ContentslistsavailableatScienceDirect
NeuroImage
journalhomepage:www.elsevier.com/locate/neuroimage
Experience-dependent modulation of the visual evoked potential: Testing effect sizes, retention over time, and associations with age in 415 healthy individuals
Mathias Valstad
a,∗, Torgeir Moberget
a,b, Daniël Roelfs
a, Nora B. Slapø
a, Clara M.F. Timpe
a,b, Dani Beck
a,b, Geneviève Richard
a, Linn Sofie Sæther
a, Beathe Haatveit
a, Knut Andre Skaug
a,c, Jan Egil Nordvik
d, Christoffer Hatlestad-Hall
b,e, Gaute T. Einevoll
f,g, Tuomo Mäki-Marttunen
a,h, Lars T. Westlye
a,b, Erik G. Jönsson
a,i, Ole A. Andreassen
a, Torbjørn Elvsåshagen
a,e,∗aNORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Norway
bDepartment of Psychology, University of Oslo, Oslo, Norway
cMentisCura, Reykjavik, Iceland
dCatoSenteret Rehabilitation Center, Son, Norway
eDepartment of Neurology, Oslo University Hospital, Oslo, Norway
fFaculty of Science and Technology, Norwegian University of Life Sciences, Ås, Norway
gDepartment of Physics, University of Oslo, Oslo, Norway
hSimula Research Laboratory, Oslo, Norway
iDepartment of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
a b s t r a c t
Experience-dependentmodulationofthevisualevokedpotential(VEP)isapromisingproxymeasureofsynapticplasticityinthecerebralcortex.However,existing studiesarelimitedbysmalltomoderatesamplesizesaswellasbyconsiderablevariabilityinhowVEPmodulationisquantified.Inthepresentstudy,weuseda largesample(n=415)ofhealthyvolunteerstocomparedifferentquantificationsofVEPmodulationwithregardstoeffectsizesandretentionofthemodulation effectovertime.WeobservedsignificantmodulationforVEPcomponentsC1(Cohen’sd=0.53),P1(d=0.66),N1(d=-0.27),N1b(d=-0.66),butnotP2(d=0.08), andinthreeclustersoftotalpowermodulation,2–4minafter2Hzprolongedvisualstimulation.ForcomponentsN1(d=-0.21)andN1b(d=-0.38),aswellforthe totalpowerclusters,thiseffectwasretainedafter54–56min,bywhichtimealsotheP2componenthadgainedmodulation(d=0.54).Moderatetohighcorrelations (0.39≤𝜌≤0.69)betweenmodulationatdifferentpostinterventionblocksrevealedarelativelyhightemporalstabilityinthemodulationeffectforeachVEPcomponent.
However,differentVEPcomponentsalsoshowedmarkedlydifferenttemporalretentionpatterns.Finally,participantagecorrelatednegativelywithC1(𝜒2=30.4), andpositivelywithP1modulation(𝜒2=13.4),whereasP2modulationwaslargerforfemaleparticipants(𝜒2=15.4).Therewerenoeffectsofeitherageorsexon N1andN1bpotentiation.TheseresultsprovidestrongsupportforVEPmodulation,andespeciallyN1bmodulation,asarobustmeasureofsynapticplasticity,but underscoretheneedtodifferentiatebetweencomponents,andtocontrolfordemographicconfounders.
1. Introduction
Duetotheessentialroleofsynapticplasticityinlearningandmem- ory(Takeuchi etal., 2013),aswell asits likelyrolein theetiology ofa rangeof psychiatricdisorders(SchizophreniaWorkingGroupof thePsychiatricGenomicsConsortium,2014;Stephanetal.,2006),sev- eral non-invasivemethodologies for studying long termpotentiation (LTP)-likesynapticplasticityinhumanshavebeendeveloped.Among theseapproaches,theapplicationofhighfrequencyorprolongedvisual stimulationto manipulatevisual evokedpotentials (VEPs)measured usingelectroencephalography(EEG) hasprovenespeciallypromising (Cooke andBear, 2012). Supporting theutility of this experimental paradigminclinicalresearch,modulationofVEPcomponentsafterhigh
∗Correspondingauthorsat:NorwegiancenterforMentalDisordersResearch,OsloUniversityHospital,PoBox4956Nydalen,Norway.
E-mailaddresses:[email protected](M.Valstad),[email protected](T.Elvsåshagen).
frequencyorprolongedvisualstimulationappearstobealteredinmood (Elvsåshagenetal.,2012;Normannetal.,2007)andpsychoticillnesses (Çavuşetal.,2012).However,thespecificVEPcomponentsexhibiting robustmodulationeffectsanddifferencesbetweenpatientsandcontrols, aswellastheretentionofmodulationeffects,havevariedbetweenstud- ies,highlightinganeedforfurthercharacterizationofVEPmodulation inducedbyprolongedvisualstimulationinalargesampleofhealthy individuals.
InastandardVEPmodulationparadigm,subjectsareexposedfirstto VEPelicitingcheckerboard(e.g.Normannetal.,2007)orgratingstim- uli(e.g.McNairetal.,2006),presentedeitherasaphasereversal(e.g.
Normannetal.,2007)orasapatternonsetwithinterstimulusinter- vals(e.g.Teyleretal.,2005).Then,subjectsareexposedtoaprolonged
https://doi.org/10.1016/j.neuroimage.2020.117302
Received6February2020;Receivedinrevisedform12August2020;Accepted18August2020 Availableonline20August2020
1053-8119/© 2020TheAuthors.PublishedbyElsevierInc.ThisisanopenaccessarticleundertheCCBYlicense.(http://creativecommons.org/licenses/by/4.0/)
Table1
OverviewofVEPmodulationstudies.
Author, year a N b P. c Intervention Modulation d
Teyler et al., 2005 6 po 2 min 9 Hz checkerboard N1b ↓ McNair et al., 2006 10 po 2 min 8.6 Hz grating N1b ↓ Normann et al., 2007 32 pr 10 min 2 Hz checkerboard C1 ↑, P1 ↑, N1 ↓ Ross et al., 2008 18 po 2 min 8.6 Hz grating N1b ↓ Çavu ş et al., 2012 41 po 2 min 8.87 Hz checkerboard C1 ↓, N1b ↓ Elvsåshagen et al., 2012 66 pr 10 min 2 Hz checkerboard P1 ↑, N1 ↓ Forsyth et al., 2015 65 po 2 min 8.87 Hz checkerboard C1 ↑, P2 ↑ de Gobbi-Porto et al., 2015 17 po 2 min 9 Hz checkerboard N1b ↓ Klöppel et al., 2015 37 pr 10 min 2 Hz checkerboard C1 ↑, P1 ↑ Smallwood et al., 2015 21 po 2 min 8.6 Hz grating N1b ↓ Forsyth et al., 2017 45 po 2 min 8.87 Hz checkerboard C1 ↑, P2 ↑ Jahshan et al., 2017 64 po 2 min 8.87 Hz checkerboard N1b ↓, P2 ↑e Wilson et al., 2017 24 po 2 min 9 Hz checkerboard N1b ↓ Spriggs et al., 2017 49 po 2 min 8.6 Hz grating N1b ↓, P2a ↑ D’Souza et al., 2018 47 po 2 min 8.87 Hz checkerboard f
Spriggs et al., 2018 40 po 2 min 9 Hz grating C1 ↓, N1 ↑, P2 ↑ Sumner et al., 2018 20 po 2 min 9 Hz grating P2 ↑ Zak et al., 2018 58 pr 10 min 2 Hz checkerboard C1 ↑, P1 ↑, N1 ↓ Abuleil et al., 2019 47 po 2 min 9 Hz checkerboard P1 ↓, N1b ↓ Spriggs et al., 2019 28 po 2 min 8.6 Hz grating N1b ↓ Wynn et al., 2019 65 po 4 min of 10 Hz grating, on/off 5s P1 ↓, N1b ↑, P2 ↑e Sumner et al., 2020 30 po 2 min 9 Hz grating N1 ↓, P2 ↑ Tableofstudiesusinghighfrequencyorprolongedvisualstimulationtomanipulatevisualevoked potentialsinhumans.aDetailsinreferences.bResultsforsomeparticipantsmayhavebeenre- portedinmorethanonepaper.cPresentation(P.)iseitherpatternonset(po),orphasereversal (pr).dDuetodifferingmethodsofanalysisbetweenstudies,theexactnatureofthemodulated componentscanvary,andduetodifferencesinstatisticalanalysisbetweenstudies,theprobabil- ityofactualmodulationhavingbeenobservedcanalsovary.Arrowsdenotedirectionofchange pre-postinterventionintheamplitudeofacomponent(e.g.anupwardarrowforacomponent thatisnegativeatbaselinemeansthatthecomponentbecamelessnegativeorevenpositiveafter intervention).eTheauthorsdonotdirectlyperformacomponentanalysis.Componentannotation isthereforetentative.fNosignificantmodulationofthereportedcomponent.
(e.g.Normannetal.,2007)orhigh-frequencyversion(e.g.Teyleretal., 2005)ofthecheckerboardorgratingstimulus.Lastly,aftersomedelay, subjectsareexposed totheinitialstimulationagain,whichnowtyp- icallyevokesasignificantly modulatedvisual potential.Importantly, themechanismsunderlying suchexperience-dependent VEPmodula- tionseemtosharemanycharacteristicswithLTP,thushavingearned theplaceholderepithetLTP-like plasticity.Inmice,bothN-methyl-D- aspartatereceptor(NMDAR)antagonistslike3-(2-carboxypiperazin-4- yl)-propyl-1-phosphonicacid(CPP),and𝛼-amino-3‑hydroxy‑5-methyl- 4-isoxazolepropionicacidreceptor(AMPAR)insertion-inhibitorGluR1- CT prevent experience-dependent VEP modulation from occurring (Frenkeletal.,2006).Also,electricalstimulation-inducedLTPattha- lamocorticalsynapsesintheprimary visualcortex(V1)enhancesvi- sualevokedpotentialsandinhibitsfurtherexperience-dependentVEP modulation(CookeandBear,2012).Inhumans,thespatialfrequency- andorientation-specificreceptivefieldsof V1neuronshavebeenex- ploitedtodemonstrateaspecificityofexperience-dependentVEPmod- ulationthatisconsistentwiththesynapticspecificitycharacteristicof LTP(McNairetal.,2006;Rossetal.,2008).
Although most published studies have reported experience- dependentVEPmodulation,theexacttimewindowsandcomponents modulatedandthedurationofmodulationhavevariedbetweenexper- iments(Table1).Inhumans,theVEPischaracterizedbycomponents separatedintime,voltagepolarity,andlikelyneuralgenerators,with thelargelynegativeC1probablyoriginatingintheprimaryvisualcor- tex(DiRusso,Martínez,Sereno,Pitzalis,andHillyard,2002)andoc- curringat ~50–90mspost-stimulus,thepositiveP1at~80–120ms andthenegativeN1at~130–200ms,bothprobablyoriginatinginstri- ateandextrastriateareas(DiRussoetal.,2002),andthepositiveand likelyverycomplexP2at~200–300mspost-stimulus.Whilesomere- searchers(McNairetal.,2006;Rossetal.,2008;Teyleretal.,2005) demonstratedmodulationoftherelativelylate-occurringN1bcompo-
nent exclusively, others have demonstrated an effect that is earlier andmorewidespread,withmodulationoftheP1andN1components (Elvsåshagenetal.,2012),andevenoftheC1component(Çavuşetal., 2012;Normannetal.,2007).However,inthesetwostudiesdemonstrat- ingC1modulation,oppositedirectionsofeffectwereobserved.Thedu- rationofVEPmodulationhasalsovariedbetweenstudies.Amongthe studiesmeasuringVEPwithinthetimerangeofclassicalLTP,thatis, atleast30min(Lisman,2017)afterprolongedorhighfrequencyvisual stimulation,onedemonstratedretentionofthemodulation(Teyleretal., 2005),whileanotherdidnot(Rossetal.,2008).Thus,itisalsounclear towhichextentearly(<30minafterhighfrequencyorprolongedstim- ulation)andlate(>30minafterhighfrequencyorprolongedstimula- tion)VEPmodulationareassociated,suchthatearlyVEPmodulation couldbetakenasindicativeoflateVEPmodulation.Asubstantialpro- portionoftheobserveddifferencesbetweenstudiesmaybeattributable tovariationsinexperimentcharacteristicssuchasthespecificvisual stimulusused(gratingorcheckerboard),thepresentationofthevisual stimulus(patternonsetorphasereversal),thedurationandfrequency ofstimulationattheinterventionandatbaselineassessments,aswellas inthemethodofanalysisemployed.However,heterogeneityofresults between studiesthataresimilar inthese respectsseems toimplicate errorvariance.
Indeed,someofthestudiesathandmayhavebeenunderpowered with respect todifferentiation between modulation of separate VEP components,andmaynothavecontrolledforadequateconfounders.
PotentialconfoundersoftheVEPmodulationeffectincludetheageand sexofparticipants.Withage,thereisageneraldeclineinneuralplas- ticityinanimals(BurkeandBarnes,2006).UsingtheVEPmodulation paradigminhumans,visualcorticalplasticityhasbeendemonstratedin olderindividualsinonesample(deGobbi-Portoetal.,2015),butnot inanother(Spriggsetal.,2017),andtherelationshipcouldbefurther elucidatedwithacontinuousagedistributionamongparticipants.Fur-
ther,sexdifferencesinanatomicalfeaturessuchascorticalgyrification (Ludersetal.,2004)mightimpactorientationofneuraltissue,electrical conduction,andultimatelyscalpEEGsignals.Anotherfactorthatcould impactobservedVEPmodulationisthelevelofattentionaffordedthe visualstimulus,especiallyduringhighfrequencyorprolongedvisual stimulation,whichmightbeindexedbyvisualstimulation-drivensteady stateresponses(Çavuşetal.,2012).Theimpactofsuchpotentialcon- foundersshouldbefurthercharacterizedtoadequatelyevaluateeffects ofhighfrequencyorprolongedvisualstimulationindifferentpopula- tions.
TherearemultiplepossiblewaysofquantifyingVEPmodulation.For instance,whilesomeresearchershavefocusedontheN1bcomponentof theVEP,whichistypicallyoperationalizedasmeanamplitudebetween thefirstnegativeandhalfwaytothefirstpositivepeakafterP1(e.g.
McNairetal.,2006;Spriggsetal.,2017),othershavefocusedontheN1 component,operationalizedastheamplitudeofthefirstnegativepeak afterP1(Elvsåshagenetal.,2012).QuantificationsofVEPmodulationto considerincludechangesfrombaselineamplitudestopostintervention amplitudesintheC1,P1,N1,N1b,andP2components,aswellasinthe peaktopeakdifferenceP1-N1.
SinceVEPmodulationislikelytooccuralsooutsideoftheelectrodes andtimewindows towhichclassicalVEP componentsaresensitive, someresearchershavesubstitutedorcomplementedcomponentanal- yseswithanalysesacrossall channelsandpost-stimulustimepoints, whilekeepingfalsediscoveryrateslowusingpermutationbasedinfer- entialstatistics(Jahshanetal., 2017;Wynnetal., 2019).Moreover, sincesomenon-phaselockedmodulation,aboveandbeyondthephase lockedVEPmodulation,mightbepresentintheEEGafterprolongedvi- sualstimulation,time-frequencyanalysesofthepost-stimulusEEGcan beemployed,complementingtime-domainanalyses,tofurtherincrease sensitivity.
ModulationofVEPcomponentsC1,P1,N1,N1b,andP2,aswellas continuousmodulationsinthetimeandtime-frequencydomainshave notbeendirectly comparedinalarge sampleofhealthyindividuals.
Itisthereforecurrentlyunknownwhichofthemanypotentialindices ofLTP-likesynapticplasticityismostsensitiveandrobust.Moreover, typicalsamplesizeswithinthefieldmightmakesomestudiesvulner- abletowinner’scurseandrandomeffects(Ioannidis,2008).Here,we conductedthelargeststudyofVEPmodulationtodatein415healthy volunteersanddirectlycomparedseveralquantificationsofVEPmodu- lation,enablingustoobtainrealisticeffectsizesandtodeterminewhich quantificationsarebestsuitedforindexingLTP-likesynapticplasticity inhumans.
Thepresentstudyhadthreemainaims:first,todeterminewhichEEG measuresexhibitrobustmodulationfollowingprolongedvisualstimula- tion;second,toassesstheretentionofsuchVEPmodulationeffectsover intervalsreachingthetimerangeofLTP,andthecorrelationsbetween themagnitudeofearlyandlateVEPmodulation;andthird,toexamine theextenttowhichage,sex,andmarkersofattentionmightinfluence VEPmodulation.
2. Methods 2.1. Participants
415participantswererecruitedtothisstudyfromStatisticsNorway andannouncementsinnationalnewsoutlets,andincludedafterscreen- ingforpsychiatricandsomaticdisordersinasemi-structuredinterview.
Weusedthefollowingexclusioncriteria:a)ahistoryofschizophrenia, bipolardisorder,ormajordepressivedisorder,b)ahistoryofchronic medicaldisorders,includingcancer,cardiovascular disease,diabetes, anduntreatedhypertension,c)ahistoryofneurologicaldisorders,such asParkinson’sdisease,epilepsy,andstroke,d)ahistoryofmoderate andsevereheadinjurieswithlossofconsciousness>10min,ande)first degreerelativewithSCZ,BD,orMDD.59%ofparticipantswerefemale – theiragesrangedfrom18to83years(mean=49.7,sd=16.2),while
theagesofmaleparticipantsrangedfrom18to88years(mean47.9, sd =17.8,seealsoFig.5).Allparticipantshadnormalorcorrected- to-normalvision.TheexperimentwasapprovedbytheRegionalEthical CommitteeofSouth-EasternNorway,andallparticipantsprovidedwrit- teninformedconsent.
2.2. Experimentalprocedures
The VEP modulation paradigm was adopted from Normann et al. (2007). Over a period of 67 min, 11 VEP blocks, i.e.,2baselineblocks,1interventionblockofprolongedvisualstim- ulation,and8postintervention blocks,werepresented ona 24inch 144HzAOCLCDscreenwith1msgray-to-grayresponsetime(Fig.1).
All blocks,includingtheinterventionblock,consistedof areversing checkerboardpatternwithaspatialfrequencyof1cycle/degreeovera
~28° visualangle.Thereversalfrequencywasfixedat2reversalsper secondfortheinterventionblock,whereasthebaselineandpostinter- ventionblockshadjitteredstimulusonsetasynchroniesof500–1500ms (mean = 1000 ms). All baseline and postintervention blocks lasted
~40 s (i.e.,40 checkerboard reversals), while thestimulation block lasted 10 min (i.e., 1200 reversals). Postintervention blocks were presentedat2min,3min40s,6min20s,8min,~30min,~32min,
~54 min, and ~56 min after the intervention block. Through all blocks, the participants fixed their gaze on a red dot in the center of the screen, and pressed a key on a gaming controller when its colorchangedfromredtogreen.Betweentheseventhandeight,and betweentheninthandtenthblocks,participantsunderwentmismatch negativity(Näätänenetal.,1978)andprepulseinhibition(Grahamand Murray,1977)tasks,respectively.
2.3. Dataacquisition
EEG recordings were acquired using a 64 channel BioSemi Ac- tiveTwoamplifier,withAg-AgClsinteredelectrodesdistributedacross thescalpaccordingtotheinternational10–20system. Externalelec- trodeswereplacedattheoutercanthiofbotheyes(LO1,LO2),andbe- lowandabovethelefteye(IO1,SO1)inordertoacquirehorizontaland verticalelectro-oculogramsforeyemovementandeyeblinkcorrection.
Potentialsatelectrodesitesweremeasuredwithrespecttoacommon modesense,withadrivenrightlegelectrodeminimizingcommonmode voltages,andsampledat2048Hz.
2.4. Signalprocessing
Signalprocessingwasperformedusing MATLABandtheEEGLAB toolboxforMATLAB(DelormeandMakeig,2004),whilestatisticalanal- ysiswasperformedusingRversion3.6.0(RCoreTeam,2019).Offline, filesweredownsampledto512Hz.Noisychannelswereidentifiedwith PrepPipelinealgorithms(Bigdely-Shamloetal.,2015)usingdefaultcri- teria,andremoved.Remainingchannelswerefirstreferencedtotheir common average voltage, before interpolation of removed channels fromsurroundingchannelpotentials,andfinallyallchannelswerereref- erencedtothenewcommonaverageafterinterpolationofbadchannels.
Datadestinedfortimedomainanalysiswereband-passfilteredbetween 0.1and40Hz,whiledataforspectralanalysiswerehigh-passfiltered at0.1Hz.Afixed20msdelayinthevisualpresentationrelativetothe eventmarkerswasdetectedusingaBioSemiPINdiodeplacedinfrontof thescreenwhilerunningtheparadigm,andeventmarkerswereadjusted offlinetoaccountforthis.Next,epochswereextractedat200mspre-to 500mspost-stimulus.Muscle,eyeblinkandeyemovementartifactual componentswereremovedwithSASICAdefaults(Chaumonetal.,2015) aftersubjectingtheepocheddatatoindependentcomponentanalyses withtheSOBIalgorithm(Belouchranietal.,1993).Then,epochswith amplitudediversionsexceeding100𝜇Vwereremoved.Finally,allchan- nelswerereferencedtotheAFzelectrode(however,oneofthechannel
Fig.1. Experimentaltimeline.VEP:visualevokedpotentialparadigm,MMN:mismatchnegativityparadigm,PPI:prepulseinhibitionparadigm,REST:restingstate EEG.
bypoststimuluslatencyanalyseswasperformeddirectlyonaverageref- erenceddata).
2.5. Dataanalysis
ThreedifferentmodesofEEGanalysiswerepursued:timedomain analysesatgroupandindividuallevels,frequencydomainanalysesat theindividuallevel,andtime-frequencyanalysesatgroupandindivid- uallevels.SincethebaselineconsistedoftwoVEPblocks,postinterven- tionblockswerealsocollapsedintoseriesoftwoblocksforequalcom- parison,resultinginonebaselineassessmentandfourpostintervention assessments.
Fortimedomainanalysis,C1wasdefined asminimumamplitude between50and100mspost-stimulus,P1asmaximumamplitudebe- tween80and140ms,N1astheamplitudeofthefirstnegativepeakafter P1,N1basmeanamplitudebetweenthefirstnegativeandhalfwayto thefirstpositivepeakafterP1(effectively150–190mspost-stimulus), andP2asmeanamplitudeinthe50msafterandincludingthefirst positivepeakafterP1(effectively228–278mspost-stimulus),reflect- ingincreasedlatencyvariabilitieswithlatercomponents.Forasensitiv- ityanalysis,andforallregressionmodels,outliersinpostintervention changefrombaselinewereidentified,withineachcomponent,accord- ingtothemedianabsolutedeviationprocedureimplementedinRpack- age‘Routliers’(DelacreandKlein,2019),yielding28outliersforC1, 19forP1,44forN1,19forN1b,and20forP2,andremovedwithin each component.Further,all channelsweresubjectedtogroup-level componentanalysis,andthechannelwithhighestamplitudesandmost pronouncedVEPcomponentmodulation(i.e.,Oz)wasselectedforall lateranalyses(Fig.3).Inadditiontothesecomponentanalyses,weper- formedacompletelydata-driven,exploratoryanalysis,wherevoltages ateachchannelandeachpost-stimulustimepointwerecalculatedand assessedforpostinterventionchanges,thensubjectedtopermutation test-based(2000simulations) strongcontrolofthefamilywiseerror rate(Groppeetal.,2011).
Forfrequencydomainanalyses,entirecontinuousstretches of in- tervention block EEG were subjected to a Fast Fourier Transform (Cohen, 2014) before extraction of mean power within the narrow steadystatebandcentered on the2Hz visualstimulation frequency (1.8–2.2Hz).
For time-frequency analyses, high-pass filtered epochs from all participants were convolved with 5-cycle complex Morlet wavelets (Cohen,2014)ateachintegerfrequencybetween10and120Hz.Fre- quenciesbelow10Hz wereignoredduetotheparadigm’srelatively shortstimulusonsetasynchronies.Totalpowerwasthencalculatedas themedianlengthoftheresultinginnerproductswithinassessments, andinter-trialphasecoherencewascalculatedasthelengthofthemean, withinassessments,ofei𝜃 oftheresulting innerproductangles𝜃.In- ducedpowerwas calculatedastotalpower, exceptthateachpartici- pant’sERPateachassessmentwassubtractedfromeachtrialwithinthat assessmentbeforeconvolution.Totalandinducedpowerwerethendeci- belconvertedwithabaselinebetween150and100mspre-stimulus.Fi- nally,evokedpowerwascalculatedforeachtimeandfrequencywithin eachassessmentforeachparticipantbysubtractingdecibelconverted induced powerfrom decibelconverted total power. T-values forthe changefrombaselinetothefirstpostinterventionassessmentforallre-
sultingpixels(representingaspecifictime-frequencycombination)in total,evoked,andinducedpower,andinter-trialphasecoherence,were thencalculated,thensubjectedtopermutationtest-based(2000simula- tions)strongcontrolofthefamilywiseerrorrate(Groppeetal.,2011).
Attheindividualparticipantlevel,averagevalueswithintheresulting clustersofmodulationintotalpower,inducedpower, evokedpower, andinter-trialphasecoherence,werethenextractedatallpostinterven- tionassessments.
2.6. Outcomes
Primary outcomeswerei)modulationof componentsC1,P1,N1, N1b,andP2,andintheP1-N1composite,betweenbaselineandeach postinterventionassessment,aswellaspairwisedifferencesinmodula- tionofcomponentsC1,P1,N1,N1b,andP2,ii)modulation,between baselineandpostinterventionassessments,inamplitudesateachchan- nelandeachpost-stimuluslatencybetween0and500ms,iii)modu- lationofwithintime-frequencyclusterstotalpowerbetweenbaseline andeachpostinterventionassessment, andalinearmodelfortheef- fectsofinducedandevokedpowerforsuchdifferences,iv)correlations betweenbaselinetopostinterventionamplitudechangesforallcompo- nentsatallpostinterventionassessments,andv)effectsofage,gender, andsteady-statebandpowersduringprolongedvisualstimulationon thesubsequentmodulationofcomponentsC1,P1,N1,N1b,andP2.
Rawvaluesarereportedalongwithstandarderrors,calculatedas standarddeviationsoverthesquarerootofthesamplesize.Baselineto postinterventionchanges(i.e.,modulationeffects),aswellasdifferences inmodulationbetweenVEPcomponents,areexpressedasCohen’sdz (henceforthdenotedd),calculatedasdifferencemeansoverdifference standarddeviations(Cohen,1988).Inaddition,modulationeffectsare expressed asresponserates (rr),defined astheproportionofpartici- pantsexhibiting thedirectionofbaselinetopostinterventionchanges thatwouldbeexpectedfromaveragechangesacrossparticipants.Pair- wisecomparisonsbetweenthemodulationofdifferentcomponentswas performedbypermutingmodulationscores,fromthroughoutallpostin- terventionassessments,acrosscomponents,withswitchedpolarityfor componentswithnegativemeanmodulation(i.e.N1andN1b).Correla- tionsareexpressedasSpearman’s𝜌.FiveregressionmodelsforC1,P1, N1,N1b,andP2modulationscoreswerefittedusingthegenerallinear model,functionglm()inR,withtime(Post1–4),age,gender,andin- terventionblocksteadystatepoweraspredictors.Toavoidredundancy, sincetheeffectsoftimearereportedinothertests,werefrainfromre- portingregressionmodeltimeeffects.Further,oneregressionmodelfor modulationof thefirstcluster of totalpowermodulationwas fitted, withcorrespondingclustersofevokedandinducedpowermodulation aspredictors.ModelfitisindexedusingNagelkerkeR2,andeffectisex- pressedas𝜒2.P-valueswerecalculatedusingthefunctionsperm.test() orperm.cor.test()ofRpackage‘jmuOutlier’(Garren,2019),fordiffer- encesandcorrelations,respectively,andtheAnovafunctionofRpack- age‘car’(FoxandWeisberg,2019)forregressionmodels.Alphalevels wereadjustedtocontrolformultiplecomparisonsaccordingtotheeffec- tivenumberofindependentcomparisons,derivedusingeigenvaluesof thecorrelationmatrixoftheentirecontinuousdataset(LiandJi,2005), yieldinganexperiment-widesignificancethresholdat𝛼=7.2×10−4.
−5 0 5 10
−0.5 0.0 0.5
0 10 20 30 40
−200 0 200 400
−200 0 200 400
−200 0 200 400
ms µVCohen'sd−log10(p)
Assessment Baseline Post 1 Post 2 Post 3 Post 4
Assessment Post 1 Post 2 Post 3 Post 4
Assessment Post 1 Post 2 Post 3 Post 4
A
B
C
Fig.2. A.Grandaveragevisualevokedpo- tentialsmeasuredattheocciput(Oz)with anteriorreference(AFz)atbaseline,post 1 (2–4min after prolonged visual stim- ulation), post 2 (6–8 min),post 3 (30–
32min),andpost4(54–56min).B.Co- hen’sdfrombaselineVEPtothe postin- terventionassessments.C.P-valuesforthe differencebetweenbaselineVEPandeach ofthepostinterventionassessments,thresh- olded(i.e.significantifnon-zero)accord- ingtopermutationtest-based(2000simu- lations)strongcontrolofthefamilywiseer- rorrate,andlogtransformedforvisualiza- tionpurposes.
Table2
VEP component amplitudes and latencies at baseline.
Component Latency (ms) Amplitude ( 𝜇V) C1 66.6 ± 0.51 − 3.91 ± 0.24 P1 99.0 ± 0.41 8.42 ± 0.30 N1 140.3 ± 0.81 − 5.92 ± 0.24 N1b NA − 1.65 ± 0.20
P2 NA 1.41 ± 0.17
TableofVEPcomponentamplitudesandlaten- ciesatbaseline,measuredattheocciput(Oz) withanteriorreference(AFz).NA:notapplica- ble.
3. Results
3.1. VEPmodulationafterprolongedvisualstimulation
ThecheckerboardreversalstimulationevokedtheexpectedC1,P1, N1,andP2componentsof theVEP(Fig.2;see Table2forlatencies andamplitudes).Initialgrouplevelanalysesdemonstratedthat,across VEPcomponents,thehighest amplitudesandthelargest modulation effectswereexhibitedattheoccipitalOzelectrode(Fig.3A-B),which wasaccordinglyselectedforindividuallevelanalyses.
WhentestingformodulationeffectsacrossalltimepointsoftheVEP atthefirstpostinterventionassessmentafterprolongedvisualstimula- tion,significantchangesatlatenciesof55–127ms,141–231ms,and
264–369 mswereobservedattheocciput(Oz)(Fig.2),withrelated changesatotherchannelsatcomparabletimewindows(Fig.4).Cor- respondingly,experience-dependentVEPmodulationwasapparentas amplitudechanges frombaseline tothefirstpostinterventionassess- mentforboththeC1(d=0.53,rr=0.70),P1(d=0.66,rr=0.76), N1 (d= −0.27,rr =0.62), N1b(d =−0.66, rr= 0.77),butnot P2 (d=0.08,p=0.10,rr=0.53)components,withhighlysimilareffects for boththeC1(d= 0.44,rr= 0.67),P1(d= 0.55,rr= 0.72),N1 (d=−0.26,rr=0.61),N1b(d=−0.71,rr=0.77)andtheP2(d=0.08, p=0.10,rr=0.54)componentsattheimmediatelyfollowingsecond postinterventionassessment.Some,butnotall,changesafterprolonged visualstimulationwereretainedatthethirdandfourthpostinterven- tionassessments.C1modulationwassignificantatthethirdpostinter- ventionassessment(d=0.20,rr=0.58),butfailedtopasscorrected alphathresholdsatthefourthpostinterventionassessment(d =0.16, p=0.001,rr=0.56).TheP1componentdidnotretainmodulationat thethird(d=0.04,p=0.36,rr=0.54),noratthefourth(d=−0.06, p=0.22,rr=0.48)postinterventionassessment.TheN1component retainedmodulation atthethird (d =−0.17, rr= 0.60), andfourth (d=−0.21,rr=0.66)postinterventionassessment.TheN1bcomponent retainedmodulationatboththethird(d=−0.53,rr=0.75),andthe fourth(d=−0.38,rr=0.68)postinterventionassessment.Finally,the P2componentgainedmodulationatthethird(d=0.30,rr=0.65)and thefourth(d=0.54,rr=0.75)postinterventionassessment(Table3, Fig.3).Almostalloftheseresults,theonlyexceptionbeingretention ofC1modulationatthethirdpostinterventionassessment,wererepro- ducedwithoutliersremoved(TableS1).
Fig.3. A.Scalptopographicaldistributionof C1,P1,N1,N1b,andP2unscaledamplitude differences (in 𝜇V) frombaseline to postin- terventionassessments1(2–4minafterpro- longedvisualstimulation),2(6–8min),3(30–
32min),and4(54–56min).B.Scalp topo- graphicaldistributionofC1,P1,N1,N1b,and P2 amplitudes at baseline and each of the postinterventionassessments1–4.
Fig.4. Four panels displayingVEP modulation(expressed ast-scores,thresholdedaccordingtopermutationtest-based strong control of the family wise error rate) across post- stimuluslatencies(x-axis)andchannels(y-axis).Thefirstcol- umnofpanelsdisplaymodulationatpostinterventionassess- mentpost1(2–4minafterprolongedvisualstimulation).The secondcolumnofpanelsdisplaymodulationatpostinterven- tionassessmentpost4(54–56min).Thefirstrowofpanels displaymodulationwithanAFzreference.Thesecondrowof panelsdisplaymodulationwithanaveragereference.Chan- nelsareorderedfromnasiontoinion.
Data-driventime-domainanalysesrevealedaclusterofpositivemod- ulationtowhichcomponentsC1andP1wouldbesensitive,andaclus- terofnegativemodulationtowhichcomponentsN1andN1bwouldbe sensitive.Further,alargeclusterofpositivemodulationwascentered atalatencyaround~300mspoststimulus,towhichtheP2component wouldonlybepartiallysensitive(Fig.4).
Permutationofmodulationscoresinapairwisemanner,acrosscom- ponentsC1,P1,N1,N1b,andP2,demonstratedsignificantdifferences inmodulationin 5outof 10comparisons. First,P1modulationwas largerthanP2modulation(d=0.09,p=0.0001).Further,N1bmod- ulationwaslargerthanmodulationofallothercomponents,including C1(d=0.18,p<5×10−5),P1(d=0.12,p<5×10−5),N1(d=0.34, p<5×10−5),andP2(d=0.20,p<5×10−5).
TheP1-N1compositeexhibitedsignificantmodulationatthefirst (d=0.70,rr=0.80),second(d=0.60,rr=0.78),andthird(d=0.19,
rr=0.61),butnotthelast(d=0.14,rr=0.60)postinterventionassess- ment.
3.2. WithinassessmentschangesintheVEP
Therewerealsodifferencesbetweencomponentamplitudeswithin assessments(Fig.6),withsignificantchangesfromthefirsttothesecond baselineblock(i.e.withinthebaselineassessment)forcomponentsP1 (d=0.21),N1(d=−0.32),N1b(d=−0.28),andP2(d=0.17),fromthe firsttothesecondpostinterventionblock(i.e.withinthefirstpostinter- ventionassessment)forcomponentsC1(d=0.18),N1(d=0.24),and fromtheseventhtotheeighthpostinterventionblock(i.e.withinthe fourthpostinterventionassessment)forcomponentsC1(d=0.24),P1 (d=0.31),N1(d=−0.19),andN1b(d=−0.35).Theseeffectswere weakerthaneffectsoftheprolongedvisualstimulationforcomponents
Table3
VEPcomponentmodulationafterprolongedvisualstimulation.
C1 P1 N1 N1b P2
Post 1 (2–4 min) d 0.53 0.66 − 0.27 − 0.66 0.08
rr 0.70 0.76 0.62 0.77 0.53
p < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 0.10
-log(p ∗) 23.1 33.7 7.1 33.7 1
Post 2 (6–8 min) d 0.44 0.55 − 0.26 − 0.71 0.08
rr 0.67 0.72 0.61 0.77 0.54
p < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 0.10
-log(p ∗) 16.9 24.6 6.8 37.8 1
Post 3 (30–32 min) d 0.20 0.04 − 0.17 − 0.53 0.30
rr 0.58 0.54 0.60 0.75 0.65
p < 5 ×10 −5 0.38 0.0003 < 5 ×10 −5 < 5 ×10 −5
-log(p ∗) 4.16 0.4 3.2 23.0 8.9
Post 4 (54–56 min) d 0.16 − 0.06 − 0.21 − 0.38 0.54
rr 0.56 0.48 0.66 0.68 0.75
p 0.001 0.22 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5
-log(p ∗) 2.9 0.7 4.8 12.9 24.3
TableofVEPcomponentmodulationafterprolongedvisualstimulation.d:Cohen’sd,rr:responserate,p: p-valueafter20,000permutations,-log(p∗):negativedecimallogarithmoft-testp-value(forillustration, notallmodulationsarenormallydistributed).
Table4
Time-frequencyclustermodulationafterprolongedvisualstimulation.
A1 A2 A3 I1 E1 ITPC1 ITPC2
Post 1 (2–4 min) d − 0.51 − 0.26 − 0.27 − 0.27 − 0.23 − 0.41 − 0.33
rr 0.73 0.66 0.61 0.62 0.59 0.64 0.62
p < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5
-log(p ∗) 20.9 6.6 7.0 7.0 5.2 14.2 9.6
Post 2 (6–8 min) d − 0.55 − 0.21 − 0.18 − 0.32 − 0.29 − 0.39 − 0.26
rr 0.74 0.58 0.58 0.62 0.64 0.68 0.64
p < 5 ×10 −5 < 5 ×10 −5 0.0003 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5
-log(p ∗) 23.8 4.6 3.4 9.3 7.9 12.9 6.6
Post 3 (30–32 min) d − 0.48 − 0.32 − 0.29 − 0.23 − 0.20 − 0.31 − 0.24
rr 0.72 0.61 0.63 0.60 0.57 0.63 0.62
p < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 0.0001 < 5 ×10 −5 < 5 ×10 −5
-log(p ∗) 19.1 9.4 7.74 5.0 4.0 8.7 5.5
Post 4 (54–56 min) d − 0.38 − 0.24 − 0.29 − 0.08 − 0.27 − 0.32 − 0.10
rr 0.66 0.61 0.64 0.54 0.62 0.62 0.56
p < 5 ×10 −5 < 5 ×10 −5 < 5 ×10 −5 0.12 < 5 ×10 −5 < 5 ×10 −5 0.046
-log(p ∗) 12.4 5.7 7.9 0.9 6.8 9.1 1.3
Tableofclusterpowermodulationsafterprolongedvisualstimulation.d:Cohen’sd,rr:responserate,p:p-valueafter20,000per- mutations,-log(p∗):negativedecimallogarithmoft-testp-value(forillustration,notallpotentiationsarenormallydistributed), A1–3:Totalpowermodulationclusters,I1:Inducedpowermodulationcluster,E2:Evokedpowercluster.ITPC1–2:Intertrialphase coherenceclusters.
C1(p=2.1×10−5),N1b(p=3.0×10−14),andP2(p=2.6×10−6),but notforcomponentsP1(p=0.10)orN1(p=0.004;two-tailedtests).
3.3. Clustersoftime-frequencypowermodulationafterprolongedvisual stimulation
Thetime-frequencyanalysisexploringthemaineffectofprolonged visualstimulationyieldedthreeclustersofsignificantmodulationofto- talpower,thefirstcenteredaround~26Hzand65mspost-stimulus,the secondcenteredaround~15Hzand245mspost-stimulus,andthethird centeredaround~12Hzand229mspost-stimulus(Fig.7).Resultsfrom analysesusingindividualparticipants’valuesaveragedwithinclusters ofmodulationoftotalpower,aswellasinducedpower,evokedpower, andinter-trialphasecoherence,arepresentedinTable4.Theseanaly- sesrevealedthatmodulationofthefirsttotalpowerclusterwassignifi- cantatallpostinterventionassessments,includingthefirst(d=−0.51, rr=0.73),second(d=−0.55,rr=0.74),third(d=−0.48,rr=0.72),and fourth(d=−0.37,rr=0.66).Further,modulationofthesecondtotal powercomponentwasalsosignficantatthefirst(d=−0.26,rr=0.62), second(d=−0.21,rr=0.58),third(d=−0.32,rr=0.61),andfourth (d=−0.24.rr=0.61)postinterventionassessments.Finally,modula- tionof thethird total powercomponentwas significant atthe first,
second,andfourth,butnotthethird,postinterventionassessment.The firsttotalpowerclusteroverlappedwithaninducedpowerclusterand aseparateevokedpowercluster,andthepowerreductionwithinthis clusterafterprolongedvisualstimulationwasreasonablywellmodelled (R2=0.38)bypowerchangesinthecorrespondingevoked(𝜒2=26.4, p=2.8×10−7)andespeciallyinduced(𝜒2=154.3,p=2.0×10−35) cluster.
3.4. AssociationsbetweenVEPmodulationacrosscomponentsand assessments
Correlations across assessments for baseline to postintervention modulationeffectsweremoderatewithincomponentsC1(0.47≤𝜌≤ 0.69),P1(0.39≤𝜌≤0.67),N1(0.42≤𝜌≤0.62),N1b(0.44≤𝜌≤0.66), andP2(0.45≤𝜌≤0.60)(Fig.8).Allcorrelationsaboveandincluding r=0.17remainedsignificantaftermultiplecomparisoncorrection.
3.5. AssociationsbetweenVEPmodulationandage,sex,andintervention blocksteadystatepower
The regression model for C1 modulationrevealed effects of age (𝜒2=30.4,p=3.5×10−8),withmodulationdecreasingwithhigher
Fig.5. Distributionsofamplitudedifferences(in𝜇V)between baselineandpostinterventionassessmentspost1(2–4minaf- terprolongedvisualstimulation),post2(6–8min),post3(30–
32min),andpost4(54–56min),andtheirassociationswith age(inyears)bysex,forVEPcomponentsC1,P1,N1,N1b, andP2.Linearregressionshowedsignificantassociationsbe- tweenageandC1modulation(𝜒2=30.4,p=3.5×10−8),age andP1modulation(𝜒2=13.4,p=2.6×10−4),andsexandP2 modulation(𝜒2=15.4,p=8.5×10−5).Outliersnotincluded.
age(Fig.5),butnotofsex(p=0.07)orinterventionsteadystatepower (p =0.76). TheregressionmodelforP1modulationrevealedeffects ofage(𝜒2=13.4,p=2.6×10−4),withmodulationincreasingwith higherage,butnotofsex(p=0.10)orinterventionsteadystatepower (p=0.76).TheregressionmodelforN1modulationrevealedno sig- nificanteffectsofeitherage(p=0.05),sex(p=0.88)orintervention steadystatepower(p=0.03).Similarily,theregressionmodelforN1b modulationrevealednosignificanteffectsofeitherage(p=0.03),sex (p=0.05),orinterventionsteadystatepower(p=0.21).Finally,there- gressionmodelforP2modulationrevealednosignificanteffectsofage (p=0.002),butsignificanteffectsofsex(𝜒2=15.4,p=8.5×10−5), andinterventionsteadystatepower(𝜒2=11.7,p=6.2×10−4),with greatermodulationforfemaleparticipantsandparticipantswithhigher interventionsteadystatepower,respectively.Fortheattentionaltask, weonlyobtainedhitratedatafor45.8%ofparticipants,duetoerror inthegamingcontroller.Thus,weperformedasetofcontrolanalyses toensurethattheparticipantsforwhichattentionaldatawasnotob- taineddidnotdifferfrom theparticipantsforwhichattentionaldata wasobtained.Theseshowedthattherewasnodifferencebetweenthese groupsin P1,N1,N1b,orP2modulation,butonlyanominaldiffer- enceinC1modulation(p=0.04),andthatclearVEPswereevokedfor 96%ofparticipantsforwhichattentionaldatawasnotobtained.Among participantsforwhichattentionaldatawasobtained,themeanhitrate was98.4%.Together,theseresultsindicateoverallsatisfyinglevelsof attention.
4. Discussion
Thecurrentstudyyieldedfourmainfindings.First,wedemonstrate robustexperience-dependentmodulationofthevisualevokedpotential inalargesampleofhealthyvolunteers(n=415).Second,thereten- tionofthismodulationeffectovertimevariedacrossVEPcomponents,
stronglysuggestingthatVEPmodulationisnotaunitaryphenomenon andlikelyinvolvesseveraldifferentplasticitymechanisms.Third,age andsex,aswellasinterventionsteadystatepower,emergedassignif- icantlyassociatedwithsome,butnotall,quantificationsofVEPmod- ulation.Finally,weidentifytheN1bcomponentasthemostsensitive quantificationofVEPmodulation.
4.1. Experience-dependentmodulationofvisualevokedpotentials
Atthefirstandsecondpostinterventionassessments,respectively2 and6minafterprolongedvisualstimulation,moderatetostrongmodu- lationwasobservedinVEPcomponentsC1,P1,N1,andN1b,aswellas inthecompositeP1-N1.Suchexperience-dependentmodulationshave previouslybeenshowntosharemanycharacteristicswithLTP,includ- ingNMDAR-dependence(Frenkeletal.,2006),post-synapticAMPAR insertion dependence(Frenkel etal., 2006),and stimulusspecificity (McNairetal.,2006;Rossetal.,2008),andhavethereforebeenre- gardedasindicesofLTP-likecorticalsynapticplasticity.
Inthepresentstudy,somewidelyusedquantificationsofVEPmodu- lation– modulationsoftheC1,P1,N1,andN1bcomponents– coincide inlatencywithclustersofmodulationasrevealedbydata-driventime domainanalyses.Ontheotherhand,wehaveshownthatalargetime- domainclusterofmodulation,centeredaroundapost-stimuluslatency of~300msandexpandingintimeinlaterpostinterventionassessments, isnotverywellcapturedbytheP2component.Animportantcaveat, however,isthatsuchresultsmightnotbeimmediatelygeneralizableto differentVEPmodulationparadigms,suchasthoseusingpatternonset sinegratingsratherthancheckerboardreversals.
Time-frequencyanalysesalsorevealedmodulationoftotalpowerin threetime-frequencyclusters,allofwhichexhibitedeffectsofprolonged visualstimulationthatwerecomparabletoeffectsseenontimedomain VEPcomponents,andthat,likeN1andN1bmodulation,wereretained
Fig. 6.Component amplitudes at separate checkerboard stimulation blocks,normalized tothefirstblock,witherrorbarsshowingstan- dard errorof measurement. Thepolarity of N1andN1bmodulationhasbeenflippedfor easycomparisonwithmodulationoftheother components.Asterisksdenotesignificant(p<
7.2×10−4)amplitudechangewithinassess- ments,thatis,withinthebaselineassessment (fromtheblockat−12min40stotheblock at−11min),withinthefirstpostintervention assessment(fromtheblockat2min40stothe blockatpostat4min20s,andsoon.
at ~54–56min postintervention. The first cluster of time-frequency modulation,centeredat~65msand26Hz,overlappedwithbothclus- tersofevokedandclustersofinducedmodulation.Sincemodulationin inducedpowermadethestrongestcontributiontomodulationintotal power,itislikelythattheobservedtotalpowermodulationmightre- flectneuraldynamicstowhichtimedomainVEPmodulationsarenot sensitive.
4.2. Experience-dependentVEPmodulation:retentionslopesand correlations
Weobserveddifferentialresponsepatternsbetweenquantifications ofVEPmodulation,indicatingdifferencesinunderlying mechanisms.
Retention at the third and fourthpostintervention assessments, i.e.,
~30–32and~54–56minafterprolongedvisualstimulation,wasob- servedforcomponentsN1andN1b.Incontrast toN1andN1bmod- ulation,C1modulationwasnotsignificantlyretainedat~54–56min postintervention.Theretentionof N1andN1bmodulationat30and 54minpostinterventionisconsistentwithLTP-likesynapticprocesses asunderlying mechanisms,sincethisdurationgoesbeyondtheusual decayofpresynapticshort-termpotentiation(CitriandMalenka,2008; Regehr,2012).Spearmancorrelationsaround0.42–0.49betweenN1 and N1b modulations at 2 and ~54–56 min postintervention sug- gestaconnectionbetween earlyandlatermodulationeffects, which hasbeen establishedformost forms of synapticplasticity (Citri and Malenka,2008),furthercorroboratingtheclaimthatN1andN1bmod- ulationsreflectLTP-likecorticalplasticity.
Withasharpvoltageincreaseintheinterventionblockandsubse- quentreturntonear baselinein thefirsttwopostinterventionassess- ments,andrenewedamplitudeincreasesinthethirdandlast postin- terventionassessments(Figs.5,6),theresponsepatternfortheP2com- ponent,similartowhathasbeenobservedpreviously(Forsythetal., 2015;Forsythetal.,2017),constitutesaclearexception.Thereis,al- readyinthefirsttwopostinterventionassessments,detectablemodu- lationinthetime-domainclusteradjacenttoandpartiallyoverlapping withP2,butsincethisclusterisalsoexpandingintimeandineffectsizes fromearlytolatepostinterventionassessments,thepictureofgrowing effectisnot contradicted.AlthoughNMDAR-dependent LTPtypically exhibitsagradualdecay(CitriandMalenka,2008),theresponsepat- ternfortheP2componentis,however,notinconsistentwithNMDAR- dependentLTPasamechanism,sinceP2modulationmightsummate acrosssynapticpotentiationanddepressionwithdifferentialtimeranges (Forsythetal.,2015).Indeed,NMDARagonistD-cycloserinehasprevi-
ouslybeenshowntoincreaseP2modulation(Forsythetal.,2015).Fur- ther,theP2componentappearstolackinputspecificityforsomeVEP modulationparadigms(Sumneretal.,2018),althoughthisdoesnotnec- essarilyprecludeinputspecificityforother,similarparadigms.Thus,we cannotbasedonthepresentdataexcludethepossibilitythattheeffect of timeonP2amplitudesmightinvolveNMDAR-dependentLTP asa mechanism.Alongsimilarlines,theretentionslopeofP1,withacom- pletedecaybetween6and30minafterprolongedvisualstimulation, isalsoconsistentwithsynapticplasticityasunderlyingmechanism.For example,P1modulationmightreflectsomeshort-termplasticitysuchas post-tetanicpotentiation(CitriandMalenka,2008).Further,theearly P1modulationmightreflectanearlyphaseofLTP,thatatlaterstages presentinaqualitativelydifferentmanner(Boschetal.,2014),bothat molecularandelectrophysiologicallevels.Forexample,P2modulation couldpotentiallyberelatedtolaterphasesofthecomplexgeneexpres- sionpatternsandsynapticchangesunderlyingLTP(Boschetal.,2104), However,whilethesespeculationsmightprovidetestablehypotheses forfutureresearch,itshouldbenotedthattheycannotbedirectlyad- dressedinthepresentdata.Indeed,thecurrentresultscouldbecompat- iblewithmanydifferentpatternsofinteractionbetweendifferentforms ofplasticitywithopposingeffectsontheEEG.
4.3. Age,sex,andsteadystatepowerareassociatedwithsome,butnotall, VEPcomponents
LinearregressionshowedanegativemaineffectofageonC1mod- ulation,andapositivemaineffectofageonP1modulation,suggest- ingthatC1modulationacrosspostinterventionassessmentsisreduced withage,whileP1modulationisincreasedwithage.Noeffectsofage wereobservedonmodulationofeithertheN1,N1b,ortheP2compo- nents.Theseresultsareinlinewithapreviousdemonstrationofrobust VEPmodulationamongolderindividuals(deGobbi-Portoetal.,2015).
Ontheotherhand,theyseemtocontrastwiththelackofN1bmodula- tionpreviouslyobservedinolderparticipants(Spriggsetal.,2017),and withthemoregeneraldeclineinneuralplasticityassociatedwithag- ing(BurkeandBarnes,2006).Further,regressionmodelsdemonstrated largerincreaseinP2amplitudesamongfemaleparticipantsthanamong maleparticipants.Together,these resultsunderscoretheneedtodif- ferentiatebetween VEPcomponents,andtocontrolfordemographic variableslikeageandsex,especiallyincase-controlstudiesofVEPmod- ulation.
Linear regression models also revealed an effect of intervention steadystatepoweronP2modulation,withhigherP2modulationamong
Fig. 7. Changes at the occiput (Oz) in to- tal power,induced power,phase coherence, andevokedpower,infrequencies10–120Hz, beforetoafter prolonged visualstimulation, givenast-scoresforeachpixel.Significantclus- terscircumscribedwithblacklines.
participantswithhighersteadystatepower,butnotonmodulationof anyoftheothercomponents.Inapreviousstudyof VEPmodulation using8.7Hzvisualstimulation(Çavuşetal.,2012),interventionblock steadystatepowerwasassociatedwithN1bmodulationinhealthycon- trols.Together,theseresultsindicatethatthedegreeofneuralentrain- menttoprolongedorhighfrequencyvisualstimulationmightimpact themagnitudeofVEPmodulation.
4.4. RobustandenduringmodulationofcomponentN1b
OurquantificationsofVEPmodulationseemtoberelativelyspecific inthat theyexhibitdistincteffects,retention slopesandassociations withageandsex.ModulationoftheN1bcomponentafterprolongedvi- sualstimulationwasoverallthestrongesteffect.Effectsizedifferences, relativelyhighcorrelations,andcomparableassociationswithageand sexbetweencomponentsN1andN1bsuggestthatN1bquantifications ofVEPmodulationmightbepreferable,atleastunderconditionssim- ilartothosepresentinthisstudy.Althoughsomeobservedeffectsof timemighthavebeencausedbyotherexperimentalcharacteristicsthan theprolongedvisualstimulation,theN1bcomponenthasrepeatedly beenshowntoincreaseinamplitudewithhighfrequencyvisualstimu- lation,andnotwithout(Teyleretal.,2005),andnotwithvisualstimu- lationofadifferentorientation(Rossetal.,2008)orspatialfrequency (McNairetal.,2006),supportingthenotionthatatleastN1bmodula- tionisduetothehighfrequencyorprolongedvisualstimulation.
4.5. Possibleinfluenceofpostinterventionblocksonretention
Inthepresentstudy weobserved modulationof componentsC1, P1,N1,N1b,andP2evenbetweenblocksof shortdurationchecker- boardstimulation.Thus,thereisreasontoquestionwhetherthereten- tion,especiallyforcomponentsN1andN1bwhichexhibitlongduration modulation,couldhavebeenincreasedbythepostinterventionstimulus blocks.Postinterventionblockshavebeenshowntodecreaseretention
ofN1bmodulation(Teyleretal.,2005),butwithfrequencydifferences betweeninterventionandpostinterventionblocks(i.e.9vs1Hz)that weregreaterthaninthepresentstudy(samemeanfrequency),sosome influenceinfavorofretentioncannotberuledoutwiththepresentdata.
4.6. Limitations
Alimitationofthisstudyisthatfrequenciesbelow10Hzwerenot consideredinthetime-frequencyanalyses,duetotheparadigm’srel- atively short stimulusonset asynchronies. Further,as we have only studiedVEP modulationin oneof several potentialVEP modulation paradigms,generalizationtoother,similarparadigms,shouldbedone withcaution.
4.7. Conclusion
Theresultsofthecurrentstudyshowrobustmodulationafterpro- longed visualstimulation in VEP componentsC1,P1, N1,andN1b, aswellasinthreetime-frequencyclustersoftotalpowermodulation.
Moreover, weobserved differentialretention slopes,effect sizes,and associations toage and sexfor themodulation of VEPcomponents, stronglysuggestingthatVEPmodulationisnotaunitaryphenomenon.
Takentogetherwithresultsfromaseriesofinvasivestudiesinrodents, ourcurrentresultssupporttheuseofprolongedvisualstimulationin- ducedVEPmodulation,andespeciallyN1bmodulation,asarobust,non- invasiveindexofLTP-likecorticalplasticityinhumans.
Creditauthorstatement
MathiasValstad:conceptualization,software,formalanalysis,inves- tigation,visualization,andwriting– originaldraft.
TorgeirMoberget:conceptualization,methodology,writing– review
&editing,andsupervision
DaniëlRoelfs:investigationandvisualization
1.00 1.00 0.60 1.00 0.45 0.47 1.00 0.57 0.47 0.51 1.00 0.22 0.17 0.22 0.38 1.00 0.54 0.21 0.15 0.41 0.15 1.00 0.56 0.44 0.14 0.31 0.10 0.04 1.00 0.66 0.53 0.49 0.35 0.16 0.12 0.06 1.00 0.30 0.28 0.32 0.53 0.13 0.14 0.17 0.26 1.00 0.53 0.31 0.33 0.60 0.34 0.09 0.07 0.24 0.08 1.00 0.52 0.43 0.36 0.56 0.30 0.22 0.09 0.24 0.10 0.06 1.00 0.62 0.48 0.42 0.54 0.31 0.24 0.21 0.21 0.07 0.05 0.08 1.00 0.10 0.12 0.10 0.18 0.16 0.22 0.14 0.18 0.15 0.19 0.15 0.15 1.00 0.50 0.11 0.12 0.24 0.08 0.08 0.14 0.29 0.10 0.15 0.18 0.32 0.16 1.00 0.45 0.45 0.10 0.21 0.20 0.13 0.05 0.16 0.15 0.11 0.15 0.30 0.24 0.14 1.00 0.67 0.39 0.42 0.16 0.04 0.12 0.10 0.15 0.04 0.07 0.14 0.27 0.16 0.19 0.13 1.00 0.10 0.09 0.18 0.21 0.22 0.18 0.23 0.31 0.13 0.12 0.20 0.30 0.18 0.11 0.13 0.24 1.00 0.47 0.20 0.19 0.30 0.11 0.25 0.24 0.42 0.16 0.20 0.22 0.39 0.20 0.22 0.11 0.29 0.19 1.00 0.47 0.50 0.10 0.21 0.15 0.03 0.28 0.36 0.22 0.25 0.13 0.24 0.20 0.19 0.20 0.25 0.22 0.27 1.00 0.69 0.48 0.52 0.28 0.17 0.13 0.04 0.38 0.22 0.21 0.24 0.24 0.09 0.17 0.23 0.28 0.11 0.15 0.22 C1po
st 1 C1pos
t 2 C1po
st 3 C1pos
t 4 P1po
st 1 P1po
st 2 P1po
st 3 P1po
st 4 N1po
st 1 N1pos
t 2 N1po
st 3 N1pos
t 4 N1b
post 1 N1b
post 2 N1b
post 3 N1bpost
4 P2po
st 1 P2pos
t 2 P2po
st 3 P2po
st 4
P2 post 4 P2 post 3 P2 post 2 P2 post 1 N1b post 4 N1b post 3 N1b post 2 N1b post 1 N1 post 4 N1 post 3 N1 post 2 N1 post 1 P1 post 4 P1 post 3 P1 post 2 P1 post 1 C1 post 4 C1 post 3 C1 post 2 C1 post 1
−1.0
−0.5 0.0 0.5 1.0 Spearman Correlation
Fig.8. Spearman’s𝜌correlationsbetweenmodulationsofVEPcomponentsC1,P1,N1,N1b,andP2atpostinterventionassessments1–4.Sincethesearecorrelations betweenrawmodulationeffects,somecould,inprinciple,havebeennegative,butnonegativecorrelationswerefound.
NoraB.Slapø:investigation ClaraM.F.Timpe:investigation DaniBeck:investigation GenevièveRichard:investigation LinnSofieSæther:investigation BeatheHaatveit:investigation KnutAndreSkaug:investigation JanEgilNordvik:projectadministration ChristofferHatlestad-Hall:software GauteT.Einevoll:conceptualization TuomoMäki-Marttunen:conceptualization LarsT.Westlye:projectadministration ErikG.Jönsson:projectadministration
OleA.Andreassen:conceptualization,projectadministration,writ- ing– review&editing,andsupervision
Torbjørn Elvsåshagen: conceptualization, methodology,investiga- tion,writing – review& editing, supervision,projectadministration, andfundingacquisition
Acknowledgments
ThisstudywasfundedbytheResearchCouncilofNorway,theSouth- EasternNorwayRegional Health Authority, OsloUniversityHospital (2015–078),andaresearchgrantfromMrs.Throne-Holst.Theauthors reportnobiomedicalfinancialinterestsorpotentialconflictsofinterest.
Supplementarymaterials
Supplementarymaterialassociatedwiththisarticlecanbefound,in theonlineversion,atdoi:10.1016/j.neuroimage.2020.117302.
References
Abuleil, D. , McCulloch, D.L. , Thompson, B. , 2019. Older adults exhibit greater visual cor- tex inhibition and reduced visual cortex plasticity compared to younger adults. Front.
Neurosci. 13, 607 .
Belouchrani, A. , Abed-Meraim, K. , Cardoso, J.F. , Moulines, E. , 1993. Second order blind separation of temporally correlated sources. Proc. Int. Conf. Digital Signal Proc.
346–351 .
Bigdely-Shamlo, N., Mullen, T., Kothe, C., Su, K.-M., Robbins, K.A., 2015. The PREP pipeline: standardized preprocessing for large-scale EEG analysis. Front. Neuroinform.
9, 16. http://doi.org/10.3389/fninf.2015.00016 .
Bosch, M. , Castro, J. , Saneyoshi, T. , Matsuno, H. , Sur, M. , Hayashi, Y , 2014. Structural and molecular remodeling of dendritic spine substructures during long-term potentiation.
Neuron 82 (2), 444–459 .
Burke, S.N., Barnes, C.A., 2006. Neural plasticity in the ageing brain. Nat. Rev. Neurosci.
7 (1), 30–40. http://doi.org/10.1038/nrn1809 .
Chaumon, M., Bishop, D.V.M., Busch, N.A., 2015. A practical guide to the selection of inde- pendent components of the electroencephalogram for artifact correction. J. Neurosci.
Methods 250, 47–63. http://doi.org/10.1016/j.jneumeth.2015.02.025 .
Citri, A., Malenka, R.C., 2008. Synaptic plasticity: multiple forms, func- tions, and mechanisms. Neuropsychopharmacology 33 (1), 18–41.
http://doi.org/10.1038/sj.npp.1301559 .
Cohen, J. , 1988. Statistical Power Analysis For the Behavioral Sciences, 2nd Lawrence Erlbaum Associates .
Cohen, M.X. , 2014. Analyzing Neural Time Series Data: Theory and Practice. MIT .
