Altered Resting-State Connectivity During Interictal Generalized Spike-Wave Discharges in Drug-Naïve Childhood Absence Epilepsy

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1 Human Bain Mapping 34: (2013) Alteed Resting-State Connectivity Duing Inteictal Genealized Spike-Wave Dischages in Dug-Naïve Childhood Absence Epilepsy Tianhua Yang, 1 Cheng Luo, 2 Qifu Li, 1 Zhiwei Guo, 2 Ling Liu, 1 Qiyong Gong, 3 Dezhong Yao, 2 and Dong Zhou 1 * 1 Depatment of Neuology, West China Hospital, Si Chuan Univesity, Cheng du, Sichuan, People s Republic of China 2 School of Life Science and Technology School of Mathematics, Univesity of Electonic Science and Technology of China, Chengdu, Sichuan, People s Republic of China 3 Depatment of Radiology, Huaxi MR Reseach Cente (HMRRC), West China Hospital of Sichuan Univesity, People s Republic of China Abstact: Pupose: To investigate the intinsic bain connections at the time of inteictal genealized spike-wave dischages (GSWDs) to undestand thei mechanism of effect on bain function in unteated childhood absence epilepsy (CAE). Methods: The EEG-functional MRI (fmri) was used to measue the esting state functional connectivity duing inteictal GSWDs in dug-naïve CAE, and thee diffeent bain netwoks the default mode netwok (DMN), cognitive contol netwok (CCN), and affective netwok (AN) wee investigated. Results: Coss-coelation functional connectivity analysis with pioi seed evealed deceased functional connectivity within each of these thee netwoks in the CAE patients duing inteictal GSWDS. It included pecuneus-dosolateal pefontal cotex (DLPFC), dosomedial pefontal cotex (DMPFC), and infeio paietal lobule in the DMN; DLPFC-infeio fontal junction (IFJ), and pe-supplementay moto aea (pe-sma) subegions connectivity disuption in CCN; ACC-ventolateal pefontal cotex (VLPFC) and DMPFC in AN; Thee wee also some egions, pimaily the paahippcampus, paacental in AN, and the left fontal mid ob in the CCN, which showed inceased connectivity. Conclusions: The cuent findings demonstate significant alteations of esting-state netwoks in dug naïve CAE subjects duing inteictal GSWDs and inteictal GSWDs can cause dysfunction in specific netwoks impotant fo psychosocial function. Impaiment of these netwoks may cause deficits both duing and between seizues. Ou study may contibute to the undestanding of neuo-pathophysiological mechanism of psychosocial function impaiments in patients with CAE. Hum Bain Mapp 34: , VC 2012 Wiley Peiodicals, Inc. Key wods: EEG-fMRI; CAE; functional connectivity; inteictal GSWDs; esting state Contact gant sponso: National Natual Science Foundation of China; Contact gant numbes: , /H091, , and ; Contact gant sponso: The Sichuan Univesity Reseach Fund; Contact gant numbe: 2010SCU11034; Contact gant sponso: China Postdoctoal Science Foundation; Contact gant numbe: *Coespondence to: Dong Zhou, Depatment of Neuology, West China Hospital, Si chuan Univesity, Chengdu, Sichuan, People s Republic of China. zhoudong66@yahoo.de Received fo publication 16 Febuay 2011; Revised 17 Novembe 2011; Accepted 29 Novembe 2011 DOI: /hbm Published online 19 Mach 2012 in Wiley Online Libay (wileyonlinelibay.com). VC 2012 Wiley Peiodicals, Inc.

2 Yang et al. INTRODUCTION Multiple active subsystems exist in the bain at est, esembling specific neuoanatomical netwoks [Biswal et al., 1995]. Thus, though examining the human bain as an integative netwok of functionally inteacting bain egions, we can obtain new insights about lage-scale neuonal communication in the bain. Resting state functional connectivity MRI (fcmri) is widely used to investigate bain netwoks that exhibit coelated fluctuations. It has been used to examine how functional connectivity and infomation integation elates to human behavio and how this oganization may be alteed in bain diseases [Gotman et al., 2006]. Simultaneous ecodings of the electoencephalogam (EEG) and functional MRI (EEG-fMRI) can investigate diffeent bain netwoks involved in metabolic changes esulting fom the epileptic dischages seen in the scalp EEG. The default mode netwok (DMN) is a medial cotical netwok, which has been found to be active at est [Raichle et al., 2001], and to be deactivated when subjects pefom attention-demanding, goal-oiented tasks [Shulman et al., 1997]. It takes an impotant pat in self-efeential activities, including evaluating salience of intenal and extenal cues, emembeing the past, and planning the futue [Buckne et al., 2008; Ralchle and Snyde, 2007; Raichle et al., 2001; Speng and Gady, 2010]. In addition to the DMN, the othe impotant system, the cognitive contol netwok (CCN), seves attention demanding cognitive tasks and exhibits activity inceases in fontal and paietal egions associated with top-down modulation of attention and woking memoy tasks [Cobetta and Shulman, 2002]. A thid system, the affective netwok (AN) is involved in emotional pocessing [Bush et al., 2000; Maybeg et al., 1999; Ongu et al., 2003; Phillips et al., 2003] and, though its connections with othe egions, egulates fea, vigilance, and autonomic and visceal function. Childhood absence epilepsy (CAE) is the most common childhood epilepsy syndome, accounting fo 10 17% of all childhood onset epilepsy. It has a boad ange of unteated cognitive, linguistic, and behavioal/emotional comobidities [Caplan et al., 2008]. Unfotunately, the fundamental mechanisms of alteed bain function in CAE ae not yet known. It has the typical 3Hz genealized spike and wave dischages (GSWDs) in scalp EEG without clinical signs that is called inteictal GSWDs. And the subclinical dischages may involve selective cotical and subcotical netwoks, while spaing othe egions and contibute to the psychosocial poblems in CAE. Theefoe, we hypothesized that inteictal GSWDs can cause dysfunction in specific netwoks impotant fo psychosocial function. Impaiment of these netwoks may cause deficits both duing and between seizues. In the pesent study, we used EEG-fcMRI to investigate alteed esting-state functional connectivity in unteated CAE duing inteictal GSWDs. We examined the thee diffeent netwoks mentioned above: the CCN, the DMN, and the AN. MATERIAL AND METHODS Patients Diagnosis was established accoding to the diagnostic scheme published by the Intenational League Against Epilepsy in 2001 [Engel, 2001]. All the patients wee newly diagnosed and had not eceived epilepsy medications. The study was conducted in patients with CAE ecuited fom the epilepsy clinics at the West China Hospital fo Neuology of Sichuan Univesity. All patients undewent outine clinical neuoimaging and 24-h video-eeg monitoing to ensue that thee wee no stuctual abnomalities, but the fequent and steeotypical inteictal GSWDs wee confimed. Patients wee administeed the Wechsle Intelligence Scale fo Childen China-Revised (WISC-CR) test [Gong and Cai, 1993] and the tests wee scoed by a neuopsychologist and used along with age, gende and handedness to match cohots of patients and contols. Patients with self-epoted mental disodes o cognitive handicaps wee excluded. This study was appoved by a esponsible govenmental agency at the Sichuan Univesity. Infomed consent fo the study was obtained fom each subject. EEG Acquisition The EEG was ecoded using a 10/20 system with 21 Ag/ AgCl electodes soldeed to 12 kv cuent-limiting esistos appliedonthescalpwithconductiveceam.theeegdevice was an EBNeuo Miza 40 (Floence, Italy), with 32 channels adapted fo MR and a sampling ate of 4 khz, which allowed suitable time esolution fo detecting the switching effect of the eadout gadient in the high slew ate condition. The EEG dynamic ange was 65.5 mv to pevent MRI atifact wavefoms fom satuating the EEG/ECG. The amplifie was connected to the ecoding compute outside the scanne oom via a fibe-optic cable. The MR atifact was filteed online [Gaeffa et al., 2003]. The pulse atifact was minimized by using a locked aangement of paticula wies and an elastic cap. If no spikes wee found in one session, that un s fmri data was excluded in the futue analysis. fmri Acquisition A 3.0 T GE MRI scanne (EXCITE, Milwaukee) was used to acquie BOLD sensitive echo-plana images (EPI) with continuous, simultaneous EEG. Foam padding was used to help secue the EEG leads, minimize motion, and impove patient comfot. At the same time, the patient s eas wee packed with cotton balls and the patient assumed a esting state with thei eyes closed. The gadient echo EPI sequence s paametes wee as follows: 30 slices, 200 volumes, TR ¼ 2,000ms, TE ¼ 40 ms, FOV ¼ 24 cm, matix ¼ 64 64, in-plane esolution ¼ 22 mm, and a flip angle ¼ 90.The stuctual image was also acquied duing the inteval of the fist and second un (TR ¼ 8.5 ms, TE ¼ 3.4 ms, FOV ¼ 24 cm 24 cm, flip angle ¼ 12, matix ¼ ,

3 Alteed Resting-State Connectivity in Childhood Absence Epilepsy slices). BOLD fmri data wee collected in successive uns of 6 min and 40 s. Additional scanning sessions wee acquied in the same patient if no spikes wee ecoded duing the eal-time EEG in one session. Data Pepocess Analysis, Seed Defined, and Seed Coelation Analysis Pe-pocessing of fmri data wee conducted using the SPM8 softwae package [statistical paametic mapping The slice time coection, 3D motion detection and coection, spatial nomalization to the Monteal Neuological Institute (MNI) template supplied by SPM, and spatial smoothing using an isotopic Gaussian kenel (8 mm full width at half maximum) wee included. Seveal pocedues wee used to emove the possible vaiances fom time couse of each voxel. (i) Tempoal band-pass filteing (pass band Hz) was conducted though a phase-insensitive filteing (ii) Though linea egession, the time seies was futhe coected to eliminate the effect of six head motion paametes obtained in the ealigning step and the effect of the signals fom a CSF egion, and a white matte (WM) egion. The esiduals of the egessions wee linealy detended, and then used fo the next functional connectivity analysis. On the basis of the liteatue [Sheline et al., 2010], thee egions wee selected as seeds to identify thee diffeent netwoks, the bilateal dosolateal pefontal cotex (DLPFC) (36, 27, 29) in the CCN, the pecuneus (7, 60, 21) in the DMN, and the subgennual anteio cingulate cotex (ACC) (10, 35, 2) in the affective ACC netwok. Fo each egion, the time couse fom the bilateal spheical egion-of-inteest (adius 10 mm) was aveaged. Subsequently, a seed coelation analysis was pefomed between the mean time couse and data of all voxels in individual level. Individual coelation coefficients wee nomalized to Z-scoes by using Fishe s Z tansfomation. Finally, the individual Z scoes wee enteed to andom effect one-sample t-test in SPM8. Statistical map of significant functional connectivity fo each seed was ceated. Significance level was set at P < 0.05, coected fo multiple compaisons using the FDR-citeion [Genovese et al., 2002]. Accoding to whethe GSWDS s was detected duing a paticula session o not, the fmri data was divided into inteictal dischages goup and non-dischage goup. To examine the diffeence between goups, two-sample t-test in SPM8 was used espectively in thee netwoks. Significance level was set at P < 0.05, coected fo multiple compaisons using the false discovey ate (FDR)-citeion [Genovese et al., 2002]. RESULTS Clinical Featues Ten patients diagnosed with CAE wee ecuited (4 males, 6 females, mean age 7.65, ange 5 11). None of them has eceived antiepileptic medications. Twenty-eight sessions of EEG-fMRI scanning in 10 patients wee caied out. And inteictal GSWDs wee identified in twenty sessions in all patients. The inteictal EEGs demonstated genealized 3 Hz spike and waves, and the numbe of inteictal GSWD epochs anged fom 3 to 11 (median, 6), and the duation of an epoch anged fom 0.6 to 3.8 s. Functional Connectivity of the DMN A connectivity map fo each goup was geneated, and the connectivity pattens of positive and negative coelations appeaed to be simila duing visual inspection of the two goups (Fig. 1A,B). The DMN netwok was consistent with pevious studies [Uddin et al., 2009]. The between-goup diffeence in DMN was obtained, which was defined by the coss-coelation functional connectivity analysis with seed at pecuneus. Compaed with the contol goup, no incease in connectivity was found. Howeve, deceased connectivity wee detected at the bilateal DLPFC, dosomedial pefontal cotex (DMPFC) and infeio paietal lobule (Fig. 1C). Results evealed that DMN functional connectivity was educed in the unteated CAE patients duing inteictal GSWDs. Functional Connectivity of the CCN CCN was obseved in bain egions peviously defined as within the CCN fo both goups [Cole and Schneide, 2007]. Although the spatial maps look simila between the two goups (Fig. 2A,B), significant diffeences wee obseved in specific subegions of these aeas (Fig. 2C). The between-goup diffeence in CCN was obtained, which was defined by the coss-coelation functional connectivity analysis with seed at bilateal DLPFC. Compaed with the contol goup, deceased connectivity was detected at the bilateal infeio fontal junction (IFJ), DLPFC, and pe-supplementay moto aea (pe-sma) subegions. And the incease in connectivity was found in the left fontal middle obital gyus (Fig. 2C). Results evealed that CCN functional connectivity was alteed in the unteated CAE patients duing inteictal GSWDs. Functional Connectivity of the AN AN (Fig. 3A,B) and between-goup diffeences (Fig. 3C) wee also epoted. The TRN aeas ae simila to pevious epots [Bush et al., 2000; Modinos et al., 2010]. Fo the between-goup compaison, the bilateal ventolateal pefontal cotex (VLPFC), and DMPFC aea ae significantly moe anti-coelated with the ACC in tial goup than in contol goup. Thee wee also some egions, pimaily the paahippcampus, paacental in AN which showed inceased connectivity (Fig. 3C). Results evealed that AN functional connectivity was alteed in the CAE patients duing inteictal GSWDs. 1763

4 Yang et al. Compaison of connectivity maps in DMN. Connectivity of the DMN fo inteictal dischages goup (A), non-dischage goup (B), and between-goup diffeences (C). Netwoks wee identified by seed egions placed in the pecuneus. No inceased connection was found, and deceased connectivity was showed (blue) Figue 1. in DLPFC, DMPFC, and infeio paietal lobule in unteated CAE patients. The statistical theshold was P < 0.05 (FDR-coected, 20 adjacent voxels). [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.] Compaison of connectivity maps in CCN. Connectivity of the CCN fo inteictal dischages goup (A), non-dischage goup (B), and between-goup diffeences (C); Netwoks wee identified by seed egions placed in the DLPFC. Deceased connectivity was showed (blue) in DLPFC, IFJ, and pe-sma subegions Figue 2. and inceased connectivity was found in the left fontal middle obital gyus (ed). The statistical theshold was P < 0.05 (FDRcoected, 20 adjacent voxels). [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.] 1764

5 Alteed Resting-State Connectivity in Childhood Absence Epilepsy Figue 3. Compaison of connectivity maps in AN. Connectivity of the AN fo inteictal dischages goup (A), non-dischage goup (B), and between-goup diffeences (C). Netwoks wee identified by seed egions placed in the ACC. Deceased connectivity was showed (blue) in ACC, VLPFC, and DMPFC. Some egions, pimaily the paahippcampus, paacental aea showed inceased connectivity (ed). The statistical theshold was P < 0.05 (FDRcoected, 20 adjacent voxels). [Colo figue can be viewed in the online issue, which is available at wileyonlinelibay.com.] DISCUSSION To ou knowledge, this is the fist study diectly investigating esting-state functional connectivity of dug naïve CAE patients duing inteictal GSWDs, and thee diffeent netwoks including the CCN, the DMN, and the AN wee examined. We found that duing inteictal GSWDs, CAE subjects mainly exhibited deceased connectivity within the thee diffeent netwoks. The findings indicate that inteictal GSWDs can cause dysfunction in specific netwoks impotant fo psychosocial function and impaiment of these netwoks may cause deficits both duing and between seizues. Pevious EEG-fMRI studies in epilepsy patients with GSWDs evealed BOLD signal activation in the thalamus and deactivation in fontopaietal aeas, the pecuneus and the caudate nucleus [Aghakhani et al., 2004; Gotman et al., 2005; Hamandi et al., 2006; Laufs et al., 2006; Li et al., 2009; Moelle et al., 2008, 2010]. And in dug naïve childen with newly diagnosed absence epilepsy, this patten was also found [Moelle et al., 2008]. These findings suggest that the bain egions involved in the patten of deactivation ae attibuted to the DMN. Activity and connectivity of the DMN has been suggested to be involved in the integation of cognitive and emotional pocessing [Geicius et al., 2003] and monitoing the wold aound us [Gusnad and Raichle, 2001]. Ou pevious wok has found that DMN abnomalities in patients with absence epilepsy duing esting inteictal duations without inteictal epileptic dischages [Luo et al., 2011]. In this study, we futhe found deceased connectivity in DMN duing inteictal GSWDs in dug naïve CAE patients. The deceased connectivity in DMN duing inteictal GSWDs may lead to an inteuption of cognitive pocesses and the subclinical impaiment of consciousness. In ou study, alteations of connectivity wee detected at the subegions of CCN [Uddin et al., 2009]. In this netwok, DLPFC is fo sustained attention and woking memoy [Cutis and D Esposito, 2003] and pe-sma plays an impotant ole in cognitive moto contol which involves sensoy discimination and decision making o moto selection fo the action afte stimuli [Ikeda et al., 1999]. IFJ is involved in the cognitive contol and it is involved in the updating of task epesentations [Defuss et al., 2005]. Specifically, the ight IFJ plays a cucial ole in inhibitoy contol and suppession of inappopiate esponses [Aon et al., 2004]. Ou esults evealed cognitive contol netwok changed duing the inteictal epileptic dischages, and this may be esponsible fo the subclinical behavio changes. Anothe impotant netwok system, the AN, is impotant in fea, vigilance, and autonomic and visceal egulation. In ou study, we found deceased functional connectivity of ACC, VLPFC, and DMPFC in AN netwok; These aeas ae within a pedominantly pefontal netwok, and has a consistent and pominent ole in the down-egulation of 1765

6 Yang et al. negative emotion [Ochsne and Goss, 2005]. Thee wee also some egions, pimaily the paahippcampus, paacental in AN netwok which showed inceased connectivity. The AN has stong local connections to many limbic stuctues [Ongu et al., 2003; Pessoa, 2008], and is paticulaly involved in the elationship of emotion/mood to visceal function [Phillips et al., 2003; Pice and Devets, 2010]. Paahippocampal gyus belongs to the ventomedial neual system, which is implicated in the ealy appaisal and encoding of emotional significance duing egulation of behavioal esponses to an emotional stimulus [Almeida et al., 2009]. Thus, ou esults indicate that AN netwok was alteed duing the GSWDs in CAE patients, and this may account fo the behavioal/emotional comobidities in CAE patients. On the othe hand, fom a netwokelated point of view, ou esults found the DLPFC with deceased connectivity to the netwoks of DMN and CCN, the DMPFC with deceased connectivity to the netwoks of DMN and AN. This may indicate that DMN foms the coe esting state netwok aound which the othe netwoks amalgamate [Deshpande et al., 2011] and specific netwoks ae linked togethe. This may explain why the cognitive and behavioal/emotional comobidities aising in distinct netwoks in CAE can occu concuently and behave synegistically. Inteictal epileptic dischages (IED) can affect activity in bain egions [Babaosie and Avoli, 1997; Babaosie et al., 2000]. In this study, ou esults evealed mainly deceased functional connectivity within each of these thee netwoks in the CAE patients duing inteictal GSWDs. If the signals induced by IED wee only the andom noise, the coelation coefficient between signals should be deceased. Howeve, the egions in these netwoks showed deceased activation esponding to the IED in pevious studies [Gotman et al., 2005; Li et al., 2009] and these esults mean that the IED cause the invese hemodynamic esponse function. Theefoe, the change of netwok connections may be an inheent mechanism to weaken netwok connections and pevent oveexcitability and the netwok connections attenuation seems to be negative feedback mechanisms that might pevent seizues in CAE. On the othe hand, thee is inceasing evidence that IED can have a negative effect on ceebal function, which includes two types (tansitoy inteuption of cognitive function and alteation of the physiological mechanisms involved in bain plasticity and memoy) [Holmes and Lenck-Santim, 2006]. Recently, it has been found that hippocampal spikes that occued duing memoy etieval stongly impaied pefomance [Kleen et al., 2010]. Howeve, thee is no evidence yet to justify outine use of antiepileptic dugs to teat cognitive o behavioal poblems in people with subclinical EEG dischages. Peliminay tials have confimed the possibility of impoving psychosocial function by suppessing IED with medication [Maston et al., 1993; Pessle et al., 2005]. Ou esults poved that esting-state connectivity was alteed and netwok-specific deceases of synchonization wee found in diffeent netwoks duing inteictal GSWDs in dug-naïve CAE without outspoken cognitive impaiment. This may contibute to the cognitive and behavioal/emotional comobidities in CAE. Ou data indicate that suppession of dischages may be associated with significant impovement in psychosocial function and dug teatment is desiable o effective. CONCLUSIONS The cuent findings demonstate significant alteations of esting-state netwoks in dug naïve CAE subjects duing inteictal GSWDs and inteictal GSWDs can cause dysfunction in specific netwoks impotant fo psychosocial function. Impaiment of these netwoks may cause deficits both duing and between seizues. Ou study may contibute to the undestanding of neuo-pathophysiological mechanism of psychosocial function impaiments in patients with CAE. 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