Asymmetric development of dorsal and ventral attention networks in the human brain

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ContentslistsavailableatScienceDirect

Developmental

Cognitive

Neuroscience

jo u r n al ho me p ag e :htt p : / / w w w . e l s e v i e r . c o m / l o c a t e / d c n

Asymmetric

development

of

dorsal

and

ventral

attention

networks

in

the

human

brain

Kristafor

Farrant

a

_,

_Lucina

_Q.

_Uddin

a,b,∗

a_Department_of_Psychology,_University_of_Miami,_Coral_Gables,_FL,_United_States

b_Neuroscience_Program,_University_of_Miami,_Miller_School_of_Medicine,_Miami,_FL,_United_States

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received30June2014

Receivedinrevisedform26January2015 Accepted4February2015

Availableonline12February2015 Keywords:

Dorsalattentionnetwork Ventralattentionnetwork Saliencenetwork RestingstatefMRI Typicaldevelopment Functionalconnectivity

a

b

s

t

r

a

c

t

Twoneuralsystemsforgoal-directedandstimulus-drivenattentionhavebeendescribedin theadulthumanbrain;thedorsalattentionnetwork(DAN)centeredinthefrontaleyeﬁelds (FEF)andintraparietalsulcus(IPS),andtheventralattentionnetwork(VAN)anchoredinthe temporoparietaljunction(TPJ)andventralfrontalcortex(VFC).Littleisknownregarding theprocessesgoverningtypicaldevelopmentoftheseattentionnetworksinthebrain.Here weuserestingstatefunctionalMRIdatacollectedfromthirty7to12year-oldchildrenand thirty18to31year-oldadultstoexaminetwokeyregionsofinterestfromthedorsal andventralattentionnetworks.WefoundthatfortheDANnodes(IPSandFEF),children showedgreaterfunctionalconnectivitywithregionswithinthenetworkcomparedwith adults,whereasadultsshowedgreaterfunctionalconnectivitybetweentheFEFand extra-networkregionsincludingtheposteriorcingulatecortex.FortheVANnodes(TPJandVFC), adultsshowedgreaterfunctionalconnectivitywithregionswithinthenetworkcompared withchildren.ChildrenshowedgreaterfunctionalconnectivitybetweenVFCandnodes ofthesaliencenetwork.Thisasymmetricpatternofdevelopmentofattentionnetworks maybeaneuralsignatureoftheshiftfromover-representationofbottom-upattention mechanismstogreatertop-downattentionalcapacitieswithdevelopment.

1. Introduction

It is well established that there are two partially segregated attentionnetworks in thehumanbrain; the so-calleddorsalandventralattentionnetworks(Corbetta andShulman,2002).Thedorsalattentionnetwork(DAN) includesbilateralintraparietalsulcus(IPS)andthefrontal eyeﬁelds (FEF),andis concernedwithorientatingones focusonaparticulartask.Previousworkhasdemonstrated thattheFEFandIPSexerttop-downinﬂuencesonvisual areasduringvisualorientingofattention(Bressleretal.,

∗ Correspondingauthorat:UniversityofMiami,P.O.Box248185-0751, CoralGables,FL33124,UnitedStates.Tel.:+13052843265.

E-mailaddress:l.uddin@miami.edu(L.Q.Uddin).

2008).TheDANshowssustainedactivationwhenfocusing attentiononanobject(Corbettaetal.,2008),andisthought toberesponsibleforgoal-directed,top-downprocessing (Corbetta andShulman,2002).Thesecondnetwork, the ventralattentionnetwork(VAN),iscomprisedofthe tem-poroparietaljunction(TPJ)andventralfrontalcortex(VFC), andrespondstorelevantexternalenvironmentalstimuli. TheVANisdominantintherighthemisphere,andis gen-erally activated when an unexpected event occurs and breaksonesattentionfromthecurrenttask(i.e. bottom-upprocessing)(forafullreview oftheDAN&VANsee Corbettaet al., 2008).Thisnetwork’s key functionis to directattentiontostimulioutsideofthecurrentfocusof processingandisreferredtoasthe‘circuitbreaking’section ofthetwoattentionnetworks(Shulmanetal.,2002). Cor-bettaandcolleaguesarguethatonlybehaviorallyrelevant http://dx.doi.org/10.1016/j.dcn.2015.02.001

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environmental stimuli trigger the VAN, and that the responseoftheVANissuppressedwhenirrelevant infor-mationispresented(Corbettaetal.,2008).TheVFChas beenidentiﬁed tobemainlyactive whenreorienting is unexpectedandrequirescognitivecontroloris coupled toaresponse(CorbettaandShulman,2002).Thetwocore regionsoftheVANaretypicallyco-activated,aswellas functionallyconnected(Foxetal.,2006;Heetal.,2007).

Anotherbrain system termedthe ‘salience network’ hasalsobeenlinkedwithfunctionsthatpartiallyoverlap withfunctionsascribedtotheVAN,includingresponding tobehaviorallyrelevantstimuli(Seeleyetal.,2007).The saliencenetwork is comprised ofdorsal anterior cingu-late,subcortical,andlimbicstructures,aswellasbilateral anteriorinsularcorticesadjacenttooroverlappingtheVFC nodeoftheVAN(Uddin,2015),andhasbeendemonstrated to show within- and between-network developmental changesincludingincreases infunctional andstructural connectivitywith age(Uddin et al.,2011).While some investigatorsseethehighdegreeoffunctionaland anatom-icaloverlap between theVAN and salience network as evidencethattheyarepartofthesamesystem(Kucyietal., 2012),themajorityhaveconceptualizedthesenetworksas distinctentities(Coleetal.,2013;Poweretal.,2011).

RestingstatefMRI(R-fMRI)studiescapitalizeonthefact thatlarge-scaleneurocognitivenetworkscanbereliably identifiedintheabsenceoftask-relatedprocessing(Biswal etal.,1995;Damoiseauxetal.,2006;Smithetal.,2009). Foxetal.(2006)werethefirsttouseR-fMRItoexamine attentionnetworksinthehumanbrain.Theyidentifieda bilateralDANandrightlateralizedVANsolelyonthebasis ofseed-basedfunctionalconnectivityanalysesofresting statefMRIdata,thusprovidingevidencethatthese atten-tionnetworksareintrinsicallycoupledinthebrain.

TheuseofR-fMRItoaddressdevelopmentalquestions allows us to avoid many of the issues related to task performancethatcanconfoundinterpretationof develop-mentalneuroimagingﬁndings(Caseyetal.,2005;Uddin etal.,2010).R-fMRIstudieshavedemonstratedthatover thelifespan,thelong-rangeconnectionswithintheDAN becomemoredominantuntilaroundtheageof∼30years (Caoetal.,2014).Caoandcolleaguesfoundinverted U-shapedtrajectoriesmainlywithintheDANandlanguage regions,whicharearguedtobeamongstthelastregions tomature(Caseyetal.,2000).Thisresearchisinlinewith previousstudieswhichsuggestthatshort-distance func-tionalconnectivityisgreaterinchildrenthanitisinadults (Dosenbachetal.,2010;Fairetal.,2009;Supekaretal., 2009) and that thelong-rangeconnections observed in adultsareenhancedthroughoutdevelopment(Fairetal., 2009;Kellyetal.,2009;Supekaretal.,2009).Itisargued thattheprocessofsynaptic“pruning”inwhichthe abun-danceofshort-rangeconnectionsintypicallydeveloping childrenareeliminated,generallyinthepubertalstageof development,contributestotheprominenceoflong-range connectivityinadults(Huttenlocher,1990).

Thoughthereisanabundanceofliterature surround-inghumanattentionnetworks,thereissurprisinglylittle researchthatfocusesonthetypicaldevelopmentofthese networks(Konradetal.,2005).A previousindependent componentanalysis(ICA)studyexaminingdevelopmental

differencesinthedorsalattentionnetworkfoundstronger within-networkconnectivityintheDANin11–13year-old childrencomparedwith19–25yearoldadults(Jollesetal., 2011).Seed-based approachescan offercomplementary informationtothatderivedfromICA,namelyallowingfor hypothesis-drivenanalysesofspeciﬁcfunctionalnetworks ofinterest(Uddinetal.,2010).Tothebestofourknowledge, nopreviousstudieshaveusedseed-basedapproachesto exploredevelopmentaldifferencesinfunctional connectiv-ityofDANandVANnodes,orinter-networkrelationships. HereweuseR-fMRItoexplorethetypicaldevelopment of theDANand VANin thehumanbrain. Weaimedto testthefollowinghypotheses:(1)R-fMRIcanbeusedto identifytheDANandVANinchildren,andthesenetworks haveasimilartopologicalorganizationtothatobservedin adults;(2)long-rangefunctionalconnectivityofDANand VANnodeswill bemorepredominantin adultsthan in children;and(3)between-andwithin-networkfunctional connectivitypatternswillshowdevelopmentalchanges.

2. Materialsandmethods

2.1. Participantsanddataacquisition

The present study included a total of 60 healthy, right-handed neurotypical individuals from the pub-lically available Autism Brain Imaging Data Exchange (ABIDE; http://fcon1000.projects.nitrc.org/indi/abide/) (DiMartinoetal.,2014).Weexaminedonlydatacollected from the New York University Langone Medical Center (NYU)forconsistency.Allparticipantshadafull-scaleIQ scoreof>80,andthegroupsdidnotdiffersigniﬁcantlyon IQ.Thegroupof60wassplitintotwogroupsofchildren (mean age: 10.2, range 7–12, 11 females) and adults (mean age: 24.2, range 18–31, 6 females) consisting of 30 participants each (Table 1). Participants were also carefullyselectedbasedonmotionparameters.No partic-ipantwasselectedwithabsolutedisplacement>1.95mm. Therangeofmotionparametersforthechildgroupwas 0.09–1.95mmmeanabsolutedisplacement(0.27±0.33). Therangeofmotionparametersfortheadultgroupwas 0.15–0.89mmmeanabsolutedisplacement(0.30±0.18). No group differences in absolute displacement were observed (p=0.7). The NYU institutional review board approved all procedures for data collection and shar-ing. Written informed consentwas obtainedfrom each participant. Table1 Participantcharacteristics. Characteristic Children(n=30) (standarddeviation) [range] Adults(n=30)(standard deviation)[range] Age(years) 10.2(1.74) 24.2(3.34) [7.19–12.97] [18.59–31.78] Sex(No.) Male 19 24 Female 11 6 Full-ScaleIQ 116.17(13.89) 114.93(10.09) [80–142] [91–139]

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Inclusionasatypicallydevelopingindividual(TD)was basedontheabsenceofanycurrent Axis-Idisorders as determinedbytheKiddie-ScheduleforAffectiveDisorders andSchizophrenia-PresentandLifetimeVersion (KSADS-PL)administeredtoeachchildandhis/herparent,andthe StructuredClinicalInterviewforDSM-IVAxis1 Disorders-Non-patientEdition(SCID-I/NP)andAdultADHDClinical DiagnosticScale(ACDS)interviewsforadults.

All subjects were scanned using a 3T Allegra, in a separate visit following the diagnostic assessment (typicallywithin3months).TheR-fMRIscanswere col-lected using an echo-planner imaging (EPI) sequence (TR=2000ms;TE=15ms;ﬂipangle=90◦;FOV=240mm; voxel size=3mm×3mm×4mm; number of slices=33, 4mm slice thickness). The scan lasted for 6min, which consistedof180volumes.Participantswereaskedtorelax withtheireyes open,whilea whitecrosshairagainsta blackbackgroundwasprojectedonascreen.

A high-resolution T1-weighted anatomical image

was acquired using a magnetization prepared gradient echo sequence (TR=2530ms; TE=3.25ms; inversion time=8.07min; ﬂip angle=7◦; 128 slices; 1 volume FOV=256mm). Alldetails regarding scanning protocols areoutlinedin(DiMartinoetal.,2014).

2.2. Region-of-interest(ROI)selection

FourROIswereselectedbasedonpreviousresearch con-ducted by Fox and colleagues(Foxet al., 2006). Inthis earlierstudy,fourROIs(twointheDANandtwointheVAN) weredeterminedviameta-analyses.IntheDAN,theROIs werelocatedinrightintraparietalsulcus(IPS;32,−56,54) andfrontaleyeﬁelds(FEF;28,−8,52),andintheVANthe ROIswerelocatedinrighttemporoparietaljunction(TPJ; 60,−48,22)andventralfrontalcortex(VFC;42,20,−6). Forthecurrentstudy,sphericalROIswerecreatedwitha radiusof6mmbasedonthesecoordinatesasreportedby Foxetal.(2006).Exploratoryfollow-upanalysesrelated tothesaliencenetworkwereconductedusingaseedin theanteriorcingulatecortex(ACC;6,24,32)derivedfrom apreviousstudy(Uddinetal.,2011).Allcoordinatesare reportedinMNIstandardspace.

2.3. Datapreprocessing

Data were preprocessed using the Data Processing Assistant for Resting-state fMRI Advanced Edition (DPARSF-A)toolbox,whichispartoftheDataProcessing andAnalysisofBrainImaging(DPABI)toolboxversion3.1, (http://rfmri.org/dpabi) (Chao-Gan and Yu-Feng, 2010). The first 5 volumeswere removed from each subject’s resting-statefMRIdata.Datawerepreprocessedinseries ofstepsincludingslice-timingcorrection,brainextraction of T1 images, and segmentation using SPM priors for cerebrospinalfluid(CSF)andwhitematter(WM).Weused theWMandcerebralCSFmeantime-seriesasnuisance regressorsinthegenerallinearmodel(GLM)toreducethe influenceof physiological noise(Marguliesetal., 2007). Globalsignalregressionwasnotused(Saadetal.,2012). Additionally, we regressed out the nuisance covariates usingtheFriston24-parametermodel(Fristonetal.,1996)

andappliedabandpassﬁltercapturingthefMRIsignal between the frequencies 0.01–0.08Hz. The data were spatiallysmoothedwitha5mmfull-widthhalf-maximum Gaussian kernel. To further reduce motion-related arti-factswe“scrubbed”ourdatausingthecut(delete)option available in the DPABI-A toolbox using the following parameters:FDthresholdforbadtimepoints=0.5, scrub-bingtimepointsbeforebadtimepoints=1,scrubbingtime pointsafterbadtimepoints=2(Poweretal.,2012).The datawereregisteredtothesubject’sindividualanatomical spaceandthenintoMNIstandardspace.

2.4. Individualandgroup-levelanalysesforseed-based whole-brainfunctionalconnectivityanalyses

Foreachparticipant,weextractedthemeantime-series of each of the four attention network ROIs individu-allyusingthefunctional connectivityvoxel-wiseoption in the REST toolbox version 1.8 (http://www.restfmri. net/forum/RESTV1.8). We then compared whole-brain functionalconnectivitypatternsbetweenadultsand chil-dren for each ROI. Data were corrected for multiple comparisonsusingGaussianRandomFieldTheoryMultiple ComparisonCorrection(voxel-levelp-value=.01; cluster-levelp-value=.05,two-tailed).Two-tailedt-testsbetween resultsforthechildrenandadultgroupswereconducted foreachROI.TheseanalysesproducedthresholdedZ-score mapsforeachofthefourROIs.

2.5. Seed-to-seedanalyseswithinnetworks

Inadditiontotheseed-based whole-brainfunctional connectivityanalyses,whichshoweddevelopmental dif-ferencesinfunctionalconnectivityofspeciﬁcDANandVAN ROIs,wealsoconductedanalysesbetweenseedregions withintheDANandwithintheVAN.Weusedthesame coordinateslistedinSection2.2torepresentthetwoseeds withineachnetwork. Using theREST toolboxwe calcu-latedpair-wisefunctionalconnectivitybetweentheseeds withintheDAN(rIPS-rFEF)andwithintheVAN(rVFC-rTPJ). Two-samplet-testswereconductedtoexploregroup dif-ferencesinwithin-networkfunctionalconnectivityinthe twoattentionnetworks.

2.6. Seed-to-seedanalysesbetweennetworks

To explore potential group differences in between-network functional connectivity, we conducted the fol-lowingseed-to-seedcorrelationanalysesofthefollowing ROIpairs:rIPS-rVFC,rFEF-rTPJ,rIPS-rTPJ,rFEF-rVFC. Two-samplet-testswereconductedtoexploregroupdifferences inbetween-networkfunctionalconnectivity.

3. Results

3.1. DANandVANtopologicalorganizationinchildren andadults

TovisualizetheorganizationoftheDANandVANin chil-drenandadults,thewhole-brainfunctionalconnectivity mapsassociatedwitheachregionofinterestwithineach

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networkaredepictedinFig.1.AscanbeseeninFig.1A, the overlap of the functional connectivity map of the IPSseed(blue)andtheFEFseed(purple)delineatesthe regions described in(Corbetta and Shulman,2002)and (Fox etal.,2006)asbelongingtotheDAN.Theareasof overlap(violet)includebilateralIPS,bilateralFEF,and ven-tral temporal visual areas, in both children and adults. Ascanbeseen in Fig.1B, theoverlapof thefunctional connectivitymapsoftheTPJ(blue)andVFC(purple) delin-eatestheregionspreviouslydescribedasbelongingtothe VAN.Theareasofoverlap(violet)includemiddlefrontal gyrus,anteriorinsula,VFCandTPJ,inbothchildrenand adults.

3.2. Developmentaldifferencesinwhole-brainfunctional connectivityofdorsalattentionnetworknodes

Forbothadultsandchildren,IPSshowedstrong func-tionalconnectivitywithotherregionsoftheDANincluding frontaleyeﬁeldsandvisualcorticalregions.Forbothadults andchildren,FEFshowedstrongfunctional connectivity withtheentireDANincludingintraparietalandvisual cor-ticalregions.

WefoundthatforbothROIsrepresentingtheDAN(IPS andFEF),children showedgreaterfunctional connectiv-itywithinthenetwork(e.g.withtheIPS)thandidadults. AdultsshowedgreaterfunctionalconnectivityoftheFEF with regions outside of the DAN (e.g. posterior cingu-latecortex, PCC)than didchildren (Fig.2).Table2lists coordinatesofsigniﬁcantgroupdifferencesinfunctional connectivityforeachROI.

3.3. Developmentaldifferencesinwhole-brainfunctional connectivityofventralattentionnetworknodes

For both adults and children, TPJ showed strong functional connectivity with other regions of the VAN

Fig.1.Conjunctionofcorrelationmaps.(A)Voxelssignificantlycorrelated withtheIPS(blue),FEF(purple),andboth,definedasthedorsalattention network(DAN;violet).(B)VoxelssignificantlycorrelatedwiththeTPJ (blue),VFC(purple),andboth,definedastheventralattentionnetwork (VAN;violet).(Forinterpretationofthereferencestocolorinthisfigure legend,thereaderisreferredtothewebversionofthisarticle.)

Fig.2.IndividualandgroupcomparisonsofrestingstatefunctionalconnectivityofseedROIsIPS(A)andFEF(B).Yellowmaps(ﬁrstpanel)showindividual onesamplet-testforadults.Redmaps(secondpanel)showindividualonesamplet-testforchildren.Remainingpanelsshowtwo-samplet-testscomparing adultswithchildren.(Forinterpretationofthereferencestocolorinthisﬁgurelegend,thereaderisreferredtothewebversionofthisarticle.)

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Table2

GroupdifferencesinfunctionalconnectivityofDANandVANROIs.

Seed Contrast Functionalconnectivity MNIcoordinates Z-score Clustersize

(voxels)

x y z

FEF Children>adults Leftsuperiorparietallobule/superiorLOC −30 −58 58 4.7216 611

Children>adults Rightprecentralgyrus 24 −10 44 5.4054 492

Adults>children Leftposteriorcingulategyrus −6 −40 40 3.7597 338

Adults>children Leftpostcentralgyrus −40 −18 40 3.5311 332

Adults>children Leftposteriorcingulategyrus −2 −20 40 3.1041 23

IPS Children>adults RightsuperiorLOC 22 −74 58 3.9278 521

TPJ Adults>children Leftposteriorcingulategyrus −4 −18 32 4.5237 295

VFC Children>adults Leftthalamus 0 −24 12 4.8568 1736

Children>adults Leftinsularcortex −28 24 6 5.1591 814

Children>adults Rightinsularcortex 28 26 6 4.6307 551

Adults>children Righttemporalpole 34 4 −38 3.7281 332

including VFC and middle frontal gyrus. Strong func-tional connectivity was alsoobserved between TPJ and regions of the default mode network (posterior cin-gulate and medial prefrontal cortex). For both adults and children, VFC showed strong functional connectiv-ity with other regions of the VAN including middle frontal gyrus and TPJ (Fox et al., 2006). In addition, strong functional connectivity was observed between VFCand theanteriorcingulatecortex(ACC) andinsular cortex.

WefoundthatforbothROIsrepresentingtheVAN(TPJ and VFC),adults showedgreaterfunctionalconnectivity withregions withinthe network thanchildren. For the VFC ROI, children showed greaterfunctional connectiv-itythanadultswiththeanteriorinsulaandACC,regions comprising the salience network (Seeley et al., 2007) (Fig.3B).

3.4. Developmentaldifferencesinwithin-and between-networkROI-to-ROIconnections

To examine whether between- and within-network functional connectivity patterns show developmental changes, we conducted ROI-to-ROI analyses. No group differenceswerefoundforwithinDAN(IPS-FEF)orwithin VAN(TPJ-VFC)connections.Inotherwords,childrenand adultsdidnotdifferonstrengthoffunctionalconnectivity within either of the attention networks. Likewise, the between-network ROI comparisons (rIPS-rVFC, rFEF-rTPJ, rIPS-rTPJ, rFEF-rVFC) yielded no signiﬁcant group differences(Fig.4).

3.5. RelationshipbetweenVANandsaliencenetwork On the basis of our ﬁnding that children showed greaterfunctionalconnectivityofVFCwithregionsofthe

Fig.3. IndividualandgroupcomparisonsofrestingstatefunctionalconnectivityofseedROIsTPJ(A)andVFC(B).Yellowmaps(ﬁrstpanel)showindividual onesamplet-testforadults.Redmaps(secondpanel)showindividualonesamplet-testforchildren.Remainingpanelsshowtwo-samplet-testscomparing adultswithchildren.(Forinterpretationofthereferencestocolorinthisﬁgurelegend,thereaderisreferredtothewebversionofthisarticle.)

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Fig.4.ROI-to-ROIconnectivitywithindorsalandventralattentionnetworksnodesandbetweendorsalandventralattentionnetworknodes.

saliencenetworkcomparedwithadults,wesoughtto fur-therexplore this findingusingROI-to-ROI comparisons. Uponcloserinspection,wenotedthattheseedfromthe Fox 2006 paper correspondingto the VFC (42, 20, −6) fallswithintheanteriorinsularcortex,akeynodeofthe saliencenetwork.TotestwhetherthisVFCROImore accu-ratelyreflectsaVANnodeorasaliencenetworknode,we computedfunctionalconnectivityofthefollowing: VFC-TPJ(withinVAN)andVFC-ACC(withinsaliencenetwork). WereasonedthatifVFC-ACCcouplingwasstrongerthan VFC-TPJcoupling, thanthe VFC nodemight actually be morerepresentativeofthesaliencenetworkthanofthe VAN.We foundthat neitherVFC-TPJnorVFC-ACC com-parisonsshowedsignificantgroupdifferences.However, as can be seen in Fig. 5, the VFC ROI showed signifi-cantlystrongerfunctionalconnectivitywithACC(asalience

Fig.5.ROI-to-ROIconnectivitybetweenVFCandVANnode(TPJ)and betweenVFCandsaliencenetworknode(ACC).

networknode)thanwithTPJ(aVANnode)inbothadults and children (p<0.01). There was a trend suggesting greaterconnectivityofVFCwithACCinchildrencompared withadults(p=0.09).

4. Discussion

Considerableevidencefrombehavioral, electrophysio-logical,andneuroimagingworksuggeststwoanatomically separable fronto-parietal systems for attention exist in the humanbrain,(1) a dorsal attentionnetwork (DAN) involved intop-downorienting, and(2)a ventral atten-tion network (VAN) for bottom-up salience detection (Corbetta and Shulman, 2002).While these neural sys-temshavebeenwellcharacterizedinneuroimagingstudies of adults (Corbetta et al., 2008), little is known about the typical developmentof these brain networks. Here weexploredthefunctionalconnectivityofthedorsaland ventralattention networksin adultsand children using seed-basedfunctionalconnectivitytoexplorewithin-and between-network developmental changes. The current resultsprovideuniqueinsightsintothetypical develop-mentoftheDANandVANin thehumanbrain.Wefind asymmetriesinfunctionalconnectivitypatternsassociated withkeynodesoftheseattentionnetworks.Inboth chil-drenandadults,theattentionnetworkscouldbeidentified astheoverlapoffunctionalconnectivitymapsassociated withtheIPSandFEF(DAN)andTPJandVFC(VAN).Thus, children and adults seemtoexhibit DANand VAN net-worktopologythatisanchoredinthesekeynodesandis quitesimilarinoverallspatialextent.FortheDANnodes (IPSandFEF),childrenshowedgreaterfunctional connec-tivity with regions within the network compared with adults,whereasadultsshowedgreaterfunctional connec-tivitybetweentheFEFandextra-networkregionsincluding the posterior cingulate cortex. For the VAN, the most strikingdevelopmentalfindingwasthatchildrenshowed greaterfunctionalconnectivitybetweenVFCandnodesof thesaliencenetwork(anteriorinsulaandACC),suggesting

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reducedsegregationoftheVANandsaliencenetworksin childhoodcomparedwithadulthood.

4.1. Developmentalstudiesofattention

Evidence from behavioral and neuroimaging studies suggests that speciﬁc attention processes undergo pro-tractedperiodsofdevelopmentalmaturation.Inparticular, children are more susceptible to interference and less abletoinhibitresponsesthanadults(Bungeetal.,2002). Childrenshowdevelopmentaldifferencessuchthatthey exhibitgreateractivationthanadultsinanteriorcingulate cortexandlateralprefrontalcorticesduringselective atten-tion (Boothet al.,2003)and response inhibition (Casey etal.,1997).Thisworkisinlinewiththegeneral develop-mentalprinciplethatbrainactivationduringaparticular cognitive task tends to progress from more diffuse to morefocalwithage(Durstonetal.,2006).Takentogether, the ﬁndingsof decreased task-related frontalactivation withagearethoughttoindexthematurationofcognitive strategies fromchildhood throughadolescenceand into adulthood(Dumontheiletal.,2010).Thedevelopmentof cognitivecontrolprocesseshasbeenthefocusofthe major-ityofpreviousinvestigations(DurstonandCasey,2006).

Surprisingly little neuroimaging work hasexamined developmentaldifferencesintherelativecontributionsof theDANandVAN.Apreviousstudyconductedby(Konrad etal.,2005)usedataskbasedfMRIparadigmtoexplore thedevelopmentofattentionnetworksforalerting (fronto-parietal),orienting(TPJandVFC),andexecutiveattention (anteriorcingulate/lateralprefrontal)in adultsand chil-dren. Theyfoundthatchildrenshowedsigniﬁcantlyless activationintherightmid-brainregionsduringalerting, intherightTPJduringreorienting, andinDLPFCduring executivecontrol.Atthesametime,childrenexhibited sig-niﬁcantlymoreactivationinsuperiorfrontalgyrusduring reorientingandsuperiortemporalgyrusduringexecutive controlofattention.ThedatapresentedbyKonradetal. (2005)suggestthatthereisatransitionfromthe imma-turefunctionalsystemsthatsupportattentionalfunctions inchildrentomorematuresystemsinadults.

4.2. RestingstatefMRIandbrainnetworkdevelopment Overthepasttenyears,restingstatefMRIhasemerged as a powerfulcomplementary approach toexamination oftask-activation.Akeyprinciplethathasemergedfrom thisliteratureisthatanterior–posteriorlong-range func-tionalconnectivityisslowtodevelop,particularlyinbrain networksunderlyinghighercognitivefunctions(Fairetal., 2008; Kelly et al., 2009; Supekar et al., 2010). Human brainnetwork developmentappearstoinvolve simulta-neoussegregation(decreaseofshort-rangeconnections) andintegration(increaseoflong-rangeconnections)(Fair etal.,2007).Astudyusingindependentcomponent analy-sis(ICA)foundevidenceforincreasedconnectivitywithin theDAN inchildren comparedwithadults(Jolles etal., 2011),providingevidenceforearlysegregationoftheDAN. Inthecurrentstudywealsoﬁndgreaterwithin-network connectivityoftheDANinchildren,particularlyintheIPS region,as revealedby groupdifferences inwhole-brain

functional connectivity of key DAN nodes. The ROI-to-ROIconnectivity(IPS-FEF)corroboratedtheseﬁndingsof greaterwithin-DANconnectivityinchildren,thoughthe effectwasnotsigniﬁcant.

For the DAN, adults showedgreater functional con-nectivity of the FEF with regions outside the network includingthePCC,akeyhubofthedefaultmodenetwork (Greiciusetal.,2003;Raichleetal.,2001).Thisincreased communicationbetweentheDANandthedefaultmode networkobservedinadultscomparedwithchildrenmight enablegreatertop-downattentionalcapacitiesin adult-hood(Rubia, 2013).Theabilitytomodulateorsuppress defaultmodenetworkactivityhasbeenlinkedwith suc-cessful goal-directed attention and cognition (Anticevic etal.,2012).Thesamedirectionofeffectswasobserved fortheVAN,whereweobservedgreaterfunctional connec-tivityoftheTPJwithPCCandtheVFCwithtemporalpole inadultscomparedwithchildren.Overall,itappearsthat adultsexhibitedmoreﬂexiblepatternsofextra-network connectionsof attentionnetwork nodescompared with children.Theseresultsarelargelyconsistentwithprevious workdemonstratingincreasinglong-rangefunctional con-nectivitystrengthwithdevelopment(Uddinetal.,2010). 4.3. Ventralattentionnetworkandsaliencenetwork

TheVFCintheVANshowedgreaterfunctional connec-tivityinchildrencomparedwithadults,particularlywith ACCandanteriorinsula.TheROIselectedtorepresentVFC wascenteredatMNIcoordinates42,20,−6basedon previ-ouswork(Foxetal.,2006).Uponcloserexamination,this regionappearstofallwithintheanteriorinsularcortex, andisanatomicallyveryclosetoaregionlocatedat39, 23,−4thathasbeenimplicatedinplayingacausalrolein switchingbetweenthecentralexecutivenetworkandthe defaultmodenetworkinadultsandchildren(Uddinetal., 2011).Alargebodyofworkindicatesthattheinsulaplays adominantroleindetectionofnovelsalientstimuliacross multiplemodalities(Crottaz-HerbetteandMenon,2006; Downaretal.,2000).Theroleoftheinsulaindetectionof salientstimulianditsinclusioninthe“saliencenetwork” alongwiththeanteriorcingulatecortexhasnowbeenwell documented(MenonandUddin,2010;Seeleyetal.,2007). Itisworthnotingthatthereisstillworktobedoneto dis-tinguishwhetherandtowhatextentthesaliencenetwork andtheso-called“cingulo-opercularnetwork”(Dosenbach etal.,2008)shouldbeconceptualizedasdistinctentities (Uddin,2015).Tofurtherexplorethepotentialoverlapof theVFC nodewithregionsof thesalience network,we conductedROI-to-ROIanalyseslookingatVFC-TPJand VFC-ACCconnectivitytoseewhichnetwork(theVANorthe saliencenetwork)wasmostcloselyassociated withthis ROI.Weﬁndthatinbothadultsandchildren,theVFCshows strongerfunctional connectionstothesaliencenetwork thantotheVAN.Wealsoobservedatrendtowardgreater VFC-ACCconnectivityinchildrencomparedwithadults.

We propose that theVAN and thesalience network have overlapping nodes in the region surrounding the VFC and anterior insula. We speculate that in children, thesetwonetworksmaybelesssegregatedthaninadults, and thatbottom-up salienceprocesses and attentionto

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environmental stimuli may be over-represented in the child’sbrain.Consistentwiththe“circuitbreaker”function attributedtotheVAN,ithasbeendemonstratedinadults thatsignalsintheVANcausallyinﬂuenceactivityinthe DAN(Sridharanetal.,2007).Perhapstheover-connectivity in the VAN in children compared with adults that we observe is a neural signature of the differential and asymmetricmaturation of attentionprocesses through-out development. The fact that children exhibit more widespreadconnectivityin theVFC regionmayexplain whytheyarebehaviorallymoresusceptibleto interrup-tionbyenvironmentalstimuli andlessabletomaintain activitiesrequiring top-downattentionalcontrol(Bunge etal., 2002).Analternative speculationis thatthis VFC regionmayneedtobeextensivelyconnectedinchildhood toensuredetectionofsalientenvironmentalstimuli,which wouldbeimportantforbasicsurvival.

Ourresultsare somewhatconsistentwiththe previ-oustaskactivationstudy(Konradetal.,2005).However, weprovideevidencetosuggestthatthesecond anatom-icalcomponent of thereorienting network, VFC, shows greaterfunctionalconnectivityforchildrenthaninadults withregionsofthesaliencenetwork.Wearguethatthe reason for this region showing more widespread func-tionalconnectivityinchildren thanin adultsis because ofitsanatomicallocation.WeshowthattheVFC,which isanatomicallyveryclosetotheanteriorinsulacortex,is signiﬁcantlycorrelatedwiththeACC.Theanteriorinsular cortexandACChasbeendescribedasthecorethatforms thesaliencenetwork,whichisimportantforthe facilita-tionanddetectionofenvironmentalstimuli(Uddin,2015). Theattentioncharacteristicsofthesaliencenetworkare somewhatsimilartothosecharacteristicsoftheVAN;both arethoughttobeimportantfordetectionofstimulioutside ofdirectfocus.Theanatomicalproximityofanteriorinsula andVFCpointstowardalinkagebetweenthetworegions andpossiblythesharedresponsibilitiesofsalience detec-tion.Weseethatinchildren,thesetwosaliencedetection systemsarelesssegregatedthaninadults.Futureworkwill exploretheextenttowhichsegregationbetweentheVAN andsaliencenetworkthroughoutdevelopmentrelatesto increasedattentionalabilitiesusingbehavioraland task-basedneuroimagingparadigms.

4.4. Limitations

Theﬁeldhasnotyetcometoaconsensusastobest practicesfordealingwithmotionartifactsinresting-state fMRIdata,thoughit isclearthatsuchartifactscanbias results(Poweretal.,2012; VanDijketal.,2012).There havenotyetbeenvalidationstudiestodeterminetheexact effectsofthemotionscrubbingprocedurethathasbeenput forthasapotentialsolution.Webelievethattheeffects ofmotionscrubbingongroupdifferencesfunctional con-nectivityindevelopmentalcontextswillrequireadditional methodologicalstudy.

A limitation of the current study is that age is dichotomized, rather than continuously examined. We optedtoexaminethedevelopmentofattentionnetworks usingtwoagecategoriesinthecurrentstudyforthe fol-lowingreasons.Onewastoavoidtheperiodofpuberty,

whichoccursduringadolescence,andisaccompaniedby protracted (andnot verywell-characterized)changes in functionalconnectivitypatterns(Blakemoreetal.,2010). Giventheasyetunknowneffectsofpubertyon develop-mentofattentionnetworksinthebrain,andthefactthat inthecurrentsampleparticipants’pubertalstatuswasnot explicitlycharacterized,wechosetoavoidexaminingthe adolescentagerangeinthecurrentstudy.Webelievethat carefulconsiderationofpubertalstatusisaveryimportant questionforfutureresearch(Uddinetal.,2013).

Thesecondreasonagewasdichotomizedwasdueto thesampleavailableinthepublicdatasetthatwasutilized inthestudy.Astherewerenotalargeenoughnumberof subjectstoexamineagecontinuously, wechoseto sim-plifybycomparingchildren andadultgroups,asseveral previousdevelopmentalneuroimagingstudieshavedone (Jollesetal.,2011;Kellyetal.,2009;Supekaretal.,2010; Uddinetal.,2011).Webelievethatanimportant direc-tionforfutureresearchwillbetoexaminethisquestion inlargerdatasetscontainingmoreindividualsatvarious developmentalstagesinordertoexaminemorecomplex maturationalpatterns.

5. Conclusion

Thecurrentstudydemonstratesasymmetric develop-mentalpatternsoffunctionalconnectivityofthedorsaland ventralattentionnetworksofthehumanbrain.Whereas for theDANnodes(IPSand FEF),children showgreater functionalconnectivitywithregionswithinthenetwork compared withadults,and adultsshowedgreater func-tional connectivitybetweenwithextra-network regions includingnodesofthedefaultmodenetwork,fortheVAN nodes (TPJ and VFC), adults showed greater functional connectivitywithregionswithinthenetwork compared with children and children showed greater functional connectivitybetweenVFCandnodesofthesalience net-work. We suggest thatbecause theVFC is withinclose proximity of anterior insula, an important hub within thesaliencenetwork,theremaybeoverlapbetweenthe VANand salience network at this node. This asymmet-ricpatternofdevelopmentofattentionnetworksmaybe a neuralsignatureoftheshiftfromover-representation ofbottom-upattentionmechanismstogreatertop-down attentionalcapacitiesthatemergebetweenchildhoodand adulthood.Futureresearchshouldexplorehowalterations indevelopmentoftheseattentionnetworksmightimpact developmentaldisordersofattentionincludingattention deﬁcit/hyperactivitydisorder(ADHD)(Vaidya,2012).

Conﬂictofinterest

Nonedeclared.

Acknowledgments

We gratefully acknowledge the Autism Brain Imag-ing Data Exchange (ABIDE; http://fcon1000.projects. nitrc.org/indi/abide/)forproviding thepubliclyavailable datausedinthecurrentwork.Thisworkwassupportedby aNationalInstituteofMentalHealthCareerDevelopment

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Award(K01MH092288)and aSlifka/RitvoInnovation in AutismResearchAwardtofromtheInternationalSociety forAutismResearchtoLQU.

AppendixA. Supplementarydata

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.dcn.2015.02.001.

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