ContentslistsavailableatScienceDirect
Developmental
Cognitive
Neuroscience
jou rn a l h om ep ag e : h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / d c n
Neural
activation
patterns
of
successful
episodic
encoding:
Reorganization
during
childhood,
maintenance
in
old
age
Yee
Lee
Shing
a,b,∗,
Yvonne
Brehmer
a,c,d,
Hauke
R.
Heekeren
e,
Lars
Bäckman
c,
Ulman
Lindenberger
a,faCenterforLifespanPsychology,MaxPlanckInstituteforHumanDevelopment,Berlin,Germany bDivisionofPsychology,FacultyofNaturalSciences,UniversityofStirling,UK
cAgingResearchCenter,KarolinskaInstitutetandStockholmUniversity,Sweden
dOttoHahnResearchGrouponAssociativeMemoryinOldAge,MaxPlanckInstituteforHumanDevelopment,Berlin,Germany eDepartmentofEducationandPsychology,FreieUniversitätBerlin,Germany
fEuropeanUniversityInstitute,SanDomenicodiFiesole(FI),Italy
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received20November2015 Receivedinrevisedform22June2016 Accepted26June2016
Availableonline29June2016 Keywords: Aging Development Episodicmemory fMRI Lifespan Subsequentmemory
a
b
s
t
r
a
c
t
Thetwo-componentframeworkofepisodicmemory(EM)developmentpositsthatthecontributionsof medialtemporallobe(MTL)andprefrontalcortex(PFC)tosuccessfulencodingdifferacrossthelifespan. Totesttheframework’shypotheses,wecomparedsubsequentmemoryeffects(SME)of10–12year-old children,youngeradults,andolderadultsusingfunctionalmagneticresonanceimaging(fMRI).Memory wasprobedbycuedrecall,andSMEweredefinedasregionalactivationdifferencesduringencoding betweensubsequentlycorrectlyrecalledversusomitteditems.InMTLareas,children’sSMEdidnot differinmagnitudefromthoseofyoungerandolderadults.Incontrast,children’sSMEinPFCwere weakerthanthecorrespondingSMEinyoungerandolderadults,inlinewiththehypothesisthatPFC contributeslesstosuccessfulencodinginchildhood.DifferencesinSMEbetweenyoungerandolderadults werenegligible.Thepresentresultssuggestthat,amongindividualswithhighmemoryfunctioning,the neuralcircuitrycontributingtosuccessfulepisodicencodingisreorganizedfrommiddlechildhoodto adulthood.Successfulepisodicencodinginlateradulthood,however,ischaracterizedbytheabilityto maintaintheactivationpatternsthatemergedinyoungadulthood.
©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Episodicmemory(EM)emergesandincreasesduringchildhood (e.g.,SchneiderandPressley,1997)anddeterioratesinaging(e.g., Rönnlundetal.,2005).Onthesurface,childreninmiddle child-hoodandolderadultsshowcomparablememorylevels,withboth groups performing worsethan younger adults (Liet al., 2004). However,directlifespancomparisonsofneuralcorrelatesofEM areentirelylacking,leavinganuntestedassumptionthatneural mechanismsunderlyingmemoryinchildrenandolderadultsare thesame,giventheirsimilaritiesinperformance(butsee behav-ioralcomparisonsbyBrehmeretal.,2007;Fandakovaetal.,2013; Shingetal.,2008).Therefore,lifespanstudiesarestronglyneeded inthefieldofdevelopmentalcognitiveneuroscience,which has
∗ Correspondingauthorat:DivisionofPsychology,FacultyofNaturalSciences, UniversityofStirling,UK.
E-mailaddress:yee.shing@stir.ac.uk(Y.L.Shing).
tendedtofocuseitheroncomparisonsonthelowerend(children vs.youngadults)orthehigherend(youngervs.olderadults)of thedevelopmentalspectrum.Here,weexaminedtheneural corre-latesofsubsequent-memoryeffects(SME),definedasdifferences infMRIactivationbetweensubsequentlyrememberedandomitted trialsduringencoding,in10–12yearsoldchildren,youngeradults between21and26years,andolderadultsabove60yearsofage. OurfocuswastocompareSMEwithinthememorysystemsofthe variousagegroupswhentheyoperatesuccessfullytoformdurable memoryrepresentation.
Accordingtothetwo-componentframeworkofEM develop-ment,theontogenyofEMreflectsinteractionsbetweenassociative andstrategiccomponents(Shingetal.,2010;Shingetal.,2008; Werkle-Bergner et al.,2006).The associative component refers tobinding mechanismsthat integratefeatures of episodesinto coherentrepresentations(Treisman,1996;Zimmeretal.,2006), andthestrategiccomponentreferstocognitive-controlprocesses thataidandregulatememoryfunctions(SimonsandSpiers,2003). In linewithestablishedconceptionsof EM(Eichenbaum,2002; http://dx.doi.org/10.1016/j.dcn.2016.06.003
1878-9293/©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4. 0/).
Moscovitch,1992;Simonsand Spiers,2003)and meta-analyses of fMRI studies on SME (Kim, 2011; Spaniol et al., 2009), we assumethatthelateralPFCandMTL(particularlythehippocampus, HC)supportstrategicandassociativecomponentsofEM, respec-tively.TheHCandassociatedstructurescontributetotheformation ofmemoryrepresentations,particularlyestablishingassociations betweenfeatures(e.g.,Davachi,2006).LateralPFC,ontheother hand,supportscognitivecontrolprocessesinserviceofmemory (FletcherandHenson,2001),suchasimplementationofattention selectionprocessesintheVLPFCandorganizationofinformation inworkingmemoryintheDLPFC(e.g.,BlumenfeldandRanganath, 2007).
BothPFCandMTLundergoprofoundreorganizationin child-hood(Johnson, 2001;Nelson, 2001) and aging (Buckner, 2004; Cabezaetal.,2004).ThestructuralintegrityofPFC(particularly thedorsolateralregions)undergoesmaturationalchangeswellinto adolescence.Ontheotherhand,MTLregionsmatureatfasterrates particularlyinthefirstfewyearsoflife(Gogtayetal.,2006;Sowell etal.,2003).Therefore,weassumethatsuccessfulmemory forma-tioninchildrenshouldrelymoreontheassociativecomponentof MTLandlessonthestrategiccomponentofPFCthatisstill develop-ing(Ofen,2012;Shingetal.,2010;butseeGhettiandBunge,2012). Thus far,resultsare mixed regarding MTLdifferences between childhoodandyoungadulthoodinSME,withsomestudies find-ingagedifferences(e.g.,Ghettietal.,2010)andothersnot(e.g., Ofenetal.,2007).Thisstandsincontrasttothemoreconsistent agedifferencesfoundinPFCacrossdevelopment.Therefore,our empiricalinvestigationwillshedlightonthistopic.
Ontheotherhand,lowerEMperformanceinagingisassumed toreflectsenescentchangesintheassociativeaswellasstrategic components(Shingetal.,2010).Graymatterdifferencesare espe-ciallypronouncedinbothHCandPFCregions(Fjelletal.,2009; Razetal.,2005;but seeRazetal.,2010forlackoflongitudinal changeinPFC).However,findingsregardingfunctionalalterations intheseregionsduringepisodic encodingin oldagehavebeen mixed.Inpart,theinconsistenciesacrossstudiesmayreflectthe heterogeneityofmemoryfunctioninginold age(Persson etal., 2011;Razetal.,2010;Rönnlundetal.,2005).Thispartlygaverise toamaintenanceviewonEMproposedbyNybergetal.(2012), underscoringthenotionthatpreservedbrainfunctioningisthe pri-marycharacteristicofsuccessfulmemoryaging.Whilethisview focusesonbetween-persondifferences,awithin-personaspectof maintenancewouldsuggestthat,amonghealthyolderadults, suc-cessfulepisodicencodingshouldengageboththeassociativeand strategiccomponentsoptimally,reflectingastatethatisyouth-like. Therefore,ourstudyaimedtoshedlightsonthemixedfindingsby comparingagegroupsacrossthelifespantoidentifytheir com-monalitiesanddifferencesinneuralmechanismscontributingto successfulmemoryformation.
Importantly,incontrasttomostSMEstudiesthattested mem-orywitharecognitionprocedure,weoptedforcuedrecallinwhich participantsstudiedwordpairs(e.g.dog-crown)andsubsequently hadtorecallthetarget(crown)whenshownthecue(dog).This requiredindividuals’memorysystemtooperateatitsbestduring encodinginordertoformstrong,distinctivememory representa-tionsthatcanberecalled lateron.Inyounger adults,compared torecognition,cued-recallimposesstrongerdemandsonbothPFC andMTL(HabibandNyberg,2007;StaresinaandDavachi,2006). Basedonourframework,weexpectedthatSMEinchildren, rel-ativetoyoungerandolderadults,wouldrelymoreonMTLand lessonPFCregions.Incontrast,SME-relatedactivationofhealthy olderadultsshouldbelargelysimilartothoseofyoungeradults. ThisisbecausetheneuralcircuitrycontributingtoSME, particu-larlyforformingstrongmemoryrepresentations,shouldnotalter fundamentallyinhealthyaging(cf.MailletandRajah,2014).Asa secondarygoal,wealsoexploredpotentialagedifferencesin
func-tionalconnectivityinEMnetworks.Thusfarlittleisknownabout memory-relatedconnectivityinchildren,whileolderadultsseem toshowincreasedconnectivityinfronto-temporalnetworksfor successfulmemoryencoding(Dennisetal.,2008;OhandJagust, 2013).Therefore,inadditiontofunctionalactivation,ouranalyses willextendthetwo-componentframeworkofEMlifespan devel-opmenttoexamineMTL-PFCinteractions.
2. Methods 2.1. Participants
ThisfMRIstudywaspartofa largerscaleEMtrainingstudy. Theinitialsampleconsistedof95childrenaged10–12years (fifth-gradersintheGermanGymnasiumeducationtrack),49younger adultsaged21–26years(universityorcollegestudents),and165 olderadultsaged63–74years (retiredcommunity dwellers liv-inginBerlin).Theseparticipantstookpartinascreeningsession andwereinvitedtoparticipateinthefMRIstudyiftheyfulfilled allofthefollowingcriteria:(a)aminimumrawscoreof34 cor-rectlysolvedsymbolsonthedigitsymboltest(maximumscore94; Wechsler,1955);(b)recallingatleast3wordpairsfromalistof 10pairs;andadditionallyforadultsonly(c)morethan27points ontheMini-MentalStateExam(maximumscore30;Folsteinetal., 1975);(d)30pointsorhigherontheCES-Dscaleondepression (Radloff,1977).Thefirsttwocriteriawereestablishedafter exten-sivepilotingandwereadoptedtoincreasethelikelihoodthatour scannedparticipantswouldproduceenoughrememberedtrialsfor thefMRIanalyses.
56 children, 35 youngeradults, and 55 olderadults fulfilled thescreening criteria and participated in the fMRI assessment. These participantswereright-handed,native Germanspeakers, andreportednothavingneurologicalorpsychiatricdisorders(e.g. Alzheimer,multiplesclerosis,Parkinson’sdisease,dyslexia,mood disorders etc.). For the current analysis of SME, three children had to beexcluded due toexcessive motion artifacts,and one younger adultdue to technicalerror in scanning.Furthermore, weincludedonlythoseparticipantswhoprovidedsufficient num-bers ofremembered aswellas omittedresponsesfor thefMRI analysis(i.e.a minimumoftworunswithatleastsixtrialsper run;seeMurphyandGaravan,2005onnumberofeventsforfMRI designs).Therefore,fortheanalysesbelow,weuseddatafrom31 children(Mage=11.09,SDage=0.39),33youngeradults(Mage=24.0, SDage=1.33), and 25 older adults (Mage=66.8, SDage=2.15). As showninTable1,comparedtotheexcludedsample,thefinal sam-plewaspositivelyselectedonmemoryperformance,particularly inthecaseofchildren andolderadults.Withineachagegroup, theexcludedandfinalsampleswerecomparableintermsof gen-derradio,performanceonamarkertestofcrystallizedintelligence (verbalknowledge;Lehrl,1977),amarkertestoffluidintelligence (digitsymbol;Wechsler,1955),andyearsofeducation.Wefound expectedlifespanpatternswithrespecttocrystallizedandfluid intelligence,namely(a)acontinuousincreaseinverbalknowledge acrossthelifespan,and(b)aninvertedU-shapedlifespanfunction fortheDigitSymbolscores,withchildrenandolderadultsshowing loweredperformanceincomparisontoyoungeradults.
2.2. Materialsandprocedure
StimuliwerehighlyimaginableconcreteGermannounspaired togethertoformunrelatedwordpairs.Wordsweredrawnfrom Germannormdatabasesandpreviousstudieshadestablishedtheir comprehensibilityforchildren ofsimilaragesasthoseincluded here(seeBrehmeretal.,2004,2007;Hasselhornetal.,1990;Shing etal.,2008).Screenedbyseveralraters,wordpairswerechecked
Table1
Basicdemographicandcognitiveperformanceofparticipantsexcludedfromandincludedinfinalanalyses.
AgeGroup Excluded Final
Mean SE Mean SE
FemaleRatio
CH 0.31 – 0.40 –
YA 0.33 – 0.49 –
OA 0.58 – 0.40 –
YearsofFormalEducation
CH 5 – 5 – YA 16.25 0.75 16.27 0.49 OA 15.68 0.72 17.32 0.73 DigitSymbol CH 41.15 1.47 40.24 1.48 YA 68.67 9.68 70.24 1.80 OA 50.90 1.63 49.68 1.54 VocabularyKnowledge CH 9.30 0.95 9.91 0.76 YA 24.17 1.10 22.23 0.63 OA 28.06 0.53 28.70 0.56 MemoryPerformance CH 0.06 0.01 0.24 0.02 YA 0.29 0.15 0.41 0.03 OA 0.12 0.03 0.32 0.02
Notes:CH=children,YA=youngeradults,OA=olderadults.Scaleofdigitsymbolrangedbetween0and94,andthescorereferstonumberofsymbolscorrectlysolved.Scale ofvocabularyknowledgerangedbetween0and35,andthescorereferstonumberofitemscorrectlysolved.Memoryperformancereferstopercentagecorrect.Excluded andfinalsampleonlydifferedsignificantlyonmemoryperformance,particularlyinchildren,t(51)=−6.43,p<0.001andolderadults,t(49)=−4.93,p<0.001.Notethatthe numberofyoungeradultsintheexcludedsamplewasverysmall(n=2).
againstsemanticorassociativerelatedness,havingthesame start-ingletter,orrhyming,assuchpairingsmaybeeasiertoremember. Lengthofstudylistwasadjustedtorenderthetaskcomparably difficultforeachagegroup(Lunaetal.,2010;Nageletal.,2009; Poldrack,2015)whilefacilitatehavingsufficientnumberoftrials forfMRIanalysis.Asthepresentstudywasembeddedinatraining project(Brehmeret al.,2016), we aimedfor a baseline perfor-mancelevelofbetween25and 45percenttoprovideroomfor training-inducedimprovement.Basedonextensivepilotingwith variationsinlistlength,wesettledon72pairsforchildren,96pairs foryoungeradults,and28pairsforolderadults.Inordertoboost thenumberoftrialsforfMRIanalysis,werepeatedtheencoding runtwiceforchildrenandyoungeradultsandfourtimesforolder adults(eachruncontaineduniquewordpairs;i.e.atotalof144 pairsforchildren,and192pairsforyoungeradults,112pairsfor olderadults).Twofillerwordpairswereaddedatthebeginning andendofeachencodingruntominimizeprimacyandrecency effects.
Beforescanning,participantsweretrainedongetting comfort-ablewiththeMRIenvironmentandpracticedontheencodingtask insideascannersimulator(NordicNeuroLab).Motionwasdetected withacameraandfeedbackwasgivenwhentheymovedtoomuch. Inthenextsession,participantsperformedtheactualword-pair encodingtaskinsidethescanner.Eachwordpairwaspresented forsixseconds,withonewordappearingatthetopandtheother atthebottomofthescreen.Thiswasfollowedbyaquestionfortwo seconds(‘howsureareyouthatyouwilllaterremembertheword pair?’)toensurethatparticipantsremainedattentivetothetask. Participantsrespondedbypressing‘verysure’,‘sure’,or‘unsure’.An explicitbaselineconditionwasincluded(datanotusedinthe cur-rentanalyses),inwhichparticipantssawpairsofletterstrings(e.g., xxxxx–kkkkk).Sixtrialsofsuchletterstringpairs(lastingforone secondeach)werepresentedsequentially,formingoneblock.In1/3 oftheseblocks,thereweretrialswherethepairsofletterstrings consistedofthesameletters(e.g.,xxxxx–xxxxx).Participantswere askedtomonitortheoccurrenceofthesetrialsandtopressa but-tonwhentheysawone.In 2/3oftheblocks,alltrialsconsisted ofpairsofletterstringswithdifferentletters(e.g.xxxxx–kkkkk), hencenobuttonpresseswererequiredandtheseblocksconstituted
theexplicitbaselinecondition.Scanningtimeforthebaselinetask wasroughly1/3ofscanningtimeoftheactualmemorytask.Trials wereseparatedbyajitteredfixationperiod,rangingfrom500to 1500msec(in500mssteps).
Aftereach encoding list,participantsweretestedin a cued-recallprocedure,whichdifferedslightlyforchildrencomparedto youngerandolderadults.Foryoungerandolderadults,retrieval was done inside the scanner without scanning. For children, retrievalwasdoneonacomputerinaquietroomclosetothe scan-ner.Basedonpiloting,lyinginthescannerforboththeencoding andretrievalphaseswastoostrenuousforchildren,lowering scan-nerqualityduetomovementartifacts.Therefore,childrenentered thescanneragainaftercompletingretrievalofthefirstlist. Partic-ipantssawonewordatthetopofthescreenandhadtorecallthe otherword.Theyindicatedwhethertheycouldremembertheword bypressingeither‘yes’or‘no’.When‘yes’waspressed,theywere askedtoverballyreporttheanswer.Participantswerealsoaskedto indicatetheirconfidenceingettingtheanswercorrectbypressing ‘verysure’,‘sure’,or‘unsure’.When‘no’waspressed,thenexttrial appeared.Afterfinishingthememorytask,participantswereasked todescribethestrategies theyhad usedfor encodingtheword pairsinanopen-endedformat.Thesestrategieswerelateroncoded intothreebroadcategoriesbasedonDunloskyandHertzog(1998), namelyvisual,semantic,andshallowstrategies(suchasrote repe-titionorfocusingongraphemicaspectsofthewords).Participants couldreportusingthesestrategiesinanycombination(e.g.using oneofthemexclusively,orcombiningsomeofthem).Each partici-pantreceivedascoreforeachofthestrategycategory,denotingthe proportionofusingstrategiesintherespectivecategoryrelativeto allstrategiesreportedbytheindividual.
2.3. fMRIdataacquisitionandpreprocessing
Whole-brain MRI data were collected with a Siemens 3T Trio Magnetom. Functional data were acquired using an echo-planarimagingsequence(TR=2000ms;TE=30ms;flipangle=80◦; FOV=216mm; matrix=72×72; voxel size=3×3x 3mm3; 36 slices). Before acquisition of each functional sequence, a new localizer was acquired to adjust the slice orientation
(align-ment based on genu-splenium of the corpus callosum). For registrationoffunctionalimages,2structuralsequenceswere col-lected;oneT2-weightedturbo-spinechosequence(TR=8170ms; TE=93ms; matrix=256×256; in-plane resolution=1×1mm, slice thickness=3mm) in the same orientation as the func-tionalsequences;andonehighresolutionT1-weightedMPRAGE sequence(TR=1550ms;TE=2.34ms;matrix=256×256,in-plane resolution=1mm,slice thickness=1mm).Gradientechoimages were also measured for correction of magnetic field inhomo-geneities.
Qualityofthefunctionaldatawasfirstcheckedbyinspecting spikesusingdataQuality,aMatlab-basedtool(http://cbi.nyu.edu/ software/dataQuality.php).Inshort,eachsliceofeachvolumewas dividedintobrain,ghosting,orbackgroundregions.Asmallregion ofinterestinthebackgroundwasdefinedtodetectspikes,that iswhenthesignalwaslargerthan10standarddeviationsabove themean(acrosstime).Detectedspikeswerecorrectedby substi-tutingthevaluewithanaverageoftheintensityofthetwotime pointsbeforeandafteraproblematictimepoint,butonlyifthey themselveswerefreefromspikes.Repaireddatawerethenchecked againtoensurethatnomorespikeswerefound.Withintheruns detectedwithspikes,thenumberofspikesoccurredbetween1and 3times.Therefore,theoccurrenceofspikeswaslikelyrandom. 2.4. fMRIdataanalysis
Dataofeachrunfromeachparticipantwerethenpreprocessed andanalyzedusingFEAT inFSL(Version 5.98,FMRIB’sSoftware Library,http://www.fmrib.ox.ac.uk/fsl,Smithetal.,2004). Prepro-cessingincludednonbraintissueremoval,slicetimeandmotion correction,correctionoffieldinhomogeneity,andspatial smooth-ingusingan8-mmfull-widthhalf-maximumGaussianfilter.Runs withmotionmorethan3mm(absolutedisplacement)inany direc-tionwerehandledbyeitherremovingthatparticularrunentirelyif motionwasdetectedthroughout,orleavingout(without replace-ment)thevolumesaffectedbymotion(andthesubsequentones)if ithadoccurredinthesecondhalfofthemeasurement.Thisaffected 2children(1hadoneruninwhichthelast47volofthe497vols wereremoved,1had onerunremovedentirelyand inanother runthelast246volwereremoved)and3youngeradult(1had oneruninwhichthelast244volofthe648volwereremoved, 1had one runin which thelast 224volwere removed,1 had onerunremovedentirely).Meanframewisedisplacementshowed asignificantageeffect,F(2,84)=5.97,p=0.004.Despite theage difference,allthreeagegroupsshowedrelativelylowframewise displacement (children: mean=0.07, range=0.03–0.27; younger adults:mean=0.05, range=0.03–0.11;older adults:mean=0.09, range=0.04–0.24). Post-hoc comparison with Tukey HSD indi-cated that the age effect was driven by older adults showing higher motion than younger adults (p<0.05). Children did not differfromyoungerorolderadults(ps>0.05).Tocontrolfor dif-ferencesduetomotion,eachindividual’sframewisedisplacement wasenteredasaregressorofnointerestingroup-levelanalyses. Apre-whitening technique wasusedto accountfor the intrin-sictemporalautocorrelationinfunctionalimaging.Low-frequency artifactswereremoved byapplying a high-passtemporal filter (Gaussian-weightedstraight-linefitting,sigma=50s).Age-specific braintemplateswerecreatedfromparticipants’T1imagesusing thenon-linerregistrationANTSprogram(Avantsetal.,2011) fol-lowingtheiterativeproceduresofSanchezetal.(2012).Functional scanswereregisteredtotheirownT1scans,thentotheage-specific braintemplates,andfinallytotheMNIstandardspace.
First-levelstatistical analyseswere performedoneach indi-vidual’sdatafromeachrunusingthegenerallinearmodel.Time seriesweremodeled withseparateregressors fortheencoding phaseofeachtrial,separatelyforsubsequentlyremembered,
omis-sions,andwronglyansweredtrials(post-hocsortingbasedonthe responseparticipantsgaveduringcued-recall). Otherregressors wereincludedtomodelthequestionphase,theexplicitbaseline phase(withandwithoutbuttonpress,separately,see Supplemen-taryMaterial),andfillerpairsatthebeginningandendoftherun. Theregressorsweregenerated byconvolvingtheimpulse func-tionrelatedtotheonsetsandlengthsofeventsofinterestwith aGammahemodynamicresponsefunction.Thecriticalcontrast foranalyzingSMEwascorrectlyremembered>omissions(R>O). Incorrectlyansweredtrialswerenotincludedinthecontrastdue toambiguityinthereasonsforgettingatrialwrong(e.g.,intrusion vs.interferenceerror;seebehavioralerroranalysis).Additionally sixmotionparameterswereincludedasregressorsofnointerest. Contrastimageswerecomputedforeachrunpersubject,spatially normalized,transformedintoMNIspace(2mmisotropicvoxel)and submittedtoawithin-subjectfixed-effectsanalysis(i.e.averaging) acrossruns.Higher-levelanalysisacrosssubjectswascarriedout usingamixed-effectmodelinFSL(FLAME).First,tocharacterize overallSME,wecomputedawhole-braincontrastforR>Oacross all participants, regardless of age. Participants’ mean-centered exactageandmemoryperformance(numberofcorrectly remem-beredtrialsovertotalnumberoftrials)wereenteredasadditional regressors.Functional activation was determinedby threshold-ingtheGaussianizedT-statisticimageofthegroupanalysis,using clustersdeterminedbyZ>2.3(p<0.01)andacorrectedcluster sig-nificancethresholdofp<0.05.AllcoordinatesarereportedinMNI space.
Next,regionofinterest(ROI)analyseswereperformedto exam-ineagedifferencesinSMEwithinregionsthatweremostrelevant toourhypotheses.TheseregionsincludedleftlateralPFC(superior, middle,andinferiorfrontalgyri),bilateralparahippocampalgyrus (PHG), and bilateralhippocampi.First, we prepared anatomical ROIsusingtheHarvard-OxfordCorticalandSubcorticalStructural Atlas(http://www.cma.mgh.harvard.edu/fslatlas.html),with vox-elsthresholdedataminimum25%probabilityofbeingwithina specificregion.Aconjunctionwasthenmadebetweenthe anatomi-calROIsandthegroup-levelSMEfunctionalmapacrossallrunsand participants(asdescribedabove).Thisensuredthatpercentsignal change(PSC)foreachROIisextractedfromactivevoxelswithin thatregion.PSCofeachparticipantfromeachROIwassubjectedto subsequentANOVAs(withagegroupasafactor).Effectswere con-sideredsignificantatanalphalevelof0.01(afteradjustingfrom 0.05formultiplecomparisonsforfivePFCandMTLROIs).Outliers wereidentifiedatp<0.001(i.e.,3standarddeviationsbeyondthe mean,2-tailedtest).Onechildwasidentifiedasanoutlieracrossall ROIswithunusuallyhighvaluesabovethemeanofwholesample, hencewasexcludedfromthefMRIanalysis.Next,tocomplement theROI analysis, ageeffects in SME were exploredin all task-positiveregions,usingthegeneralsubsequent-memoryactivation mapfromallparticipants(asdescribedabove)asapre-threshold mask.AnF-testwithagegroupasafactorwasconducted.
Finally, to explore possible age differences in functional connectivity of MTL as a function of memory formation, we conducted a generalized psycho-physiological interaction (PPI) analysis(McLarenetal.,2012).Weidentifiedleftandright hip-pocampalseedROIsforthePPIanalysesbasedonaspherewith aradiusof4mmaroundthepeakhippocampalvoxel(separately for left and righthemispheres) that wereactive at the group-levelR>Omap[coordinatesoflefthippocampalpeakvoxel:−26, −26,−12;coordinatesofrighthippocampalpeakvoxel:32,−16, −18].ThegeneralizedPPIanalysiscomparedthetemporal corre-lationbetweenthehippocampalseedsandotherbrainregionsfor rememberedversusomissionstrials.Atthefirstlevel,thePPIdesign matrix contained three types of regressors: (a) ‘psychological’ regressorsthatrepresentthefulldesignincludingalleventtypes (i.e.remembered,omissionerrors,wronglyanswered,and
ques-Fig.1. (a)Percentagecorrectcuedrecallacrossage(errorbarsrepresentstandarderrors);(b)Percentagereportedstrategies(overallreportedstrategies)acrossage. CH=Children,YA=YoungerAdults,OA=OlderAdults.
tion);(b)atime-series‘physiological’variablethatrepresentsthe timecourseofthehippocampalseeds;and(c)interactionvariables thatrepresenttheinteractionofthepsychologicaland physiologi-calvariables.Adirectcontrasttocapturedifferenceinconnectivity wasformedbycontrastingremembertrialsfromomissions. Addi-tionally,sixmotionparameterswereincludedasregressorsofno interest.Individual betaimagesof thecontrasttermwerethen enteredintoagroup-levelwhole-brainanalysis,treating partici-pantsasrandom.Participants’mean-centeredpercentagecorrect recall,sex,andframewisemotiondisplacementwereenteredas additionalregressors.Toconstrainthesearchspacetotask-positive regions,thePPIanalyseswereconstrainedusingabinarymaskfrom thegroup-levelsubsequent-memorynetwork.Connectivitymaps werethresholdedat2.3(p<0.01)atthevoxellevelandp<0.05at theclusterlevel.
3. Results
3.1. Behavioralresults
PercentagecuedrecallforeachagegroupispresentedinFig.1a. Notethatperformancecomparisonsacrossagegroupsshouldbe takencautiously, aswe adjustedlistlength foreach agegroup with theaim of obtaining accuracy levels between 25 and 45 percent.Nevertheless,anANOVArevealeda significanteffectof age, F(2, 84)=7.93, p<0.05. Post-hoc comparisons using Tukey HSDindicatedthatchildren(M=0.25,SE=0.03)showedlower per-formancethanyoungeradults(M=0.41,SE=0.03),p<0.05.Older adults(M=0.32,SE=0.03)showedatrendoflowerperformance thanyoungeradults,p=0.09,whereaschildrenandolderadults did not differ reliably, p>0.05. For any incorrect trial, partici-pantscouldeither produceanincorrectanswer(intrusions),an answerthatwaspairedwithanotherwordfromthecurrentor precedingencodinglist(interference),ornoresponse(omission). AmixedANOVA(withinperson:errortype;betweenperson:age group)revealedmaineffectsoferrortype,F(2,83)=551.93,p<0.05,
andofagegroup,F(2,84)=7.93,p<0.05.Themostfrequenterror type was omissions (M=0.60, SE=0.02), followed by intrusions (M=0.05,SE=0.01),andinterferenceerrors(M=0.03,SE=0.003). Children(M=0.25,SE=0.01)andolderadults(M=0.23,SE=0.01) produced more errors than younger adults (M=0.20, SE=0.01). We alsofounda significantinteractionbetweenagegroupand error type,F(4, 166)=2.88, p<0.05. Tofollow up onthis inter-action, weexaminedtheeffectof agegroupineach errortype separately.Specifically,thethreeagegroupsdifferedsignificantly in omission [F(2, 84)=4.69, p<0.05], but not in intrusion [F(2, 84)=1.02, p>.05] orinterferenceerror [F(2,84)=1.08, p<0.05]. Post-hoccomparisonsonomissionerrorusingTukeyHSD indi-catedthatchildren(M=0.67,SE=0.03)hadmoreomissionsthan youngeradults(M=0.53,SE=0.03;p<0.05),whereasyoungerand olderadults(M=0.61,SE=0.03)didnotdifferreliably(p<0.05).
Next,weexaminedstrategyusetocharacterizehowthethree agegroupsmightdifferinhowtheyencodedthepairs(seeFig.1b). InamixedANOVA(withinperson:strategytype;betweenperson: agegroup),asignificantmaineffectofstrategytype[F(2,81)=44.9, p<0.05]andaninteractionbetweenstrategytypeandagegroup [F(4,162)=4.83,p<0.01]werefound.Themostcommonlyreported strategy was semantic (M=0.67, SE=0.04), followed by visual (M=0.22, SE=0.04), and shallow strategies (M=0.11, SE=0.03). Totracethesourceof theinteraction,weexaminedage differ-encesforeachstrategytypeseparately.Significantageeffectswere foundforvisual[F(2,82)=4.27,p<0.05]andshallowstrategies[F(2, 82)=6.87, p<0.05]. For visual strategies, post-hoc comparisons indicatedthatyoungeradults(M=0.36,SE=0.08)reported signif-icantlymoreuseofthisstrategythanchildren(M=0.09,SE=0.05; p<0.05);olderadults(M=0.21,SE=0.07)didnotdifferfromeither oftheotheragegroups(p>0.10).Forshallowstrategies,post-hoc comparisonsindicatedthatchildren(M=0.25,SE=0.06)reported useofshallowstrategiesmoreoftenthanbothyounger(M=0.06, SE=0.04)andolderadults(M=0.02,SE=0.02),ps<0.05,withthe twoadultgroupsnotdifferingfromeachother.
Table2
Peakactivationsforsubsequent-memoryeffects(correctlyremembered>omissions,R>O)acrossallparticipants,withexactageandmemoryperformanceascovariates. Activationmapswerethresholdatavoxel-levelthresholdofz>2.3,correctedatthecluster-levelwithFWE,p<0.05.Tobettercharacterizethepeakclusters,welistclusters thatsurvivedavoxel-levelthresholdofz>4.3,correctedatthecluster-levelwithFWE,p<0.05.
Cluster Region BA Zmax MNIcoordinates(mm) Numberofvoxels
X Y Z
1 Leftinferiorfrontalgyrus 44/45/46 8.7 −54 20 20 12981
Leftmiddlefrontalgyrus 6/9 7 −42 4 52
Leftpostcentralgyrus 40 6.27 −32 −26 52
2 Leftinferiortemporalgyrus 20/37 8.09 −48 −54 −18 7067
Lefttemporalfusiformcortex 35/36 7.84 −30 −34 −24
Bilateralputamen n.a. 7.39 −16 10 −2
Leftparahippocampalgyrus/hippocampus n.a. 6.17 −26 −32 −14
3 Rightparahippocampalgyrus/hippocampus n.a. 5.46 36 −18 −22 2392
Righttemporalfusiformcortex 35/36 7.40 36 −32 −26
4 Leftlateralsuperioroccipitalcortex 19 6.11 −28 −70 44 1843
5 Rightlingualgyrus 18 5.15 14 −84 0 290
6 Rightfrontalorbitalcortex 47 5.51 28 32 −14 145
7 Bilateralcaudate n.a. 4.86 20 2 16 72
8 Leftfrontalmedialcortex 11 4.93 −4 42 −24 61
Next,weexaminedwhetherparticipantsreportingusingmore orlesseffectivestrategies indeeddifferedintheirperformance. Eachparticipantwasclassifiedaseitherreportingusingonly shal-lowstrategies(N=4),usingbotheffectiveandshallowstrategies (N=12), or usingonly effective strategies (visual and semantic strategiescombined;N=70).Therewasasignificantperformance differenceamongthethreegroupsofparticipants,F(2,82)=3.42, p<0.05,aftercontrollingforchronologicalage.Post-hoc compar-isons indicated that participants reporting using only effective strategies(Madjusted=0.35,SE=0.02) showedbetterperformance
thanthosereportingusingonlyshallowstrategies(Madjusted=0.16,
SE=0.09),p<0.05.Thoseusingbotheffectiveandshallowstrategies (Madjusted=0.26,SE=0.05)didnotdifferfromtheothertwogroups
(p>0.05).
Finally,we alsoexamined JOLduring encoding accordingto whether the trial was subsequently remembered or forgotten. Ina mixed ANOVA(withinperson:trialtype;betweenperson: agegroup),significantmaineffectsoftrialtype[F(1,84)=129.04, p<0.01]andagegroup[F(2,84)=16.91,p<0.01]werefound. Sub-sequentlyrememberedtrials(M=1.66,SE=0.04)wereratedhigher inJOLthansubsequentlyomittedtrials(M=1.35,SE=0.03).
Chil-dren(M=1.74,SE=0.05)showedhigheraverageJOLthanyounger (M=1.5, SE=0.05) andolder adults(M=1.28,SE=0.06),p<0.05, withthetwoadultgroupsalsobeingsignificantlydifferentfrom eachother,p<0.05.Thelackofinteractionbetweentrialtypeand agegroup[F(2,84)=0.29,p=0.75]suggeststhatrelativeJOLisage invariantfrommiddlechildhoodtooldage.
3.2. Subsequentmemoryeffects(R>O)acrossallparticipants: whole-braincontrasts
First, to characterize overall activation differences between remembereditemsandomissionerrors,wecomputedwhole-brain fMRI contrasts for SME(R>O) acrossallparticipants,including mean-centeredexactageandperformance(percentagecorrect)as covariates.Inlinewiththeliterature(Spanioletal.,2009),SME wereassociatedwithsignificantactivationinleftlateralPFC (span-ningacrosssuperior,middle,andinferiorfrontalgyri),leftlateral parietalcortex(postcentralandsupramarginalgyri),andbilateral temporalregions(bothlateralandmedialwalls),aswellasin sub-corticalregions,includingbothhippocampi(Fig.2,seecoordinates ofclustersinTable2).ToensurethattheoverallSMEmap
encom-Fig.2.Subsequent-memoryactivation(wholebraincontrastofR>O)acrossallparticipants,aftercontrollingforexactageandpercentagecorrect.Activationmapsare renderedonMNIstandardbrain,withcoordinatespresentedatthebottomofeachsection.Sagittalviewsareshownfromtheleftsideofbrain.Az-valuescaleispresentedon theright.Activationswerethresholdedatavoxel-levelthresholdofZ>2.3,correctedatthecluster-levelatp<0.05.Tovisualizeclusters,wedepictactivationsthatsurvived avoxel-levelthresholdofZ>4.3,correctedatthecluster-levelp<0.05.
Fig.3.Extractedpercentsignalchangeforsubsequent-memoryeffects(R>O)forregionsintheROIanalysis.Significantagedifferenceswerefoundinleftmiddlefrontal gyrus,withchildrenshowingweakerSMEthanyoungerandolderadults.CH=Children,YA=YoungAdults,OA=OlderAdults.
passestheSMEofeachagegroup,wecalculatedthespatialoverlap betweentheoverallactivationmap(A)andeachagegroup’s acti-vationmap(B),whichisA∩B.Wethencalculated,foreachgroup, theproportionofactivationoverlappingwiththeoverallactivation maprelativetotheirownentireactivation(i.e.A∩B/B).Thisratio measurewas0.86,0.93,and0.86forchildren,youngeradults,and olderadults,respectively.Therefore,mostoftheactivationofeach agegroupwasspatiallyrepresentedwithintheoverallactivation map.Inparticular,allthreeagegroupsshowedrobustSMEinleft lateralPFC,thehippocampi,andPHG,regionsthatweexamined nextasROIs.
3.3. AgecomparisonsoflateralPFCandMTL:ROIanalyses
Based on the SME map defined across all participants, we conductedagecomparisonsin theROIs, namelyleft lateralPFC (superior,middle,andinferiorfrontalgyri)andbilateralMTL(HC andPHG),inwhich PSCwasextractedforeach participant.We examinedagedifferencesinPSCintheseregionsusingone-way ANOVAs(withagegroupasafactor).AcrossallROIs,theonlyregion thatshowedasignificantageeffectwasleftmiddlefrontalgyrus, F(2,84)=4.96,p<0.01(Fig.3).Particularly,post-hoccomparisons indicatedthatchildrenshowedlowerSMEinthisregion(M=0.04, SE=0.02)thanbothyounger(M=0.11,SE=0.02,p<0.01)andolder (M=0.12,SE=0.02,p<0.01)adults,withnodifferencebetweenthe twoadultgroups(p>0.10).Theagedifferenceremainedafter con-trollingformeancenteredmemoryperformance(percentcorrect), gender,framewisemotion,andrelativeJOL(i.e.,thedifferencein JOLforrememberedversusomittedtrials)[F(2,80)=5.72,p<0.01]. Theagedifferencealso remainedincludingabsolute(i.e.,mean
levelacrossrememberedandomittedtrials)insteadofrelativeJOL asacovariate[F(2,80)=6.26,p<0.01].Forsuperiorandinferior frontalgyrusaswellasMTL,therewerenoagedifferencesinSME (ps>0.20).TofurtherexaminetheMTL,wealsotestedforage differ-encesusingananatomicalMTLmaskforsmall-volumecorrection, whichdidnotyieldsignificantagedifferenceinSMEwithinthe MTL.
We also exploredagedifferences withan F-testin all task-positive (SME) regions. There wasno cluster that survived the threshold(Z>2.3andap<0.05clusterthreshold).Finally,wehad examinedtherelationshipbetweenmemoryperformanceand sub-sequentmemoryeffectwithineachgroupaswellasacrossgroups controllingforage.Therewasnoconsistentpatternofrelationship thatemerged.
3.4. Hippocampalconnectivityasafunctionofsubsequent memory
To characterize overall connectivity, a PPI analysiswas run acrossallparticipants(withleftandrightHCasseedregions), enter-ingparticipants’sex,recallaccuracy,andframewisemotion(mean centeredaspreviousmodels)asadditionalregressors.Atavoxel thresholdof2.3 (p<0.01)anda clusterthresholdofp<0.05, no reliablememory-dependent(i.e.R>O)variationinfunctional con-nectivitywasobserved.Thiswasalsothecasewhenthemodel wasrunforeachagegroupseparately.Therewerealsonoreliable groupdifferencesinconnectivity,withorwithoutrecallaccuracy ascovariate.
Thedifficultyinidentifyingconsistentconnectivitypatternmay be related to individual differences in the encoding processes
Fig.4.Performance-relatedincreaseinconnectivitybetweenbilateralhippocampiandleftlateralPFC(middleandinferiorfrontalgyrus)aswellasleftmedialPFC(superior frontalgyrus).Bluecolordenotesclustersfoundwithlefthippocampusasseed,redcolordenotesclustersfoundwithrighthippocampusasseed(overlaidontopat60% transparency).(Forinterpretationofthereferencestocolourinthisfigurelegend,thereaderisreferredtothewebversionofthisarticle.)
thatparticipantsengagedin(bothwithinandacrossagegroups), leadingtodifferentialpatternsofconnectivityacrossparticipants (Schott etal.,2013).Asdifferentialtaskprocessingisrelatedto memoryperformance,wethenexploredtheextenttowhich func-tionalconnectivitywasrelatedtoperformanceacrossparticipants, controllingforgenderandmotion(mean-centered).Asshownin Fig.4,forleftHC,wefoundaperformance-relatedincreasein con-nectivitytoleftlateralPFC(middleandinferiorfrontalgyri,BA 44)andleftmedialPFC(superiorfrontalgyrus,BA6).Similarly,for rightHC,wefoundaperformance-relatedincreaseinconnectivity toleftlateralPFC(middleandinferiorfrontalgyri,BA9/46)andleft medialPFC(superiorfrontalgyrus,BA6).Theseregionsoverlapped withthosefoundforleftHC.Therefore,individualswithbetter per-formanceshowedstrongerconnectivitybetweenHCandlateralas wellasmedialPFCforrememberedcomparedtoomittedtrials.
4. Discussion
Thisstudyinvestigatedage-relateddifferencesinactivation pat-ternsduringencodingthatpredictsuccessfulmemoryformation forwordpairs.Wedirectlycomparedtheextremeendsoflifespan andprobedmemorywithcuedrecall,alesscommonlyused proce-dureinSMEstudies.Thisisanimportantextensiontopastresearch, becausecuedrecallrequiresstrongerandmoreaccessibletraces thanrecognition.Inlinewithourpredictions,activationpatterns relatedtoSMEdifferedbetween10and12year-oldchildrenand adults,butnotbetweenyoungerandolderadults.Inchildren,PFC activationsduringstudywerelesspredictiveofsuccessfulrecall thaninadults.Specifically,children,comparedtotheadultgroups, showedsmallerSMEinleftmiddlefrontalgyrus.Incontrast,MTL activationswereequallypredictiveofsuccessfulrecallinallthree agegroups.
ThefindingthatchildrenshowedweakerSMEinmiddlefrontal gyrusis consistent withthe two-componentframework of EM (ShingandLindenberger,2011;Shingetal.,2010),which states thatmemoryfunctioninginchildrenentailslessstrategic elabo-rationthaninadults.Thisreflectsthematurationallagbetween frontalandMTLregionsinneuraldevelopment.Inthisline,Ofen et al. (2007)showed that activation associated withsuccessful
memoryformationincreasedwithageinPFC,butnotMTL(Chiu etal.,2006;GulerandThomas,2013).Supportingthenotionthat increaseinstrategicelaborationparallelsPFCinvolvementacross development,weobservedthatchildrenwhoreportedusingonly effectivestrategies(n=18),relativetotheiragepeerswhoreported usingshallowstrategies(exclusivelyorincombinationwith effec-tivestrategies,n=12),showedstrongerSMEinaclusterwithinthe middlefrontalgyrus(37voxels,z=2.3,uncorrected),theregionin whichagedifferencesinSMEwerefound.Thiseffectwasnotfound inanyotherROIs.Thus,childrenwhoshowedsomeextentofSMEin PFCappearedtohavestartedearlierthantheiragepeersinusing effectivestrategies.Itisimportanttotreatthiseffectas prelimi-naryduetothesmalleffectandlimitedsamplesize.However,it isconceivablethatchildrenarelesscapableofformingmediators forencodingthewordpairsbecausetheypossessfewermental schematatosupportsemanticelaboration,whileatthesametime thereislargeindividualdifferenceinthisaspectamongchildren evenofthesameage(Brodetal.,2013;CraikandBialystok,2006). Weassumethat,basedontheextensivememorydevelopment lit-erature,childrenundergoprogressioninstrategyuseacrosstime, startingfromusingshallow,rote repetitiontodeep,elaborative strategies.Age-relateddifferenceinstrategyusehasbeenshown tobeanimportantfactorthatdrivesmemorydevelopment(e.g., SchneiderandPressley,1997).Suchprogressislikely supported bydevelopmentinthestructuralandfunctionalintegritiesofthe PFC,explainingourobservationofchildrenshowedlessSMEinthe middlefrontalgyrus.Tostrengthenthisobservation,future stud-ieswithalongitudinaldesignandlargersamplesizesareneeded toaddressindividualdifferencesintheprogressionofchildren’s strategyuseanditsrelationstomemoryperformanceattheneural level.
FindingsontheinvolvementofMTLinmemorydevelopment in childhood arenot unequivocal. Evidence suggeststhat there maybeprotractedmaturationforsome,butnotall,MTLfunctions (Ghettietal.,2010;Mariletal.,2010).Forexample,memory pro-cessesinvolvingdetailed memorieswithcontextualinformation aresuggestedtobeassociatedwithagedifferencesinMTL activa-tion(GhettiandBunge,2012).Weacknowledgethatourparadigm differsinimportantwaysfromtheoneofGhettietal.(2010),which
includedpictorialstimulipresentedwithperceptualdetails. Nev-ertheless,ascuedrecallreliesuponmemoriesthatlikelycontain contextualdetails,ourdataseemstobeatoddswiththis view. Therefore,theorganizingprinciplesofwhenMTLactivationsdoor donotincreaseduringdevelopmentremaintobeclarified.Future studiesshouldmanipulatestrengthand detailsinmemory rep-resentationsexperimentallytodissociatetheeffectsofthesetwo factorsandtheagedifferencestherein.
Ontheaging side,wefoundlittledifferences betweenolder andyoungeradults’SME,suggestingthathigh-functioningolder adults,suchasthoseinourstudy,engagemuchofthesame neu-ralcircuitryasyoungeradultswhenformingrepresentationsthat canbesubsequentlyrecalled.Suchfindingmayseematoddwith thetwo-componentframeworkthatpositsadualdeficitin asso-ciativeandstrategiccomponentsinaging(followingevidenceof structuraldeclineinthePFCandMTL).However,whiletheremay bedeteriorationinthetwocomponents,theframeworkdoesnot precludeawithin-personmaintenancepatternofsuccessful encod-ingin aging, suchthat theneuralsubstrate that contributesto memoryformation,whensuccessful,remainslargelysimilar.Such age-invariantSMEinleftfrontalandMTLregionswaspreviously reported(deChastelaineetal.,2011;Duverneetal.,2009;Morcom et al., 2003). It would be interesting to examine thepotential dissociationbetweenage-relateddifferencesinthetwomemory componentsingeneral(suchas attemptingtorememberwhen oneisinencodingmode)versusagedifferencesinthetwo com-ponentsinrelationtoencodingsuccess(whenmemoryformation issuccessful).However,ourdataisnotoptimallysuitableforthis purpose,astheencoding successtrialsarealargesubsetofthe encodingmodetrials.Infuturestudies,onewouldideallyinclude anindependentmemorytaskthattapsintoencodingmodewith ablockdesign,oramixedblockandevent-relateddesigntotease apartsustained(i.e.mode)versustransient(i.e.success)processes withinthesametask(PetersenandDubis,2012).
Ourresultsalsostandin contrasttofindingsofincreasedor morebilateralPFCSMEinolderadults,startingfrommiddleage (Parketal.,2013).Thesedivergencesmayreflectdifferencesinthe natureofthetasks.Successfulmemoryformation,assessedwith thepresent cued-recallprocedure, mayimposehigherdemands onthequality of memoryrepresentationsneeded toreachthe thresholdforproducingacorrectresponse.Ourresultssuggestthat, inbothyoungerandolderadults,suchhigh-qualityengramsare formedbyinvolvingbothPFCandMTLduringencoding.A recogni-tionprocedure,ontheotherhand,maymorereadilyprobepartially accessiblememoryrepresentations.Interestingly,ameta-analysis byMailletandRajah(2014)showedthatregionsconsistently over-recruitedbyolderadultsareeitheroverlappingorclosetoregions involvedinunsuccessfulencodinginyoungeradults(e.g.medial frontalgyrus,precuneus).Thismayreflectanage-relatedshiftaway fromperceptualdetailstowardsevaluativeandpersonalthoughts andfeelingsduringencoding.However,theseoperationsareless efficientmeansofencoding information (e.g.,Hashtroudi etal., 1995;Kensinger,2009).Memoryrepresentationsboundin such waysmaybesufficientlyaccessibleinarecognitionbutnotina cued-recallprocedure, explainingwhy olderadultsin our sam-pledidnotshowengagementofadditionalregionsreportedinthe agingliteratureonSME(MailletandRajah,2014).
Our procedure of adapting list length minimized task per-formance difference across groups, which carries important advantages for interpreting groupdifferences inactivation (see Nageletal.,2009; Lunaetal., 2010;Poldrack, 2015).However, therearelimitationstoconsider.First,wecouldnotfully equal-izethetotalnumberofto-be-rememberedwordpairsacrossage groups,asadditionalrunswouldhavebeentoostrenuousforthe childrenandtheolderadults.Thismighthaveloweredthepower ofdetectingSMEinolderadultsduetohavingtheleastnumberof
trials.However,giventhatolderadultsshowedasrobustanSME asyoungeradults,wethinkthatthevalidityofthepresentresults isnotcompromised.Wealsoranvalidationanalysesbyleavingout trialsinchildrenandyoungeradultssothatallagegroupswere representedbythesamenumberoftrialsforthefirstlevelR>O contrast(seeSupplementaryMaterial).Resultsremainedlargely unchanged,withsimilarSMEregionsfoundaswellassame pat-ternsofagedifferencesinROIanalysis,supportingthevalidityof theanalyses.Nevertheless,futurelifespancomparisonswill bene-fitfromotherroutestoadapttaskdifficultywithoutconfounding numberoftrials.
Thesecondlimitationreferstothefactthatoursamples, par-ticularlytheolderadults,werehighlyselective.Intotal,97outof 165olderadultswerenotinvitedtoparticipateinthefMRIstudy due tofailure in meeting thescreening criteria. Similarly, chil-drenretainedwerepossiblylessrepresentativeoftheircohortthan theyoungeradults(althoughthelatterwereuniversitystudents andhencealsopositivelyselected).Itislikelythattheselection procedures used in this study, while contributing to its inter-nalvalidity,reducedthegeneralizabilityofthepresentfindings tothegeneralpopulation.Forolderadults,Salamiet al.,(2012) showedthatmoreactivityincognitive-controlnetworks(including frontoparietalcortices)correlated negatively withmemory per-formance.Thatis,amongolderadults,betterperformingpersons showedlessadditionalengagementofthecontrolnetwork rela-tivetoyoungeradults.Inlightofthisfinding,itisconceivablethat thehigh-functioningnatureoftheolderadultshascontributedto thesimilarityoftheirSMEpatternstothepatternsobservedin youngeradults.Thisisinlinewiththebetween-personaspectof brainmaintenanceproposedbyNybergetal.(2012).Giventhat maintenancelikelydoesnotexistinabsoluteterms,future stud-iesareneededtodelineatetheboundaryconditionswithinwhich healthyolderadultsmayexhibityouth-likeneuralpatterns. Like-wise,theobservedfMRIdifferencesbetweenchildrenandyounger adultsmaynotberestrictedtodifferencesinsuccessfulmemory formation.Inparticular,thehigh-performingchildren participat-inginthepresentstudymaynothaveunder-recruitedthemiddle frontalgyrusduringSMErelativetoyoungeradults,butrathermay havebeenquickertodisengagefromencodingafterthememory wasformed.
Finally, to reduce movement artifacts that are particularly prominentinchildren,theirretrievalwasconductedoutsidethe scanner,leadingtoachangeinretrievalcontextandslightlylonger delaybetweenencoding and retrievalthatmight havelowered children’sperformance.Althoughwethinkthatthiscannotfully accounttheagedifferencefounduniquelyinmiddlefrontalgyrus, butnototherfrontalorMTLregions,suchdifferenceinprocedure isbestavoidedinfuturestudies.Takentogether,itisachallenging tasktoinvestigateage-relateddifferencesinmemorymechanisms acrossthelifespan.Participantsofdifferentagesdifferinawealth offactorsin additiontothephenomenonof interest(seeShing andLindenberger,2011).Ourstudyisthefirstattemptat creat-ingexperimentalsetupsthatallowmeaningfulcross-sectionalage comparisonsinsuccessfulmemoryformation acrossthehuman lifespan. We believe that the utility and feasibility of suchan approacharedemonstrated,whilethechallengesandlimitations that we encountered, particularly theselection bias across age groupsandproceduraldifferencesasconfounds,serveas impor-tantlessonsforfuturestudies,andindicatethatthereisroomfor furtherimprovementsinresearchdesign.
DespitefindingrobustSMEinallgroups,wedidnotdetecta consistentpattern offunctional connectivityatthegrouplevel, bothfortheentiresampleorwithineachagegroup.Thedifficulty indetectingfunctionalconnectivitylikelyreflectslargeindividual differences inhow participantsprocessedthe task.Such differ-encesalsopositachallengeformean-activationdetection,butare
magnifiedforconnectivityanalysisduetotheneedformore pre-cisetemporalcovariation.Varyinglevelofprocessing,Schottetal. (2013)showedthatsuccessfulencodingduringdeepversus shal-lowprocessingwasaccompaniedbygreaterconnectivityofleftHC toventrolateralPFCandtemporoparietalcortex.Therefore, spe-cificprocessesthatoneengagesinduringencodingareassociated withdifferentialpatternsofconnectivity,supportingourreasoning fornotfindingaconsistentconnectivitypatternsatthegrouplevel. Interestingly,betterperformancewasrelatedtogreater connectiv-itybetweenHCandmedialandlateralfrontalgyrus(inparticular, BA9/44/46).Basedonpreviousliterature,weassumethatthishas todowiththeseregions’rolesintheorganizationofmultiplepieces ofinformationinworkingmemorysuchasbuildingsemantic rela-tionsbetweenpairsofwords,whichinturnenhancesmemoryfor associationsamongitemsintheHC.Suchdeepprocessingisshown tobenefit memoryperformance, potentially accountingfor our observationthatindividualdifferenceinperformanceisassociated withthestrengthofconnectivitybetweenHCandPFCregions.
In conclusion, our findings demonstrated that, in high-functioningchildren,theneuralcircuitrycontributingtosuccessful episodicencodingisreorganizedduringthetransitionfrom mid-dlechildhoodtoadulthood,progressingfromrelianceontheMTL toincreasingengagementofthePFCinformingdurablememory representations.Ontheotherhand,olderadultswithhigh mem-oryfunctioningshowpreservedabilitytoengagethePFCandMTL when memoryformation issuccessful, supportingthe proposi-tionthatmaintenanceofyouth-likeactivationpatternscontributes positivelytoEMfunctioninginoldage(Fandakova etal.,2015; Lindenberger,2014;Nybergetal.,2012).
Conflictofintereststatement
Wedeclarenopotentialfinancialandpersonalconflictof inter-est.
Acknowledgements
Thiswork wassupported by the GermanResearch Founda-tion(grantnumberDFGSH550/2-1)toYLSandYB,aswellasby agrantfromtheSwedishResearch,anAlexandervonHumboldt ResearchAward,andadonationfromtheafJochnickFoundation toLB,andbygrantsfromtheMaxPlanckSociety,theFederal Min-istryofEducationandResearch,andaGottfriedWilhelmLeibniz Award2010oftheGermanResearchFoundation(DFG)toUL.YB alsoreceivedpostdoctoralfundingfromERA-AGE,FutureLeaders ofAgeingResearchinEurope(FLARE)/SwedishCouncilof Work-ingLifeandSocialResearch.Thestudywasconductedwithinthe “Cognitiveand NeuronalDynamics ofMemoryacrossthe Lifes-pan”(CONMEM)projectattheCenterforLifespanPsychology,Max PlanckInstituteforHumanDevelopment.WethankAnnetteRentz andLene-MarieGassnerfortheirinvaluablehelpforthestudy. AppendixA. Supplementarydata
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