Escueta A,Tassinari CA, Thomas P, et al, editors. Epileptic syndromes in infancy, childhood andadolescence. 5th ed. Montrouge, France: John Libbey Eurotext Ltd.; 2012. p. 255–75.[4] Nobili L, Baglietto MG, Beelke M, De Carli F, De Negri E, Gaggero R, et al. Distribu-tion of epileptiform discharges during nREM sleep in the CSWSS syndrome: rela-tionship with sigma and delta activities. Epilepsy Res 2001;44:119–28.[5] Rechtschaffen A, Kales A. Terminology. In: Rechtschaffen A, Kales A, editors. Amanual of standardized terminology, techniques and scoring system of sleepstages in human subjects. Los Angeles: BIS/BRI; 1968. p. 1–2.[6] Archer JS, Briellman RS, Abbott DF, Syngeniotis A, Wellard RM, Jackson GD. Benignepilepsy with centro-temporal spikes: spike triggered fMRI shows somato-sensorycortex activity. Epilepsia 2003;44:200–4.[7] Boor S, Vucurevic G, Pﬂeiderer C, Stoeter P, Kutschke G, Boor R. EEG-related func-tional MRI in benign childhood epilepsy with centrotemporal spikes. Epilepsia2003;44:688–92.[8] Boor R, Jacobs J, Hinzmann A, Bauermann T, Scherg M, Boor S, et al. Combinedspike-related functional MRI and multiple source analysis in the non-invasivespike localization of benign rolandic epilepsy. Clin Neurophysiol 2007;118:901–9.[9] Masterton RAJ, Harvey AS, Archer JS, Lillywhite LM, Abbott DA, Scheffer IE, et al.Focal epileptiform spikes do not show a canonical BOLD response in patientswith benign rolandic epilepsy (BECTS). Neuroimage 2010;51:252–60.[10] Steriade M, Contreras D, Amzica F. Synchronized sleep oscillations and their par-oxysmal developments. Trends Neurosci 1994;17:199–208.[11] Nobili L, Ferrillo F, Baglietto MG, Beelke M, De Carli F, De Negri E, et al. Relation-ship of sleep interictal epileptiform discharges to sigma activity (12–16 Hz) inbenign epilepsy of childhood with rolandic spikes. Clin Neurophysiol 1999;110:39–46.[12] SiniatchkinM, GroeningM,Moehring J,Moeller F, Boor R, Brodbeck V, et al. Neuronalnetworks in children with continuous spikes and waves during slow sleep. Brain2010;133:2798–813.[13] Tsai MH, Vears DV, Turner SJ, Smith RL, Berkovic SL, Sadleir LG, et al. Clinicalgenetic study of the epilepsy-aphasia spectrum. Epilepsia 2013;54:280–7.[14] Avanzini G, Manganotti P, Meletti S, Moshé SL, Panzica F, Wolf P, et al. The systemepilepsies: a pathophysiological hypothesis. Epilepsia 2012;53:771–8.

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Centrotemporal spikes during NREM sleep: The promoting action of thalamus revealed by simultaneous EEG and fMRI coregistration

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