a combined rTMS and cTBS study | SpringerLink

2019), and also TMS (Ruitenberg et al. 2014; Verwey et al. 2002). ... 2002) was actually caused by stimulation of SMAproper. Skiptomaincontent Advertisement SearchSpringerLink Search ConsolidationofmotorsequencelearningeliminatessusceptibilityofSMApropertoTMS:acombinedrTMSandcTBSstudy DownloadPDF DownloadPDF AbstractEarlierresearchsuggestedthatafter210practicetrials,thesupplementarymotorarea(SMA)isinvolvedinexecutingallresponsesoffamiliar6-keysequencesinadiscretesequenceproduction(DSP)task(Verwey,Lammens,andvanHonk,2002).Thiswasindicatedbyslowingofeachresponse20and25 minaftertheSMAhadbeenstimulatedfor20 minusingrepetitivetranscranialmagneticstimulation(rTMS).ThepresentstudyusedasimilarapproachtoassesstheeffectsofTMStothemoreposteriorSMAproperattheendofpracticeandalso24 hlater.AsexpectedstimulationofSMAproperwith20 minof1 HzrTMSand40 sofcontinuousthetaburststimulation(cTBS)immediatelyafterpracticeslowedsequenceexecutionrelativetoashamTMScondition,butstimulationonthedayfollowingpracticedidnotcauseslowing.ThisindicatesthatofflineconsolidationmakeslearningrobustagainststimulationofSMAproper.Executionofallresponsesinthesequencewasdisrupted0,20,and40 minafterrTMS,butaftercTBS,thisoccurredonlyafter40 min.TheresultssuggestthatitisimplicitsequenceknowledgethatisprocessedbytheSMAproperandthatconsolidates. IntroductionTranscranialmagneticstimulation,orTMS,involvesadministeringshortmagneticpulsesthroughtheskulltocorticaltissue.Thisinfluencescorticalprocessingthroughenhancementordepressionofsynapticactivityduringandafterthestimulationprocess,dependingonthestimulationprotocol(DiLazzaroetal.2011).TMSopensthewayforvarioustherapeutictreatments(e.g.,KobayashiandPascual-Leone,2003;Takeuchietal.2008).Italsoprovidesawayofinvestigatingthefunctionsofcorticalareasforhumanbehavior,becauseitcanestablishacausallinkbetweenbrainfunctionandbehavior(Pascual-Leoneetal.1992;WalshandCowey2000).Thepresentstudyspecificallylookedintothecontributionoftheposteriorpartofthesupplementarymotorarea(SMA),theSMAproper,totheexecutionoftwofamiliar6-keysequencesandwhetherthiscontributionconsolidatesover24 h.ThiswasexploredwithtwoinhibitoryTMSprotocolstoexaminewhetherthebehavioraleffectsofthetraditional20 minoffline1 HzrepetitiveTMS(rTMS)protocol(Pascual-Leone1999;Pascual‐Leoneetal.1991)canbeachievedalsowitha40 sofflinecontinuousthetaburststimulation(cTBS)protocol(Huangetal.2005).TheeffectsofTMSontheDSPtaskThediscretesequenceproduction(DSP)taskweusedinitiallyinvolvesreactingtotwofixedseriesof,typically,6or7stimuli(Abrahamseetal.2013;Verwey1999).Duringpractice,participantslearntoselectandexecutethesekeyingsequencesasiftheseconstituteasingleresponse.Thistaskhasbeenusedforovertwodecadesinresearchonmotorsequencelearning(Verwey1996,1999).BehavioralresearchwiththisDSPtaskresultedinvariouscognitivemodels(Abrahamseetal.2013;Verwey2001;Verweyetal.2015).Inaddition,avarietyofDSPstudieshaveexploredtheneuralsubstrateofmotorsequencelearningusingEEG(e.g.,DeKleineandVanderLubbe2011;Sobierajewiczetal.2017),fMRI(Jouenetal.2013;Verweyetal.2019),andalsoTMS(Ruitenbergetal.2014;Verweyetal.2002).ThosestudiesconfirmedthattheSMAisinvolvedinexecutingpracticedDSPsequences.ThefirstDSPstudythatassessedtheeffectsofTMSoftheSMAinvolvedparticipantsinitiallylearningtwofixedseriesofsevenletters(Verweyetal.2002).Thefirstletterwasusedlaterasimperativestimulusforthe6-keysequencethatwasrepresentedbytheensuingsixletters.Weusedlearnedletterseries,insteadofthemoretypicaldisplayofkey-specificstimuli,becauseatthetime,thesestimuliweresuspectedtoreducethecontributionoftheSMA.Thisconjecturerecentlyreceivedsupportfromthefindingthattheonsetofallkey-specificstimuliintheDSPtaskcaptureattentionandthistriggerseachresponseevenafterextendedpractice(Verweyetal.2020).TheresultsofthisTMSstudyconfirmedinvolvementoftheSMAintheDSPtaskinthat20and25 minafter20 minof1 HzofflineTMSofthisareaallresponsesofthetwofamiliar6-keysequences wereslowedby19 ms.OnlyimmediatelyafterrTMSslowingwasnotobserved.GiventhefunctionaldistinctionbetweentheanteriorpartofSMA,preSMA,andtheposteriorpart,SMAproper(Hardwicketal.2013;ShimaandTanji2000),theVerweyetal.(2002)studywasfollowedbytwoTMSstudiesthatspecificallystimulatedpreSMA(Kennerleyetal.2004;Ruitenbergetal.2014).Thosestudieswerecarriedout,becauseitwasshownthatfamiliardiscretemotorsequencesthatincludemorethan4or5responsesareincreasinglyexecutedastwosuccessivesegments(or‘chunks’)ofwhichthefirstresponseisrelativelyslow(BoandSeidler2009;Verweyetal.2009;VerweyandEikelboom2003).StimulatingthepreSMAappearedtoslowonlythefirstresponseofbothsegmentsandnottheotherresponses.ThisledtotheconclusionthatinthecaseoffamiliarDSPsequences,thepreSMAinitiateseachsegment.However,thisalsosuggeststhattheeffectofSMAstimulationoneachresponseinthesequence(Verweyetal.2002)wasactuallycausedbystimulationofSMAproper.StimulationofthepreSMAinRuitenbergetal.(2014)andoftheSMAinVerweyetal.(2002)occurredatlocationsonly1.5 cmapart,thatis,5.5and4 cmanterioroftheCzlocation,respectively.However,TMSstudiesareknowntooftenproducevariableresults(deJesusetal.2014;Klomjaietal.2015;Langetal.2006),possiblyalsobecauseofindividualdifferencesincorticalphysiology(Latorreetal.2019;Maedaetal.2000).We,thereforeconsidereditimportanttoshowthatallresponsesinapracticedDSPsequencesareindeedslowedwhenTMSisespeciallytargetingSMAproper(i.e.,3 cmanteriorofCz,Lefaucheuretal.,2020).ConsolidationOfflineconsolidationisthephenomenonthatmemorytracesthatareinitiallylabileinthattheyaresusceptibletosubsequentlyexecutedtasksandbrainstimulation,becomerobusttothisinterferenceduringthe4–8 hthatfollowpractice.Offlineconsolidationsometimesalsoenhancesskill(Brashers-Krugetal.1996;Handaetal.2016;Robertsonetal.2004;Walkeretal.2003),andformotorsequences,thisenhancementmaydevelopacrossaperiodaslongas72 h(Kimetal.2016;WrightandKim2019).Consolidationhasbeenshowntocontributetothewell-knownbenefitofrandomoverblockedpracticeinthecontextualinterferenceparadigm(Kantaketal.2010;KimandWright2020;Linetal.2011;Verweyetal.2021).Thisbenefitofrandompracticeismostlikelyduetotherepeatedpreparationofmotorsequencesduringrandompracticewhichdoesnotoccurwithshortsequencesintheblockedpracticeregime(Verweyetal.,2021).Verweyetal.(2002)usedawithin-subjectdesigntopreventshort-termeffectsofTMSonthesubsequentshamconditionbyadministeringrealandshamstimulationonsuccessivedays.Inretrospect,offlineconsolidationmayhaveeliminatedtheeffectofTMSintheparticipantswhowerestimulatedontheseconddayandaveragingacrossgroupswithdifferentstimulationorderobscuredthis.We,therefore,testedwhetherresponseslowingbyTMSofSMAproperwouldbereducedonthedayafterpractice.rTMSandcTBSTheearlierTMSstudyinvolvedtheclassicofflinerTMSprotocol(Verweyetal.2002).Thisprotocolinvolvesadministeringfor20 minbriefmagneticpulsesat1 Hz(Hoogendametal.2010;Pascual-Leone1999;Pascual‐Leoneetal.1991).Itiscalledanofflineprocedure,becauseitisadministeredbeforetheparticipantcarriesoutthetaskofinterest.AmorerecentlydevelopedprotocolisofflinecTBS(Casulaetal.2014;Dafotakisetal.2008;Heetal.2020;Strzalkowskietal.2019;Zafaretal.2008).Thisprotocolinvolvesonly40 sstimulationduringwhich5 Hzburstsofmagneticpulsesareadministered(Huangetal.2005).Obviously,researchersprefertheshortdurationcTBSoverthelongerlastingrTMSiftheyknowthattheseprotocolshavethesameeffects,alsobecausesuchashortdurationsimplifiesTMScoilfixation.Yet,littleisknownaboutthebehavioraldifferencesbetweenthesestimulationprotocolsinmotorsequencingstudies.We,therefore,investigatedinthepresentstudywhethertheinhibitoryeffectof40 sofflinecTBSiscomparablewiththatfollowing20 minofflinerTMS.GiventhatVerweyetal.(2002)foundeffectsofrTMSonlyafter20and25 minandnotimmediatelyafterstimulation,andthatafter-effectsofTMShavebeenfoundtolastupto1.5 h(Hamadaetal.2008),wecomparedtheeffectsofrTMSandcTBSonthediscretekeyingsequences0,20,and40 minaftercompletionofbothstimulationprotocols.ThepresentexperimentParticipantspracticedtwo6-keyDSPsequencesfor210trialspersequenceaftertheyhadlearnedverbalsequencesconsistingof1stimulusletterand6key-specificletters,justlikeinVerweyetal.(2002).Yet,thistimeweplacedtheTMScoil3 cm,insteadof4 cm,anteriorofCztospecificallytargetSMAproperandtoreducepossiblestimulationofpreSMA.WeexploredwhetherTMSoftheSMAproperimmediatelyafterpracticewouldbemoreinhibitingthanTMSadministered24 hlatertoexaminewhetherofflineconsolidationprotectsmemoryagainstthedisruptiveeffectofTMS.WefurtherassessedwhetherTMStargetingSMAproperwouldslowallkeypressesofpracticedDSPsequences,whetherthedisruptingeffectof20 minrTMScouldbeobtainedalsobythemoreefficient40 scTBS,andwhethertheinhibitoryeffectdevelopsinthesamewayforbothstimulationprotocolsbyassessingtheTMSeffect0,20,and40 minaftertheendofstimulation.WetestedawarenessofthesequencesattheendoftheexperimenttoexplorewhethertheSMAproperisinvolvedintheapplicationofimplicitorexplicitsequenceknowledge.MethodsParticipantsThesamplecomprised32participants(24females)intheagerangeof18–34 years(M = 25.0,SD = 3.6).Theparticipantswererecruitedviasocialmediaadvertisementsandweremonetarilycompensatedfortakingpartinthestudyorawardedwithstudycredits.Allparticipantswereright-handed,andhadnormalorcorrectedtonormalvisualacuity.Medicalexaminationrevealedagoodphysicalandmentalhealthconditionforallparticipants.Themedicalexaminationsincludedastandardpre-screeningquestionnaireconcerningpresenceandhistoryofdiseases,andpresenceofexclusioncriteriaforTMS,assessmentofbloodpressure,andaneurologicalexaminationofcoordination,vision,sensoryandmotorskills.Alcohol,nicotineanddrugaddictionandtheintakeofmedicationaffectingthecentralnervoussystemledtoexclusion.InlinewithgeneralTMSsafetyguidelines(Rossietal.2009),participantswereaskedwhethertheyhadbeendiagnosedwithchronicorresidualneurologicaldiseases,epilepsy(orpriorevidenceofepilepticseizures),skullfracturesorbraintissuelesions,intracerebralischemiaorbleedingandlocalorglobalaphasia,andwhethertheyhadimplantedpacemakersordeepbrainstimulation.Eventually,noneoftheparticipantswasexcludedfromtheanalysis.ThestudywasapprovedbytheIfADoethicscommittee(proposalnumber2020–172).TheresearchconformedtotheDeclarationofHelsinkiguidelines.Writteninformedconsentwasobtainedfromallparticipantsbeforeparticipation.ApparatusStimuluspresentationandresponseregistrationwerecontrolledbyE-prime©2.0thatwasinstalledonacomputerrunningWindows7.Thecomputerwasdisconnectedfromtheinternet,andmostbackgroundapplicationsweredisabled.ThekeyingsequenceswerepressedonastandardQWERTZ-keyboardwithafastPS2connection.ThestimuliwerepresentedonanIiyamaHM703UTtubemonitorwithascreendiagonalof43 cm.rTMSandcTBSweredeliveredusingaMagandMorePowerMAGClinicalppTMSdevicewitha70 mmfigure-of-eightcoil.Thecoilwasstaticallyplacedontheparticipants’headusingaMagandMorecoilholder.Theheadoftheparticipantwasfixatedutilizingavacuumpillow.DesignWeassessedeffectsofstimulationonresponsetimes(RTs)anderrorrateusingamixed,single-blinded,sham-controlledresearchdesignFootnote1.Oneparticipantgroupreceiveda20 min1-HzrTMSinterventionandtheothergroupa40 s50-HzcTBSintervention.Participantsinbothgroupsreceivedbothrealandshamstimulation.Therealandshamstimulationsessionstookplaceonconsecutivedayswith24 hbetweensessionsandtheirorderwascounterbalancedacrosstheparticipants.Allparticipantswererandomlyassignedtooneofthegroupsandwerekeptblindtothetypeofstimulation(cTBS/rTMS)andwhetherstimulationwasrealorasham.OnDays1and2,everyparticipantperformedabaselineblockbefore,andthreetestblocks0,20and40 minafter,stimulation.BehavioraltasksTheexperimentemployedthesamediscretesequenceproduction(DSP)taskasinVerweyetal.(2002).Itinvolvedparticipantspressingwiththelefthandtwo6-keysequencesinresponsetoasinglesequence-specificstimulus.Tothatend,participantsfirstlearnedtwo7-letterseries.Theseseriesstartedwithasequence-specificstimulus(oneofthelettersO,X,E,D,G,I,L,orM)followedbyaseriesof6lettersrepresentingthe6keystobepressed(consistingofthelettersC,V,B,andN,e.g.,ONCBNCB).Onesequenceinvolveda2 × 3,theothera1 × 6sequence.The2 × 3sequenceconsistedofa3-keysegmentthatwasrepeated.Itwasoneofasetof4alternativesequences(NCBNCB,CVNCVN,VBCVBCorBNVBNV).The1 × 6sequencedidnotinvolvesucharepetitionandwasoneof4alternativestoo(BCVNVC,NVBCBV,CBNVNBorVNCBCN).The2 × 3and1 × 6sequencesalwaysstartedwithanotherkeyforeachparticipant.Duringpracticeandtestblocks,theparticipantsexecutedtheirtwo6-keysequencesinresponsetothesequence-specificstimulus.Sequencecompletionanderrormessageswerefollowedbya1500 msintervalbeforethenextsequence-specificstimuluswaspresented.Eachtrialconsistedofexecutinganentiresequence.Practiceinvolvedthree140-trialblocks,yieldingatotalof210practicetrialspersequence.Thefourtestblocksincluded40trialseach.TheparticipantswereurgedinthegeneralinstructionatthestartoftheexperimentandbytheRTanderrorpercentagefeedbackattheendofeachtrialblocktoalwaysstaybelow8%errorrate.The8%itselfwasarbitrarybutseemedareasonablepercentagetoobtainfewerrorsandareasonablyfastexecutionofthekeyingsequences.Aftertheendofthelasttestblockondaytwo,theparticipantsperformedacomputerizedawarenesstaskthatincludedtwoteststhatwereadministeredinacounterbalancedorder(VerweyandDronkers2019).Bothtestsinvolvedclickingwiththemouse,inaself-chosensequenceorder,sixsuccessiveelement-specificsquaresonthedisplayintheorderparticipantsthoughttheyhadpressedkeys.Duringthespatialawarenesstest,thementionedelementsweredisplayedasfour-squareplaceholderslinedupnexttoeachother,justlikeinthepracticeandtestblocks.Theparticipantswereaskedtoclickthetwosequencesthattheyhadlearnedandexecutedthroughouttheexperimentinthesamesuccessionwiththecomputermouse.Eachplaceholderwasemptyandrepresentedonekeyonthekeyboard(c,v,b,andn).Thistestexaminedexplicitknowledgeofthelocationsofthesuccessivelypressedkeys,thatis,explicitspatialsequenceknowledge.Duringtheverbalawarenesstest,fourplaceholdersweredisplayedatthetop,left,bottomandrightacrossthescreeninarhombusshape.Thistime,eachplaceholdercontainedoneofthelettersofthetwosequences(c,v,b,n).Theparticipantswereagainaskedtoclicktheplaceholderbasedonthesuccessionofthetwolearnedsequences.Thistestexaminedexplicitverbalknowledgeoftheorderofthestimulusletters.Finally,participantswereaskedtoindicatewhetherreproducingthesequencesinthisawarenesstaskhadinvolvedeither(a)recallingthesuccessivelettersofthekeypressed,(b)recallingthelocationsofthestimuliandorkeyspressed,orreconstructingthesequencebyeither(c)tappingthesequenceonthetabletopor(d)inthemind.Thefinaloptionwasthat(e)theyhadnoidea.Theyfilledthisinseparatelyforthespatialawarenesstestandtheverbalawarenesstest,andwerethenaskedhowcertaintheyhadbeenoftheiranswers.Finally,theyweretoldabouttheshamandrealstimulationandindicatedwhethertheythoughtthattherealstimulationhadtakenplaceonthefirstorseconddayorwhethertheyhadnoidea.Duringtheawarenesstask,thekeyboardwascoveredtoensurethattheparticipantsreliedonmemoryrecallinsteadofrecognition.TMSForrTMSandcTBSofSMAthecenterofthefigure-of-eightcoilwaspositioned3 cmanteriortoCz,accordingtotheinternational10–20systemofelectrodeplacement.Forthecontrolcondition,ashamcoilwasusedwhichproducedthesamesoundasthenormalcoilbutnomagneticpulse.Thejunctionareaofthecoilwaspositionedwiththehandlepointingbackwardsandparalleltothesagittalaxis.WhileVerweyetal.(2002)stimulatedSMAattheFCzlocation,whichis10%ofthedistancebetweeninionandnasion(i.e.about4 cmanteriortoCz),weherefollowedtherecentlymoreoftenreportedlocationforthestimulationofSMAproper(Lefaucheuretal.2020).ThestimulationintensityforcTBSwasdefinedas80%oftheindividual’sactivemotorthreshold(AMT)(Huangetal.2005).StimulationintensityforrTMSwasdefinedas90%oftheindividual’srestingmotorthreshold(RMT)(Ziemannetal.1998).WhileVerweyetal.(2002)determinedthemotorthresholdastheintensitythatshowedmovementofthethumb,wristoranyfingerin5outof10trials(Pridmoreetal.1998),wehereusedmotorthresholddeterminationusingelectromyographic(EMG)activity.InordertodetermineRMTandAMT,thecortical“motorhotspot”ofthemusculusabductordigitiminimi(ADM)wasdeterminedforeachparticipantusingEMG(DeGennaroetal.2003;Sohnetal.2004).Bipolarelectrodeswereattachedinabelly-tendonmontagetotherightADM.SubsequentlythelocationoftheleftmotorcortexADMrepresentationwassearchedinstepsof1 cmstartingatCzuntilthecoilpositionwhichresultedinthelargestmotorevokedpotential(MEP)amplitudewithagivenmediumTMSintensitywasidentifiedbytheEMG.Forthisexploration,thefigure-of-eightTMScoilwasusedwhileproducingsinglepulsesinfivesecondintervals.First,thehotspot(thecoilpositionovertheprimarymotorareathatproducesthelargestMEPintherightADMwithagivenmediumTMSintensity)wasidentifiedwithTMS.Then,thestimulationintensitywasadjustedtoevokeMEPswithapeak-to-peakamplitudeof∼1 mV.DuringMEPrecordingsoftheADM,thefigureofeightcoilwaspositionedoverthepredefinedcorticalrepresentationofADMwiththehandlepointingbackwards,and45 degreesfrommidlineinalateralmedialdirection.Followingthisstep,RMTandAMTwereobtained.RMT,usedfordeterminingrTMSintensity,wasdeterminedwiththeTMSMotorThresholdAssessmentTool(MTAT2.0,http://www.clinicalresearcher.org/software.htm).ThesoftwareproposesvariousTMS-pulseintensitiestoapplyonthemotorhotspotattheparticipants’head.ThesoftwaremeasurestheintensitiesoftheEMGresponsestothegivenpulsesandestimatesthe95%-confidenceintervalfortherestingmotorthresholdbasedonthecollecteddata.AMTwasusedtodeterminecTBSintensity.TheAMTwasdeterminedbyapplyingsingle-pulsebiphasicTMStothepredefinedcorticalrepresentationoftheADMmuscleandrecordedMEPwithEMGelectrodes.TheTMScoilwasagainpositioned45degreesfrommidlineinalateraltomedialdirection.ThelowestTMSpulseintensitythatevokedatleast3MEPsofanamplitudeof∼200–300 μVvia6TMSpulsesduringmoderatetoniccontractionoftheADM(∼20%oftheEMGamplitudeaccomplishedbymaximalcontractionofthatmuscle)wasdefinedastheindividualAMT.cTBSinvolved40 sstimulationyielding600magneticpulsesintotal(seeFig. 1fordetails).TherTMSprotocolinvolved1 Hzpulseadministrationfor20 min,whichresultedin1200pulses.Noadverseeventsoccurredduringtheapplicationofthenon-invasivebrainstimulationprocedures.Fig.1Graphicalrepresentationofthecourseofthecontinuousthetaburst(cTBS)protocolshowingthebuildupoftheinter-burstinterval(5 Hz;200 ms)andintra-burststimuli(50 Hz;20 ms).BasedonWuetal.(2018)FullsizeimageProcedureWhentheparticipantsarrivedattheinstitute,theyreceivedanoralexplanationofthestudyprocedure.Theythenreceivedawrittendescriptionofthecourseofeventsinthestudyandsignedtheinformedconsent.Subsequently,participantsweremedicallyexamined,asdescribedabove.Theywereaskedtoverballyreproducethesequencesthatweregiventothemseveraldaysbeforetheycametothelab.Iftheywerenotabletoreproducethesequencesfourtimeswithoutanerror,theyreceived15additionalminutesforlearningandwereretested.Thisappearednecessaryforonlyoneparticipant.Thenextstepwasdeterminingtheindividualstimulationintensity.TheparticipantswereseatedinachairdesignedforTMSapplicationandtheirheadwasfixated.Themotorhotspotwasmarkedoneachparticipant’shead.Then,dependingoftheparticipant’sgroupRMTorAMTwasdetermined.ThelocationoftheSMAwasdeterminedbyidentifyingCzandmarkingthespotofSMAthreecentimetersanteriortoCzwithawaterproofmarker.Next,thelightsweredimmedandtheparticipantswereseatedinfrontoftheexperimentalsetup,thetaskinstructionsweregiven,andasshowninFig. 2theparticipantsstartedpracticingthesequencesbypressingthekeysinresponsetothesequence-specificstimulus.Thelittle,ring,middleandindexfingerofthelefthandwereusedtopressthec,v,bandnkeys,respectively.Participantspracticedeachofthetwosequences210timesinrandomizedorderanddividedacrossthree140-trialpracticeblocks.Eachblockinvolveda20 sbreakhalfwaythroughandwasfollowedbya5 minpause.Inbothsituationsthescreenshowedasecondcountergoingbackto0.Attheendofthe20 sbreaktheexperimentautomaticallycontinued.Afterthe5 minbreaktheexperimenterenteredtheroomandstartedthenextblock,whichallowedhimtoregularlyinteractwiththeparticipant.Fig.2Procedureoftheexperimentexcludingpreparatorysteps(sequencelearning,medicalexamination,determinationofAMTandRMT).OnDay1,8participantsreceivedreal1-HzrTMS,8participantsreceivedsham1-HzrTMS,8participantsreceivedrealcTBS,and8participantsreceivedshamcTBS.Testblockonewasusedforbaselineperformancemeasurement.OnDay2,actualandshamstimulationwerereversedforeachparticipant.Thepost-TMStestblockswereperformed0,20and40 minaftercompletionofthestimulationblockFullsizeimageThefirsttestblockservedasbaselineforthesubsequenttestblocksandwasfollowedbytheactualorshamstimulationperiod.ThisinvolvedfixatingtheheadoftheparticipantandpositioningthecoilwiththecoilholderontheskullovertheSMAintheorientationdescribedbefore.Thestimulationtookplaceinthechairthetaskwasperformedtoavoidrelocatingtheparticipant.TheorderofrealandshamstimulationwascounterbalancedacrossdaysinthecTBSandrTMSgroups.Directlyafterthestimulation,theparticipantsperformedTestBlock2.TestBlocks3and4wereperformed20and40 minaftertheendofTMS.ThetestblocksinvolvedthesametwoDSPsequencesasthepracticeblocksbutatestblockcontainedonly40trials,again withthetwosequencesinrandomorder.Afterthefourtestblocksonday1hadbeenfinishedtheparticipantswerethankedfortheircooperationandwereinstructedabouttheexperimentalsessiononday2.Thisincludeddesistingfromwashingone’shairtopreservethemarksontheheadthatindicatedthelocationofthemotorhotspotandtheSMA.TheAMTorRMTweredeterminedagainatthebeginningofday2usingthe“motorhotspot”mark.Next,thesametestprocedurewasusedasonday1,includingthefirstbaselinetestblock,therequiredstimulation,andtestblocks2,3and4.Participantsstatedthattheytoleratedthestimulationprecedingthetestphaseswell.Aftercompletionofthetestblocksonday2theparticipantsperformedtheawarenessassessmenttaskontheexperimentalcomputer.AllexperimentalprocedurestookplaceunderCOVID-19-relatedsafetymeasures.DataanalysisMeanRTforeveryparticipant,sequenceandkeypresswascalculatedforeachpracticeandtestblock.Thefirstresponsetimeinvolvedthetimetoreacttotheimperativestimulusandproducethefirstresponse.ForthesecondandlaterresponsesRTinvolvedthetimebetweenonsetoftwosuccessiveresponses.SequencescontaininganerrorwereabortedandexcludedfromtheRTanalyses.Boxplotvisualizationshowednooutliers.AmixedANOVAwasusedtoanalyzeRTsandarcsinetransformederrorproportions(Wineretal.1991).InlinewithotherDSPstudies,weusedKey(i.e.,sequencepositions1to6)asindependentvariableinordertoalsoassesspotentialdifferencesofourmanipulationsofthefirstandlaterresponsesinthesequence.DatapreparationandcleaningwasdoneusingE-Prime2.0-DataAid,RandMicrosoftExcel.Greenhouse–Geissercorrectedp’swereusedwhensphericityassumptionswereviolated.ResultsPracticephaseAmixedANOVAonRTswascarriedoutwithTMSGroup(2:rTMSvs.cTBS)andStimOrderGroup(2:RS-Group/Day1RealStimulationvs.SR-Group/Day1Sham)asbetween-subjectvariables.Block(3practiceblocks),Structure(2:1 × 6vs.2 × 3sequence),andKey(6)werewithin-subjectvariables.Asexpected,Blockshowedasignificantmaineffectindicatingimprovementwithpractice,F(2,56) = 177.35,p  19.92,ps  0.42.R56wereexecuted27 msfasterthanR23(236 msvs.263 ms),F(1,28) = 40.63,p  23.0,ps  0.45.ApriorigroupdifferenceswerenotobservedbetweenthetwoTMS-Groups,buttheydidoccurforthetwostimulation-ordergroups.TheSRgroupappearedfasterthantheRSgroupevenbeforeTMS,especiallysoin2 × 3andthiswascausedbyafasterR123intheSRgroup.ThiswasindicatedbyamarginallysignificantStimOrder-Groupmaineffect(SR:330 msvs.RS:383 ms),F(1,28) = 3.19,p = 0.08,ηp2 = 0.10,andaStimOrder-GroupxStructurexKeyinteraction,F(5,140) = 2.70,p = 0.05,ηp2 = 0.09,thatwassupersededbyStimOrder-GroupxStructure,F(1,28) = 8.60,p = 0.007,ηp2 = 0.23,andStimOrder-GroupxKeyinteractions,F(5,140) = 4.34,p = 0.027,ηp2 = 0.13.AnANOVAwiththesamedesignonarcsinetransformederrorsshowedthaterrorsreducedfrom1.9%perkeypressinBlock1to1.0%inbothBlocks2and3,F(2,56) = 31.29,p  4.91,ps  0.15.ItshouldbenotedthattheRTdifferencebetweenrealandshamstimulationinthepre-TMSblockthatisvisibleinFig. 3wasnotsignificant,F(1,28) = 2.69,p = 0.11.ForthecTBSgroup,theslowingbyrealstimulationrelativetopre-stimulationwassignificantafter40 min(28 msslowing),F(1,28) = 4.33,p  0.24.Hence,acrosstheRSandSRgroupsrTMSslowedsequenceexecutionafter0,20and40 min.Instead,cTBSslowedsequenceexecutiononlyafter40 min.Fig.3Responsetimebeforeand0,20and40 minaftercompletionofrTMSandcTBSadministrationintherealandshamstimulationconditionsondays1and2FullsizeimageImportantly,aStimOrder-GroupxStimulationxDelayinteractionconfirmedthattheeffectofrealstimulation,relativetoshamstimulation,differedforparticipantsactuallystimulatedonday1(theRSgroup)andonday2(SRgroup),F(3,84) = 7.27,p = 0.01,ηp2 = 0.21.ThisStimOrder-GroupxStimulationxDelayinteractionwassignificantalsoforbothTMSgroupsseparately,Fs(3,84) > 3.68,ps > 0.02,ηps2 > 0.12.Figure 3showsthecausesoftheseinteractions.ApartfromconfirmingthattheSRgroupwasgenerallyfasterthantheRSgroup,thisfigureshowsthatfortheRSgrouprealstimulationwithrTMSonday1increasedRTsatalldelaysrelativetopre-TMS(topleftframe),whereasaftershamrTMSonday2,RTsshowedthenormalpracticeeffectacrosstestblocks(toprightframe).ThecTBSgroupalsoshowedthatslowingbyTMSoccurredonlyonday1whereitwas,asreportedabove,limitedtothe40 mindelay.Onday2,shamcTBSwasfollowedbythenormalRTsimprovementacrosstestblocks.PlannedcomparisonsconfirmedthesefindingsinthatfortheRSgrouptheeffectofdelaywasdifferentafterrealstimulationonday1andshamstimulationonday2forboththerTMSgroup,F(3,83) = 6.76,p  0.46.Correlationsbetweenthenumberofcorrectresponsesintheawarenesstestandtotalexecutiontimesinthethreepracticeblocksandinthetestblocksondays1and2wereneversignificant(ps > 0.16).Table1indicatesthatthestrategiesparticipantsclaimedtohaveusedwhenperformingthespatialandtheverbaltests,andhowcertaintheyhadbeenabouttheiranswers.Theseresultsshowthatparticipantsreliedmostlyontheletterseriestheyhadlearnedearlierandonimaginingtoexecutethesequences.Theyalsoindicatethatthehighcertaintyofatleast7ofthe32participants(13'verycertain'participants minus 6participantswithcorrectexplicitknowledge)wasunjustified.Theparticipantsseemednotalwaysabletoestimatethereliabilityoftheirawareness.Finally,outofthe16rTMSparticipants,8correctlyidentifiedtherealstimulationsession(‘today’vs.‘yesterday’)and8didthisincorrectly.WithcTBS,8were6werecorrectand10incorrect.Thisindicates thatparticipantshadverylittleawarenessofthetruestimulationsession.Table1Numbersofparticipantsshowingfullexplicitknowledge,thestrategytheysaidtohaveusedtoperformthespatialandverbalawarenesstests,andhowcertaintheyhadbeenabouttheirawarenessFullsizetableDiscussionAprimegoalofthepresentstudywastotestwhethersusceptibilityoftheSMApropertoTMSreducesduetoofflineconsolidation.AsecondgoalwaswhetherspecificallytargetingSMAproperwouldslowallresponsesofapracticedDSPsequence.Lastly,theexperimentwasusedtoinvestigatewhetherthe40 scTBSprotocolwouldhavethesamebehavioraleffects0,20and40 minafterstimulationasthe20 minrTMSprotocol.ConsolidationAspredicted,bothrTMSandcTBSslowedexecutionoftheDSPsequenceswhenadministeredimmediatelyafterpracticeonday1,whilethiswasnotobservedonday2.ThisconfirmsoursuspicionthattheslowingofresponsesbyrTMSreportedinVerweyetal.(2002)wasbasedsolelyontheresultsofthetestsessiononday1.ThiscorroboratesthatofflineconsolidationfollowingpracticestabilizeslearningandmakesitrobustagainstinterferenceofSMAproperbyTMS.Offlineconsolidationhasrecentlybeenarguedtoresultfromrepeatedlypreparingkeyingsequencesinshorttermmemory(Verweyetal.2021).WedidnotobserveindicationsthatstimulationofSMAonday1hamperedtheensuingofflineconsolidation(KimandWright2020).ThepresentresultssuggestthatSMAproperisinvolvedintheapplicationandconsolidationofimplicit,andnotofexplicit,sequenceknowledge.Eventhoughparticipantsinitiallyrequiredexplicitverbalsequenceknowledgetolearnexecutingthesequences,attheendofday2performanceoftheparticipantsontheawarenesstaskwasunexpectedlypoor.Only6of32participantsshowedperfectreproductionofthetwosequencesintheawarenesstest.Theamountofdirectlyavailableexplicitsequenceknowledgewasprobablyevenlessasearlierresearchshowedthatduringawarenesstestsparticipantstendtoreconstructtheirsequencesusingimplicitknowledge(Verwey2015;Verweyetal.2015).Inaddition,explicitknowledgehasbeenshowntocontributelittletorapidlyexecutedDSPsequences(e.g.,CleeremansandSarrazin2007;Verwey2015;VerweyandWright2014).Finally,thereisnoreasonfromotherstudiestoexpectSMAtobeinvolvedinexplicitverbalknowledge.Inlinewiththesearguments,correlationsweresmallandinsignificantbetweenawarenessattheendofday2andexecutionrateduringpracticeindividualtestblocks.TheroleofSMAproperTherTMSconditionreplicatedmostoftheeffectsoftheearlierstudy(Verweyetal.2002).Wealsofoundthespontaneousdevelopmentofarelativelyslowfourthresponsethatistakenasindicationforsegmentation(Abrahamseetal.2013;Verweyetal.2009).Still,incontrasttowhenpreSMAwasstimulated(Kennerleyetal.2004;Ruitenbergetal.2014),thepresentstimulationoftheSMAproperdidnotslowthefirstandfourthresponsesmorethantheotherkeypresses.TheseresultsareconsistentwiththenotionthatTMSaffectedtheroleofSMAproperintriggeringresponsesinM1but,giventheprovenanatomicalconnectivitybetweenSMAproperandM1(Araietal.2012),thebehavioraleffectsofTMSmayhaveemergedalsofromanenduringeffectontheexcitabilityofM1.Whenaveragedacrossbothdaysandthethreetestdelays,thepresentrTMS-inducedslowingofindividualkeypressesbyabout30 msseemstoexceedthe19 msslowinginVerweyetal.(2002).Inaddition,inthepresentstudyrTMSslowedtheresponsesimmediatelyafterstimulationtoo.ThesestrongereffectsofrTMSinthepresentstudymayhaveresultedfromstimulating1 cmmoreposteriorlywhichaffectedSMApropermore,butwecannotexcludethattheywerecausedbythemoresophisticatedmotorthresholdassessmentprocedureyieldinganotherstimulationintensity.TheTMSprotocolsTheresultssuggestthat40 scTBScannotalwaysbeusedtoreplace20 minrTMSstimulation.Whileofflineconsolidationandslowing40 minafterTMSweresimilarinthecTBSandrTMSconditions,cTBSdidnotshowsequenceslowing0and20 minafterstimulationlikerTMSdid.ThedelaysafterwhichtheTMSeffectswereassessedwererelativetotheendofthecTBSandrTMSstimulationperiodsbecausewewereinterestedinthepossibilitytoreplace20 minofrTMSby40 sofcTBS.However,evenifwecomparetheRTeffectsrelativetothestartofstimulation,thesignificantslowingbycTBSdidnotoccuryetafter20 min,whileitdidoccur20 minafterthestartofrTMS(i.e.,0 minafterrTMScompletion).Therefore,evenrelativetotheonsetofthestimulationperiodtheslowingeffectofcTBSdevelopedmoreslowlythanofrTMS.Still,giventheknownvariabilityofTMSeffectsthisdifferencemayhaveresultedfromthelimitedpowerofthepresentstudyandfutureresearchshoulddeterminewhetherthesedifferencesbetweenrTMSandcTBSarerobust.ConclusionsThepresentresultsreplicatedmostoftheresultsoftheearlierDSPstudythatusedrTMStostimulateSMA(Verweyetal.2002).Theyaddthreenewconclusions.First,theyconfirmthatpracticeisfollowedbyofflineconsolidation inthe24hoursfollowingpracticethatmakessequenceexecutionrobustagainststimulationofSMAproperwithrTMSandcTBS.Second,SMAproperisinvolvedintriggeringeachresponseinafamiliarDSPsequenceusingimplicitsequenceknowledge.Third,theeffectsof40 scTBSdifferedfromthoseof20 minrTMSinthatcTBSslowedsequenceexecutiononly40 minafterstimulationonthedayofpractice,whereasrTMSslowedsequenceexecution0,20and40 minafterstimulationonthatday. 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Article  GoogleScholar  DownloadreferencesAuthorinformationAuthorsandAffiliationsFacultyofBehavioural,ManagementandSocialSciences,DepartmentofLearning,Data-AnalyticsandTechnology,Cognition,DataandEducationSection,UniversityofTwente,POBox217,7500AE,Enschede,TheNetherlandsWillemB.Verwey & BenediktGlinskiDepartmentofKinesiology,Non-InvasiveBrainStimulationLaboratory,TexasA&MUniversity,CollegeStation,TX,USAWillemB.VerweyDepartmentofPsychologyandNeurosciences,LeibnizResearchCentreforWorkingEnvironmentandHumanFactors,Dortmund,GermanyBenediktGlinski, Min-FangKuo, MohammadAliSalehinejad & MichaelA.NitscheDepartmentofNeurology,UniversityMedicalHospitalBergmannsheil,Bochum,GermanyMichaelA.NitscheAuthorsWillemB.VerweyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarBenediktGlinskiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMin-FangKuoViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMohammadAliSalehinejadViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMichaelA.NitscheViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsWV:conceptualization,methodology,software,formalanalysis,writing-originaldraft,andwriting-reviewandediting.BG:formalanalysis,projectadministration,investigation,datacuration,writing,andwriting-reviewandediting.MK:conceptualization,investigation,andwriting.MS:conceptualization,investigation,andwriting-reviewandediting.MN:conceptualization,resources,andwriting-reviewandediting.CorrespondingauthorCorrespondenceto WillemB.Verwey.Ethicsdeclarations Conflictofinterest AuthorsWillemB.Verwey,BenediktGlinski,Min-FangKuo,MohammadAliSalehinejadandMichaelA.Nitschedeclarethattheyhavenoconflictsofinterest. 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ReprintsandPermissionsAboutthisarticleCitethisarticleVerwey,W.B.,Glinski,B.,Kuo,MF.etal.ConsolidationofmotorsequencelearningeliminatessusceptibilityofSMApropertoTMS:acombinedrTMSandcTBSstudy. ExpBrainRes240,1743–1755(2022).https://doi.org/10.1007/s00221-022-06358-yDownloadcitationReceived:25November2021Accepted:23March2022Published:07April2022IssueDate:June2022DOI:https://doi.org/10.1007/s00221-022-06358-ySharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsConsolidationTranscranialmagneticstimulationContinuousthetaburststimulationDiscretesequenceproductiontaskMotorsequences DownloadPDF Advertisement