Dynamic Modulation of Amygdala–Hippocampal Connectivity by Emotional Arousal

13 Pages·2014·1.6 MB·English

TheJournalofNeuroscience,October15,2014•34(42):13935–13947•13935
Systems/Circuits
Dynamic Modulation of Amygdala–Hippocampal
Connectivity by Emotional Arousal
MatthiasFastenrath,1,2DavidCoynel,1,2KlaraSpalek,1,2XAnnetteMilnik,2,4LeoGschwind,1,2BennoRoozendaal,3
AndreasPapassotiropoulos,2,4,5,6andDominiqueJ.F.deQuervain1,4,6
1DivisionofCognitiveNeuroscience,DepartmentofPsychology,UniversityofBasel,4055Basel,Switzerland,2DivisionofMolecularNeuroscience,
DepartmentofPsychology,UniversityofBasel,4055Basel,Switzerland,3RadboudUniversityNijmegen,DepartmentofCognitiveNeuroscienceand
DondersInstituteforBrain,CognitionandBehaviour,6525EZNijmegen,TheNetherlands,4PsychiatricUniversityClinics,UniversityofBasel,4012Basel,
Switzerland,5DepartmentBiozentrum,LifeSciencesTrainingFacility,UniversityofBasel,4056Basel,Switzerland,and6TransfacultyResearchPlatform,
UniversityofBasel,4055Basel,Switzerland
Positiveandnegativeemotionaleventsarebetterrememberedthanneutralevents.Studiesinanimalssuggestthatthisphenomenon
dependsontheinfluenceoftheamygdalauponthehippocampus.Inhumans,however,itislargelyunknownhowthesetwobrain
structuresfunctionallyinteractandwhethertheseinteractionsaresimilarbetweenpositiveandnegativeinformation.Usingdynamic
causalmodelingoffMRIdatain586healthysubjects,weshowthatthestrengthoftheconnectionfromtheamygdalatothehippocampus
wasrapidlyandrobustlyincreasedduringtheencodingofbothpositiveandnegativepicturesinrelationtoneutralpictures.Wealso
observedanincreaseinconnectionstrengthfromthehippocampustotheamygdala,albeitatasmallerscale.Thesefindingsindicatethat,
duringencoding,emotionallyarousinginformationleadstoarobustincreaseineffectiveconnectivityfromtheamygdalatothehip-
pocampus,regardlessofitsvalence.
Keywords: amygdala;dynamiccausalmodeling;effectiveconnectivity;emotion;hippocampus;memory
Introduction Anatomical investigations have revealed that the amygdala
Enhancedmemoryforemotionaleventsisawell-recognizedphe- andthehippocampusarereciprocallyconnected(Saundersetal.,
nomenon, which has obvious adaptive value in evolutionary 1988;Nieuwenhuysetal.,2008).Todate,thereisnostudyassess-
terms,asitisvitaltorememberbothdangerousandfavorable ing the bidirectional influence of emotional information on
situations(McGaugh,2003;deQuervainetal.,2007).Studiesin amygdala–hippocampalconnectivityduringencodinginhealthy
animalsinvestigatingtheneurobiologicalmechanismsunder- humans.Moreover,itisnotknownwhetherpositiveandnegative
lying the enhancing effect of emotional arousal on memory information has similar or different effects on amygdala–hip-
consolidation have indicated that this effect depends on the pocampalconnectivity.Weinvestigatedthefacilitatoryeffectof
influence of the amygdala upon the hippocampus in case of emotionallyarousingnegativeandpositiveinformationduring
contextualandspatialinformation(McGaugh,2002;Phelps, encodingbyexaminingthestrengthofthereciprocalconnections
2004). In addition to these well-documented effects of emo- betweentheamygdalaandthehippocampus.Thiswasachieved
tional arousal on the consolidation of long-term memory in byapplyingdynamiccausalmodeling(DCM)offMRIdataina
animals, there is considerable evidence from human studies largepopulationof586healthyhumansubjectswhoparticipated
that emotional arousal regulates memory-modulatory pro- inamemorytaskwitharapidandintermingledpresentationof
cessesalreadyduringencoding(Hamannetal.,1999;Canliet positive,neutral,andnegativepictures.DCMcanbeappliedto
al., 2000; Hamann, 2001; Phelps, 2004; de Quervain et al.,
test specific hypotheses about the presence, direction, and the
2007;Toddetal.,2013).
modulatorsofeffectiveconnectivitybetweenasetofpredefined
brainregions.DCMisdescribedindetailpreviously(e.g.,Friston
etal.,2003;foranontechnicalintroduction,seeStephanetal.,
ReceivedFeb.26,2014;revisedAug.29,2014;acceptedSept.3,2014.
Authorcontributions:A.P.andD.J.F.d.Q.designedresearch;K.S.performedresearch;M.F.,D.C.,andA.M.ana- 2010).Inbrief,neuralinteractionsbetweenregionsareexpressed
lyzeddata;M.F.,D.C.,K.S.,A.M.,L.G.,B.R.,A.P.,andD.J.F.d.Q.wrotethepaper. bydifferentialequations,whichdescribe(1)howtheactivityin
ThisworkwassupportedbySwissNationalScienceFoundationSinergiaGrantCRSI33_130080toD.J.F.d.Q.and onebrainregioncausesdynamics(i.e.,rateofchange)inanother
A.P.WethankElmarMerkle,ChristophStippich,andOliverBieriforgrantingaccesstothefMRIfacilitiesofthe
brain region and (2) how these interactions change under the
UniversityHospitalBasel.
Theauthorsdeclarenocompetingfinancialinterests. influenceofexperimentalconditions.Inthisstudy,wefocused
CorrespondenceshouldbeaddressedtoeitherMatthiasFastenrathorDr.DominiqueJ.F.deQuervain,Divisionof ontheinteractionsbetweentheamygdalaandthehippocampus
CognitiveNeuroscience,DepartmentofPsychology,UniversityofBasel,Birmannsgasse8,4055Basel,Switzerland, because:(1)encodingofemotionalpicturesleadstoacoactiva-
E-mail:[email protected]@unibas.ch.
tionofthetworegionsinhealthyhumans(Dolcosetal.,2004);
DOI:10.1523/JNEUROSCI.0786-14.2014
Copyright©2014theauthors 0270-6474/14/3413935-13$15.00/0 (2)thehippocampusisknowntoplayakeyroleinhumanepi-
13936•J.Neurosci.,October15,2014•34(42):13935–13947 Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity
sodicmemory(Eichenbaum,2004);and(3)theimportanceof arousal(large,medium,small)ona3-pointscale(self-assessmentman-
themodulatoryinfluenceoftheamygdalauponthehippocam- ikin) by pressing a button with a finger of their dominant hand. For
pus in the enhancement of contextual and spatial memory of scrambledpictures,participantsratedform(vertical,symmetric,orhor-
emotionallyarousingeventshasbeenwellestablishedinanimal izontal)andsize(large,medium,small)ofthegeometricalobjectinthe
foreground.
experiments(RoozendaalandMcGaugh,2011).
MRIacquisition
MaterialsandMethods
Measurements were performed on a Siemens Magnetom Verio 3 T
Participants
whole-bodyMRunitequippedwitha12-channelheadcoil.Functional
Werecruitedhealthy,youngsubjectsinSwitzerland(364females,222 timeserieswereacquiredwithasingle-shotecho-planarsequenceusing
males,meanage(cid:2)22.37years,SD(cid:2)3.17years).Thesubjectswerefree parallelimaging(GRAPPA).Weusedthefollowingacquisitionparame-
ofanyneurologicalorpsychiatricillness,didnottakeanymedicationat ters:TE(echotime)(cid:2)35ms,FOV(fieldofview)(cid:2)22cm,acquisition
thetimeoftheexperiment(excepthormonalcontraceptives),andwere matrix(cid:2)80(cid:6)80,interpolatedto128(cid:6)128,voxelsize:2.75(cid:6)2.75(cid:6)4
between 18 and 35 years old. The experiments were approved by the mm3,GRAPPAaccelerationfactorr(cid:2)2.0.Usingamidsaggitalscout
ethicscommitteeoftheCantonofBasel.Allsubjectsgavewrittenin- image, 32 contiguous axial slices placed along the anterior–posterior
formedconsentbeforeparticipationinthestudy. commissureplanecoveringtheentirebrainwithaTR(cid:2)3000ms((cid:2)(cid:2)
82°)wereacquiredusinganascendinginterleavedsequence.Thefirst
Procedure
two acquisitions were discarded due to T1 saturation effects. A high-
Subjectsunderwentfourconsecutivetasks:apictureencodingtask,a
resolutionT1-weightedanatomicalimagewasacquiredusingamagne-
workingmemorytask,afreerecallmemorytest,andarecognitiontask.
tizationpreparedgradientechosequence(MP-RAGE,TR(cid:2)2000ms;
Participantswerefirstinstructedandthentrainedonthepictureencod-
TE(cid:2)3.37ms;TI(cid:2)1000ms;flipangle(cid:2)8;176slices;FOV(cid:2)256mm;
ingtask.Aftertraining,theywerepositionedinthescannerandreceived
voxelsize(cid:2)1(cid:6)1(cid:6)1mm3).
earplugsandheadphonestoreducescannernoise.Theirheadwasfixated
inthecoilusingsmallcushions,andtheyweretoldnottomovetheir
Preprocessingandfirst-levelanalysis
heads.PictureswerepresentedinthescannerusingMR-compatibleliq-
WeusedSPM8(StatisticalParametricMapping,WellcomeTrustCentre
uidcrystaldisplaygoggles(VisualSystem;NordicNeuroLab).Eyecor-
for Neuroimaging, London; http://www.fil.ion.ucl.ac.uk/spm/) imple-
rectionwasusedwhennecessary.Thepictureencodingtasklastedfor
(cid:3)20min.Immediatelyafterward,subjectsperformedtheworkingmem- mentedinMATLABR2011b(MathWorks).
orytaskfor(cid:3)10additionalminutes.Afterleavingthescanner,partici- GeneralanalysisstepsusedtoprocessEPIvolumes.Volumeswereslice-
timecorrectedtothefirstslice,realignedusingthe“registertomean”
pantsweregivenasurprisefreerecallmemorytestofthepicturesina
option,andcoregisteredtotheanatomicalimagebyapplyinganormal-
separateroom(notimelimitwassetforthistask).Afterward,partici-
ized mutual information 3D rigid-body transformation. Successful
pantswererepositionedinthescannerandperformedarecognitiontask.
coregistrationwasvisuallyverifiedforeachsubject.
Todocumentthefreerecall,subjectshadtowriteadescriptionofthe
Specificanalysisstepsappliedtodeterminetheactivitypeaksatthegroup
rememberedpictures.Apicturewasscoredascorrectlyrecalledifthe
level.First,wesmoothedthevoxelsoftheamygdalaeandhippocampi
ratercouldidentifythepresentedpictureonthebasisofthesubject’s
separately from each other (for details, see ROI specific smoothing).
description.Twotrainedinvestigatorsindependentlyratedthedescrip-
tionsforrecallsuccess(inter-raterreliability(cid:4)98%).Athirdindepen- Next,wemodeledeventtypes,correspondingtothepresentationofpic-
turesandscrambledstimuli,withacanonicalhemodynamicresponse
dentraterdecidedonpicturesthatwererateddifferently.Participants
functionwithinthecontextofaGLM(fordetails,seeGLMspecifica-
received25CHF/hforparticipation.
tion).Theresultingparameterestimateswerecontrasted(picturesminus
Experimentaldesignofthepictureencodingtask scrambled).Finally,wenormalizedthecontrastimagestoMNIspaceby
Stimuliconsistedof72picturesthatwereselectedfromtheIAPS(Langet applyingDARTEL(Ashburner,2007)(fordetails,seeNormalizationto
al.,2008),aswellasfromin-housestandardizedpicturesetsthatallowed MNIspace).
ustoequatethepicturesforvisualcomplexityandcontent(e.g.,human ROIspecificsmoothing.Slice-timecorrected,realigned,andcoregis-
presence).PicturesreceivedfromIAPSwereclassifiedaccordingtothe teredEPIvolumesweresmoothedinaregion-specificmannertodeter-
IAPS valence rating; the remaining eight neutral pictures were rated mineactivitypeaksatthegrouplevel.Theamygdalaeandhippocampiin
basedonanin-housevalencerating.Onthebasisofnormativevalence bothhemispheresweresmoothedindependentlyfromotherregionsin
scores (from 1 to 9), pictures were assigned to negative (2.3 (cid:5) 0.6), thebrain,therebyavoidingamixtureofdataacrossdifferentregions.
neutral(5.0(cid:5)0.3),andpositive(7.6(cid:5)0.4)conditions,resultingin24 Inaddition,sevenotherstructureswerealsosmoothedseparately:thal-
picturesforeachvalence.Positivestimuliwereinitiallyselectedtomatch amus,caudate,putamen,pallidum,entorhinalcortex,parahippocampal
arousalratingsofnegativestimulibasedondataofapilotstudyin20 cortex,andtemporalpolecortex.Theseadditionalregionswerenotof
subjects.Fouradditionalpicturesshowingneutralobjectswereusedto interestinthecurrentstudybutwerenonethelessincludedforcompu-
controlforprimacyandrecencyeffectsinmemory.Twoofthesepictures tationalexpedienceastheyareofinterestforotherprojects.Smoothing
werepresentedinthebeginningandtwoattheendofthepicturetask. wasappliedwithineachregionasdelimitedbyitsFreeSurfer(version4.5,
Examplesofpicturesareasfollows:erotica,sports,andappealingani- http://surfer.nmr.mgh.harvard.edu/)(Fischletal.,2002)segmentation
malsforthepositivevalence;bodilyinjury,snake,attackscenesforthe withanisotropic8mmfull-widthathalf-maximumGaussianfilterusing
negativevalence;andneutralfaces,householdobjects,andbuildingsfor theSPMfunctionsspm_smoothandspm_mask.Theremainingbrain
theneutralcondition.Inaddition,24scrambledpictureswereused.The volumewassmoothedbycreatingamaskcontainingallvoxelswithinthe
backgroundofthescrambledpicturescontainedthecolorinformationof brainthatwerenotpartofanyoftheaforementionedregions.Afterthat,
all pictures used in the experiment (except primacy and recency pic- the separately smoothed EPI volumes were recombined into single
tures), overlaid with a crystal and distortion filter (Adobe Photoshop volumes.
CS3).Intheforeground,amostlytransparentgeometricalobject(rect- GLMspecification.GLMswerespecifiedtodeterminethepeaksatthe
angleorellipseofdifferentsizesandorientations)wasshown. grouplevelandtolocatethelocalmaximaofeachsubjectwhenextract-
Thepictureswerepresentedfor2.5sinaquasi-randomizedorderso ingtimecourses.IntrinsicautocorrelationswereaccountedforbyAR(1),
thatatmaximumfourpicturesofthesamecategoryoccurredconsecu- andlow-frequencydriftswereremovedviahigh-passfilter(timecon-
tively.Afixationcrossappearedonthescreenfor500msbeforeeach stant128s).Theeffectofpictureswasinvestigatedbyconstructingsep-
picturepresentation.Trialswereseparatedbyavariableintertrialperiod arate regressors for the picture and the scramble condition. For each
of9–12s(jitter)thatwasequallydistributedforeachstimuluscategory. subject,evokedhemodynamicresponsestoeventtypesweremodeled
Duringtheintertrialperiod,participantssubjectivelyratedthepicture witha(cid:3)functioncorrespondingtopresentationofeachstimuluscate-
showing scenes according to valence (negative, neutral, positive) and goryconvolvedwithacanonicalhemodynamicresponsefunctionwithin
Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity J.Neurosci.,October15,2014•34(42):13935–13947•13937
thecontextofaGLM.Buttonpressesandratingscalepresentationdur- group-levelpeaksinMNIspaceweremappedtothecorrespondingco-
ingvalenceandarousalratingsweremodeledseparately.Inaddition,six ordinatesinthenativesubjectspacebyinvertingthenormalizationwarp
movementparametersfromspatialrealigningwereincludedasregres- fieldofeachsubject(fordetails,seeMNIspacetonativesubjectspace
sorsofnointerest.Picturesaccountingforpossibleprimacyandrecency mapping). The mapping from an atlas coordinate in MNI space to a
effectswereexcludedfromstatisticalanalysis. native subject space coordinate (corresponding to the same region as
Methodologicalconsiderations.Theinterleavedsequenceusedtoac- identifiedintheatlas)wasonlyfeasiblebecausewehadusedanin-house
quirefunctionaltimeseriesmadeitaprerequisitetouseslice-timecor- atlasbasedontheanatomydataofoursample(fordetails,seeConstruc-
rection as a first preprocessing step (Kiebel et al., 2007). Slice-timing tionofapopulation-averageanatomicalprobabilisticatlas).Theresult-
correctionmethodscansuccessfullycompensateforslice-timingeffects ingcoordinateservedasastartingpointtosearchforthesubject-specific
(Sladkyetal.,2011).Importantly,inDCMforfMRI,thedirectionof localmaximawithinadistanceof8mm,toaccommodateforinterindi-
causalityisnotidentifiedbytemporalprecedence.Instead,causalityis vidualdifferences(thelocalmaximawasdefinedastheeffectofpositive,
embodiedbythemathematicalformofthedifferentialstateequationof negative,andneutralpicturesvsscrambledpictures).Wethenextracted
eachregion.Thestateequationsofagivenmodeldefinethesystem’s timecoursesbycomputingtheprincipaleigenvariateofthedataacross
structure(e.g.,theconnectivitybetweenregions),prescribingexplicitly allsignificantvoxels(p(cid:7)0.05uncorrected,minimumclustersize3)
howdynamicsarisewithinthesystem(Stephanetal.,2010).Therefore,a withina10mmsphereandwithinthesubject-specificanatomicalmask
numberofDCMstudieswithsimilarTRswerepreviouslyconducted (masksfortheleftandrightamygdalaeandhippocampiwereretrieved
(e.g.,Leffetal.,2008;SeghierandPrice,2010;Richardsonetal.,2011). from the FreeSurfer segmentations). The extracted time courses were
adjustedtotheF-contrast(i.e.,effectsofinterest)ofeachsubject,which
Anatomy:segmentationofanatomicalimage effectivelymean-correctsthedataandremovesmovementartifactsbased
Eachparticipant’sanatomicalimagewasautomaticallysegmentedinto ontheparameterestimatesfromspatialrealignment.ROItimecourses
corticalandsubcorticalstructuresusingFreeSurferversion4.5(Fischlet werethenenteredintotheDCMmodels.DatafromallROIsinallsub-
al.,2002).LabelingofthecorticalgyriwasbasedontheDesikan–Killiany jectsareaprerequisitetorunDCM,asthepurposeofDCMistocompare
atlas (Desikan et al., 2006), yielding 35 regions per hemisphere. The differentmodelsforanobservedactivation(Fristonetal.,2003;Stephan
appliedsegmentationandlabelingtechniqueprovidesanaccuracycom- etal.,2010).Wethereforeexcludedthosesubjectsfromfurtheranalysis
parablewithmanuallabelingbyexperts(Fischletal.,2002;Desikanetal., thatdidnotshowactivationinlinewiththecriteriadefinedabove.This
2006). wasthecasefor2%ofoursubjects(seeResults).Potentialreasonsforthe
lackofsufficientlystrongactivationinsomesubjectspertaintonoisein
NormalizationtoMNIspace
thedataordatalossbutmightalsoreflecttheuseofdifferentcognitive
NormalizationwasconductedbyapplyingDARTEL,whichleadstoan
strategies.
improvedregistrationbetweensubjects(Ashburner,2007;Kleinetal.,
MNIspacetonativesubjectspacemapping.Thegroup-levelpeaksin
2009).Normalizationincorporatedthefollowingsteps:(1)anatomical
MNI space were mapped to the corresponding coordinates in native
imagesofeachsubjectweresegmentedusingthe“NewSegment”proce-
subjectspace.Procedure:(1)thevolumecontainingtheMNIcoordinate
dureinSPM8;(2)theresultinggrayandwhitematterimageswereused
wastransformedtogrouptemplatespacebyinvertingtheaffinetrans-
toderiveastudy-specificgrouptemplate;(3)anaffinetransformation
formthatmapsfromthegrouptemplatespacetoMNIspace;(2)the
wasappliedtomapthegrouptemplatetoMNIspace;(4)subject-to-
volumewastransformedtoDARTELimportedspacebyinvertingthe
templateandtemplate-to-MNItransformationswerecombinedtocre-
subjectspecificDARTELflowfieldusingnearest-neighborinterpolation
ateasinglenormalizationtransformationforeachsubject;and(5)the
asimplementedintheSPMDeformationsutility;(3)coregistrationof
normalizationtransformationforeachsubjectwasthenappliedtomap
thevolumetothec1s*imageinnativesubjectspace;and(4)extractionof
thefollowing:(a)anatomicalimages,(b)corticalandsubcorticalstruc-
the coordinate in native space. See the SPM 8 manual for details on
tures retrieved from the segmentation of FreeSurfer, and (c) contrast
DARTELspaces(http://www.fil.ion.ucl.ac.uk/spm/).
mapsfromthefirst-levelanalysistoMNIspace.Thestudy-specificgroup
templatewascomputedfromalargerpopulationof612subjects,which
DCM:modelspace
includedthe586subjectsofthepresentstudy.
Weappliedbilinear,deterministicDCMwithtwostates(versionDCM10
fMRIgroupstatistics r5236) (Marreiros et al., 2008). Each of our models consisted of two
nodes, corresponding to the amygdala and the hippocampus, respec-
Todeterminetheactivitypeaksatthegrouplevel,contrastmapsinMNI
tively.Basedonanatomicalinformation,wespecifiedreciprocalintrinsic
space were entered in a random effects model (second-level analysis)
connectionsbetweentheregions(Saundersetal.,1988;Nieuwenhuyset
usingGLMFlex(MartinosCenterandMassGeneralHospital,Charles-
al.,2008).Extrinsicinputstoregionsdrivethenetworkandquantifyhow
town, MA; http://nmr.mgh.harvard.edu/harvardagingbrain/People/
brainregionsrespondtoexternalstimuli.Theinputregressorwascon-
AaronSchultz/GLM_Flex.html). The significance threshold was set at
p(cid:7)0.05,smallvolumeBonferroni-correctedformultiplecomparisons structedbyconcatenatingtheonsetsofallpositive,negative,andneutral
pictures.Theinputregressorenteredthenetworkbyprojectingeither
within the ROIs (number of voxels, 507). We used GLM Flex as EPI
intooneoftheregionsortobothregions,givingatotalofthreeinput
sequencessufferfromsignallossinthepresenceofmagneticfieldinho-
possibilitiestothenetwork.Next,weconstructedmodelsthatexpressed
mogeneitiesthatcanoccurclosetoair-tissueboundaries.Thenormal-
different assumptions with regard to the modulation of connection
izationprocedureappliedinDARTELaccuratelytransformsbothvoxels
strengthbetweenregions,inducedbytheencodingofpositive,negative,
withsignalandvoxelswithsignallosstoMNIspace.InSPM8,signalloss
or neutral pictures. The forward and the backward connections were
ataMNIcoordinateinafunctionalimageofonlyonesubjectleadstothe
eithermodulatedbyallthree,two,one,ornocondition.Modulatorsof
exclusionofthevoxelatthiscoordinatefromthegroup-levelanalysis.
theforwardandbackwardconnectionswerevariedindependentlyfrom
Therefore,theprobabilityofavoxelbeingexcludedincreaseswithsam-
eachother.Thus,wetestedallpossibleconfigurationsofmodulatory
plesize.GLMFlexcircumventsthisproblembyallowingavariablenum-
effects.Theensuing64modelswerethencrossedwiththethreemodels
berofsubjectsateachvoxel.Theminimumnumberofsubjectspervoxel
representingthedifferentinputpossibilities.Therefore,foreachsubject
wassettobe293(50%ofallsubjects).
andhemisphere,wegeneratedandestimated192modelsthathadthe
TimecourseextractionfromROIsforDCM sameintrinsicconnectionsbutdifferedwithregardto(1)thesiteofthe
Smoothingcanbeverydamagingtoconnectivityestimationasitleadsto drivinginputand(2)themodulatoryeffects.
a mixing of BOLD time courses between regions in close proximity
(Smithetal.,2011).Wethereforeextractedthetimecoursesfromun- DCM:modelcomparison
smoothedandunnormalizeddata. DCMisbasedonBayesianstatistics.Themodelevidencedenotesthe
Weusedacombinationoffunctionalandanatomicalconstraintsto probabilityofthedatagiventhemodelwhileadjustingformodelcom-
ensurethecomparabilityofextractedtimecoursesacrosssubjects.The plexityanddependenciesamongparameters(Stephanetal.,2009;Penny
13938•J.Neurosci.,October15,2014•34(42):13935–13947 Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity
Table1.Comparisonbetweenlinearmixed-effectsmodelsthateitherdo,ordonot,compriseavariancecovariate,relatedtoresults:parameterinferencea
Akaikeinformationcriterion Bayesianinformationcriterion Log-likelihood Likelihoodratio pvalue
Lefthemisphere
Modelcomprisingnovariancecovariate (cid:8)9549.83 (cid:8)9500.69 4782.92 — —
Modelcomprisingthevariancecovariate (cid:8)13828.47 (cid:8)13742.48 6928.24 4290.64 (cid:7)4.94e-324
Righthemisphere
Modelcomprisingnovariancecovariate (cid:8)8066.88 (cid:8)8017.76 4041.44 — —
Modelcomprisingthevariancecovariate (cid:8)14439.52 (cid:8)14353.54 7233.76 6384.63 (cid:7)4.94e-324
aComparisonbetweenmodelsshowsthatmodelswithacovariatearesuperior.ThesmallertheAkaikeinformationcriterionorBayesianinformationcriterion,thebetterthefit.
etal.,2010).Modelswerecomparedbyconductingrandom-effectsfam- Constructionofapopulation-averageanatomical
ilylevelinference(Stephanetal.,2009;Pennyetal.,2010).Themodel probabilisticatlas
spacedescribedabovewaspartitionedintothreefamiliesbasedondif- SegmentationsofcorticalandsubcorticalstructuresretrievedfromFree-
ferences in the location of the driving input. This allowed us to test Surferwereusedtobuildapopulation-averageprobabilisticanatomical
whethercertaininputconfigurationsweremorelikelythanotherswhile atlas.Individualsegmentedanatomicalimageswerethennormalizedto
controllingfortheeffectofmodulatoryparameters.Thelikelihoodis thestudy-specificanatomicaltemplatespaceusingthesubject’sprevi-
expressedastheexceedanceprobability,whichdenotestheprobability ously computed warp field, and affine-registered to the MNI space.
thataparticularmodelfamilyismorelikelythananyothertestedmodel Nearest-neighborinterpolationwasappliedtopreservelabelingofthe
family.Theexceedanceprobabilitiesareeasilyinterpretableastheysum differentstructures.Thenormalizedsegmentationswerefinallyaveraged
tooneoverallmodelfamiliestested. acrosssubjectstocreateapopulation-averageprobabilisticatlas.Each
voxelofthetemplatecouldconsequentlybeassignedaprobabilityof
DCM:parameteranalysis
belongingtoagivenanatomicalstructure,basedontheindividualinfor-
WeappliedBayesianmodelaveraging(BMA)toobtainasummarymea- mationfromthe612subjects.ThevoxelswithinthecontoursinFigure5
sureoflikelyconnectivityvalues(Pennyetal.,2010).Theconnectivity couldbeassignedtoeithertheamygdalaorthehippocampusinatleast
parameters of each of the 64 models within the winning family were 75%ofthesubjects.
weightedbytheposteriormodelprobabilityandthenaveragedwithin
eachsubject.Thosemodelsforwhichtheposteriorprobabilitywasvery Exclusioncriteria
low((cid:7)1/20ofthemaximumprobability)wereexcludedfromthecalcu- Atotalof26subjectswereexcludedafterthepreprocessingofthedata
lationsforcomputationalexpedience.Overall,theBMAweightingpro- and were not part of the DCM analysis. Reasons for exclusion were
cedure resulted in subject-specific connectivity estimates that were definedasfollows:missingorcorruptedfunctionaldata;subjectstook
independentofaparticularmodelwithinthewinningfamilywhileen- part in a similar experiment and were therefore informed about the
suringthatmodelswithahighprobabilitycontributedmorethanmodels surprisefreerecalltest;insufficientqualityofanatomicalimage;failed
withalowerprobability. coregistration; subjects that did not recall a single picture within one
valencecategory.
DCM:group-levelinferenceonparameters
Results
TheBMAmodulatoryparameterestimatesofeachsubjectwereentered
intoalinearmixed-effectsanalysisusingR’s(http://www.r-project.org) Behavioraldata:enhancedmemoryrecallforemotionally
lme function in the nlme package (R Core Team, 2012). By default, arousingpictures
two-stateDCMBMAparameterestimatesareinlog-space,andthese Thebehavioralresultsacrossallsubjects(N(cid:2)586)confirmthat
valueswereusedtocomputestatistics.Asfixedeffects,weentereddirec- emotionallyarousingpictureswererecalledmoreoftenthanneu-
tion(AmytoHip,HiptoAmy),stimuluscategory(positive,neutral, tralpictures(Fig.3).Memorywasassessedinasurprisefreerecall
negative),andtheinteractiontermbetweendirectionandstimuluscat-
memorytest10minafterencoding,where24picturesforeach
egory.Subjectswereenteredasrandomeffect.Themodelswereesti-
stimuluscategoryhadbeenpresented.Neutralpictureswereleast
mated using restricted maximum likelihood. Visual inspection of oftenrecalled(neutral:6.85(cid:5)0.12,mean(cid:5)SD;positivevsneu-
residual plots revealed deviations from homoscedasticity. To avoid a
tral,p(cid:2)1.78e-170;negativevsneutral,p(cid:2)1.40e-135).Positive
violationofstatisticalassumptions,wespecifiedanexponentialfunction
ofthefittedvaluesasavariancecovariateforthefactorsvalenceand pictureswereslightlymoreoftenrememberedthannegativepic-
directionusingthevarFuncfunction.Bothvisualinspectionofresidual tures(positive:12.02(cid:5)0.14;negative:11.15(cid:5)0.13;positivevs
plotsandlikelihoodratiotestsbetweenthemodelsassumingeitherhet- negative, p (cid:2) 1.16e-10). Furthermore, on a 3-point scale (2 (cid:2)
eroscedasticity or homoscedasticity showed that the models with the large,1(cid:2)medium,0(cid:2)small),neutralpictureswereratedasleast
variancecovariateweresuperior(Table1;Fig.1).Wecheckedforviola- arousing (neutral: 0.38 (cid:5) 0.01; negative vs neutral, p (cid:2) 1.96e-
tionofnormalitybyplottingtheresidualsofthemixed-effectsmodels 311;positivevsneutral,p(cid:2)2.04e-184;Fig.4).Negativepictures
(Fig.2).pvalueswereobtainedwith(cid:4)2testsusingtheANOVAfunction
were rated as more arousing than positive pictures (negative:
implementedinthecarpackage.Two-sidedpairedttestswereusedfor 1.36(cid:5)0.01;positive:0.92(cid:5)0.02;negativevspositive,p(cid:2)9.10e-
focusedtestsbetweenmodulatorsofconnectionstrength.
124). p values denote the results from two-sided paired t tests.
Behavioraldata Theseresultsshowthatemotionallyarousingpicturesarebetter
Two-sidedpairedttestswereappliedtotestfordifferencesbetweenthe rememberedthanlessarousingneutralpictures.Wedidnotob-
number of pictures recalled per stimulus category. Picture-specific servesignificantassociationsbetweeninterindividualdifferences
arousalratingswereaveragedacrossallpicturesofastimuluscategory inmeanarousalratingsperstimuluscategoryandinterindividual
withineachsubjectandthenenteredintwo-sidedpairedtteststoassess
differencesinthenumberofrecalledpicturesperstimuluscate-
differences in the arousal per stimulus category. Furthermore, we
gory(i.e.,subjectswhogenerallyratedpicturesasmorearousing
computedaPearsonlinearcorrelationcoefficienttoassesswhether
did not have a better memory performance than subjects who
the subject-specific average arousal rating is associated with the
generallyratedpicturesaslessarousing)(positive:r(cid:2)0.1,p(cid:2)
subject-specificnumberofrecalledpictures.pvaluesforthecorrela-
tionwereobtainedusingtwo-sidedtests.Datafrompicturerecalland 0.02;neutral:r(cid:2)0.09,p(cid:2)0.03;negative:r(cid:2)0.01,p(cid:2)0.75;
arousal ratings were plotted and were found to be approximately Bonferroni multiple comparison corrected significance thresh-
normallydistributed. oldforthreetests,p(cid:2)0.017).
Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity J.Neurosci.,October15,2014•34(42):13935–13947•13939
Figure1. Boxplotsrepresentingthevarianceofresidualsperfactorlevelofthelinearmixed-effectsmodels.Resultsobtainedinthelefthemisphere(a,b,N(cid:2)574)andrighthemisphere(c,d,
N(cid:2)573).ANOVAofmodulatorvaluesisbasedonthemodelscomprisingthevariancecovariate(b,d).Modelswithoutavariancecovariate(a,c)wererejected.Pearsonstandardizedresidualsare
shownforeachlevelofthetwomodeledfactors:stimuluscategory(positive,neutral,negative)anddirectionofinfluence(AmytoHip,HiptoAmy).Boxesrepresenttheinterquartilerangebetween
thefirstandthirdquartiles,andthehorizontallineswithinboxesindicatethemedian.Horizontalbarsoutsidetheboxesrepresentthelowestandhighestvalueswithin1.5(cid:6)interquartilerange
fromthefirstandthirdquartiles,respectively.Circlesrepresentoutsidevalues.Amy,Amygdala;Hip,hippocampus.
Peakactivitywithintheamygdalaandthehippocampus TimecourseextractionfromROIsintheamygdalaand
First,wedeterminedthelocationsoftheactivitypeakswithinthe thehippocampus
amygdalaandthehippocampus,asmeasuredbyfMRIrecordings BeforetheactualmodelingofconnectivitywithintheDCMframe-
during encoding. The local maxima for the effect of pictures work,timecourses(i.e.,theBOLDresponsesmeasuredduringthe
(positive(cid:9)negative(cid:9)neutralvsscrambledpictures)werelo- courseoftheexperiment)wereextractedfromthelocationsofthe
cated at MNI (cid:8)19.25, (cid:8)8.25, (cid:8)16 in the left amygdala (t (cid:2) activitypeaks.Withinthelefthemisphere,timecoursesweresuc-
38.86)andatMNI(cid:8)22,(cid:8)16.5,(cid:8)16inthelefthippocampus(t(cid:2) cessfullyextractedfrom574ofatotalof586subjects(98%).Twelve
49.08;Fig.5).Localmaximaintherighthemispherewerelocated subjects(8females,4males)wereexcludedfromfurtheranalysis,as
atMNI22,(cid:8)8.25,(cid:8)16intheamygdala(t(cid:2)39.81)andatMNI theydidnotshowrobusttask-dependentactivationintheamygdala
22,(cid:8)16.5,(cid:8)16inthehippocampus(t(cid:2)47.97).Alltvalueswere inaccordancewithourcriteria(seeTimecourseextractionfrom
significant (p (cid:7) 0.05, small volume Bonferroni-corrected, ROIsforDCM).Inaddition,thehippocampuswasalsonotrobustly
threshold t (cid:2) 3.9). The coordinates of the four local maxima activatedinoneofthesesubjects.Withintherighthemisphere,time
correspondedtothelocationoftherespectiveanatomicalstruc- coursesweresuccessfullyextractedfrom573subjects(98%).Twelve
ture in all subjects (regional probability in accordance to in- subjects(7females,5males)didnotshowrobustactivationwithin
house atlas: 100%; see Materials and Methods). For activation theamygdala,andoneadditionalmalesubjectdidnotshowrobust
peaksoutsideofamygdalaandhippocampus,seeTable2. activationinthehippocampus.
13940•J.Neurosci.,October15,2014•34(42):13935–13947 Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity
Figure2. Distributionofmodelresiduals.Plotsrepresentingthedistributionofmodelresidualsinthelefthemisphere(N(cid:2)574)andrighthemisphere(N(cid:2)573).Theplotsrefertothelinear
mixed-effectsmodelscomprisingavariancecovariate.Residualsofallfactorlevelsareshownjointly.
Figure3. Averagenumberofrecalledpicturesperstimuluscategory.Twenty-fourpictures
foreachstimuluscategory(positive,neutral,negative)werepresentedduringtheencoding
phase.Memorywasassessedinasurprisefreerecallmemorytest10minafterencoding.p Figure4. Averagearousalratingpervalencecategory.Participantssubjectivelyratedeach
valuesindicatetheresultsfromtwo-sidedpairedttests,whichwereconductedtoexamine picturewithregardtoarousal(2(cid:2)large;1(cid:2)medium;0(cid:2)small)ona3-pointscale.pvalues
differencesinthenumberofrecalledpicturesperstimuluscategory(N(cid:2)586).Errorbars indicatetheresultsfromtwo-sidedpairedttests,whichwereconductedtoexaminedifferences
indicatetheSEM. inthearousalratingperstimuluscategory(N(cid:2)586).ErrorbarsindicatetheSEM.
Parameterinference:theneuromodulatoryeffectofemotions
DCMmodelcomparison:determiningthemostlikelysite onconnectionstrength
ofinput Modulators of effective connectivity describe whether the
WithintheDCMframework,differentcompetingmodelscanbe strength of the connection, (i.e., the influence that one region
specifiedandformallycomparedbyusingaBayesianmodelse- exertsuponanother)increasesordecreasesundertheinfluence
lectionprocedure,whichidentifiesthemostplausiblefamilyof of experimental manipulations. Modulator estimates are based
modelsgiventheextractedtimecourses.Intheabsenceofapriori on the complete set of positive, neutral, and negative pictures
information about the exact site of input to the network, we presentedintheencodingtask.
comparedthreedifferentmodelfamilies,eachrepresentingone The influence of the amygdala upon the hippocampus was
ofthethreepossibleinputconfigurations:(1)inputentersonly particularlystrongduringtheencodingofbothpositiveandneg-
the amygdala; (2) input enters only the hippocampus; and (3) ativepictures(Figs.7and8),whichisreflectedintheresultsofan
inputentersboththeamygdalaandthehippocampus.Compar- ANOVAwiththefactorsdirectionandstimuluscategory(main
isonbetweenthethreemodelfamiliesclearlyindicatedthatthose effectofdirection:lefthemisphere,(cid:4)2(cid:2)132.31,p(cid:2)1.28e-30;
modelswheretheinputentersonlytheamygdalaaremostlikely right hemisphere, (cid:4)2 (cid:2) 298.87, p (cid:2) 5.82e-67; main effect of
(lefthemispherefamilyexceedanceprobability(cid:2)0.9998,right stimulus category: left hemisphere, (cid:4)2 (cid:2) 91.49, p (cid:2) 1.36e-20;
hemispherefamilyexceedanceprobability(cid:2)0.8146;Fig.6). righthemisphere,(cid:4)2(cid:2)74.19,p(cid:2)7.74e-17;interactionbetween
Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity J.Neurosci.,October15,2014•34(42):13935–13947•13941
nificantlybetter(p(cid:2)0.07).Wetherefore
used the more parsimonious ANOVA
models, which did not include main or
interactioneffectsofsexasadditionalfac-
tors, to analyze modulator values, as the
varianceexplainedbysexappearedtobe
minor.
Althoughthevalence-dependentcha-
ngesinconnectionstrengthsbetweenthe
amygdala and the hippocampus were
morepronouncedinthelefthemisphere,
Figure5. Brainactivityrelatedtopictureencoding(picturesofallvalencecategoriescomparedwithscrambledpictures). we refrained from exploring potential
Random-effectsanalysisacrossall586subjects(p(cid:7)0.05,whole-brainBonferronicorrection),illustratedusingcolor-codedt hemisphericdifferences,asacomparison
values.Theimageiscenteredattheactivitypeakwithinthelefthippocampus(MNIspace:(cid:8)22,(cid:8)17,(cid:8)16).Thewhiteandviolet ofmodelsandparametersinthecontext
contourscomprisevoxelsbelongingtotheamygdalaandtothehippocampus,respectively.Contoursareretrievedfroman ofDCMoffMRIdataisonlyvalidwhen
in-houseatlas(seeMaterialsandMethods).Activationsareoverlaidoncoronal(left),sagittal(middle),andaxialsectionsofthe
allmodelsarefittedtothesamesetoftime
study-specificgrouptemplate.L,Lefthemisphere;R,righthemisphere.
courses(Fristonetal.,2003).
Inadditiontomodulatorsofconnec-
directionandstimuluscategory:lefthemisphere,(cid:4)2(cid:2)83.31,p(cid:2) tionstrength,DCMalsoestimatesintrinsicconnectivityparam-
8.11e-19;righthemisphere,(cid:4)2(cid:2)15.35,p(cid:2)4.64e-04). eters. They represent the connectivity in the absence of
Weconductedtwo-sidedpairedposthocttestsbetweenmod- experimental perturbations. The effective connection strength
ulators within each connection to obtain more focused results associatedtoanexperimentalconditioncanbecalculatedasthe
(Bonferronimultiplecomparisoncorrectedsignificancethresh- sumofthevalueoftheintrinsicconnectionandthevalueofthe
old for six tests: p (cid:2) 0.008). Within the connection from the modulator.WeobservedthefollowingmeanBMAintrinsicpa-
amygdalatothehippocampus,theseanalysesshowedthatmod- rameterestimates:connectionfromamygdalatohippocampus,
ulators of positive and negative pictures were not significantly 0.4188(lefthemisphere),0.4643(righthemisphere);connection
differentfromeachother(lefthemisphere,p(cid:2)0.43;righthemi- from hippocampus to amygdala, 0.0355 (left hemisphere),
sphere,p(cid:2)0.34),whereasneutralpictureshadacomparatively 0.0173(righthemisphere).Theresultsfortheintrinsicparame-
smallereffectonconnectionstrength(lefthemisphere,positive ters suggest that the influence of the amygdala upon the hip-
vsneutral,p(cid:2)4.11e-14;negativevsneutral,p(cid:2)3.48e-14;right pocampus is (cid:4)10 times stronger than the influence of the
hemisphere,positivevsneutral,p(cid:2)0.0015;negativevsneutral, hippocampusupontheamygdala,evenintheabsenceofexperi-
p(cid:2)6.36e-05).Withintheconnectionfromthehippocampusto mentalperturbations.AcompletelistofBMAparametervalues
theamygdala,positive,neutral,andnegativepictureshadadif- forcondition-specificmodulators,intrinsicconnections,and
ferential effect in the left hemisphere (positive vs neutral, p (cid:2) extrinsicinputscanbefoundinTables3and4.
3.32e-06;negativevsneutral,p(cid:2)4.48e-10;negativevspositive, The enhanced memory performance for emotional pictures
p(cid:2)5.32e-05),whereasmodulatorsofpositiveandnegativepic- and the increased connection strength during the encoding of
tures were not significantly different in the right hemisphere emotional pictures suggest that subsequently remembered pic-
(positivevsneutral,p(cid:2)8.95e-06;negativevsneutral,p(cid:2)1.52e- tures should be associated with increased connection strength,
12;positivevsnegative,p(cid:2)0.07). relativetosubsequentlynotrememberedpictures.Hereweper-
Weinvestigatedwhetherourfindingsdependsubstantiallyon formedposthocanalysestotestthispredictionexplicitly.Based
thesexofoursubjects.Wedidnotfindasignificantmaineffectof on the same time courses as described above, and our prior
sex(lefthemisphere,p(cid:2)0.18;righthemisphere,p(cid:2)0.93),when knowledgewithregardtothesiteofinput,wedefinedamodel
sex was entered as a first factor in a sequential sum of squares with two modulators on each connection: (1) a modulator for
model.Wetestedforinteractioneffectsbyenteringsexandthe picturesthatweresubsequentlyremembered;and(2)amodula-
interactionsofsexwiththefactors(1)stimuluscategoryand(2) torforpicturessubsequentlynotremembered.Thismodelwas
directionasadditionalfixedeffectsintheANOVAmodels.Inthe used to reexplain our connectivity findings in terms of subse-
lefthemisphere,weobservedasmall,butsignificant,interaction quent memory. It was applied separately in each hemisphere.
effectbetweenthefactorssexandstimuluscategory((cid:4)2(cid:2)7.88, Modulatory parameter estimates of each subject were entered
p(cid:2)0.02).Allotherinteractioneffectswithsexinboththeleftand into two-sided paired t tests. The results showed that remem-
the right hemisphere were not significant (p (cid:4) 0.5). Based on beredpictureswereindeedassociatedwithincreasedconnection
theseresults,wefurtherexploredtheeffectofsexonlywithinthe strength,comparedwiththeconnectionstrengthofnotremem-
lefthemisphere.Usingposthoc,two-sidedpairedttestsbetween bered pictures (Bonferroni multiple comparison corrected sig-
modulators of connection strength, we found a difference be- nificance threshold for two separate hypothesis tests per
tweenthevaluesofmenandwomenwithrespecttotheparam- hemisphere,p(cid:2)0.025).Connectionfromtheamygdalatothe
eterforpositivepicturesthatmodulatestheconnectionfromthe hippocampus:lefthemisphererememberedversusnotremem-
hippocampustotheamygdala(means:femalesBMA(cid:2)(cid:8)7.62e- bered, p (cid:2) 0.0024; modulator remembered, 0.0776 (cid:5) 0.0052;
04;malesBMA(cid:2)0.0014;p(cid:2)0.001,Bonferroni-correctedforsix modulatornotremembered,0.0572(cid:5)0.0046;righthemisphere
tests).Asthemainandinteractioneffectsofsexappearedrather remembered versus not remembered, p (cid:2) 0.0025; modulator
small,weperformedlikelihoodratiotestsbetweenthemodels, remembered, 0.0940 (cid:5) 0.0059; modulator not remembered,
whicheither(1)doincludesexandtheinteractionsofsexwith 0.0723 (cid:5) 0.0051. Connection from the hippocampus to the
thefactorsstimuluscategoryanddirectionor(2)donotinclude amygdala:lefthemisphererememberedversusnotremembered,
anymainorinteractioneffectsofsex.Ouranalysisrevealedthat p(cid:2)1.3864e-08;modulatorremembered,0.0026(cid:5)0.0007;mod-
modelscontainingsexanditsinteractionsasfactorsarenotsig- ulator not remembered, (cid:8)0.0039 (cid:5) 0.0007; right hemisphere
13942•J.Neurosci.,October15,2014•34(42):13935–13947 Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity
Table2.Regionsshowingtask-dependentactivationsrelatedtotheencodingofpictures(positive(cid:2)negative(cid:2)neutral(cid:3)scrambledpictures),inadditiontoourROI
analysisa
MNIcoordinatesatmaximum
Clusterno. Maximumtvaluewithincluster Regionalcorrespondenceofthemaximum x y z No.ofvoxels
1 62.17 ctx-lh-superiorfrontal(4%) (cid:8)8.25 55 28 549
2 53.54 ctx-lh-isthmuscingulate(94%);ctx-lh-precuneus(6%) (cid:8)2.75 (cid:8)49.5 24 142
3 50.45 ctx-lh-parsorbitalis(10%);ctx-ctx-lh-parstriangularis(3%);lh-lateralorbitofrontal(2%) (cid:8)41.25 27.5 (cid:8)12 175
4 49.24 ctx-rh-lateraloccipital(23%) 38.5 (cid:8)82.5 (cid:8)8 144
5 47.28 right-cerebellum-cortex(99%) 24.75 (cid:8)79.75 (cid:8)36 23
6 45.52 ctx-lh-middletemporal(60%);ctx-lh-superiortemporal(4%) (cid:8)57.75 (cid:8)11 (cid:8)16 46
7 45.09 ctx-rh-middletemporal(70%);ctx-rh-superiortemporal(4%) 55 (cid:8)5.5 (cid:8)20 47
8 44.12 ctx-lh-inferiorparietal(65%);ctx-ctx-lh-supramarginal(3%);lh-middletemporal(2%) (cid:8)49.5 (cid:8)63.25 24 34
9 43.03 ctx-rh-superiorparietal(42%);ctx-rh-lateraloccipital(38%);ctx-rh-cuneus(2%) 19.25 (cid:8)93.5 28 14
10 42.75 ctx-lh-parahippocampal(99%) (cid:8)19.25 (cid:8)35.75 (cid:8)16 8
11 42.37 left-cerebellum-cortex(96%) (cid:8)24.75 (cid:8)79.75 (cid:8)36 8
12 41.67 ctx-rh-parahippocampal(99%) 22 (cid:8)33 (cid:8)16 3
13 40.70 ctx-lh-lateraloccipital(24%);ctx-lh-superiorparietal(17%) (cid:8)13.75 (cid:8)93.5 24 10
14 40.70 ctx-rh-inferiorparietal(53%);ctx-rh-middletemporal(7%) 55 (cid:8)60.5 16 22
15 40.63 ctx-rh-parstriangularis(55%) 52.25 27.5 0 7
16 40.39 ctx-rh-superiortemporal(78%);ctx-rh-middletemporal(5%) 46.75 11 (cid:8)28 4
17 40.33 ctx-rh-isthmuscingulate(5%) 13.75 (cid:8)46.75 8 6
18 40.09 ctx-lh-lateraloccipital(93%);ctx-lh-inferiorparietal(3%) (cid:8)46.75 (cid:8)82.5 4 3
19 40.01 ctx-rh-fusiform(94%);ctx-rh-inferiortemporal(3%) 38.5 (cid:8)49.5 (cid:8)20 3
20 39.81 ctx-rh-superiorfrontal(88%) 8.25 16.5 64 2
aTask-relatedassociationsacrossthewholebrain.Becauseofthesamplesizeandrespectivestatisticalpower,wefindlargeclustersofsignificantvoxelsthroughoutthebrain(seeFigure5).Thesmallesttvaluewithinourregionsofinterest
servedastheminimumthreshold(t(cid:2)38.86,p(cid:7)0.05,whole-brainBonferronicorrected)tohighlightregionswithcomparableorlargertask-relatedassociations.Regionsandprobabilitiesareinaccordancewiththein-houseatlas.ctx,
Cortex;lh,lefthemisphere;rh,righthemisphere.
Figure6. Modelcomparison:familyexceedanceprobability.Comparisonbetweenthethreemodelfamilies,representingcompetinginputpossibilitiestothenetworkin(a)lefthemisphere
(N(cid:2)574)and(b)righthemisphere(N(cid:2)573).Lefthemisphere:(1)inputtohippocampus(0.0002);(2)inputtoamygdala(0.9998);(3)inputtobothamygdalaandhippocampus(0).Right
hemisphere:(1)inputtohippocampus(0.0013);(2)inputtoamygdala(0.8146);(3)inputtobothamygdalaandhippocampus(0.1841).Amygdala(Amy),Hippocampus(Hip).
rememberedversusnotremembered,p(cid:2)1.9457e-08;modula- and our prior knowledge with regard to the site of input, we
torremembered,0.0033(cid:5)0.0006;modulatornotremembered, definedamodelthatusesseparatemodulatorsforsubsequently
(cid:8)0.0029(cid:5)0.0005.Valuesaremean(cid:5)SEM.Modulatorsdidnot remembered and subsequently not remembered pictures per
differsignificantlybetweenfemalesandmales(p(cid:4)0.29). stimulus category (i.e., six modulators in total per connection;
Above,wereportedthatpositiveandnegativepictureshada Tables5and6).Themodelwasappliedseparatelyineachhemi-
similareffectonthestrengthoftheconnectionprojectingfrom sphere. Within the connection from the amygdala to the hip-
theamygdalatothehippocampus.Giventhehypothesizedrele- pocampus, the modulators for (1) positive remembered, (2)
vanceofthisconnectionforbothemotionalandmemorypro- positivenotremembered,(3)negativeremembered,and(4)neg-
cesses, we tested whether the effect of positive and negative ative not remembered pictures were entered in ANOVA with
picturesalsodependsonwhethertheyaresubsequentlyremem- stimulus type (levels: positive/negative) as one factor, memory
beredornot.Basedonthesametimecoursesasdescribedabove, (levels: remembered/not remembered) as the other factor, and
Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity J.Neurosci.,October15,2014•34(42):13935–13947•13943
pocampus. The valence- and direction-
dependent changes in connectivity were
observedinboththeleftandrighthemi-
spheres. Within-subject analyses indi-
cated that positive and negative pictures
wereratedasmorearousingandwerebet-
ter remembered than neutral pictures
(Figs.3and4).However,between-subject
analysesrevealedthatsubjectswhorated
picturesasmorearousingdidnothavea
bettermemoryperformancethansubjects
whoratedpicturesaslessarousing.Thus,
thesubjectivearousalratingdidnotcor-
relate with interindividual differences in
memoryperformance.
Theobservationthatpositiveandneg-
ativepictureshaveasimilareffectoncon-
Figure7. Changeinconnectionstrengthbetweentheamygdala(red)andthehippocampus(blue)duringtheencodingof nection strength might be in line with
positive,negative,andneutralpictures.Figurerepresentstheresultsobtainedinthelefthemisphere.Top,Arrowindicatesthe earlierstudiesdemonstratingthatamygdala
influencethattheamygdalaexertsuponthehippocampus.Bottom,Arrowindicatestheconnectionfromthehippocampustothe
activation is associated with arousal com-
amygdala.Valuesaremodelestimates,representingthechangeinconnectionstrengthpercondition(meanoftheBMAmodulator
montobothnegativeandpositiveevents,
valuesacrossall574subjects).SeealsoTable3andFigure8a;fortherighthemisphere,seeFigure8bandTable4.
but not valence itself (Anderson et al.,
2003; Small et al., 2003; Kensinger and
theinteractiontermbetweenstimulustypeandmemory.Sub- Corkin, 2004; Kensinger and Schacter,
jects were entered as random effect. Most of the variance was 2006;Lewisetal.,2007).However,althoughpositiveimageswere
explained by the factor memory (left hemisphere, (cid:4)2 (cid:2) 17.28, ratedaslessarousingthannegativeimagesinourstudy,they
p(cid:2)3.22e-05;righthemisphere,(cid:4)2(cid:2)19.75,p(cid:2)8.83e-06).The wereslightlybetterrememberedthannegativepictures.This
factorstimulustypeexplainedlessvariance,andthiseffectdid suggeststhatourbehavioralandconnectivityfindingsarenot
notreachsignificanceintherighthemisphere(lefthemisphere, onlyaconsequenceofarousalbutmayalsobeinfluencedby
(cid:4)2(cid:2)5.29,p(cid:2)0.02;righthemisphere,(cid:4)2(cid:2)0.59,p(cid:2)0.44).We additionalfactors,suchascomplexity,self-relevance,itemfa-
observedthattheeffectofstimulustypediddependonmemory miliarity,andsemanticrelatednessofthepictures(Kensinger,
(interaction between stimulus type and memory: left hemi- 2009). Nonetheless, differences with regard to arousal and
sphere,(cid:4)2(cid:2)8.27,p(cid:2)0.004;righthemisphere,(cid:4)2(cid:2)4.77,p(cid:2) memorywereconsiderablysmallerbetweenpositiveandneg-
0.03). We conducted two-sided paired post hoc t tests between ative pictures than between emotional and neutral pictures
modulatorstoobtainmorefocusedresults(Bonferronimultiple (Figs.3and4).
comparison corrected significance threshold for two separate hy- Previousstudiesinhumansfoundenhancedepisodicmem-
pothesistestsperhemisphere:p(cid:2)0.025).Inthecaseofremem- oryforemotionalitemsalreadyafewminutesafterpresentation
beredpictures,positiveandnegativestimulihadasimilareffect (Hamannetal.,1999;deQuervainetal.,2007).Moreover,en-
onconnectionstrength(lefthemisphere,p(cid:2)0.60;righthemi- hancedmemoryforemotionalitemshasbeenfoundinexperi-
sphere,p(cid:2)0.28).Inthecaseofsubsequentlynotremembered mentaldesignsthatalternaterapidly(withinseconds)between
pictures,negativestimulihadastrongerimpactonconnection emotionalandneutralstimuli(Canlietal.,2000;deQuervainet
strength than positive stimuli in the left hemisphere (p (cid:2) al., 2007), suggesting that such memory-modulatory processes
0.0004),whereastheireffectappearedtobesimilarintheright duringencodingmustberegulatedinaquickanddynamicman-
hemisphere(p(cid:2)0.06). ner.Ourpresentresultsindicatethattheamygdala–hippocampal
Weusedthecontrast(positive(cid:9)negative(cid:9)neutralminus connectivitycanquicklychange(withinseconds)inresponsetoa
scrambled) to identify significantly activated voxels. As emo- rapidsequenceofintermingledarousingandnonarousingstim-
tionalconditionshadtwicetheweightoftheneutralcondition, uli and that the modulatory influence of the amygdala on the
theextractedtimecoursesmayhavebeenbiased.Weperformed activity in the hippocampus is already present at the stage of
additionalanalyseswithoutthisbiasbycomputingtheeffectof stimulus presentation. This is in line with the idea that the
(1) positive and neutral and (2) negative and neutral pictures amygdala alters the encoding of hippocampal-dependent, epi-
separatelyintwosetsofdistinctanalyses.Theseanalysesshowed sodicmemorybyinfluencingperceptionandattention,suchthat
thatourconclusionswerenotaffectedbythispotentialbias. emotionaleventsreceivepriority(Hamann,2001;Phelps,2004;
Todd et al., 2013). It remains to be investigated whether this
Discussion influence during encoding serves as an “emotional tagging” to
ByapplyingDCMoffMRIdata,thepresentstudyrevealedthat supportaselectivestrengtheningofemotionallyarousinginfor-
theconnectionfromtheamygdalatothehippocampus(i.e.,the mationduringmemoryconsolidation(Bergadoetal.,2011).Al-
influence that the amygdala exerts upon the hippocampus) is though memory of emotional events can be enhanced without
strongerduringtheencodingofemotionalpicturesthanduring rehearsal(HarrisandPashler,2005),theprocessofrehearsalhas
theencodingofneutralpictures.Importantly,thesefindingsap- tobeconsideredasapotentialmechanismenhancingmemory
plybothtotheemotionallynegativeandpositivevalence.Our foremotionallyarousinginformation.Inthepresentstudy,the
findings in humans therefore support the prediction of the distractingworkingmemorytaskbetweenpictureencodingand
memory-modulation hypothesis generated in animals, which retrievalandtherapidsuccessionofencodingeventsmadere-
statesthattheamygdalaregulatesinformationprocessinginthehip- hearsalunlikely.
13944•J.Neurosci.,October15,2014•34(42):13935–13947 Fastenrathetal.•EmotionandAmygdala–HippocampalConnectivity
Figure8. PlotsillustratingthemeanoftheBMAmodulatorvaluesperstimuluscategoryanddirectionofconnectivityacrossallsubjects.Resultsobtainedin(a)lefthemisphere(N(cid:2)574)and
(b)righthemisphere(N(cid:2)573).Darkgraybarsrepresentmodulatorvaluesoftheconnectionprojectingfromtheamygdalatothehippocampus(AmytoHip).Lightgraybarsrepresentmodulator
valuesoftheconnectionthatprojectsfromthehippocampustotheamygdala(HiptoAmy).ErrorbarsindicatetheSEM.SeealsoTables3and4.
Table3.BMAparametervaluesobtainedinthelefthemisphere,relatedtoresults:parameterinference(Figs.7and8)a
Parametervalues(lefthemisphere)
Strengthofdrivinginputtoamygdala 0.4868(cid:5)0.0137
Directionofconnection Amygdalatohippocampus Hippocampustoamygdala
Strengthofintrinsicconnectivity 0.4188(cid:5)0.0216 0.0355(cid:5)0.0073
Positive Neutral Negative Positive Neutral Negative
Changeinconnectionstrength 0.0439(cid:5)0.0041 0.0013(cid:5)0.0024 0.0397(cid:5)0.0036 0.0001(cid:5)0.0003 (cid:8)0.0043(cid:5)0.0009 0.0031(cid:5)0.0005
(modulators)percondition
aValuesrepresentthemean(cid:5)SEMoftheBMAparametervaluesacrossall574subjects,basedonmodelsusingonemodulatorperstimuluscategoryanddirection.
Table4.BMAparametervaluesobtainedintherighthemisphere,relatedtoresults:parameterinference(Fig.8)a
Parametervalues(righthemisphere)
Strengthofdrivinginputtoamygdala 0.5263(cid:5)0.0142
Directionofconnection Amygdalatohippocampus Hippocampustoamygdala
Strengthofintrinsicconnectivity 0.4643(cid:5)0.0230 0.0173(cid:5)0.0033
Positive Neutral Negative Positive Neutral Negative
Changeinconnectionstrength 0.0486(cid:5)0.0043 0.0293(cid:5)0.0037 0.0551(cid:5)0.0050 0.0001(cid:5)0.0004 (cid:8)0.0025(cid:5)0.0003 0.0013(cid:5)0.0003
(modulators)percondition
aValuesrepresentthemean(cid:5)SEMoftheBMAparametervaluesacrossall573subjects,basedonmodelsusingonemodulatorperstimuluscategoryanddirection.
Furthermore,wereportedthatthemodulationinconnection independentoftaskrequirements,werereflectedinanincreasein
strengthfromtheamygdalatothehippocampusduringtheen- connectionstrengthfromthehippocampustotheamygdala(Smith
codingofemotionalpicturesissubstantiallystrongerthaninthe etal.,2006).Whenretrievalofemotionalinformationwasrelevant
oppositedirection.Nevertheless,wealsoobservedasignificant tocurrentbehavior,amygdala–hippocampalconnectivityincreased
increase in connection strength from the hippocampus to the bidirectionally.Acontext-dependentinfluenceofthehippocampus
amygdala, although at a much smaller scale. This observation upontheamygdalahasalsobeenobservedinanimals(forreview,see
mightbeinlinewiththefindingthathippocampallesionspre- Marenetal.,2013).Theobservationthatthehippocampustransmits
ventoptimalamygdalaactivationduringencodingofemotional contextualinformationtotheamygdalamightbeinlinewiththe
material(Richardsonetal.,2004).Previousstudiesdemonstrate ideathatthebrainusesaninternalmodeloftheenvironmentwhen
thattheconnectivitybetweentheamygdalaandthehippocam- recognizingsensoryinput(Kiebeletal.,2009).Overall,theseprevi-
pus varies depending on context. Processing differences in the ousfindingsindicatethatthecurrentconnectivityresultsmayalso
retrievalofitemsassociatedwithnegativeversusneutralcontexts, dependonspecificfactorsofthetask.