Chen AJW, Navokavic-Agopian T, Nycum TJ, Song S, Turner GR, Hills NK, Rome S, Abrams

14 Pages·2011·0.53 MB·English

Brain Advance Access published April 22, 2011
doi:10.1093/brain/awr067 Brain2011:Page1of14 | 1
BRAIN
AJOURNALOFNEUROLOGY
Training of goal-directed attention regulation
enhances control over neural processing for
individuals with brain injury
Anthony J.-W. Chen,1,2,3,4 Tatjana Novakovic-Agopian,1,2,3,5 Terrence J. Nycum,1,4 Shawn Song,3
Gary R. Turner,6 Nancy K. Hills,3 Scott Rome,5 Gary M. Abrams1,3 and Mark D’Esposito2,4
D
ow
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1NMMCE-5Aemaa0uir9lartMoi4icnl:lo5oeuda5zgiren,3ytR,,1hoU2oa7Snd,Ay,[email protected] ealth Sciences Libraries, University of W
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theeffects ofinterventionforpatientswith variedinjurypathology wereusedto indexmodulatory controlofneural processing.
Pattern classification was utilized to decode individual functional magnetic resonance imaging data acquired during a visual
selective attention task. Results showed that modulation of neural processing in extrastriate cortex was significantly enhanced
by attention regulation training. Neural changes in prefrontal cortex, a candidate mediator for attention regulation, appeared to
depend on individual baseline state. These behavioural and neural effects did not occur with the comparison condition. These
results suggest that enhanced modulatory control over visual processing and a rebalancing of prefrontal functioning may
underlie improvements in attention and executive control.
Keywords: cognitive rehabilitation; neural plasticity; executivecontrol; attention; functional MRI; braininjury
ReceivedAugust24,2010.RevisedFebruary14,2011.AcceptedFebruary20,2011.
PublishedbyOxfordUniversityPressonbehalfoftheGuarantorsofBrain2011.
ForPermissions,pleaseemail:[email protected]
2 | Brain 2011: Page 2 of 14 A. J.-W. Chen et al.
Introduction poorly localized, as is often the case with traumatic brain injury
(Wolfe et al., 1990; Mesulam, 2000; Fork et al., 2005; Scheid
Acquired brain injuries have been a leading cause of long-term et al., 2006). If one cannot hold key information active in the
mind or protect it from distracting information, then subsequent
disability in the USA (Thurman et al., 1999) and have been an
actionsarelesslikelytobeguidedefficientlyoreffectivelytowards
increasing concern due to recent military conflicts (Okie, 2005).
goal attainment. Targeting these specific cognitive abilities may
The most common and persistent deficits tend to be in functions
therefore lead to improvements in functioning that generalize to
such as paying attention, holding information in mind, organizing
broader domains of goal-directed functioning.
and developing efficient strategies for completing activities
Theoverallobjectiveofthisstudyistodeterminetheunderlying
(Cicerone and Azulay, 2002; Mathias et al., 2004; Fork et al.,
neural mechanisms that support cognitive improvements with
2005; Vanderploeg et al., 2005). These ‘executive control’ func-
rehabilitation training of attention regulation. In a previously re-
tions are important for the regulation of other, more basic pro-
ported study of individuals with chronic acquired brain injury
cesses, and deficits may directly contribute to poor outcomes as
(Novakovic-Agopian et al., 2010), we applied a training interven-
well as impede rehabilitation at broader levels (Prigatano and
tion for improving goal-directed attention regulation that takes
Wong, 1999; Hyndman and Ashburn, 2003; Ownsworth and
into account the links connecting attention, working memory
McKenna, 2004). Effective treatments are needed.
and goal-based direction of behaviour in daily life. In contrast to
Understanding the neural bases of cognition, including the
mechanismsbywhichimprovementsoccur,mayprovideguidance training via practice on isolated tasks, this training protocol Dow
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dohcaLrneiuaeevvdssaiensfeGeeosxsahrameroomatwrsvianadnolnie.nf,,dcgr2ti2fert0f0aahe0i0sner8ee5isn;ln;egtiWaKnrpeinhnralileynytgtthgeeieeo-r,tiannn2lsaatd0hlluo.0y,bcf,6er2ar)dn0e.ines0pFuu6ulalra)tnoc.sstclt,oiTitvcpighaoitrietncyiimaoasalnlailsgyrns(nioleriyinecfiuvitciraanioaetceinwmttdceeeiarnwdmgdoiisniitfnvhgoitdKvhfuseaetialrunslliyes--- iaV22ns00ote00nrw87Cv);eer,alnRlmtwaioaotihstnnhseoettstthhpaaaeetllrc..hi,,aapl12vo90eep90mu1b3l;epa;ethRiNnoaosnebaizsspeurp(tolDseineot’dnZ,aumtlro1.ii,nl9lapd92af60uta;i0lenn7nLed;etssvsS-Giwncboheaitlwsdheefedtrbiizeraeadalri.,tn,tee12itnn90tju70aiolr10.ny;,, at Hbrain.oxfordjournals.org
rfifeninseuutejsnnuuaupccrrllittaa.teii,sroolst2nnmircae0auesm0l(lcea8tanh.ro;giealny.Sunswari´Rsonuhsmopicnamshastcerealenosnzgeafe-i.rnCueimgtr(aEaerpval.rsgrieltoco.´.un,hnvdHae2ieneimt0lthsgla0eeear0nosyl;.tf,,esiC2xu2pnt0po0aee0ptr0nibx8oe8tee)nr).ttc.tttusIaIiotmntiwfviepsoewtirrtaomhhcalvsoilacoe.anht,dcitourq2onnrut0elhci0crrlefeeeo5uagdv;nranecCrbreftdyrihurooianernomiangnsfl rptmiFanerunrageoWrciaanutjeehsilenacbueitntgrrrh-iiemoebycsnfaopposrooremeseofdttd,hptruoaatelcercttsfaaextouizetiglnnien‘oiriecdntenstsiigoaiagotlnlah-nngpwaaiaefiaptcloncnlttireaiedrtvlrdnaadiat’tisenlylkiytxszisoneeer.egtdcitdmsuiIunainttnpoliigdtvlryesiaeoiv.mdtviltdicepfeiuoendnraontslivntsoiorteoonundwla,srtfuheniuwocogenhnhuucsilrctlaieoimooatpimnnoppsdanryapolcrletvciphmitoeceoeimmprlpdofraoepgotrnlivtiemcohtexasnes-.,l ealth Sciences Libraries, University of W
sreymsteaminsedthaant uonpdeenrliqeueesxteiocnu.tivTehecomntorostl adrireecptlatsetsicts, ioffatthaelol,rizheads ctrooglnoitfivneepuerarfloprmroacnecsesinbgy.eTnohatnecstingthigsohaly-pboatsheedsimsoindutlhaetorcyurcroenn-t isconsin-M
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functional MRI studies to date have examined cognitive rehabili- indextheneuralcorrelates ofattentionalmodulation.Importantly, eptem
tehatatbiaoillni.t,atf2ioo0lnl0o8w)ininatgenrdvberenavtineionnisnfejuwornyer(eLhxaaeavcteuscteihvxeaemtcionanel.dt,rot2lh0ef0u4en;fcfteSicotrtnassnogf(mKraiemn- octohuarinnftgueernsinctdoioinvnidaaulawMlivtRhaIirniam-stiueoabnsjseucrintesmpbeaantshtisosloaoglvloiecwraletddimamuesaagtnoed.dTtoehteebccetogrnonebiutuirvsaetl ber 22, 2011
et al., 2009). One particularly important but challenging question task performed during scanning was based on the common situ-
is to understand the individual variability in mechanisms by which ation in everyday life where multiple incoming streams of infor-
differentindividualsmayachieveimprovementinfunctioningafter mation compete for attention and processing. For example,
brain injury. although multiple images (such as of faces, scenery and other
Selectiveprocessingofgoal-relevantinformation,acentralcom- objects) may be viewed, a person may be interested in learning
ponent of executive control, is a crucial gateway that filters what the faces of individuals in one moment, but identifying scenic
information gains access to more in-depth processing (Baddeley, views in another. This task requires perception of all images,
2001;Cowanetal.,2005;Vogeletal.,2005;CowanandMorey, eachresultinginrepresentationswithinbrainnetworks,butselect-
2006; Repovs and Baddeley, 2006; Awh and Vogel, 2008). ive processing of some images in preference to others depending
Information processing from perception to action requires mech- on the task goals. Thus, the processing of perceptually derived
anisms of attention for selecting information, as well as maintain- informationwouldneedtobemodulatedbasedongoal-relevance
ingandprotectingthisinformationfromdisruptionduringworking tofavourclearerrepresentationofsomeimagesoverothersduring
memory, learning, decision-making and/or problem-solving. more in-depth processing. We indexed goal-based modulation of
Deficits in these types of cognitive processes are common with neural processing using a novel functional MRI pattern classifier
acquired brain injuries, whether lesions are localized to prefrontal method to decode the clarity of information representation when
cortex, along white matter and interconnecting networks, or stimuli were goal-relevant versus non-relevant. We predicted that
Training enhances control over neural processing Brain 2011: Page 3 of 14 | 3
enhanced goal-based modulatory control of neural processing Interventions
would be evident in changes in neural representations in visual
Two intervention conditions were employed: (i) training in goal-
areas involved in stimulus processing as well as in changes in pre-
orientedattentionalself-regulation(goalstraining);and(ii)acompari-
frontal cortex, a likely source of goal-based modulatory control
son educational activity (education). The goals training protocol was
signals.
based on a goal-management training intervention (Robertson, 1996;
Levine et al., 2000, 2007), as well as principles highlighted in other
attention, mindfulness and problem-solving interventions (D’Zurilla
Materials and methods and Goldfried, 1971; Kabat-Zinn, 1990; VonCramon et al., 1991;
Rath et al., 2003; Nezu et al., 2007). The goals training protocol
involved 10 2-h sessions of group-based training, three individual
Participants 1-h training sessions and (cid:2)20h of home practice over 5 weeks.
Training was conducted in a small group format with 2–5 patients
Sixteenpatientswithchronicacquiredbraininjury(56months)parti- and two instructors per group. To ensure consistency of administra-
cipated in the study after providing informed consent according to tion, intervention manuals were written for instructors and partici-
procedures approved by the Institutional Review Boards of the pants. Clinicians experienced in working with individuals with brain
California Pacific Medical Centre, University of California, San injury (occupational therapists, neuropsychologist) were trained in ad-
Francisco and San Francisco VA Medical Centre. Of these, 12 partici- ministering the research intervention and were supervised by one of
pated in MRI and were eligible for these analyses (four declined due the authors of the instruction manual. Dow
tfsnlsdiftinoarhetfieoaettvepiibmvctgerrhfallenueeaupeseuntdywsm)rsci.yi.aotnteersLuiTntroofdeemehu,pnisrcenhiivaafnoacee,opmtgntmnbihiososetiaactaninwaosrol,eoninnaerwkcersaaoeeiigoonstg,nhitrrdvmeecihoesncmfieoiartotbnvfnheerleswesemrtaohrsaiworotbeuenhcnrseorgdrreerrhifleatemaaesxurhtdugrmeeeiaidibeancddnauj,tagelstrtentcheitt.votduep(aseTAinmtosawaculrclcowbtoaoatspulmtionesvaerouteftd4rfoli1orde8reii)dlnnlt.ls(iiitvdecfmrsffiBeaiecrtprocnrthfisaiuedmgoaciioldnirdenttuniesep2g.oisraon4pneAnsju–iagcunildst6orlorietio3viwipe,nccen)seigehsrpirynyreesaweecgvomtaaoeeinoonrogorrasnndee--r;l tsstmagtrheoetecorgilectManeaiosivtvedlefi,eniiasfntlrgddeuinsdeicitlftevnsfhtousihieiadvrnelasnlaeifvfnsloer.plfeygesrpTnodmstlihom-fiunebwaucftadtaoshihriin,sonereetegmnitdonndag.iairiotdpneItdainaiaiacotissltltrrttsnrtteergorialncatecridcrnitocopvatuittouiagaioebcnnpnnntdiilorttiin.testrriygeedliyvTen,gseehvifstunfioiiareosltanrnampenmiettnrrrsipeodvoiaanqhecftnnoggeuinaodcsosittrnvsuiiraeozneaislaidnosswnien,ndgihwiinnd-tai-orolgaenpeecwnsndllraewitlaneieisvgnfrasmctaydoctisnipeiosapnntlxelrhge,gpemmgasaortosgcnparhioaizaodhnselefte-aaidwrsonspgeaifgrezoblpieinemmrepnsvkdgtloateaiirnehannanridnngye--tt at Health Sbrain.oxfordjournals.orgnloaded from
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niversity of W
Table 1 Participant characteristics isconsin-M
ID Age/gender Brain injury history Lesion description adison on S
4 31M TBI from fall (1.5 years) LewfthfitreonmtaalttheareTmohrryhpaegreinatenndsitmieuslti-focal eptem
56 4374FF TTBBII ffrroomm fmalolt(o1r.5veyheicalres)accident (1.5 years) NLeoTftvfihsryoibpnleetarillneasteinondnssiit2niefesrior parietal white matter ber 22, 2011
2
7 45M Leucoencephalopathyfromchemotherapy(1year) Ventriculomegaly, widened sulci, small foci of
sub-frontal white matter T hyperintensity,
2
right frontal track c/w prior catheter placement
8 62M TBI from assault, s/p bi-frontal subdural Generalized moderately widened sulci, split septum
haematoma evacuation (6 months) pellucidum
9 60F TBI from motor vehicle accident (2.5 years) No visible lesions
10 63F Right temporal-parietal tumour resection Bilateral confluent white matter T hyperintensities.
2
(1.5 years) Left frontal and right temporal–parietal lesions
11 51F TBI from motor vehicle accident (1.5 years) Right frontal encephalomalacia, enlarged ventricles
and widened sulci.
12 55F TBI from fall (1 year) Left orbitofrontal encephalomalacia and
T hyperintensity
2
13 24M TBI from fall + multiple blast exposures (4 years) No visible lesions
14 41M TBI from fall + multiple blast exposures (6 years) No visible lesions
15 62F Left basal ganglia stroke (2 years) Frontal–subcortical, periventricular occipital white
matter T hyperintensities, widened sulci
2
SubjectnumbersarematchedtothelargergroupinNovakovic-Agopianetal.(2010),andyearssinceinjuryarelistedinparentheses.Additionalinformationregardinginjury
historyandbaselinefunctioningarepresentedinSupplementaryTable1.
F=female;M=male;TBI=traumaticbraininjury;c/w=consistentwith;s/p=statuspost.
4 | Brain 2011: Page 4 of 14 A. J.-W. Chen et al.
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Figure 1 RepresentativestructuralMRIimagesfromparticipantswithvisiblestructuralbrainlesions. ciences Libraries, U
niversity of W
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ctssiithonoangpllleeianncgptidhinvargiatilysyseitwluimfhaeeteitnosaint-usdcoaisitgntironaenictasitv,ceehdpaisnatrrndtaidicvti/epidogaurynatols(’vs‘SewTdrweOarihlePye-RltlmirfEaeeLi.ndAe,TXdo-rReialnEasFxsOiasptaCpnaUldypSipn’t)lghiceatona- Sidnitrteeurcvtedednyticoonndtrteohlastfiugwncantsiondaiennsgig.dnedanwiathloyutsfeeastures for training goal- eptember 22, 2011
refocus attention on the current, primary goal.
The second phase of the goals training protocol emphasized learn-
Study design
ing strategies for accomplishing individually-salient, self-generated
Eligibleparticipantswererandomizedtoreceiveeitherthegoalstrain-
complex goals. In orderto emphasize active application of these stra-
ing intervention or education during the first 5-week study period.
tegies, participants were asked to identify feasible and realistic func-
The participants then switched over to the alternative condition for
tionalgoalsasindividualprojects(e.g.planningameal,learningtouse
the second 5-week study period. Of the 12 participants, five started
anorganizerandfollowaschedule)andgroupprojects(e.g.planning
withgoalstraining andsevenstartedwitheducation.Behaviouraland
a group outing or presentation), and were then trained to apply at-
functionalMRImeasurementswereperformedatthreetimepoints:(i)
tention regulation and stepwise goal management strategies on the
Assessment1priortoanyparticipationininterventions;(ii)Assessment
functional task(s) of theirchoice. The stepwise goal management and
2attheendofthefirststudyperiod(5weeks);and(iii)Assessment3
execution strategies we chose to use were modified from Goal
at the end of the second study period (10 weeks). Some of the 12
Management Training (Robertson, 1996; Levine et al., 2000, 2007)
participants had fewer than three measurements for some tests and
and Problem Solving Therapy protocols (D’Zurilla and Goldfried,
could not be included in all analyses.
1971). Additional details are provided in the online Supplementary
Methods section, with training sessions outlined in Supplementary
Primary study analyses
Table 2.
In the alternate 5-week period, a comparison educational activity The primary analysis quantified changes that occurred from pre- to
was utilized. This involved didactic educational instruction regarding post-goals training, testing hypotheses regarding the effects of goals
Training enhances control over neural processing Brain 2011: Page 5 of 14 | 5
trainingforeachofthemeasuredvariables.Wetestedthehypothesis prior to goals training. This follows a conventional rehabilitation
thattrainingresultsinbehaviouralimprovementsrelatedtoattentional studydesignforsmallsubjectsamples,maximizingthepowerofcom-
self-regulation, evident in improved performance on non-trained parison to a control condition on a within-subjects basis while taking
neuropsychological tests of attention and executive control, also test- into account possible effects of repeated testing. Second, an across
ingforpotentialtransfertolearningandmemorytaskspredictedtobe subjects comparison of changes in each variable was performed in
influenced by these functions and more general changes such as in the first period only, comparing pre- to post-education versus goals
motor speed. With functional MRI measurements, we tested the training as per a traditional randomized design. We utilized this ana-
hypotheses that goals training would enhance modulation of neural lysisonlytocorroboratethefindingsfromtheprimaryanalyses,aswe
processing in extrastriate cortex and alter processing in prefrontal expectedhighinterindividualvariabilityrelativetointergroupvariability
cortex. so that power may not be sufficient to rule out effects even if none
We compared changes that occurred pre- to post-goals training were detected.
with those that occurred pre- to post-education. Changes were as- Baseline characteristics (age, education, attention and executive
sessed in a linear mixed model, with the primary factor of interest function test scores) as well as group means and variability in base-
being intervention condition (goals training versus education). Some line measurements for each of the behavioural and neural variables
participantsreceivedgoalstrainingfirst,andsomeaftereducation,so wereassessed.TheseareprovidedintheonlineSupplementaryResults
study periods were combined to test the effect of training. We per- section, and only data pertinent to the question of changes with
formed this analysis under the assumption that the education inter- intervention are presented here.
vention would not lead to significant behavioural or neural changes,
D
SShtwep(wabKecvraheflnayaaiealhomfsycarFpnstieciuieeonnocaotcbcolrlmhnigbrodttieennshnwdeimrdeelgeiegasbdtdewapmsyrercriaaseeyaaeeewhtosstirrtamlna.edaeyiatttvncdtdceeoFhhlpiaoao.lvsides,rrrtlnveicytseinuonia2fioatuns-la,b0aerritntedcnuoimolet0saatedcetstyrr1teo,ehweuvode‘w;rdumdeeclwsaevCiarnnbtreufnethtettyoui(ncilniioartionoonotntpeibipenlgnlcno-fesytesalt)estnehrtixusseeroffepoeeaotboxensdbanlmrtjcritsaseanmrsmootflicsten.iorrhheect(,ieexersAidaleSs2ppisenvtru.ta0aediantmheenpshta0ts’esipeeteot8oembee,almn)psreedn.sdosamgoeeumePdsinswaravsmerreseesoneenieltudbnsesc-ndotruritiaiaelnaecigstcrttGtomthouyyghoierofaoreareerenntrvltsdtlnmdhomahgteetmeabtceneoasteedthoesttfandeei.awrrtontamfrtnrgsn-fioaatatgoeRiisiovnlnecasp)adeect.silceknsseloiyoringpicrRwnonted,terpafdesehinavnf1asufegidrwitfrd9ncdotoethtot9ieuinacochneem8rattlidnege--ssr;l FIorTf(ipvwicimivmmmnaeSoafheehnreeumnaaarueallmedfyegggtsdtloptnlow,ceeehorcltmtiemssaeranoacp.fyttrtsirFeaetzetfkobTeanreotgcimucnwihcdccutanooetedheeotrorpseetynon,atshrgit,daunmreetheodttSnaiaoqwlteaeeareedilnurionscligerlet-keitntirhesflsnii,ceehvwasoMeftdv,oecbwlnop(ieaeltlpufrSydacharnamcatceRtrscottritecoovaemtijinnocinciaeItfnstcdiiaegatpo-ieiptsi‘npctcanmnpema)riaoironegttonoeninaiadntpnowotdstsidtesadnssrngca.inyrtthhvstri.siItmnooi’eniiiocacmaeTfsnemidniolwpiptnhnsal1wrtayaogeeeg-tdntiwnordsob‘eceivnt)ss(rshaesfse3eatoocreeerpsl,neiakewrdflnseeer-cvet,5tromceoi,mtaerctnitmriobenreiiacaeaonevlinutesltvtuvercscateioooedhnhvia7mkrrfnfe’tseeytdraatdetsiosdaremtesnuiomgkrdmndwiaaccnetiptatgantisiedoteohatrgethneedenrehsseiiosmtgcanne)uocnciotpiacnooogg-trrt(ncwprhydmneaFneeds.necisdisioclsgpezskeeeisareut.oTrlvdkfieteodudsbaaiiic2nnnleanloineustlf)gggdykl-s---tt.l at Health Sciences Libraries, University of Wbrain.oxfordjournals.orgownloaded from
using paired t-tests for the individuals who started with education are not reported in the current analyses. These conditions and isconsin-M
adison on S
eptem
ber 22, 2011
Figure 2 SelectiontaskperformedduringfunctionalMRIdataacquisition.Participantsviewedaseriesofimagescomposedoftwo
categories(facesandscenes).Intwoselectiveattentionconditions(selectfaces,selectscenes)participantswereinstructedtoselectively
attendandholdinmindimagesfromonecategory.Theonlydifferenceacrossconditionswasthetaskinstructions,makingparticular
imagecategoriesrelevantornon-relevant,whiletheperceptualcontentdidnotdifferacrossconditions.Solidanddashedlinesareused
onlyforpurposesofillustratingtaskrelevance,whileonlythegreyscaleimageswereusedintheactualtask.
6 | Brain 2011: Page 6 of 14 A. J.-W. Chen et al.
additional details of task design are described in the Supplementary the more certain the pattern classifier should be in recognizing that
Methods section. Session data were excluded from further analyses if information in each activity pattern.
behavioural performance accuracy did not exceed 70%. Data for one Multi-voxel signal intensity patterns from task trials were presented
session for one subject were excluded on this basis. toamulti-layerperceptronpatternclassifierforclassificationbasedon
In each block, 20 images (10 faces and 10 scenes) were presented the category of the viewed image (faces or scenes). These analyses
sequentially.Jitteringandimagecategoryorderswerebalancedacross were performed using the Multi-Voxel Pattern Analysis toolbox v1.0
condition blocks and counterbalanced across participants. Five blocks with Netlab v3.2 backend, both implemented in MATLAB (The
of each experimental condition were presented during the session, MathWorks,Inc).Procedureswereperformedforeachindividualpar-
resulting in a sample of 100 stimulus events per condition (total ticipant, separately for extrastriate and for prefrontal cortex. Training
sample of 400 stimulus events). Condition orders within runs were oftheclassifierwascompletedonpatternsfromfour ofthefivecon-
balanced over the course of the scanning session. Four alternate sets ditionblocks(20stimuliforeachblock)withtestingcarriedoutonthe
of stimuli were generated for use in multiple sessions, and set order fifthblock,ina‘leave-one-out’iterativemanner(Hansonetal.,2004).
was permuted across subjects. One hidden layer of 10 nodes with logistic activation functions was
included, and scaled conjugate gradient descent was used in error
Functional MRI data acquisition and back-propagation during training of the classifier.
During testing, sample multi-voxel patterns corresponding to the
preprocessing
viewing of an image are provided to the pattern classifier (e.g.
eitherscenesorfaces;Fig.3).Theoutputderivedfromthemulti-layer
Imaging was performed using a 3-T Siemens Magnetom Trio whole- D
perceptron is a classification assignment based on the output node ow
p1bqCmamthn8loueaaaeddanngtsdyrtalbnirirxcreeeaame,.gttsiiu6aiz;mnFrga4Ternaotn(cid:3)e(cid:5)iigr-openbwetengi6isetrc-eid4aptoiigrwcorfeaehhcnesxpaetoreigaataetndircealmaehsfiandekhecflcre=qlueudabruni1addlsioop0rc-etcfi0aaocddk0ntov-,tnaiiaemel(ecln1swlsqroalu;1iu)tcwaw4.eeitscteiTithfhtdwhhtoieoohrrheniactUoeieiknmtlqCenvrgvuae-eSerobniasFrl=lisrussdbai,mmo2iNreian7ni5neett-mitsumorTrersnwo(cid:3)2mee;c.-seccewfl;cohAriivieepvoe0eneiTd.gacr511ih(ynes-M2mtcgwe-alImPced(merFhRdi=gLaaeAeshAgnd6kcGtinI2nhieRpEae(cid:4)god))t;;l actTbcavhaeccihyeettrtewietitvvaihgncaaiinenolpttagiitruoocryyietnntsyrcsspwlta.eaaoabn(FitfnFseteoeitilgrnsycrim.nafeoo(l’xca3sffraaumg)rmtc.leehaaesspteTts,eeilhoemdctae,nhlabnaeasrldtssasewcinpfiieltsoclrchruceetaeesasottnteiirounodenattnistttfpy)eahf,udedtesitreocweicponnnniiasrtcoeFitihonetdigeniesbtr.bshnfre3coaesat,ciriwnlrloweceeruapaahrerleaccaennshtttnepitevedttodtahrehnntdesaiedstousnorppwit0sunaaoa.rtgt9stptrie0ettcuihrrflnitanpe(edsi.anncecnTttioexnwithnndegiigodeess. at Hbrain.oxfordjournals.orgnloaded from
sequence 2were acquired for each subject for characterization of n(laordgeeroudtipffuetr)e–n0c.1e0b(efatwceeennodveaoluuetspuotf)=sc0e.n8e0.aTnhdisfhaicgehcoeurttpauinttynovdaleuse) ealth S
sNimtreIuaumgcrteoaugimreadalagpatirnaneagptrowomSceoeyrsfe.tswinasglriecwe-at(siAmFceNoIn:dcouvrc2rtee0cd0te8ud-0si7na-g1n8dA-1n7are1lya0sli)igs.noeEfdchFouunscipntligaonnaaarl wsttoaeoilneusctelytdlievocebftleiyvthepaelytrtecedlaanitscdtsteietnfidodcastttcoiooennbfeeacsco.efnoHsduowintwidoheinlvweeishrv,epienwrwehdaienicngpteaaadrtpitcsaocipretbaniceneitploaiimwsntaeingrisse(t,iFrnuitgscht.treeu3dc)c.teetIrnod- ciences Libraries, U
antincinidpea-2pn(cid:4)atsrareomxtaectteieeordnae.fdfiAnodeudrirteiaognipsatrlriaodtriieotnmaiotlsoveocmofrerpnerctetplifrmooricteshsesoaifndg2m-pmormoticoentdr.auNnresolsaptaiaorrne- tnhoisdeexsacmorpelei,st0h.e40screenseulotiuntgpuintnaoldoewsecrocreeritsa0in.t6y0sacnodrethoef f0a.c2e0.ouTthpuust, niversity of W
dRAenesagctroiiobmenidcaoilnfmtihnaetsekSsruepwsptleermdeeefidnetnafirinyteioMdneftohroddsosrseocltaiotenr.al prefrontal cortex tatbahatsrtteaseieoinndsnstifmirofoeenegfrneicotgnonoctn.ieamdlT-iientrhieoeptlenhovsedianirfnctef,atefllarceveulclenoltartswsitauetilnsdhgeccneecodrratnitafla-cfireniunertllteayeyntvicossaeccnnootirroneefinstcfwhboheearamtsncwglaoaeterbiesiottnynainitnohwemfeditorohedapipnutprleoaeestsaaeoinccnrhhgy- isconsin-Madison on S
(bilateral middle frontal gyrus) and extrastriate cortex (fusiform, para- control over neural processing from pre- to post-intervention. eptem
hvoeicpcnpitporiictcaalelmsspusaluclipaepnrodiostrleilnyrg,iourtaleylm)gp(ySoruir,pobp-ooleucmcnidpenitbtayalrtyfihseMsuienrtefhesoridoasnrteseedrcigoteirolyonf).atnhdelaintterraa-l Neuropsychological tasks ber 22, 2011
An‘AttentionandExecutiveFunctionDomain’scorecomprisedscores
Functional MRI data analysis
from letter number sequencing, Wechsler Adult Intelligence Scale
(third edition) (Wechsler, 1997), auditory consonant trigrams at 9,
Analyses of information contained in patterns of
18, 36s (Stuss et al., 1988); Digit Vigilance Test—time and errors
brain activity (Heaton et al., 2004); Design and Verbal Fluency Switching (Delis
The cognitive task performed during functional MRI presents multiple et al., 2001); Trails B (Heaton et al., 2004); Stroop Inhibition/
stimuli that compete for neural processing, while only goal-relevant Switching—time and errors, and Stroop Inhibition—time and errors
stimuli must be selected for further processing. For example, if (Delis et al., 2001). A ‘memory domain’ score comprised scores
scenes are relevant, then attention likely sharpens the clarity of from verbal and visual learning and delayed recall from the Hopkins
neural representations of scenes relative to other perceived stimuli. VerbalLearningTest(BrandtandBenedict,2001)andtheBriefVisual
Incontrast,ifscenesarenotrelevant,thenscenesmayberepresented Memory Test Revised (Benedict, 1997). A ‘psycho-motor speed
with less clarity. To measure these types of effects with functional domain’ score comprised scores from the Trails A test (Heaton
MRI, we utilized a multi-layer perceptron pattern classifier (O’Toole et al., 2004) and the Visual Attention Task overall reaction time
etal.,2007forageneralreview)asan‘externalreader’todetermine (Novakovic-Agopian et al., 1999). All neuropsychological test data
theclarityofinformationrepresentationintheneuralcodesembedded were scored based on age and, when available, educational and
infunctionalMRIactivitypatterns.Wereasonedthatthemoreclearly repeated administration norms, and transformed into z-scores for
stimulus information is represented in these measured neural codes, consistency. Additional neuro-behavioural and functional performance
Training enhances control over neural processing Brain 2011: Page 7 of 14 | 7
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nloaded from
Fexigaumrpele3,iSncphuetmstaoticthoefttrhaeindeedtemrmulitni-altaiyoenropfetrhceepctlarorintyaorefisnafmorpmleadtiopnatrteeprnressefrnotmatisocneninebsrtaiminualuctsivtritiaylspa(ltetfetr)nfsrodmurineigthtehrettheestSbelloecckt.SIcnetnheiss at Health Sbrain.oxfordjournals.org
crfineoosprntrsrdeuaistmceitonepndtlein(stagobfraosoevfmaleec)caeotporsarcSreeatnilcesecucsetlanvFreeatrcassetsuiskmsccusooelnunledsdc.iitttTiioofhannec.(embTseah(lgeoi.newei.tf)uft.ehdTceehtedooiffofftsuehetrelpeeudncttitfiivnfaeelorfdeaoentrtceawencthbtiiveeoantnwtiisosecneeinsnnd(eterhsixgeaehsrdete)borryueefllttephevuceattndnttihofvfedeeecrrelssanuisncssdeifineieonxrne’cs-serrterehtleaceovincagtennyrtittw)ai.oihnTnethynoisfoartfnehcleilenavpdsasaivintfiittdceautrontaiolainss ciences Libraries, U
non-relevantdifferentialisusedastheprimarymeasureforeachbrainregionateachoftheassessmenttimepoints. niversity of W
mARgeoaepsuisarneusetalratel.s,d2e0sc1r0ib),edanidnadreetnaioltindetaailseedpahreartee. report (Novakovic- lectyhhdsaaIuennndcagcotoehrisnodanenfarrgoaewtmnosditpphccrroireenor---rsoststuobeobdoppjreooaoctsvstettse--regtbhdtoaoeuascilgssmaottfaairooailrnsninptfi(rianPanrigt5ndiciiwnni0pgge.asr0(en,n0tcs0s=ih1gwa7)nn.h)ifig.WoceInasesnttawpthlreyietsrerfgedgorrreaowmanutieatephd-r, isconsin-Madison on Septem
Changes in performance on tarnainaidndgitaionndaledaucrcoastsio-snubinjectthsecfiormstpastruisdoynpoefriocdha(nagseisnfaorragnodaol-s ber 22, 2011
mizedstudy),andfoundthatgoalstrainingalsoresultedingreater
neuropsychological tests
improvements than education (P50.0001) in this analysis.
Attention and executive function domain
Learning and memory domain
We first tested the hypothesis that participation in goals training
would improve behavioural performance on tests of attention Inordertotestfortransferoftrainingeffectstofunctionsthatare
and executive control. All 12 participants showed an increase in influenced by attention regulation, we measured performance on
performance scores in the domain of Attention and Executive testsengagingthedomainoflearningandmemory.Elevenoutof
Functionsfrompre-topost-goalstraining,while7/12participants 12 participants showed an increase in performance scores from
showed an increase from pre- to post-education (Fig. 4). To test pre- to post-goals training, while four out of 12 participants
whether this represented a significant difference, we used mixed- showed an increase from pre- to post-education (Supplementary
model regression analysis. Performance scores increased an aver- Fig.1).Performancescoresincreasedanaverageof0.70standard
ageof0.78z-scorestandardunitsmoreafterparticipationingoals units more after participation in goals training than after partici-
training than after participation in education (P50.0001). When pation in education (P=0.02). Neither initial score nor order of
entered as covariates in the regression analysis, neither the initial interventionparticipationaccountedforthesedifferencesbetween
performance score nor the order of intervention participation intervention conditions. Corroborative within-subjects analyses of
accounted for this difference between intervention conditions. the participants who started with education and crossed over to
8 | Brain 2011: Page 8 of 14 A. J.-W. Chen et al.
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nloaded from
Figure4 Changesinattentionandexecutivefunctioncompositescoresfor(A)goalstrainingand(B)education.Barsrepresentchangein at Hbrain.oxfordjournals.org
z-scores(i.e.post-interventionminuspre-interventionz-score).Theindividualdataaresortedbasedonmagnitudeofchange,inorderto ealth S
ipilnlautresttrircvaieptneatnidotenisdcceroinpnttdiifivitceiaolytniotsh.nennuummbbeerrsoafreinmdivaitdcuhaeldswtoitehacchhasnugbejsecint’sthsecoproessitpivree-oranndegpaotisvte-eddiureccattiioonnwtoithfatchileitagtoealdsirteracitncinogmipnaterirsvoenntaiocrno,sasnd ciences Libraries, U
goals training revealed significantly greater changes from pre- Changes in performance on cognitive niversity of W
tAonpaodsdt-itgiooanlasl taracrinoisns-gsutbhjaenctsprceo-mtpoarpisoosnt-eodfuccahtaionnge(sPf=or0.0go0a9l)s. task during functional MRI scanning isconsin-M
g(MIwtnrPoaeao=ionlmrts0idone.etr0garr0asstui9aponr)neie.dntdeegsdpetredeofruosffcuoralprgtmterieodoannnceiecrnaeisnlsgocirnthnehaagetnteegsdrfiteosrsismmotinfpasmrpitonusovydtecyomhroepsmnpetreosieotoddtrhoapsfnheporferwoodrecumdecsaasnttinhicogaent., Tfcrtdoeoehidprremcnoonrecmtodfoetop,dgrolnsebboittceesihveitnheatrhvgnaeettgaaetnasbsaknelseuykiwrntasdoailgusbcnrleaihidnfiasaegircncsnaigfgnuettntnhasescecdckthioboautannpolsgadeilcerbfbsMoeteariRnmseekIaaxtssanaricslumcyakelnei.nlansee,fianAtdearglnrnlw.edeOdpititahwvharoeeetnuirrrcadetilpilnc,apatownbeentrlrees--- adison on September 22, 2011
vention. Seven out of 11 participants showed an increase in task
Seven out of 12 participants showed an increase in performance
accuracy from pre- to post-goals training, while four out of five
scores in the domain of Motor Speed of Processing from pre- to
participants showed some increase in performance scores from
post-goalstraining,whiletwooutof12participantsshowedsome
pre- to post-education. We found no difference in task accuracy
increase in performance scores from pre- to post-education
for participation in goals training compared to education
(Supplementary Fig. 2). There was a non-significant trend where
(P=0.65). Corroborative within-subjects analyses of the partici-
theperformancescoresforparticipationingoalstrainingincreased
pantswhostartedwitheducationandcrossedovertogoalstrain-
more than for education (P=0.07). Corroborative within-subjects
ing did not show significant effects (P=0.41), nor did the
analyses of the participants who started with education and
across-subjects first period analysis comparing goals training to
crossed over to goals training did not show significant effects
education (P=0.40).
(P=0.28), and the across-subjects first period analysis comparing
goals training to education also did not show significant effects
(P=0.09). Neural representations in extrastriate
Data for the learning and memory as well as motor speed of cortex
processing domains is presented in Supplemental Results. Results
fortheindividualneuropsychologicalteststhatformthecomposite Wepredictedthatgoalstrainingwouldenhancetop-downmodu-
domain scores are presented in Supplementary Table 3. lation of neural processing, measured with functional MRI, which
Training enhances control over neural processing Brain 2011: Page 9 of 14 | 9
would manifest as increased clarity of representation of goal- scores, while only one out of five participants with pre- to post-
relevant relative to non-relevant information within visual cortex. education data showed a positive change in this differential
For each assessment, we calculated a functional MRI index of (Fig. 5A) Using a mixed-model regression analysis, we found
goal-directedmodulatorycontrolinextrastriatecortexbysubtract- thatgoalstrainingresultedinsignificantlygreateraveragepositive
ingtherecognition certaintyscoresgeneratedbythepattern clas- change in the differential scores of 0.11 compared to education
sifier when a stimulus category was relevant versus non-relevant (P=0.04). When entered as covariates in the regression analysis,
(e.g. faces would be relevant in the Select Faces condition, while neither the initial performance score nor the order of intervention
scenes wouldbenon-relevant, andvice versain the SelectScenes participation accounted for this difference between intervention
condition).Bydefinition,apositivedifferentialwouldindicaterela- conditions.
tivelygreaterclarityofrepresentationofgoal-relevantinformation, Oftheparticipantswhostartedwitheducation,sixoutofseven
while a negative differential would indicate relatively greater clar- participants showed a positive change in differential certainty
ity of representation of non-relevant information. Baseline meas- scores from pre- to post-goals training (P=0.02). Comparing
urements, prior to any intervention participation, indicated a across subjects in the first study period, we observed that three
significant bias towards positive scores, i.e. greater clarity of out of four participants showed a positive change in score for
goal-relevant information (presented in more detail in the online goals training, while zero out of three showed a positive change
Supplementary Results section). To determine the effects of inter- for education. Initial assessment data were not available for some
vention, change scores were then calculated by subtracting pre- subjects due to scanner technical issues, leaving a sample size too D
ow
wianntodeurlvdfeonrintiedodincuacstcaeotiraoensc.hfrTaonhmguesp,oinbsty-mindoteedfiruvnleiatntioitoinon,ntashcapotoresrsietsifvuoelrtsgchoinaanlsigntecrraesiancsoienrdeg sNmealluforraalcrroesspsurbejescet’snsttaatitsitiocanl csomipnaridsoon.rsolateral nloaded from
cncnlhooaOannrin--tvrrygeeeerlloeeavvflilnaa,rnnenmttp,inironeewdfsouehorlniamluetttaiaottaionioofnnnt1ehorg1aefatlatpgitrvaioeverasetuli-ccltrtihoepsalaernnivengtalesenvatwansnciintotih.nfroecrrpmerwaeaso-teiuotlndoinrpinecoldlaasittrci-iavtgyteoeaotloasf pAntivosrenel-ywrfegirlterhoevaantneetxtrtadrcaillfasftrercitriayeotneortiftaclereoinxprtdreeexsxe,nstcbaoytrioesnd,efpfioonrsitiiitnoivfnoermvoaafltuioetnshertehflareetcleitsvragenolata–-l at Hbrain.oxfordjournals.org
training data showed a positive change in differential certainty relevant and negative values reflect relatively greater clarity ealth S
ciences Libraries, U
niversity of W
isconsin-M
adison on S
eptem
ber 22, 2011
Figure5 Changesinindexscores(relevant–non-relevantdifferentialcertaintyscores)in(A)extrastriatecortexand(B)prefrontalcortex
forgoalstrainingandeducation.Changescoreswerecalculatedbysubtractingpre-interventionscoresfrompost-interventionscoresfor
goalstrainingandforeducation.Dataarepresentedsortedbasedonthemagnitudeofthechangeandindividualsubjectsarematched
acrossgoalstrainingandeducation.
10 | Brain 2011: Page 10 of 14 A. J.-W. Chen et al.
of representation for information that is non-relevant. Change investigated because it is involved in the recognition of object
scores were calculated to determine the directionality of any categoriesutilizedinourtask(e.g.facesversusscenes),anditsac-
changes with intervention participation for goals training or tivityisknowntobemodulatedbyattentionaldemandsinhealthy
education. individuals (O’Craven etal.,1999;Gazzaley etal.,2005a, b).We
Changes in the positive direction were observed for five out of specificallymeasuredthetuningofneuralcodesbasedonthegoal
11 participants with goals training, reflecting an increase in the relevance of the visual events, indexed as the relative balance of
representation of goal-relevant relative to non-relevant informa- representation of relevant versus non-relevant information within
tion, and changes in a negative direction were observed in six brain regions. Participants attempted to selectively maintain goal-
participants (Fig. 5B). Changes in a positive direction were relevantfacesorscenes,whilenon-relevant,distractingimagesare
observed for three out of five participants with education, and perceived. Thus, representations of relevant and non-relevant
changes in a negative direction were observed for two partici- images competed for processing within extrastriate cortex.
pants. Using a mixed-model regression analysis, we found that There area number of ways in which attention could modulate
goals training did not result in an increase in differential scores neural processing in extrastriate cortex. For example, during per-
relative to education, consistent with both positive and negative formanceofacognitivetask,neuralrepresentationsofallcompet-
changes being found following goals training. ing information might be strengthened, or in contrast, only
In a mixed-model regression analysis, we found that pre- selected representations might be strengthened. We hypothesized
intervention functional MRI differential score was associated with that attention training would lead to changes in tuning of neural D
ow
cdschitoaiornengseahnsacddorpaersed.-iAifnfetseriergvnnetifinectifaofnentctsincaotefrtreeasrctignioodnaiclsbaettetrwdaientehinnagtintpthreaern-vienentdetiruovcneantcitooionnn-. rfceaopvnorseuissrteengntotaatwli-orinethslevstahunicsthpintrfheodartimcttaiohtineo—nb.naOelauunrrcaelfintoudfnininrgegspwrweisittehhninttraateiinoxintnragwstwroiaeutrldee nloaded from
pwStphproeeeesr-tcee-igfipdoncrueaaoc-llatlisynt,ititonertnavrhvieenesrrisnceneotgliryowen(saPrsea=slanact0doe.srd0eicg3shn)(a,iFfinaiwgcnga.dehnse6tr)tef.ihrnaoesvWmetrechshpeearsenerr-eepgllaeaatrstotaiiootenpnfrlsosyohhsmitipp-teesdbbptueeerttcedwwa-teeitoeehtonnne ctvtcihoaioditrnsuitoeatrnxrlesalwsianwetaisinvhssgeiooshntopoi.cfatcArneutldoitrchrnitepo-odrauetignlebehdcevrfaoeoinnuartesr.egsooWatrahmeleaspfocltteelbraarssrieiinptzryieavnreogwtdif,caigtrpsheoasgeatmsailoe-rarndelclll,ehienstavshnaaengostebfesriwnifieifnnhfodereimtnidnhdugaei---sr at Hbrain.oxfordjournals.org
pi(cpnPoroter5esrdtre-viclg0aeto.ten0iadot0linos0gn1rto,ersafacriton=eprirern(cid:6)esgc-h0pga.oar9nena0dgld)sie,cstfsteoruidnaucinhngadirnetphgaaoatsetsirstcliiovgocewnhreiaefisdnrcigrawepencrsitetthi-ioniinnnctvaehaerannrvsnedeeggnheatcsitiogoivnhrepreersredlca-iporteirroetecno-s- wwtaphrreieeotrhacescienlsao-ssrsfitinutatygbhtijesecotocifbctusrarlaldelaiypnnlredewassdihegaencntnortiofiambtscisaeo-untnslttutseibproajlpeefncrdiotitnsecfemocwsorssemminoreagpftaiiaonrctinfosohorrriinmngoshb.aeeotTarirorhallneitueevsrcde,olpsimm,rbopaypcneretodsebvstoiifhnntoigghsr ealth Sciences Libraries, U
nRtwSeiudooeitpuntshupcballt(eetsscmicoehsaxenaetpnnctetltggaiaroreironnsypue,ldpoFSi.nitugssoBp.lapfpe3osllr)eyere.mdfbTrpeoyhornneinrstt-eaaingcfrloyotreelrlcFrrsoeovsiwgileroat.n-tenuit4xoipot)no.naswtcnhpoaaerrsleeymfssnreoeosanta,ntrstaeih(lgSinsucpiofipreercpftsfaleeeenxcnmttteesincncdoottaurherlidnyes mptomamtiomorfaooonypnaddvtleeuuietsbumlle,aaerwntteaaiethonliosoentrnrsnteneehapaoceelfrefurntentersearottreehurnngpairnasatteraleteltsetussefiinmeorlreoatniniencnpotsctagdhnihtvoyiaetordsfraninaeottigsuicselnoomrsnieoagnianbflig-csugyr.ainnenlAioldgbsennesovmt-rfitaiulrhnyreneditidntlneyeiigngravienctafsrrefonteetodhuitalnraenmsbgtmidenyabfdagtoeuittolhheptlfionoara-riw,vmtainidlo-o.ogaiurusdtFptrtrurdoaeeaqlorlnalcauwtttiteiieomooenxsrdnn---s- niversity of Wisconsin-Madison on Septem
DThisisstucduy sinvsesitoiganted the neural mechanisms underlying im- (oCfetrhfeetdaislt.r,ib2u0t1e0d),.oSvuecrhlapapminegchraenpirsemsenctoautlidonlseaodftogosahl-arrepleevnainngt ber 22, 2011
information in the brain.
provements in cognitive abilities following a training interven-
tion targeted at improving goal-directed attention regulation.
Cognitiveassessmentsconfirmedimprovementsinperformanceon Modulation of prefrontal cortex with
non-trained tasks assaying attention and executive control, with
attentional self-regulation training
evidence of transfer to learning and memory. Utilizing functional
MRI methods for measuring the representations of cognitive task The lateral prefrontal cortex has been strongly implicated as a
information in neural codes, we found that modulation of neural sourceofattentionalcontrolsignalsthatcouldbiasneuralprocess-
processing in extrastriate cortex was significantly enhanced by ing in extrastriate cortex (Desimone, 1998; Miller and Cohen,
attention regulation training whereas training effects within pre- 2001; Miller and D’Esposito, 2005; Miller et al., 2011). For pre-
frontal cortex depended on an individual’s baseline state. frontal cortex to guide neural processing in extrastriate cortex
based on goals, representations of relevant and/or non-relevant
Modulation of extrastriate cortex with informationmustbecodedinprefrontalcortexaswell,thoughthe
attentional self-regulation training specific nature of these representations should differ from the
stimulus-driven representations coded in extrastriate cortex
Our primary functional MRI biomarker indexed goal-directed (Fuster et al., 1985; Rees et al., 1997). Overall, the pattern of
modulatory control overneural processing. Extrastriate cortexwas findings within lateral prefrontal cortex were consistent with the