Tentative fMRI signatures of perceptual echoes in early visual cortex

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Tentative fMRI signatures of perceptual echoes in early

visual cortex

Canhuang Luo, Sasskia Brüers, Isabelle Berry, Rufin Vanrullen, Leila Reddy

To cite this version:

Canhuang Luo, Sasskia Brüers, Isabelle Berry, Rufin Vanrullen, Leila Reddy. Tentative fMRI

sig-natures of perceptual echoes in early visual cortex. NeuroImage, Elsevier, 2021, 237, pp.118053.

�10.1016/j.neuroimage.2021.118053�. �hal-03264342�

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ContentslistsavailableatScienceDirect

NeuroImage

journalhomepage:www.elsevier.com/locate/neuroimage

Tentative

fMRI

signatures

of

perceptual

echoes

in

early

visual

cortex

Canhuang

Luo

a,b,1

_,

_Sasskia

_Brüers

a,b,1

_,

_Isabelle

_Berry

a,b,c

_,

_Ruﬁn

_VanRullen

a,b

_,

_Leila

_Reddy

a,b,∗

a Université de Toulouse, Centre de Recherche Cerveau et Cognition, Université Paul Sabatier, 31062, Toulouse, France

b Centre National de la Recherche Scientiﬁque, Unité Mixte de Recherche 5549, Faculté de Médecine de Purpan, 31052, Toulouse Cedex, France c Toulouse NeuroImaging Center, INSERM, U825, Toulouse, France

a

r

t

i

c

l

e

i

n

f

o

Keywords: Perceptual echo Alpha EEG fMRI Oscillation Traveling wave

a

b

s

t

r

a

c

t

ThevisualImpulseResponseFunction(IRF)canbeestimatedbycross-correlatingrandomluminancesequences withconcurrentlyrecordedEEG.Ittypicallycontainsastrong10Hzoscillatorycomponent,suggestingthatvisual informationreverberatesinthehumanbrainasa“perceptualecho”.Theneuraloriginoftheseechoesremains unknown.Toaddressthisquestion,werecordedEEGandfMRIintwoseparatesessions.Inbothsessions,adisk whoseluminancefollowedarandom(whitenoise)sequencewaspresentedintheupperleftquadrant. Individ-ualIRFswerederivedfromtheEEGsession.TheseIRFswerethenusedas“responsetemplates” toreconstruct anestimateoftheEEGduringthefMRIsession,byconvolutionwiththecorrespondingrandomluminance se-quences.The7–14Hz(alpha,themainfrequencycomponentoftheIRF)envelopeofthereconstructedEEGwas finallyusedasanfMRIregressor,todeterminewhichbrainvoxelsco-variedwiththeoscillationselicitedbythe luminancesequence,i.e.,the“perceptualechoes”.ThereconstructedenvelopeofEEGalphawassignificantly correlatedwithBOLDresponsesinV1andV2.Surprisingly,thiscorrelationwasvisibleoutside,butnotwithin thedirectly(retinotopically)stimulatedregion.WetentativelyinterpretthislackofalphamodulationasaBOLD saturationeffect,sincetheoverallstimulus-inducedBOLDresponsewasinverselyrelated,acrossvoxels,tothe signalvariabilityovertime.Inconclusion,ourresultssuggestthatperceptualechoesoriginateinearlyvisual cortex,drivenbywidespreadactivityinV1andV2,notretinotopicallyrestricted,butpossiblyreflectingthe propagationofatravellingalphawave.

1. Introduction

Visualinformationis notﬂeeting, butinstead“echoes” inour vi-sualsysteminanoscillatoryfashion(VanRullenandMacdonald,2012). Whensubjectsarepresentedwithrandomluminancesequences(white noise,WN)while concurrentlyrecordingtheelectroencephalography (EEG)signal,animpulseresponsefunction(IRF)canbecalculatedby cross-correlatingtheWNsequenceswiththecorresponding EEG.The resultingIRFcontainsastrong∼10Hzcomponentthatcanlastupto onesecond,suggestingthatthebrainprocessesandcarriesvisual in-formationovertimeat∼10Hz.Thisphenomenonhasbeencalledthe “perceptualecho” (IlhanandVanRullen,2012;VanRullenand Macdon-ald,2012).

TheIRFishighlycorrelatedwithresting-stateandongoingEEG al-phainbothamplitudeandfrequency,andbothsignalsaremost promi-nent inposterior regions (VanRullen andMacdonald, 2012).Despite thefactthattheyshare thesamefrequencyrangeandtopographical location,thealpha-bandEEGsignalinresponsetotheWNsequences (IRF or “perceptual echo”) does not necessarily correspond to the

∗_{Corresponding}_author.

E-mailaddress:leila.reddy@cnrs.fr(L.Reddy). 1 _Equal_contribution

ongoingEEGalphaactivity;infact,thetwosignalscanevensometimes bedissociatedandthereareimportantfunctionaldiﬀerencesbetween them.Ongoingalphaactivityhaslongbeenconsideredtoplayan in-hibitoryroleinsensoryareas(BonnefondandJensen,2012;Jensenand Mazaheri,2010;KizukandMathewson,2017; Klimeschetal.,2002; SadaghianiandKleinschmidt,2016),whilsttheIRFsuggeststhatthe vi-sualsystemactivelyprocessesandretainsinformationovertime(Ilhan andVanRullen,2012;VanRullenandMacDonald,2012).Forinstance, inaspatialattentiontask,contralateralalphaamplitudedecreasedwhen subjectsattendedtotheleftorrightsideofthescreen,whileonthe con-trarytheIRFwasenhancedbycontralateralattention(VanRullenand MacDonald,2012).

TheIRFhasbeenassociatedwithvariousvisualphenomena.For in-stance,theIRFisthoughttoplayaroleinthetripleflashillusion:when subjectsarepresentedwithtwoflashesinsuccession,theysometimes report seeinga thirdflash(Bowen,1989).Thisillusion couldbe ex-plainedasthesuperpositionofoscillatoryimpulseresponsefunctions tothe twovisual flashes, comingin alignment tocreate athird (il-lusory)percept(Bowen,1989;Gulbinaite,İlhan,&VanRullen,2017).

https://doi.org/10.1016/j.neuroimage.2021.118053.

Received9August2020;Receivedinrevisedform4March2021;Accepted27March2021 Availableonline28April2021.

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C. Luo, S. Brüers, I. Berry et al. NeuroImage 237 (2021) 118053

Fig.1. Datacollectingandprocessingsteps. Step 1) In the EEG session, we recorded EEGsignalsandcomputedtheIRFby cross-correlatingtheEEGandtheWNluminance se-quences.TheIRFtimefrequencytransform(on channelPOz)averagedacrosssubjects,andthe IRF ofone representativesubjectareshown ontherightofthefigure.Step2)We recon-structedanestimateofEEGsignalsduringthe fMRIsessionbyconvolvingthisIRFwiththe WNluminancesequencesusedintheMRI scan-ner.BOLDfMRI signals werealsorecorded. Step3)WefilteredthereconstructedEEGinto fourfrequencybands.Step4)Finally,weused theenvelopesofthefilteredEEGasBOLD re-gressorsfortheGLM.(Forinterpretationofthe referencestocolourinthisfigurelegend,the readerisreferredtothewebversionofthis ar-ticle.)

InadditiontothetemporaldimensionoftheIRF,recentstudiesfrom our grouphave investigated its spatialdimension. Lozano-Soldevilla andVanRullen(2019)showedthattheIRFpropagatesfromoccipital tofrontalareasasatravellingwavewhenWNsequencesarepresented intheuppervisualﬁeld.AlamiaandVanRullen(2019)further demon-stratedthatwhenthereisvisualinput,boththeIRFandthealpha prop-agatefromposteriorchannelstofrontalchannels,whereaswhen sub-jectsclosetheireyes,thealphatravelsin theoppositedirection.The forwardandthebackwardpropagationshavebeenpostulated(Alamia andVanRullen,2019)torepresentfeedforwardandfeedbacksignalsin theframeworkofpredictivecoding(RaoandBallard,1999).However, despitethisprogressinunderstandingthespatialpropagationoftheIRF underdiﬀerentconditions,itsneuraloriginsremainunknown.Oneof theabovestudies(Lozano-SoldevillaandVanRullen2019)attempted toperformEEGsourcelocalizationoftheIRFtravellingwaves,butthe outcomewasambiguous,i.e.,compatiblewithbothalarge-scale propa-gationacrossmultiplebrainregions,oralocalizedpropagationwithina restrictedregion,e.g.,anoccipitalsulcus.Theaimofthecurrentstudy wastousefMRItoidentifytheneuralsourceoftheIRF.

WeconductedanEEG-fMRIstudytolocalizetheneuralsourceof theIRF(Fig.1).InsteadofconcurrentlyrecordingEEGandfMRI,which oftenleadstoartifactsandspuriouscorrelations(Fellneretal.,2016; Husteretal.,2012),werecordedEEGandfMRIintwoseparatesessions. Inbothsessions, adiskwhose luminance followedarandom (white noise) sequence was presented in the upper left quadrant. Subjects (N=20)detecteda rarenear-thresholdtarget embeddedin thedisk. IndividualIRFswerederivedfromtheEEGsessionbycross-correlating WNsequenceswiththecorrespondingEEGsignal.TheseIRFswerethen usedas“responsetemplates” (BrüersandVanRullen,2017)to recon-structanestimateoftheEEGduringthefMRIsessionbyconvolution withtherandomluminancesequencespresentedinthefMRIsession. Finally,weusedthealphaenvelopeofthereconstructedEEGasfMRI regressorstodeterminewhichbrainvoxelsco-varywiththeoscillations (i.e.,the“perceptualechoes”)elicitedbytheluminancesequence,since alphafrequencyistheprimaryfrequencycomponentoftheIRF.Ina sec-ondstep,weinvestigatedotherfrequencybands(delta:2–4Hz,theta:

4–7Hz,beta:14–20Hz).Asdescribedbelow,wefoundthatthe recon-structedenvelopeofEEGalphawassigniﬁcantlycorrelatedwithBOLD responsesinV1andV2.Otherfrequencieswerecorrelatedtoalesser extent(delta,theta)ornotatall(beta).

2. Method

2.1. Subjects

22subjects(10females,1lefthanded,agerange20–43,meanage 28.73)tookpartinthestudyafteramedicalinterview,andgiving writ-teninformedconsent.Intotal20subjectscompletedtheexperiment; twosubjectsfailedtocomebackforoneorbothexperimentalsessions afterbeingincluded.TheEEGsessionwassystematicallyconducted be-forethefMRIsession.Ofthe20subjects,14subjectsﬁnishedthetwo sessionsinoneweek,4subjectsin2weeksandtheremaining2subjects in3weeks.Thisstudywasapprovedbytheethics“Comité deProtection desPersonnesSud-MéditerranéeI” (N°2016-A01937–44).

2.2. Stimuli

InboththeEEGandthefMRIsessions,adisk(subtending2° ofvisual angle)whoseluminancefollowedarandom(whitenoise)sequencewas presentedonablackscreen,intheupperleftquadrant,at5° ofvisual anglefromfixation.Weusedasmallervisualstimulusthaninour pre-viousstudies(VanRullenandMacdonald,2012;IlhanandVanRullen, 2012;BrüersandVanRullen,2017;Lozano-SoldevillaandVanRullen, 2019; Alamia and VanRullen, 2019) because in pilot experiments we noticedwidespreadreflectionsofthedisplaylightontotheinner surfaceoftheMRIscannerbore,whichresultedindiffuseratherthan localized stimulation. Thesmallersizeof 2° allowedustominimize thisreflectionartifact.PsychToolbox(Kleineretal.,2007)forMATLAB (MathWorks,Natick,MA)wasusedtodisplaytheWNsequences. Sub-jectswererequiredtofixatethecenterofthescreen duringthetask anddetectanearthresholdlighterdisk(i.e.,atarget)surroundedby 2

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adarkerannulus.Thistargetdisklasted1frameandwasembeddedin thewhite-noisedisk.Theﬁxationpointwas0.1° ofvisualangle.

Usingastaircaseprocedureontheﬁrst100targetspresented(i.e., about30trials),wemanipulatedthevisibilityofthetargetsbychanging thecontrastbetweentheouter(darkerannulus)andinner(lighterdisk) partstoachieveacontrastatwhich subjectsperceivedthetargeton about50%oftrials.Theresultingcontrast waskeptconstantforthe remainderofthesession.Theperceptualthresholdwascomputedfor eachsessionindependentlyusingthequestfunction(PelliandWatson, 1983).

Becauseofdifferencesincomputersetup,thestimulipresentedin theEEGandthefMRIrecordingsessionswerenotidenticalintermsof temporalfrequency.IntheEEGsession,theCRTmonitorhadarefresh rateof160Hz,givingtheWNsequencesaflatpowerspectrumbetween 0and80Hz.DuringthefMRIsession,theprojectorusedhada maxi-mumpresentationrateof60Hz,whichmeanttheWNsequenceshada flatpowerspectrumbetween0and30Hz(stillwellabovethetemporal resolutionoftheBOLDactivity).Themaximalluminanceofthe stimu-luswas114.7cd/m2_in_the_EEG_session,_and_827.9_cd/m2_in_the_fMRI

session.

2.3. Experimentalprotocol

EachsubjectcompletedoneEEGandonefMRIsession(Fig.1,step 1and2).TheEEGsessionwascomposedof8runsof48WNsequences, eachsequencelasting6.25s.ThefMRIsessionconsistedof12runs.Each runwascomposedof7randomluminancesequences,eachlasting30s, withaninter-trial-intervalof12s.

2.4. EEGrecording,preprocessing,extractionofIRFandregressors

DuringtheEEGsession, theEEG signalwasrecordedusing a 64-channelBioSemiEEGsystemwith4extraocularelectrodesmonitoring thehorizontalandverticaloculograms.Signalsweredigitizedata sam-plingrateof1024Hz.

EEG pre-processing was performed using the EEGLAB toolbox (Delorme&Makeig,2004)andcustomizedMatlabscripts.Bad chan-nelswereinterpolatedwhenneeded.EEGdataweredown-sampledto 160Hztofacilitatethecross-correlationwiththestimuli.Notchﬁltering (47∼53Hz)wasappliedtoremoveartifacts.EEGdatawerethen refer-encedtotheaverageandseparatedintoepochsof−0.25sbeforeto6.5s afterthestimulusonset.Baselinecorrectionwasperformedusingthe pre-stimulussignal.Furthermore,epochscontainingocularand move-mentrelatedartifactswererejected.Onaverage6.97%(SD=5.57%)of epochshavebeenexcluded(onaverage353epochsleft)andtheworst subjecthad<20%ofepochsremoved.TheIRFswereextractedbydoing across-correlationbetweenthestandardizedpre-processedEEGepochs andthestandardizedcorrespondingWNsequences(VanRullenand Mac-Donald,2012)(Fig.1,step1).TheIRFwascutfromlags−0.2to1.5s, resultingin1.7slongIRFs.

TheIRFswerethenusedtoreconstructtheEEGsignal correspond-ingtotheWNsequencesinthefMRIsession(Fig.1,step2).Notethat theIRFsarestableovertime,asithasbeenshownthattheycan be reproduced evenafter 6months (VanRullen andMacdonald, 2012). Therefore,theIRFsin thefMRIsessionwereunlikelytobe diﬀerent fromtheIRFsoftheEEGsession.First,theIRFsweredown-sampled to60Hz tomatchthepresentationrateoftheWNsequences inthe scanner.ThereconstructedEEGwascomputedbyconvolvingtheIRF (from0to1.5s)(fromtheEEGsession)withtheexactWNsequences usedinthefMRIsession.Previous experimentshaveshown thatthis methodcanprovideareliableestimateofEEGactivityinthealpha-band (BrüersandVanRullen,2017).BrüersandVanRullen(2017)adopteda 10-foldcross-validationapproach.Oneachvalidation,theIRFwas com-putedfrom90%trialsandtheremaining10%trialswereusedto recon-structEEG,which wasthencorrelatedwiththerealEEG.Inspiteof thenoisynatureofEEGsignalsandthesingle-triallevelestimation,the

correlationbetweenthereconstructedalphaandtherealalphawasstill compelling(meanr=0.163,t(19)=8.21,p=1.14×10−7_,_95%_CI_for_r:

0.121–0.204).Becausesignalenvelopeswerestronglycorrelatedacross EEGelectrodes,wedecidedtoonlyuseoneelectrodeforeachsubject. Foreachsubjectandeachfrequencyband,wechosetheelectrodewith maximumIRFpowerinthe“IRFarea” forthatfrequencyband—deﬁned astheelectrodewithstrongestIRFpower,onaverageacrossallsubjects, inthe“late” partoftheIRFwhere“echoes” aretypicallyvisible(from 250msto1250ms),togetherwiththe8surroundingelectrodes.For ex-ample,forthealphaband,the“IRFarea” wascenteredonPOz,and alsoincludedelectrodesP1,PO3,O1,Oz,Pz,P2,PO4,O2.The cen-tralelectrodesforthedelta,thetaandbetabandswereCz,CPzandO1 respectively.

ThereconstructedEEGwasﬁlteredin4frequencybands:delta=2– 4Hz,theta=4–7,alpha=7–14Hz,beta=14–20Hz(Fig.1,step3).The absolutevalueoftheHilberttransformeddatawastakenasthe enve-lope.ThisenvelopeofthereconstructedEEGsignalwasthenusedas aregressoroftheBOLDactivity(Fig.1,step4).Finally,theregressors were‘clipped’byremoving4satthebeginningand2sattheendofeach trialtoremoveanysystematicﬁlteringartefacts,whichcouldhaveled tospuriouscorrelations.Theclippinglengthwaslongeratthe begin-ning,inordertoavoidonsettransientsatthebeginningoftheenvelope andatthebeginningoftheBOLDresponse.

2.5. fMRIrecordingandpreprocessing

InthefMRIsession, datawerecollectedin a3TPhilips (Amster-dam,TheNetherlands)ACHIEVAscannerwitha32-channelheadcoil. Highresolutionanatomicalimageswererecordedfromeachsubjectat thebeginningof thescanning:170sagittalsliceswereacquiredwith avoxelsizeof1mm3_,_a_repetition_time_(TR)_of_8.13_ms,_and_a_time_to

echo(TE)of3.7ms.Functionalimageswereacquiredinthetransverse planeusingagradient-echopulsesequence(TE=35ms,TR=2000ms). 39sliceswereacquired(80∗₈₀_image_matrix,₂₄₀∗₂₄₀_FOV,_with

3mm3 _voxels)_to_cover_the_whole_brain._Data_analysis_was_performed

with FreeSurfer and the FreeSurfer Functional Analysis Stream (FS-FAST)(http://surfer.nmr.mgh.harvard.edu)andcustomMatlabscripts. Pre-processingfollowedtheFS-FASTprocessingstream.Allimageswere motioncorrected(usingAFNIwithstandardparameters),slice-time cor-rected,intensitynormalizedandsmoothedwitha3-mmfull-widthat halfmaximumGaussiankernel.

2.5.1. ROIdeﬁnition

InafirstanalysisweusedaGLMtodefinefunctionalregionsof in-terest(ROIs)basedonvoxelsthatwereresponsivetothevisual stim-ulus. Two typesof functionalROIs were defined accordingly:group functionalROIsandindividualfunctionalROIs.TheGLMswere per-formedintheFreesurferaveragebrainspacewiththecontrastofvisual stimulationblocksversustheinter-trial-intervalsforeachsubject.The GLMfittedthehemo-dynamicresponse(HRF)withagammafunction (delta=2.25,tau=1.25)andmodeledthedriftwithanorder1 polyno-mial.Atthetimeoftheanalysis,weusedanolderversionoftheFS-FAST software,inwhichthisgammafunctionwasthedefaultmodelfor fit-tingthehemodynamicresponse.Note,however,thatwealsoreplicated ourmainanalysisusingthecanonicalHRF,andtheresultsdidnotshow anysignificantdifference.ForallotherparametersoftheGLMweused thedefaultsettingsfromFS-FAST.

Agroupanalysiswasperformedtodefinesignificantclustersusing thiscontrast.Weusedavoxel-wisepof0.001,andacluster-wisepof 0.0005todefinethevisualclustersatthegrouplevel, withthe clus-terscorrectedformultiplecomparisonsusingMonteCarloSimulation (Hagleretal.,2006).Weusedsuchaconservativecluster-wise thresh-oldatthegrouplevelbecausewewantedtoisolatethevisualcortices preciselyfortheanalysisinthegroupfunctionalROIs.

WealsodeﬁnedthreefunctionalROIsattheindividual-subjectlevel, in rightV1,V2andin rightextrastriateareas outsideofV1andV2.

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C. Luo, S. Brüers, I. Berry et al. NeuroImage 237 (2021) 118053 Foreachanatomicalregion,wefoundtheconnectedclustercontaining

themostsignificantvoxels(lowestp-value),thenincreasedthe cluster-formingp-valuethresholdgraduallyuntilapresetnumberofvoxelswas reached.Bydoingthis,weobtainedaROIinV1,withapproximately100 voxels(R1–100).Likewise,weappliedthesamemethodinV2todefine R2–100,andintheareasoutsideofV1andV2todefineR3–100.(See FigureS1fortheresultsofcorrespondingROIswith50and200voxels)

2.5.2. AnalysisofBOLDmodulationbyalphaenvelopeintheROIs

WenextanalyzedwhetherBOLDactivityintheROIswas modu-latedbythealphaenvelope.TodeterminewhichROIsco-variedwith thealphaenvelopeofthereconstructedEEG,weperformedaﬁrst-level GLMforeachsubjectintheFreesurferaveragebrainspace.The am-plitudeenvelopeinthealphabandwasusedasaparametricregressor andmotionparameterswereincludedasnuisanceregressors.TheGLM wasperformedseparatelyfortheseregressors.TheHRFwasmodeledas agammafunction(delay=2.25,tau=1.25)andthedriftwasmodeled withanorder2polynomial.Totestthestatisticalsigniﬁcanceofalpha modulationineachROI,weperformedaonesamplet-testusing𝛽

esti-matesofallvoxelsintheROIsdeﬁnedfromtheROIdeﬁnitionanalysis above.

2.5.3. WholebrainanalysisofBOLDmodulationbythealphaenvelope

AgrouplevelGLMwasappliedtotestthecorrelationbetweenthe BOLDactivityandthereconstructedEEGalphaenvelopeinthewhole braindefinedbytheFreeSurferatlas.Specifically,aonesamplegroup meananalysiswasconductedusingthemri_glm-fitcommand(withthe– osgmflag)inFreeSurfertotestwhetherthe𝛽 valuesofeachvoxelfrom each subject’sGLMweresignificantlyhigher than0over thegroup. Therunswithhighvariancewerede-weighted(withthe-wlscesvarpct flag).Weusedavoxel-wisepof0.05(uncorrected)asthethreshold tovisualizethevoxelsthatweresignificantlymodulatedbythealpha envelope.

2.5.4. CorrelatingROIBOLDactivitywithvoxel-wiseresponsevariance

Insubsequentanalyses,weinvestigatedtherelationshipbetween re-sponsevariabilityofvoxelsinV1andV2(R1andR2included)during visualstimulationandtheleveloftheBOLDresponseineachvoxel(this analysiswasintendedtoevaluatethepossibilityofasaturationeffectin stronglyactivatedvoxelswhichcouldhavemaskedalpha-related fluctu-ations).Toquantifythevariabilityofeachvoxel,wecalculatedthe stan-darddeviation(SD)ofthepercentsignalchange(PSC)withinafixed timewindow (5-28sforeachtrial,sametimewindowasthetime windowusedtodefinetheregressors).Foreachvoxel,thepreprocessed BOLDtimeseriesofeachtrialwasextractedandconvertedtoPSCby dividingtheBOLDsignalbytheprestimulusbaseline(6s).TheSDof thePSCwascalculatedacrosstimepertrialandfurtheraveragedacross trials,runsandsubjects.ToestimatetheleveloftheBOLDresponsein eachvoxel,weusedtheTvalueofthestimulus-onvs.stimulus-off con-trastforeachvoxel.Finally,wecalculatedthecorrelationbetweenthe TvalueandtheSDofthePSCacrossvoxels.

2.5.5. CorrelatingtheBOLDactivityinV1andV2withotherfrequency envelopes

Finally,wetestedifotherfrequenciessignificantlycorrelatedwith theBOLDinV1andV2.Asdoneforthealpha-bandenvelope,foreach subjectweusedthedelta,thetaandbetaenvelopesasparametric regres-sorsandperformedseparatefirstlevelGLMsforeachregressor.Motion parameterswereusedas nuisanceregressors.The HRFandthedrift weremodeledusingthesamefunctionasabove.Wenextperformeda onesamplet-testtotestwhetherthe𝛽 estimatesofallthevoxelsinV1 andV2fromthesefirstlevelGLMsweresignificantlyhigherthan0,and anonparametricpermutationtesttodetermineifthe𝛽 estimatesofany frequencywerehigherthanthoseoftheotherfrequencies.

3. Results

Wefirstdeterminedthevoxelsthatwereactivatedbythestimulus, bycontrastingstimulusonversusoff periods.Agrouplevelanalysis re-vealedtwoclustersofactivityintherighthemisphere:clusterone(C1, Fig.2A,left)waslocatedinthelingualgyrusbelowthecalcarinefissure, andextendingtowardsthefusiformgyrus(p<0.05corrected,MNI co-ordinates:x=21.9,y=−79,z=−8.3).Thesecondcluster(C2,Fig.2A, right)ofactivitywasfoundinthelateraloccipitalgyrus(p<0.05 cor-rected, MNIcoordinates:x=41.3,y=−72.6,z=−0.5).There wasno corresponding cluster in theleft hemisphere,sincethestimuluswas lateralizedtotheleft.ThesetwoclustersC1andC2wereconsidered asgroupfunctionalregions-of-interest(ROIs).Inadditiontothesetwo ROIs,wedefinedthreeothergroupfunctionalROIsbyconsideringthe overlapofC1andC2withtheFreesufer-atlasbaseddefinitionsofV1 andV2:R1andR2,theintersectionofC1withV1andV2respectively, andR3,whichwerethevoxelsinC1thatwerenotinV1orV2. Addition-ally,Freesufer-atlasbasedV1andV2weredefinedasanatomicalROIs. (Fig.2A).Finally,wedefinedfunctionalROIsattheindividual-subject level(withapre-determinedvoxelnumber:100voxels)inV1,V2andin extra-striateareasoutsideofV1andV2.Assomevoxelssharedthesame p-value,theselectionofthemostsignificantvoxelsdidnotalwaysreturn theexactnumberofexpectedvoxels.Acrosssubjects,theregions actu-allycontained103.1+−5.1voxels(R1,mean+-sd),109.4+−17.7voxels (R2)and111.2+−12.2voxels(R3).

Sincealphais themainfrequencycomponentintheIRF,wefirst used the7–14Hz(alpha)envelope ofthereconstructedEEGasa re-gressorinthefMRIanalysistodeterminewhichROIsco-varywiththe perceptualechoesinducedbythewhite-noiseluminancesequence.In ordertotestthesignificance,weconductedat-testandapermutation test.Forthepermutationtest,wecreated2000surrogatesbyshuffling the alphaenvelopes of all thetrialsfor each subjectandperformed thefirst-levelGLMontheshuffleddata.Pvaluesofthemean coeffi-cientswerecomputedfromthepercentilewithinthepermutednull dis-tributions.Inthepre-definedgroup-levelfunctionalROIs(C1,C2,R1, R2andR3)wefoundthatBOLDactivitywasnotsignificantly modu-lated bythealphaenvelope ofthereconstructedEEG(Fig.3A, mid-dle).Themeancoefficientof R1,R2,R3,C1 andC2was closeto0, withlargeinter-subjectvariability(t-testagainst0:R1t(19)=−0.0734,

p=0.9422,R2t(19)=0.3510,p=0.7295,R3t(19)=0.1249,p=0.9019, C1t(19)=0.1748,p=0.8631,C2t(19)=0.4264,p=0.6746. Permuta-tiontest:R1p=0.5400,R2 p=0.4900,R3p=0.5000,C1p=0.4800, C2p=0.4300).Likewise,theindividual-levelfunctionalROIswere in-signiﬁcant,eventhoughthealphaenvelopemodulationofR1–100was visiblyhigherthanin theotherfunctionalROIs(Fig.3A, left)(t-test against0: R1–100t(19)=1.1484, p=0.2650,R2–100t(19)=0.1195,

p=0.9061,R3–100t(19)=−0.4706,p=0.6433.Permutationtest:R1– 100 p=0.1400, R2–100p=0.5200,R3–100p=0.7500).Besides, the individual functionalROIs with 50 voxels and 200 voxels also did not show significant alpha modulation (Figure S1). However, the mean coefficientsforV1andV2weresignificantlyhigher than0in both hemispheres(Fig.3A, right). Thecorrespondingstatistical tests revealed: for Right V1, t-test against 0: t(19)=2.3976, p=0.0269, mean=0.0072,95%CI=0.0009– 0.0135.Permutationtest:p=0.01, 95%CI=−0.0060– 0.0054;RightV2,t-testagainst0:t(19)=2.2400,

p=0.0372, mean=0.0058, 95% CI=0.0004 - 0.0111. Permutation test: p=0.02,95% CI=−0.0050 – 0.0051; Left V1, t-test against0: t(19)=2.7072,p=0.0140,mean=0.0081,95%CI=0.0018– 0.0143. Permutationtest:p=0.01,95%CI=−0.0056– 0.0061;LeftV2,t-test against0:t(19)=2.2635,p=0.0355,mean=0.0057,95%CI=0.0004 -0.0110.Permutationtest:p=0.02,95%,CI=−0.0048– 0.0047.The t-testsandpermutationtestforV1andV2wereconductedusingallvoxels inV1andV2.Inagreementwiththeseﬁndings,awhole-brainanalysis revealedwide-spreadBOLDactivitymodulationbythealphaenvelope bilaterallyinV1andV2(Fig.3B).TheBOLDactivitiesmodulatedby delta,thetaandbetaintheROIsareshowninsupplementaryFigureS2, 4

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Fig. 2. A) Group level retinotopic activa-tionin earlyvisualareasof the right hemi-sphere. The light purple represents the lo-cation of the primary visual area (V1) and the darkerpurple representsthe location of thesecondaryvisualareaV2,whichwere ex-tracted with the Freesurfer atlas. Statistical analysisatthegrouplevelrevealed2clusters ofretinotopicactivityinresponsetothe stimu-lus(red/yellow):clusterone(C1)ontheleftis locatedbelowthecalcarinesulcus(MNI coor-dinates:x=21.9,y=−79,z=−8.3)withpartial overlapwithV1andV2,andcluster2canbe seenintherightpanel,possiblycorresponding tolateraloccipitalcortex(LOC).R1,R2andR3 weredefinedas:R1=V1∩C1,R2=V2∩C1, R3=C1– (V1∪V2).Thecolorbarrepresents -log10ofthepvalueofat-testagainst0.B) Dis-tributionoft-values(voxelcount)forthe con-trast between stimulus-periodsand fixation-periods. The functional ROI was definedas t>5(redshadedarea),andonlyincludes right-hemispherevoxels(asexpected,sincethe stim-uluswaslocatedinthelefthemifield).Inboth LeftandRightV1-V2voxels,thereisa signif-icanttrendtowardsnegativevalues:63%and 55%ofvoxels(respectively)hadnegative stim-ulusresponses,andthisproportionwas signifi-cantlylargerthan50%(binomialtest,p<10−10 inbothcases).(Forinterpretationofthe refer-encestocolourinthisfigurelegend,thereader isreferredtothewebversionofthisarticle.)

andseesupplementaryFigureS3forthewholebrainanalysisforthese threefrequencies.

TheseresultsindicatethatthereconstructedenvelopeofEEGalpha wassignificantlycorrelatedwithBOLDresponsesinV1andV2. Sur-prisinglyhowever,thiscorrelationwasvisibleoutside,butnotwithin thedirectly(retinotopically)stimulatedregion(C1).Thisleavestwo im-portantissuestoaddress:first,theabsenceofalphamodulationinthe stimulus-responsiveROI,wherewecould havenaturallyexpectedit; second,thepresenceofalphamodulationinunstimulatedregionsof vi-sualcortex,reachingasfarastheoppositehemisphere.Wetentatively interpretthefirstissueasaconsequenceofsignalsaturation,andthe secondasasignatureofwide-spreadinhibition,asdetailedbelow.

First, we hypothesized that the lackof alpha modulation in the stimulus-responsiveROI(C1)mayreﬂectsaturationinthesevoxelsby thecontinuedpresenceofthevisualstimulus.Asaresultofthis satura-tioneﬀect,wehypothesizedthatthesevoxelswouldnotbesusceptible tothesmallerandrapidmodulationsintheluminanceofthestimulus. Inotherwords,overthegroupofvoxels,wewouldexpectvoxelsthat havehighlevelsofresponse(e.g.,thosewithintheretinotopically stim-ulatedregions) tohave lowerresponsevariability(sincethey would not be modulated by the random changes in stimulus luminance). In contrast, voxels that are modulated (possibly indirectly) by the

luminancechangesbutnotsaturatedbystimuluspresentation,would show largersignal variability, buta lower BOLDresponse. Inother words,overthegroupofvoxels,weexpectedanegativecorrelation be-tweentheBOLDresponseandsignalvariabilityofvoxelsinV1andV2. Totestthishypothesis,weanalyzedtherelationshipbetweentheSDof PSC(ameasureofsignalvariability)andtheTvalueofthestimulus-on vs.stimulus-off contrast(ameasureofBOLDresponse)ofeachvoxelin V1andV2.TheSDofthePSCofeachvoxelinV1andV2(asexplained intheMethodsSection)wasaveragedacrosstrials,runsandsubjects. TheresultsshowedthattheTvaluewasnegativelycorrelatedwiththe SDof PSC(r=−0.1538,p< 0.01).Inotherwords, aspredicted, the overallstimulus-inducedBOLDresponsewasinverselyrelated,across voxels, to the signal variability over time. This is compatible with the notion thatsignal saturation preventedusfrom observing alpha amplitudefluctuationsintheretinotopicregionsofinterest(C1andC2). Second, we turned to the observation of widespread alpha-IRF modulationsacross V1andV2,bilaterallyin bothhemispheres. One possibleinterpretationcouldbethatitwasstimulus-dependent inhibi-tion,ratherthanexcitation,outsideofthestimulus-responsiveROIthat ledtothewidespreadalpha-IRF modulationsbyroutinginformation. To explore this possibility, we first looked into the distribution of stimulus-relatedBOLDactivityacrossearlycortex(V1-V2),thatis,the

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C. Luo, S. Brüers, I. Berry et al. NeuroImage 237 (2021) 118053

Fig.3.A)𝛽 weightsofmodulationofBOLDactivitybythealphaenvelopeofthereconstructedEEGintheregionsofinterest.Barsrepresentmean±s.e.m acrosssubjects.Noindividual-level(left)orgroup-level(middle)functionalROIsweresignificantlymodulatedbytheperceptualechoes.Incontrast,BOLDactivity inbilateralV1andV2(anatomicalROIs)wassignificantlymodulatedbythealphacomponentofthereconstructedEEG(right).Theblackasterisksrepresenta significantdifferenceagainst0,t-testacrosssubjects(N=20,p<0.05).Theredasterisksindicatethatthecoefficientissignificantlyhigherthanthenullhypothesis distributionofthesurrogates(nonparametrictest).B)Wholebrainanalysisofregionscorrelatedtofluctuationsinthealphapowerenvelopeintherightandleft hemispheres.Theactivationsextendwellbeyondthestimulusresponsiveregionsofinterests(C1outlinedingreen)intoV1andV2(outlinedinwhite).Thesignificant voxelscomputedfromthegroup-levelGLMareshowninred/yellowatathresholdofp<0.05(-log10(0.05)=1.3).Thecolorbarrepresents-log10ofthepvalue ofat-testagainst0.NotethatnosignificantnegativecorrelationsofBOLDwithalphaenvelopewereobservedinvisualareas(andonlyfewsparselydistributed negativecorrelationsovertherestofthebrain),hencethecolorscaleonlydisplayspositivecorrelations.(Forinterpretationofthereferencestocolourinthisfigure legend,thereaderisreferredtothewebversionofthisarticle.)

contrastbetween stimulusperiodsandﬁxationperiods(Fig.2B).We foundindeed,inadditiontoanumberofvoxelswithhight-valuesinthe righthemisphere(t>5.0,correspondingtoourROI),ageneralshiftof thedistributiontowardsnegativeBOLDactivations.Thisnegativetrend wassigniﬁcantlypresentinbothleftandrightV1-V2,eventhoughthe stimuluswaslateralized(63%and55%voxelsinleftV1-V2andright V1-V2respectivelyhadnegativeresponsestostimuli,binomialtest:p<

10−10_in_both_cases)._This_is_compatible_with_broadly_distributed

inhibi-tionoutsideofthestimulusregion.Eventhoughsuchinhibitioncould happenwithoutanyrelationtothestimulusﬂuctuations,thefactthat themanyvoxelsinthesamebroadregionalsoshowpositivecorrelation with the reconstructed EEG envelope hints at a possible functional

relation between neural inhibition and alpha IRF propagation. The existenceofsucharelationisfurthersupportedbytwoobservations: first,thereisaweakbutsignificantnegativecorrelationacrossvoxels betweenthet-valueofstimulusresponseandthet-valueofthealpha IRFmodulation(r=−0.018,p<0.04);second,thevoxelsthatweremost significantlymodulatedbythealphaIRF(voxelsmappedinFig.3B) tendedtohavenegativet-valuesforstimulusresponse(54.4%negative values,p=0.0001,binomialtest).

Finally,weaskedifactivityinV1andV2wasmainlymodulated by alpha,orifotherfrequency bandsalsomodulatedtheBOLD sig-nalstrongly.WeimplementedseparateGLMswiththeenvelopesofthe reconstructed EEGﬁltered in thedelta,theta,andbetabands as

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Fig.4. CoefficientsofthemodulationofBOLDactivitybythereconstructed EEGenvelopeofthedelta,theta,alphaandbetabandfrequencies.Thebars representthemean,andtheerrorbarsrepresentthestandarderrorofthemean acrosssubjects.Theblackasteriskrepresentsasignificantdifferenceagainst 0,t-testacrosssubjects(N=20,p<0.05).Theredasteriskindicatesthatthe coefficientissignificantlyhigherthanthe95thpercentileofthenullhypothesis distribution(nonparametrictestagainstotherfrequencies).Thisfigureshows thattheBOLDactivityisonlymodulatedbythealphaenvelope.Thedashlines indicatethe95%and99%CIofthenulldistribution.(Forinterpretationof thereferencestocolourinthisfigurelegend,thereaderisreferredtotheweb versionofthisarticle.)

gressorsfortheBOLDactivity.Theresults,showninFig.4,revealed thatthecoefficientsfromtheseotherfrequencybandswerenot signif-icantlyhigherthanzero(V1andV2:deltat(19)=1.1142,p=0.2791, thetat(19)=1.0316,p=0.3152,alphat(19)=2.5357,p=0.0202,beta t(19)=−0.1720, p=0.8653). A nonparametricpermutation test was conductedtodetermineifIRF-dependentBOLDmodulationsatany fre-quencywerehigherthanfortheotherfrequencies.Surrogateswere com-putedbyshufflingthecorrelationcoefficientsacrossallfrequencybands insingle-subjectdataforeachanatomicalROI(leftV1,leftV2,rightV1 andrightV2),thenaveragingacrosssubjectsandROIs.The95%and 99%CI aswellasthep-valuesweretakenfromthenulldistribution composedofthesesurrogates(Permutationtest:deltap=0.6000,theta

p=0.4200,alphap=0.0020,betap=0.9800).Thesameanalysiswas alsoperformedonthesefrequenciesinleftV1,V2andrightV1,V2 sep-arately,andtheresultisshowninsupplementaryFigureS4

4. Discussion

Inthisstudy,weconductedanEEG-fMRIexperimenttoinvestigate theneuralbasisoftheIRF.WeﬁrstmeasuredtheIRFofeachsubject in the EEG session. We thenreconstructed an estimate of the EEG signalbyconvolving theIRFwith thestimulipresentedin thefMRI session.TheenvelopesofreconstructedEEGsignalsinthetheta,alpha andbetabandsweretakenasregressorsfortheGLM.Wefoundthat theenvelopeoftheEEGalpha,morethantheotherfrequencies,was

positivelycorrelatedwithBOLDactivityinV1andV2,butsurprisingly notwithactivityintheretinopicallystimulatedregions.Wehypothesize thatthelackofeﬀectintheretinopicallystimulatedROIsmightbedue toasaturationeﬀectbythevisualstimulus.

Theactivationsfoundinearlyvisualareas(Fig.3)areinlinewiththe observationthattheIRFisavisualresponse,strongestinposterior re-gions(VanRullenandMacDonald,2012).Intriguingly,large-scale acti-vationswerefoundinleftV1andV2,i.e.,inthehemispherethatwasnot directlystimulated(Fig.3B).Letusfirstconsiderthepossibilitythat sub-jectsmayhavedirectlyperceivedthestimuliintheirrightvisualfield. Thiscouldhaveoccurredforexamplebecauseofunwantedeye move-ments,orpossiblybecauseofstimulusilluminationreflectingoff ofthe innerwallsoftheMRI.Toavoidthissecondpossibility,wehadelected tousesmallerstimulithaninourpreviousstudies(2° vs.7° inVanRullen andMacdonald,2012andsubsequentstudies).Toavoidthefirst possi-bility,weinstructedsubjectstofixateinthecenterofthescreen,and avoidunnecessaryeyemovements.Thecircumscribedstimulus-related activationsin relativelysmall sub-regionsof V1andV2of theright hemifieldwhencontrastingstimulus-onandstimulus-off periods(Fig.2) suggestthatsubjectssuccessfullymaintainedfixationandthatthe stim-uluspositionwasspatiallyrestricted,asintended.Ifsubjectshadmade systematiceyemovementsorifthestimulushadbeenreflectedat dis-tantpositions,we wouldhaveexpectedinsteadabroader patternof stimulusactivations,possiblyextendingtotheotherhemifield.Hence, thealpha-envelopeinducedactivationsinthelefthemisphere(Fig.3B) appeartobeduetoIRFpropagationacrosshemispheres.Thiswould beconsistentwithpreviouslyreportedfindingsthattheIRFpropagates asa travelingwave(AlamiaandVanRullen,2019; Lozano-Soldevilla andVanRullen,2019).Inparticular,thestudybyLozano-Soldevillaand VanRullen(2019)pointedoutthatthepropagationoftheIRFto lat-eralizedWNsequencesfollowsretinotopicrulessuchthatitcantravel fromcontra-lateraltoipsi-lateralregions,inagreementwiththecurrent results.

ItisreasonabletocompareourresultswiththoseofEEG-fMRIstudies ofthegeneratorsofthealpharhythm,becauseoftherelationbetween theIRFandthealpharhythm—eventhoughthecurrent understand-ingofalphageneratorsisincomplete.TheEEGalphapowerwasfound tobenegativelycorrelatedwithBOLDactivityinoccipitalcorticesin both resting-statestudies(deMunck etal.,2007; DiFrancescoetal., 2008;Goldmanetal.,2002;Gonçalvesetal.,2006;Laufsetal.,2003; Moosmannetal.,2003)andduringtaskperformance(Scheeringaetal., 2016;Scheeringaetal.,2009;Zumeretal.,2014).Onthecontrary,we foundtheIRFenvelopetobepositivelycorrelatedwithV1andV2BOLD signals.Thecommonneuralbasis(earlyvisualareas)togetherwiththe oppositeactivationproﬁles(i.e.,oppositecorrelationswiththeBOLD) indicatethattheIRFandtheEEGalpharhythmmightshareneural path-ways,butservedistinctfunctionalrolesinthebrain.

TheresultsofthepresentstudysuggestthattheIRFinresponseto left-visualfieldstimulimighthaveoriginatedfromoneormultiple start-ingpointsintherightearlyvisualcortex(V1,V2),fromwhichitspread overmuchoftheearlyvisualcortex.Theactivationattheorigincould notbedirectlymeasured,presumablybecauseofBOLDsaturation ef-fects,howeveritspropagationtodistantpartsofvisualcortex,including theoppositehemifield,wasreadilyvisible.Itisplausiblethatthis prop-agationofIRFoscillationstodistantpartsofthevisualcortexmaybe as-sociatedwithstimulus-dependentinhibitionofnon-task-relatedregions, thoughthisconclusionmayrequirefurtherconfirmation.Ourfindings areofimportanceforfurtherstudiestolocatetheoriginoftheIRFmore precisely.Forexample,futurestudiescouldspecificallyrecordtheIRF inV1andV2usingintracranialrecordingsduringdifferentvisualtasks, tobetterunderstandwhereandwhentheIRFappears,andhowit prop-agatestootherpartsofvisualcortex.

ItisworthemphasizingthatourmeasureoffMRIcorrelatesof per-ceptualechoesisonlyanindirectoneandthat,consequently,our con-clusionsremaintentative.First,echoesweremeasuredoﬄineoutside thescanner,andfromthecorrespondingIRFproﬁleswepredictedthe

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C. Luo, S. Brüers, I. Berry et al. NeuroImage 237 (2021) 118053 “reconstructedEEG” signalduringthefMRIsessions.Thispredictionis

statisticallyvalid(BrüersandVanRullen,2017),butonlyan approxi-mationofthetrue EEGsignal.Second,weweresurprisedtofindan absenceofBOLDsignalmodulationsinthefunctionallydefinedROIs. Whilethespeculativeinterpretationweproposedintermsofresponse saturationappearstobesupportedbyourcontrolanalyses,theremay stillbe otherexplanations,e.g., basedon stimulus-dependent inhibi-tionofnon-taskrelatedregions,oronothernon-specificeffects.Third, wefocusedonalpha-bandenvelopefluctuationsasaregressorforthe BOLDanalysis,motivatedbythestrongalphapowertypicallyobserved asthemainsignatureofperceptualechoes(VanRullenandMacdonald, 2012;BrüersandVanRullen,2017;Lozano-SoldevillaandVanRullen, 2019).However,IRFsalsocontainweakersignalsfromotherfrequency bands(delta,theta,beta),thatcanexplainasignificantproportionof variancefrom the reconstructedEEG (Brüers andVanRullen, 2017). Accordingly,wealsofoundsignificant(albeitweakerandless consis-tent)BOLDresponsestodelta-andtheta-bandenvelopemodulationsin earlyvisualcortex(SupplementaryFigures2,3and4).Finally,our fo-cusonamplitudeenvelopemodulationsleavesasideotherpotentially informativepartsoftheEEGsignal,reflectedinphasemodulationsor insecond-orderrelationssuchascross-frequencycoupling.Whilethis choicemakessenseforaninitialinvestigation,webelievethatfuture studiescouldattempttocharacterizethesemorerapidEEGsignalsand theirconsequencesonBOLDactivity.

Inconclusion,ourstudyfoundBOLDactivationswhosetimecourse wasrelatedtotheIRFenvelopeintheearlyvisualcortex.Thewidely spread activation might be due to the propagation of (possibly in-hibitory)IRFtravelingwaves(Lozano-SoldevillaandVanRullen,2019; AlamiaandVanRullen,2019).Ourstudyadvancesourknowledgeof thespatialproperties oftheIRFbynarrowingdown itsneuralbasis, thereforepavingthewayforfuturestudiestopreciselylocalizethe gen-erator(s)oftheIRFanddeepenourunderstandingofitsfunctional rel-evance.

Creditauthorstatement

CL: EEG analysis, fMRI analysis, writing-original draft, writing-reviewingandediting.SB:Dataacquisition(EEG,fMRI),EEGanalysis, fMRIanalysis,writing-originaldraft,writing-reviewingandediting.IB: participantmedicalscreening.RV:conceptualization,writing- review-ingandediting.LR:fMRIanalysis,conceptualization,writing-reviewing andediting.

Dataavailability

The data that support the findings are available on figshare (10.6084/m9.figshare.14601342)

Acknowledgments

ThisworkwassupportedbyanERCgrantP-CYCLESnumber614244 andanANRgrantOSCI-DEEPnumber19-NEUC-0004-01toRV.Weare gratefultoJean-PierreJaﬀrezouforassistanceineditingthemanuscript. CLisfundedbyChinaScholarshipCouncil.TheauthorsthankNathalie VayssiereandtheINSERM/UPSUMR1214MRIplatformfortechnical assistance.

Supplementarymaterials

Supplementarymaterialassociatedwiththisarticlecanbefound,in theonlineversion,atdoi:10.1016/j.neuroimage.2021.118053.

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