ARTICLE IN PRESS+ModelEPIRES-5130; No. of Pages 11

Epilepsy Research (2014) xxx, xxx—xxx

jo ur nal ho me p ag e: www.elsev ier .com/ locate /ep i lepsyres

Default mode network hypometabolism inepileptic encephalopathies with CSWS

Noémie Ligota, Frédérique Archambaudb,c,d, Nicola Trottaa,Serge Goldmana, Patrick Van Bogaerta, Catherine Chironb,d,e,Xavier De Tiègea,∗

a Laboratoire de Cartographie fonctionnelle du Cerveau (LCFC), UNI — ULB Neuroscience Institute,Université libre de Bruxelles (ULB), Brussels, Belgiumb Inserm U1129, Paris, Francec Université Paris Sud, Franced CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, Francee Université Paris Descartes, France

Received 4 December 2013; received in revised form 12 February 2014; accepted 16 March 2014

KEYWORDSContinuousspike-wave duringsleep;Positron emissiontomography;Default modenetwork;Thalamus;Age-related changes;Cerebral glucose

Summary Previous studies investigating cerebral metabolic changes associated with continu-ous spike-waves during sleep (CSWS) compared the metabolism of children with CSWS with thatof healthy adults, precluding any assessment in brain areas showing physiologic age-relatedmetabolic changes. Here, we investigated the metabolic and connectivity changes character-izing the acute phase of CSWS activity by comparing awake brain metabolism of children withCSWS with that of pediatric pseudo-controls.

Positron emission tomography using [18F]-fluorodeoxyglucose (FDG-PET) was performed in 17awake children with cryptogenic CSWS (5 girls, age: 5—11 years). Voxel-based analyses identifiedsignificant metabolic changes in CSWS patients compared with 18 pediatric pseudo-controls(12 girls, age: 6—11 years, non-CSWS focal cryptogenic epilepsy with normal FDG-PET). CSWS-induced changes in the contribution of brain areas displaying metabolic changes to the level of

metabolism metabolic activity in other brain areas were investigated using pathophysiological interaction.Hypermetabolism in perisylvian regions bilaterally and hypometabolism in lateral and mesial

prefrontal cortex, precuneus, posterior cingulate cortex and parahippocampal gyri character-

Please cite this article in press as: Ligot, N., et al., Default mode network hypometabolism in epileptic encephalopathieswith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.03.014

ized the acute phase of CSWS (p < 0.05 FWE). No change in thalamic metabolism was disclosed.Altered functional connectivity was found between hyper- and hypometabolic regions in CSWSpatients compared with pediatric pseudo-controls.

∗ Corresponding author at: Laboratoire de Cartographie fonctionnelle du Cerveau (LCFC), UNI — ULB Neuroscience Institute, Universitélibre de Bruxelles (ULB), 808 Lennik Street, Brussels, Belgium. Tel.: +32 2 555 89 62; fax: +32 2 555 47 01.

E-mail address: xdetiege@ulb.ac.be (X. De Tiège).

http://dx.doi.org/10.1016/j.eplepsyres.2014.03.0140920-1211/© 2014 Elsevier B.V. All rights reserved.

ARTICLE IN PRESS+ModelEPIRES-5130; No. of Pages 11

2 N. Ligot et al.

This study demonstrates hypometabolism in key nodes of the default mode network (DMN) inawake patients with CSWS, in relation with a possible phenomenon of sustained remote inhibitionfrom the epileptic foci. This hypometabolism might account for some of the acquired cognitiveor behavioral features of CSWS epileptic encephalopathies. This study failed to find any evidenceof thalamic metabolic changes, which supports the primary involvement of the cortex in CSWSgenesis.© 2014 Elsevier B.V. All rights reserved.

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pileptic encephalopathies are conditions in which thepileptic activity itself contributes to severe cognitiver behavioral impairments above and beyond what mighte expected from the underlying cause of epilepsy (Bergt al., 2010). The epileptic encephalopathies with contin-ous spike-waves during sleep (CSWS) are considered as arototype of these epileptic conditions (Holmes and Lenck-antini, 2006; Nabbout and Dulac, 2003). They are indeedge-related conditions in which epileptic EEG activity occur-ing almost exclusively during sleep and for prolongederiods of time leads to heterogeneous acquired neuropsy-hological and behavioral disturbances during the awaketate (for reviews, see Van Bogaert, 2013).

Previous positron emission tomography with [18F]-uorodeoxyglucose (FDG-PET) studies performed during thewake state in patients with CSWS have demonstrated longasting changes in brain function characterized by the asso-iation of focal increase in metabolism at the onset(s)r propagation(s) sites of CSWS activity and decreases ineuronal activity in distant associative cortical areas notrimarily involved in CSWS activity (De Tiège et al., 2004,006, 2008, 2013). One pathophysiological model proposedo explain these findings is based on the ‘‘surroundingnd remote inhibition theory’’, which suggests the exist-nce of inhibition of neurons that surround or are remotelyonnected to the hypermetabolic epileptic focus via cortico-ortical or polysynaptic pathways (for a review, see De Tièget al., 2009). These data also incite to attribute the neuro-ogical regression not only to neuronal impairment at thepileptic focus site, but also to epilepsy-induced neuro-hysiological changes in distant and connected brain areasDe Tiège et al., 2004, 2006, 2008, 2013).

Although previous FDG-PET studies contributed to thenderstanding of epileptic encephalopathies with CSWSathophysiology, the interpretation of their results wasimited by the use of a control group of young healthy adultsor the voxel-based statistical assessment of metabolic andonnectivity changes (De Tiège et al., 2004, 2006, 2008,013). This limitation was due to obvious ethical constraints,hich preclude FDG-PET data acquisition in healthy chil-ren. The comparison of FDG-PET data obtained in childrenith CSWS with that of an adult control group indeed

mpeded any assessment in brain areas with physiologic age-elated metabolic changes such as the thalamus, cingulater mesial cortical areas (De Tiège et al., 2004, 2008, 2013;

Please cite this article in press as: Ligot, N., et al., Default modwith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.

an Bogaert et al., 1998). However, several experimen-al evidences coming from functional magnetic resonancemaging combined with EEG (EEG-fMRI) suggest the exist-nce of transient changes in neuronal activity within those

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rain regions during CSWS activity (De Tiège et al., 2007;iniatchkin et al., 2010). In addition, the thalamus is con-idered as playing a key role in the pathophysiology ofSWS considering the neurophysiological activity changesithin the thalamocortical network associated with slow

leep (Maquet et al., 1995; Siniatchkin et al., 2010; Steriade,005, 2006) and the potential association between perinatalhalamic ischemic lesions and CSWS activity (Guzzetta et al.,005; Sanchez Fernandez et al., 2012). Therefore, to fullyharacterize the pathophysiology of CSWS syndromes andheir associated diurnal cognitive and behavioral regression,t appeared essential to determine if CSWS activity is asso-iated with sustained changes in metabolic activity withinhose regions.

Here, we reanalyzed awake FDG-PET data obtained in large group of children with CSWS by comparing themith a pediatric pseudo-control group composed of chil-ren with non-CSWS cryptogenic refractory focal epilepsyArchambaud et al., 2013) in order to investigate theetabolic and connectivity changes characterizing the

cute phase of CSWS. The main purpose of this compari-on was to identify the metabolic abnormalities associatedith CSWS activity.

ethods

atients and control subjects

mong the 39 patients with an epileptic encephalopathyith CSWS studied by FDG-PET at the ULB-Hôpital Erasme

Brussels, Belgium) between November 1999 and April 2010, group of 17 children (12 boys and 5 girls, mean age: 7.4ears, age range: 5—11 years) was retrospectively selectedased on the following inclusion criteria: (1) normal struc-ural cerebral MRI, (2) FDG-PET performed at the acutehase of CSWS, and (3) significant local hypermetabolismn FDG-PET based on voxel-based analysis of individualDG-PET data (see below). Only patients with local hyper-etabolism were included in this study as this metabolic

bnormality represents the hallmark of the acute phasef CSWS and its absence probably reflects an evolutionoward the recovery phase of CSWS (De Tiège et al., 2004,008). Furthermore, only patients with normal MRI wereelected for this study in order to avoid any confounding

e network hypometabolism in epileptic encephalopathieseplepsyres.2014.03.014

ounger than 5 years old were not included in order tovoid any FDG-PET normalization artifact as we used theNI (adult) template for normalization (see below). Fouratients were rejected because they only had regional

ARTICLE IN PRESS+ModelEPIRES-5130; No. of Pages 11

Epileptic encephalopathies with CSWS 3

Table 1 Summary of clinical, treatment and EEG data.

Patient Sex/agea/syndrome

AED (mg/kg/day) Neuropsychology EEG during PET 1

1 M/5/LKS None pIQ (Leiter): 93 Frequent IEDs (C3, C4)2 M/5/LKS None pIQ (WISC): 112 Rare IEDs (C3, C4)3 F/6/LKS CB (1) pIQ (WPPSI): 72 Frequent IEDs (C3, T4)4 M/8/LKS VPA (30), LEV (50) pIQ (Leiter): 75 Rare IEDs (T3, T4)5 M/8/LKS None pIQ (SON-R): 109 Frequent IEDs (T3, T4)6 M/9/LKS HC (0.8), CZP (0.1) IQ: NA Rare IEDs (T3)7 M/10/LKS LTG (5), OXC (30) IQ: NA Frequent IEDs (C3, C4)8 F/8/GMD VPA (20) pIQ (Leiter):50 Episodic IEDs (C3, C4)9 F/8/GMD LTG (3), LEV (45) pIQ (WISC): 50 Episodic IEDs (C3, C4)10 M/8/GMD LTG (5) pIQ (WISC): 50 Frequent IEDs (C3, C4, Fp1)11 M/10/GMD LEV (60) pIQ (Leiter): 53 Rare IEDs (C3)12 M/5/FS VPA (35), TPM (3.5) IQ (WPPSI): 89 Episodic IEDs (T3, T4)13 M/5/NDHS VPA (33), CBZ (22) IQ (McCarthy): 78 Episodic IEDs (C4)14 M/6/NDHS TPM (2), LTG (10) pIQ (Leiter): 70 Frequent IEDs (C4)15 M/11/ARE LTG (11), DPH (4) Disinhibition, IQ

(WISC-III): 77Frequent IEDs (C4)

16 F/6/ARE VPA (30) Agitation, impulsivity, IQ(WPPSI): 77

Frequent IEDs (C4)

17 F/8/OS VPA (27), LTG (2) pIQ (Leiter): 63 Frequent IEDs (C3, C4)

AED: antiepileptic drugs, M: male, F: female, LKS: Landau—Kleffner syndrome, FS: frontal syndrome, NDHS: non-dominant hemisphericsyndrome, OS: opercular syndrome, GMD: global mental deterioration, CB: clobazam, VPA: valproate, LEV: levetiracetam, HC: hydro-cortisone, CZP: clonazepam, LTG: lamotrigine, OXC: oxycarbamazepine, TPM: topiramate, CBZ: carbamazepine, DPH: diphantoine, pIQ:

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hypometabolism. All the FDG-PET data used in this studycame from CSWS patients that have been included in pre-vious studies from our group on FDG-PET or therapeutictrials in CSWS, patients’ clinical details can be found inthe respective papers (De Tiège et al., 2004, patients 1,3, 9, 11, 15—18; De Tiège et al., 2008, patients 3—9;Buzatu et al., 2009, patients 3, 5, 9, 10, 11, 14; DeTiège et al., 2013, patients 1—4). All patients underwenta clinical evaluation that included neurological and neu-ropsychological examinations, awake and sleep video-EEGmonitoring performed in the last 24 h preceding FDG-PET,structural cerebral MRI, and FDG-PET. The tests used for theneuropsychological evaluations were adapted to patients’age and collaboration and are detailed in previous papersfrom our groups (De Tiège et al., 2008, 2013). Accord-ing to the neurological and neuropsychological evaluations,six syndromes were considered for patients’ classificationpurpose: Landau—Kleffner syndrome (7 patients) (Landauand Kleffner, 1957), atypical rolandic epilepsy (2 patients)(Tovia et al., 2011), frontal syndrome (1 patient) (RouletPerez et al., 1993; Veggiotti et al., 2001), global mentalretardation (4 patients) (Patry et al., 1971), non-dominanthemisphere syndrome (2 patients) (Maquet et al., 1995),and opercular syndrome (1 patient) (Shafrir and Prensky,1995; Tachikawa et al., 2001). Table 1 summarizes the CSWSpatients’ clinical details.

The ULB-Hôpital Erasme Ethics Committee gave approval

Please cite this article in press as: Ligot, N., et al., Default modwith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.

for conducting this retrospective study. The ULB-HôpitalErasme Ethics Committee waived the requirement forobtaining parents’ written informed consent in the contextof this retrospective study.

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tal epileptic discharges.

A group of 18 pseudo-control children (pediatric pseudo-ontrols, 12 girls and 6 boys, mean age: 9.6 years, ageange: 6—11 years) was selected in a pediatric pseudo-ontrol group previously described by the Service Hospitalierrédéric Joliot (Archambaud et al., 2013) (Orsay, France)o match as close as possible age range and mean of theroup of CSWS patients. This pediatric pseudo-control grouponsisted of 18 children selected among 24 patients withon-CSWS refractory focal epilepsy with negative findingsn MRI and FDG-PET. The use of these FDG-PET data waspproved by the institutional ethical standards committeen human experimentation, and written informed consentas obtained from all guardians of patients participating in

he study.A group of 26 healthy adult volunteers (adult controls,

6 females and 10 males, mean age 28 years, 18—42 years)tudied with FDG-PET at the ULB-Hôpital Erasme was useds an adult control group for FDG-PET data analyses. Thisopulation of adult controls has been used in previous FDG-ET studies from our group (De Tiège et al., 2004, 2006,008, 2013). The ULB-Hôpital Erasme Ethics Committee gavepproval for the PET investigations in adult control subjects.ritten informed consent was obtained from all adult con-

rol subjects.

ET data acquisitions in CSWS patients and adult

e network hypometabolism in epileptic encephalopathieseplepsyres.2014.03.014

ontrols

ET scans were obtained using a CTI-Siemens ECAT 962 (HR+,iemens Medical Solutions, Munich, Germany) tomograph

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ARTICLEPIRES-5130; No. of Pages 11

nstalled at the ULB-Hôpital Erasme (Brussels, Belgium).ll participants were awake at the time of FDG injection,laced with the eye-closed in a quiet dark room, fastedor at least 4 h and received an intravenous bolus injec-ion of 2—3 mCi (74—111 MBq) of FDG before PET acquisitionn 3D mode. They were not sedated for PET data acquisi-ion, which started 30 min after FDG injection. The currentntiepileptic treatment was unchanged. All patients wereree of clinical seizures for at least 72 h. EEG was monitoreduring the PET procedure.

ET data acquisitions in pediatric pseudo-controls

atients were examined using ECAT 962 (HR+, Siemens Med-cal Solutions, Munich, Germany) installed at the Institute ofiomedical Imaging (I2BM, CEA, Service Hospitalier F. Joliot,rsay, France). The patients were investigated in a fastingnd resting state, in a quiet, dimly lit environment. The lasteizure had occurred more than 6 h before PET examinationxcept for 3 patients (between 1 and 6 h in 3). All patientseceived an intravenous bolus injection of 3.7 MBq/kg (max-mum 180 MBq) of FDG while lying in the scanner. Patientsere not sedated for PET data acquisition, which started0 min after FDG injection. EEG was not monitored duringhe procedure. The fact that patients had their last seizureore than 6 h before FDG-PET (except for 3 patients) and

hat EEG was not monitored during FDG incorporation is notn issue since all patients had negative FDG-PET findings.

ET data analyses

ll FDG-PET data were analyzed using SPM8 softwarehttp://www.fil.ion.ucl.ac.uk/spm, Wellcome Departmentf Imaging Neuroscience, London, UK) implemented in Mat-ab 7.1 (Mathworks, Sherborn, MA).

The PET images were first spatially normalized into theNI space and subsequently smoothed using a 16-mm fullidth at half-maximum isotropic kernel. Global activity nor-alization was performed using proportional scaling.Then, subtractive analyses were conducted both at the

ndividual and group levels using the same methodologyhat was previously described (De Tiège et al., 2004,008). Briefly, individual-level analyses first compared PETata of each CSWS patient with those of the pediatricseudo-control group. For these analyses, a design matrixontaining PET data of each CSWS patient and those ofhe pediatric pseudo-controls taken as a group was built.hen, t-contrasts identified brain regions where glucoseetabolism was significantly lower or higher in each CSWSatient than in pediatric pseudo-controls. Group-level anal-ses were subsequently performed to compare (1) PETata of CSWS patients taken as a group with those ofediatric pseudo-controls, (2) PET data of CSWS patientsaken as a group with those of adult controls, and (3) PETata of pediatric pseudo-controls taken as a group withhose of adult controls. For these analyses, a design matrixontaining PET data of CSWS patients, pediatric pseudo-

Please cite this article in press as: Ligot, N., et al., Default modwith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.

ontrols and adult controls taken as separated groups wasuilt. Using this design matrix, t-contrasts first identifiedrain regions where glucose metabolism was significantlyower or higher in CSWS patients than in the pediatric

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seudo-control group. For this analysis, age and sex weresed as covariates of no interest to avoid the poten-ial confounding effects of these variables on the results.hen, t-contrasts identified brain regions where glucoseetabolism was significantly lower or higher in CSWSatients or pediatric pseudo-controls than in the adultontrol group. Subsequently, conjunction analyses (Fristont al., 1999) between CSWS patients versus adult con-rols t-contrasts and pediatric pseudo-controls versus adultontrols t-contrasts were performed to identify metabolichanges characterizing both pediatric populations.

Finally, we searched for pathophysiological interactionsPathoPI) that we previously defined as disease-relatedhanges in the contribution of a brain area to the levelf metabolic activity in another brain area in the groupf CSWS patients compared with the pediatric pseudo-ontrol group (De Tiège et al., 2004, 2008). PathoPI analysesere conducted based on the a priori hypothesis of alteredffective connectivity between hyper- and hypometabolicrain regions (De Tiège et al., 2004). In practice, the peakoxel values of the most significant hypo and hyperme-abolic areas found in the group-level analysis comparingSWS patients with pediatric pseudo-controls were used as

covariate of interest centered around condition meansnd interacting with each condition. These covariates ofnterest were introduced in separate design matrices thatncluded CSWS patients’ scans and those of the pediatricseudo-controls taken as separated groups. PathoPI analy-es identified throughout the brain the regions that showedSWS-related differences in modulation with the consid-red hypo- and hypermetabolic areas in the group of CSWSatients compared with pediatric pseudo-controls. For thesenalyses, age and sex were used as covariates of no interesto avoid the potential confounding effect of these variablesn the results.

All results of SPM analyses were considered significant at <0.05 corrected for multiple comparisons over the entirerain volume. For PathoPI analyses, based on the a prioriypothesis of altered effective connectivity between hyper-nd hypometabolic brain regions, we also considered sig-ificant at small volume-corrected p <0.05 (10-mm radiuspherical volume of interest centered on significant hyperr hypometabolic voxels in the group of CSWS patients com-ared with pediatric pseudo-controls) the voxels that wereyper or hypometabolic in the group-level subtractive anal-sis (De Tiège et al., 2004).

esults

ndividual-level subtractive analyses comparingSWS patients with pediatric pseudo-controls

he acute phase of CSWS was characterized by hyperme-abolic brain areas in all patients that were associated withistinct hypometabolic brain areas in 13 patients. Hyperme-abolic areas were localized in the perisylvian region (PSR)n 9 patients (3 bilaterally), temporo-parietal junction (TPJ)

e network hypometabolism in epileptic encephalopathieseplepsyres.2014.03.014

n 7 patients (2 bilaterally), frontal lobe in 5 patients (leftnferior gyrus 2, right inferior gyrus 1, left middle gyrus

and right superior gyrus 1), right postcentral gyrus in 3atients, anterior cingulate cortex and right hippocampus

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ARTICLEEPIRES-5130; No. of Pages 11

Epileptic encephalopathies with CSWS

in 1 patient. Hypometabolic areas were mainly localizedin the frontal lobes (inferior frontal cortex in 6 (1 bilater-ally), medial prefrontal in 1, medial frontal, lateral frontal(middle) and insula bilaterally in 1), the TPJ (4 patients),the parieto-occipital regions (medial, 4 patients; lateral,4 patients), the cerebellum (1 patient) or the right lateraltemporal cortex (1 patient).

Group-level subtractive analyses comparing CSWSpatients with pediatric pseudo-controls

Fig. 1 illustrates the hyper- and hypometabolic abnormali-ties characterizing the acute phase of CSWS.

Hypermetabolic abnormalities were observed in theposterior PSR bilaterally. Significant decrease in glucose con-sumption was observed in key nodes of the default modenetwork (DMN) such as the lateral and mesial prefrontal cor-tices, the precuneus, the posterior cingulate cortex (PCC)and the parahippocampal gyri bilaterally. No metabolicchange in subcortical structures was found in CSWS patientscompared with pediatric pseudo-controls, even at very lowthreshold (p < 0.01 uncorrected).

Metabolic changes characterizing both pediatricpopulations

Fig. 2 illustrates the metabolic changes characterizingboth pediatric populations compared with adults. Conjunc-tion analyses revealed the existence of highly significanthypometabolism bilaterally in basal ganglia (caudate nuclei,accumbens, putamen), thalami, cerebellum and in distinctcortical regions within anterior cingulate, medial frontal,medial temporal, orbito-frontal and occipital cortices char-acterizing both CSWS patients and pediatric pseudo-controlscompared with adults. No other metabolic changes werecommon to both pediatric populations compared withadults.

PathoPI analyses

To better understand the pathophysiological relationshipbetween brain areas that exhibited metabolic abnormali-ties, PathoPI analyses were conducted at the group level.Results of the PathoPI analyses are illustrated in Fig. 3 anddetailed in Table 2.

PathoPI analyses first searched for the brain regions thatshowed altered modulation with the hypermetabolic areafound in the group of CSWS patients compared with the pedi-atric pseudo-control group. When considering the peak voxelvalue in the hypermetabolic right PSR, no suprathresholdmodification in interaction was found. By contrast, whenconsidering the peak voxel value in the hypermetabolicleft PSR, we found a significant modification in interactionswith the cerebral glucose metabolism in the right IFG andthe parahippocampal gyrus bilaterally with a negative (left

Please cite this article in press as: Ligot, N., et al., Default mode network hypometabolism in epileptic encephalopathieswith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.03.014

parahippocampal gyrus) or a loss (right IFG, right parahip-pocampal gyrus) of correlation in CSWS patients comparedwith the pediatric pseudo-control group. All the voxels show-ing significant PathoPI with the selected hypermetabolic

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ARTICLE IN PRESS+ModelEPIRES-5130; No. of Pages 11

6 N. Ligot et al.

Figure 1 Results of statistical comparison between the regional cerebral glucose metabolism of patients CSWS and non-CSWSepileptic children. Left: Significant increase in metabolism observed in the perisylvian region bilaterally. Right: Significant decreasein metabolism observed in key nodes of the DMN (lateral and mesial prefrontal cortices, the precuneus, the posterior cingulatec sectip cted

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urpose, statistical images are thresholded at p < 0.001 uncorre

oxel were included in hypometabolic areas found in theroup of CSWS patients.

Then, PathoPI analyses searched for the brain regionshat showed altered modulation with the most significantypometabolic area found in the group of CSWS patientsompared with the pediatric pseudo-control group. Whenonsidering the peak voxel value in the hypometabolic rightnferior frontal gyrus (IFG), we found a significant modifica-ion in interactions with the cerebral glucose metabolism inhe PSR bilaterally. Indeed, we observed an inversion (leftSR) or loss (right PSR) of correlation between the right

FG and the PSR bilaterally in CSWS patients compared withhe pediatric pseudo-control group, in whom there was aignificant positive correlation. The voxel showing signif-cant PathoPI with the selected hypometabolic voxel wasncluded in the hypermetabolic area found in the group ofSWS patients compared with pediatric pseudocontrols.

iscussion

Please cite this article in press as: Ligot, N., et al., Default modwith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.

group of pseudo-control children (Archambaud et al.,013) has been used to conduct a voxel-based study ofegional cerebral glucose metabolism at the acute phase ofpileptic encephalopathies with CSWS. This study disclosed

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he following original findings: (i) the existence of a com-on pattern of decreased metabolism in brain regions that

re key nodes of the DMN and (ii) the absence of evi-ence supporting any metabolic changes in the thalamusssociated with CSWS. This study also showed subcorticalnd cortical metabolic changes that were common to ourediatric epileptic populations in comparison with a groupf young healthy adults. Finally, the study confirmed pre-ious results from our groups (association of hyper- andypometabolism, altered connectivity between hyper- andypometabolic regions at the acute phase of CSWS) usingore appropriate statistical comparative methods.

ypometabolism in the default mode network inhe awake state

he DMN is a set of brain regions (medial and lateral pre-rontal cortex, PCC, precuneus, TPJ and parahippocampalyrus) characterized by a high level of metabolic activ-ty at rest and a low level of activity during goal-directed

e network hypometabolism in epileptic encephalopathieseplepsyres.2014.03.014

r externally focused cognitive tasks (for a review, seeusnard and Raichle, 2001). Several lines of evidence sug-est that DMN suppression during goal-directed tasks isunctionally relevant, particularly in terms of cognitive

ARTICLE IN PRESS+ModelEPIRES-5130; No. of Pages 11

Epileptic encephalopathies with CSWS 7

Figure 2 Metabolic changes characterizing both pediatric epileptic populations compared with adult controls. Significanthypometabolism was found bilaterally in basal ganglia (caudate nuclei, accumbens, putamen), thalami, cerebellum and in dis-

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purpose, statistical images are thresholded at p < 0.001 uncorre

performance (i.e., the more the DMN activity is suppressed,the best is the cognitive performance) (for a review, seeAnticevic et al., 2012). DMN suppression possibly reflectsadaptive disengagement of ‘‘goal-irrelevant’’ brain func-tions (e.g., mind-wandering), which would be requiredto get properly engaged in goal-directed tasks (Anticevicet al., 2012). This hypothesis is supported by the anti-correlation between the DMN and the dorsal attentionalnetwork (DAN) activity both at rest and during most tasks;

Please cite this article in press as: Ligot, N., et al., Default modwith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.

the DAN being involved in goal-driven attention (for areview, see Deco and Corbetta, 2011). This antagonisticDMN—DAN relationship might result from a competitionfor the control of shared computational processes with

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ial temporal, orbito-frontal and occipital cortices. For viewing.

ther distributed functional networks (Anticevic et al.,012).

In this study, we demonstrate, in the awake restingtate, significant hypometabolism in key nodes of the DMNmedial and lateral prefrontal cortex, PCC, precuneus, andarahippocampal gyrus). This result extends previous FDG-ET data that have shown a significant decrease in glucoseetabolism in lateral fronto-parietal associative cortices ofatients with this epileptic condition (De Tiège et al., 2004,

e network hypometabolism in epileptic encephalopathieseplepsyres.2014.03.014

008; Maquet et al., 1995). Indeed, using now an appropri-te comparison with a pseudo-control pediatric group, weemonstrate that additional key nodes of the DMN such ashe mesial prefrontal cortex, the PCC, the precuneus and

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Figure 3 Results of pathophysiological interaction (PathoPI) analyses. Left, top: regression plot of the metabolic activity inthe left perisylvian region and the right parahippocampal gyrus in CSWS patients (blue circles) and pediatric pseudocontrols (redcrosses). This plot illustrates the changes in contribution of the left perisylvian region to the level of metabolic activity in the rightparahippocampal gyrus in CSWS patients compared with pediatric pseudocontrols. Left, bottom: glass brain illustrating the locationof the hypermetabolic seed voxel selected for this PathoPI analysis. Right, top: regression plot of the metabolic activity in the rightinferior frontal gyrus and the right perisylvian region in CSWS patients (blue circles) and pediatric pseudocontrols (red crosses).This plot illustrates the changes in contribution of the right inferior frontal gyrus to the level of metabolic activity in the rightperisylvian region in CSWS patients compared with pediatric pseudocontrols. Right, bottom: glass brain illustrating the location oft . (Fort

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he hypometabolic seed voxel selected for this PathoPI analysishe reader is referred to the web version of this article.)

arahippocampal gyri also display significant decrease inetabolism. Of notice, we did not find in this study anyecrease in metabolism at the TPJ, which is a key nodef the DMN. This might be due to the population of CSWSatients included in this study since such hypometabolismas been observed in a previous study from our groupncluding some, but not all, of the patients investigatedere (see Methods) (De Tiège et al., 2008). As previouslyiscussed (De Tiège et al., 2013), several experimental evi-ences suggest that these hypometabolic abnormalities inhe awake state actually result from the intense epilepticctivity occurring during non-REM sleep. In particular, wehowed in a previous study that the occurrence of interictalpileptic discharges during FDG incorporation does not influ-nce the regional metabolic abnormalities found in CSWSatients (De Tiège et al., 2004). Furthermore, the con-oint disappearance of regional hyper- and hypometabolicbnormalities at recovery of CSWS highly suggests that theseegional metabolic abnormalities are related to the intensepileptic activity during sleep (De Tiège et al., 2008). Theathophysiological mechanisms accounting for this regionalecrease in glucose consumption observed at rest is prob-bly a phenomenon of long-lasting remote inhibition; i.e.

prolonged inhibition of neurons that are remote fromut connected to the epileptic focus (for reviews, see Deiège et al., 2009; Witte and Bruehl, 1999). This hypothesiss supported by the present and previous PathoPI analysesDe Tiège et al., 2004, 2008), which demonstrate a func-

Please cite this article in press as: Ligot, N., et al., Default modwith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.

ional link between hyper- and hypermetabolic areas; i.e.he higher is the metabolic activity at the level of thepileptic foci, the lower is the metabolic activity in DMNegions. In a study combining awake FDG-PET with sleep

a2ee

interpretation of the references to color in this figure legend,

EG recordings, the onsets of spike-wave discharges (SWD)haracterizing CSWS were indeed associated with significantncrease in metabolism during the awake state in all inves-igated patients while most of the awake hypometabolicreas were not involved in the epileptic network per se (Deiège et al., 2013). In addition, previous EEG-fMRI studiesemonstrated the existence of transient increase in bloodxygen-level dependent (BOLD) signal at the epileptic focin association with significant deactivation in DMN nodes dur-ng SWDs characterizing CSWS activity (De Tiège et al., 2007;iniatchkin et al., 2010). These latter findings support theoncept that, in this epileptic encephalopathy, CSWS activ-ty is associated with transient increase/decrease in neuralctivity within different networks that might persist overakefulness (De Tiège et al., 2013; Van Bogaert et al., 2012).he extreme repetition of the transient neural changes dur-

ng most of the slow wave sleep might induce sustainedetabolic changes throughout the sleep—wake cycle (De

iège et al., 2013; Maquet et al., 1995). Still, in the presenttudy, PathoPI analyses also demonstrated a loss of connec-ivity (from positive correlation in pediatric pseudo-controlso an absence of correlation in CSWS patients) betweenyper- and hypometabolic brain areas, which suggests thatther types of pathophysiological mechanisms could accountor the sustained decrease in metabolism.

Alteration of DMN activity is not specific to epilepticncephalopathies with CSWS as it has been observed usingEG-fMRI or ictal-SPECT in primary and secondary gener-

e network hypometabolism in epileptic encephalopathieseplepsyres.2014.03.014

lized epilepsies (Aghakhani et al., 2006; Gotman et al.,005; Hamandi et al., 2006; Laufs et al., 2006; Moellert al., 2008) as well as in focal epilepsies (Blumenfeldt al., 2004; Fahoum et al., 2012; Laufs et al., 2007). In

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those studies, DMN deactivations were transient and directlylinked to SWDs or seizures occurrence. The key finding hereis therefore that the awake DMN hypometabolism is notlikely related to a transient abnormal neuronal activity thatis temporally restricted to the FDG uptake time but is rathera long-lasting consequence of the intense epileptic activitythat occurs during non-REM sleep (De Tiège et al., 2013).Based on the present physiologic models of the DMN, it isplausible that the sustained hypoactivity of this networkin CSWS patients alters task-induced DMN activity modu-lation as well as cross-interactions between DMN and itsanti-correlated or associated functional networks (Anticevicet al., 2012). This could affect cognition, cognitive perfor-mance or sensory processes. To test this hypothesis further,it would have been interesting to correlate the metabolicfindings with the results of the neuropsychological eval-uations obtained in CSWS patients. But, considering theretrospective character of this study and the fact thatthe tests used for the neuropsychological evaluations wereadapted to patients’ age and collaboration, the heterogene-ity of the neuropsychological data across patients precludedsuch correlation analysis. Future prospective FDG-PET orneuroimaging activation studies should address this issue.

Absence of metabolic changes in the thalamus

Although the lack of evidence supporting a difference inthalamic metabolism between CSWS patients and pediatricpseudo-controls observed in this study does not obviouslyexclude thalamic involvement in CSWS activity or in pedi-atric epilepsy pathophysiology in general, it does not supporta primary and specific role of the thalamus in the develop-ment of the CSWS EEG pattern. This finding contrasts withthe structural neuroimaging studies suggesting an associa-tion between thalamic lesions and CSWS activity in patientswith symptomatic CSWS epilepsies (Guzzetta et al., 2005;Sanchez Fernandez et al., 2012).

When considering the EEG pattern of CSWS, the strik-ing feature is that it occurs exclusively during non-REMsleep, which strongly suggests that the physiological mech-anisms characterizing this period of sleep are involved inthe important increase in frequency and diffusion of theepileptic discharges. The role of sleep in triggering epilep-tic discharges is not specific to epilepsies with CSWS (for areview, see Kotagal and Yardi, 2008). This might be relatedto a particular enhancement of rhythmic responses in somecortical neurons (e.g., the fast-rhythmic-bursting neurons)during non-REM sleep that can take a paroxysmal aspect(Steriade, 2006). Interestingly, CSWS activity is age-related,a feature suggesting that non-REM sleep physiology in chil-dren may have some characteristics not encountered inother age groups. Scalp EEG studies have demonstratedmajor decrease in slow-wave activity (SWA) from child-hood to adolescence that correlate spatially and temporallywith age-related cortical maturation processes (decrease ingray-matter density) (Buchmann et al., 2011). The largestdecreases of SWA occurred over central and parietal regions,

Please cite this article in press as: Ligot, N., et al., Default modwith CSWS. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.

which are cortical areas frequently involved in CSWS activ-ity. In addition, several lines of evidence suggest that thethalamus and the thalamo-cortical pathways are experienc-ing profound maturational changes during childhood (Fair

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t al., 2010; Van Bogaert et al., 1998). Considering theseevelopmental findings and the numerous evidence favor-ng a focal cortical onset of CSWS activity (for a review, seean Bogaert, 2013), our FDG-PET data further support therimary involvement of the cortex in CSWS genesis, the thal-mus potentially playing a transient role in the propagationnd diffusion of the epileptic activity to other brain areas asuggested by the transient thalamic activation during CSWSisclosed by EEG-fMRI studies (Siniatchkin et al., 2010).

etabolic changes common to the pediatricpileptic populations

hen compared with the adult control group, thewo pediatric epileptic populations studied here showedommon decrease in metabolism in various subcorticalcaudate nuclei, accumbens, putamen and thalami), cor-ical and cerebellar areas. These cortical and subcorticalypometabolism are in close anatomical correspondenceith those reported in a previous study that investigated

he age-related changes in relative glucose metabolismrom childhood to adulthood using a group of children withdiopathic rolandic epilepsy and a group of healthy adultsVan Bogaert et al., 1998). These regional metabolic dif-erences between pediatric epileptic and adult populationsight either be related to an effect of epilepsy or epilep-

ic activity per se on regional brain glucose metabolism,r to age-related maturational processes. This is particu-arly true for the thalamic hypometabolism that has beenepeatedly described as associated with the epilepsy in var-ous pediatric or adult epileptic disorders (Alkonyi et al.,010; Ferrie et al., 1997; Semah, 2002). Only FDG-PET datan non-epileptic pediatric patients will help to disentan-le the effects of epilepsy versus maturational processesn pediatric regional metabolism. Still, our findings have aractical significance: when comparing pediatric epilepticopulations with adult controls, in the areas here pointedut, hypometabolism should not be viewed as specific ofhe epileptic disorder under consideration.

onclusion

sing appropriate statistical comparisons of FDG-PET data,his study demonstrates the existence of hypometabolismn key nodes of the DMN during the awake state in patientsith CSWS epilepsies, a finding probably related to a phe-omenon of sustained remote inhibition from the epilepticoci. This decrease in metabolic activity might account forome of the acquired cognitive or behavioral features ofSWS epileptic encephalopathies by altering task-inducedMN activity modulation or the cross-interaction of the DMNith its anticorrelated or associated functional networks.his study failed to evidence any thalamic metabolic differ-nce between CSWS patients and pediatric pseudocontrols,

finding which supports the primary involvement of theortex in CSWS genesis.

e network hypometabolism in epileptic encephalopathieseplepsyres.2014.03.014

cknowledgments

oémie Ligot is Clinical Master Specialist Applicant to Ph.D. at the Fonds de la Recherche Scientifique

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FRS-FNRS, Belgium). Xavier De Tiège is Post-doctorate Clin-cal Master Specialist at the FRS-FNRS (Belgium). This studyas supported by a research grant of the FRS-FNRS (FRS-NRS research convention: 3.4508.10). The funding sourceFRS-FNRS) had no involvement in the study design; data col-ection, analyses and interpretation; or in the writing of thisaper.

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