Neural Circuits for Cognitive Appetite Control in Healthy and Obese Individuals

16 Pages·2015·4.82 MB·English

RESEARCHARTICLE
Neural Circuits for Cognitive Appetite Control
in Healthy and Obese Individuals: An fMRI
Study
JetroJ.Tuulari1*,HenryK.Karlsson1,JussiHirvonen1,2,PaulinaSalminen3,
PirjoNuutila1,4,LauriNummenmaa1,5,6
1 TurkuPETCentre,UniversityofTurku,Turku,Finland,2 DepartmentofRadiology,TurkuUniversity
Hospital,Turku,Finland,3 DepartmentofSurgery,TurkuUniversityHospital,Turku,Finland,4 Department
ofEndocrinology,TurkuUniversityHospital,Turku,Finland,5 DepartmentofBiomedicalEngineeringand
ComputationalScience,SchoolofScience,AaltoUniversity,Aalto,Finland,6 BrainResearchUnit,O.V.
LounasmaaLaboratory,SchoolofScience,AaltoUniversity,Aalto,Finland
* [email protected]
Abstract
OPENACCESS
Themeresightoffoodsmayactivatethebrain’srewardcircuitry,andhumansoftenexperi-
Citation:TuulariJJ,KarlssonHK,HirvonenJ,
SalminenP,NuutilaP,NummenmaaL(2015)Neural encedifficultiesininhibitingurgestoeatuponencounteringvisualfoodsignals.Imbalance
CircuitsforCognitiveAppetiteControlinHealthyand betweentherewardcircuitandthosesupportinginhibitorycontrolmayunderlieobesity,yet
ObeseIndividuals:AnfMRIStudy.PLoSONE10(2):
braincircuitssupportingvolitionalcontrolofappetiteandtheirpossibledysfunctionthatcan
e0116640.doi:10.1371/journal.pone.0116640
leadtoobesityremainpoorlyspecified.Herewedelineatedthebrainbasisofvolitionalap-
AcademicEditor:XiaWu,BeijingNormalUniversity,
petitecontrolinhealthyandobeseindividualswithfunctionalmagneticresonanceimaging
Beijing100875,CHINA
(fMRI).Twenty-sevenmorbidlyobesewomen(meanBMI=41.4)andfourteenage-
Received:June9,2014
matchednormal-weightwomen(meanBMI=22.6)werescannedwith1.5TeslafMRIwhile
Accepted:December11,2014 viewingfoodpictures.Theywereinstructedtoinhibittheirurgetoeatthefoods,viewthesti-
Published:February6,2015 mulipassivelyorimagineeatingthefoods.Acrossallsubjects,afrontalcorticalcontrolcir-
cuitwasactivatedduringappetiteinhibitionversuspassiveviewingofthefoods.Inhibition
Copyright:©2015Tuularietal.Thisisanopen
accessarticledistributedunderthetermsofthe minusimaginedeating(appetitecontrol)activatedbilateralprecuneiandparietalcortices
CreativeCommonsAttributionLicense,whichpermits andfrontalregionsspanninganteriorcingulateandsuperiormedialfrontalcortices.During
unrestricteduse,distribution,andreproductioninany
appetitecontrol,obesesubjectshadlowerresponsesinthemedialfrontal,middlecingulate
medium,providedtheoriginalauthorandsourceare
anddorsalcaudatenuclei.Functionalconnectivityofthecontrolcircuitwasincreasedin
credited.
morbidlyobeseversuscontrolsubjectsduringappetitecontrol,whichmightreflectimpaired
DataAvailabilityStatement:Thepatientdatafrom
integrativeandexecutivefunctioninobesity.
theSleevePET2study(NCT01373892)arestoredon
PETCentreserverandanonymized1stlevelcontrast
dataareavailableintermswiththeinformed
consentsandprivacyregulationsuponrequestfrom
HumanEmotionSystemslaboratoryatTurkuPET
CentreandUniversityHospitalofTurku.Requests
[email protected]. Introduction
Funding:Thisstudywasfinanciallysupportedbythe
Inourmodernsocietyhumansaresurroundedbyfoodadvertisementandpalatablevisual
AcademyofFinland(grants#256147and#251125to
foodcuesarereadilyavailableandondisplayinsupermarketsandrestaurants.Despitecom-
LN),theSigridJuseliusFoundation,theUniversity
plexhomeostaticmechanismsthatgoverneatingandappetite[1],themerevisualcuesofpalat-
HospitalofTurkuandtheUniversityofTurku(grant
10463toJJT).Thefundershadnoroleinstudy ablefoodsmaytriggerastrongurgetoeatnotwithstandingcurrentnutritionalstate,thus
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BrainCircuitforAppetiteControl
design,datacollectionandanalysis,decisionto momentarilyoverridinghomeostaticcontrolandpreviousconsciousdecisionsregardingeat-
publish,orpreparationofthemanuscript. ingbehavior[2].Asvisualandolfactoryfoodcuesareomnipresentinoureverydayenviron-
CompetingInterests:Theauthorshavedeclared ment,theymayplayakeyroleindrivingincreasedfoodconsumptionbytriggeringappetitive
thatnocompetinginterestsexist. behavior.Thismayalsocontributetotheincreasingprevalenceofobesityintheindustrialized
world[3].Consequently,understandingthephysiologicalandpsychologicalmechanismsun-
derlyingvolitionalrestraintofenergyintakeiscriticalinfightingthe‘obesityepidemic’.
Thesightoffoodcuesengagesthebrain’srewardcircuitanditshowsgreateractivationen-
counteringpalatableversusblandfoods[2],especiallyinobeseindividuals[4,5].Ithasbeen
suggestedthat,inadditiontoahypersensitiverewardcircuit,animbalancebetweenthereward
circuitryandfrontalbrainsystemssupportinginhibitorycontrolmaybeafeatureofobesity
[2,4–6].Itiswidelyacceptedthat,thepre-supplementalmotorarea(preSMA)andanterior
cingulatecortexformthekeyregionsinthebrain’scognitiveinhibitionnetwork[7–9],typical-
lymeasuredbyGo/No-Gotask[10].However,theseregionsmayalsosupportmoregeneral
cognitiveprocessesinvolvedininhibitoryprocesses,suchasmemoryretrievalandworking
memory[11].Astheaforementionedfrontalregionsareanatomicallyconnectedtobasalgan-
gliaandthustothestriatalrewardcircuit[11]–knowntobehyperactiveinobeseindividuals
[2]–itispossiblethattheycouldservecognitiveappetitecontrolaswell.Inlinewiththis,
priorstudiesoncognitiveappetitecontrolwhileviewingfoodpictureshaveindeedimplicated
thefrontalbrainregions’involvementwhenthinkingoflong-termcostsandbenefitsofeating
thepresentedfoods[12]andfronto-striatalactivationsduringcognitivereappraisaltasks[13].
Theevidenceoftheinfluenceofobesityonthefunctioningofthefrontocorticalappetite
controlsystemsremainsmixed,nevertheless.SomestudieshavereportednoeffectsofBody
MassIndex(BMI)oncorticalinhibitorycircuits[12],whilesomehaveobservedsmaller[14]
andotherslarger[13]responsesinthiscircuitinobeseindividuals.Althoughpriorstudies
haverevealedthatobesityaltersfunctionalconnectivityoftherewardcircuit[2],ourunder-
standingofhowobesitycouldinfluencefunctionalconnectivityofthecognitivecontrolnet-
worksandtherewardcircuithasremainedelusive.Itisindeedpossiblethatthepreviously
reportedelevatedrewardcircuitresponsestopalatablefoodsinobeseindividuals[4–6]could
reflectalteredinhibitoryconnectionsfromthefrontalcognitivecontrolregions,ratherthan
meredifferencesinregionalhemodynamicresponses.
Here,weusedfunctionalmagneticresonanceimaging(fMRI)tostudybraincircuitssupport-
ingcognitiveappetitecontrolinnormal-weightandmorbidlyobeseindividuals.Participants
viewedpicturesoffoods,whiletheirtaskwastoeitherinhibittheirurgestoeat,imagineeating
thefoodsorwatchthefoodspassively.Wehypothesizedthatvolitionalcontrolofappetitewould
engagethefronto-corticalcircuits,andthatobeseindividualswouldhavelowerfrontalactiva-
tionsreflectingfailuretovolitionallyinhibittheirurgestoeat.Inlinewiththis,wealsopredicted
thatfunctionalconnectivityofthecontrolcircuitwouldbeloweredinobeseindividuals.
MaterialsandMethods
ThestudywasconductedinaccordancewiththeDeclarationofHelsinkiandapproved
bytheEthicalCommitteeoftheHospitalDistrictofSouth-WesternFinland(SleevePET2
NCT01373892,http://www.clinicaltrials.gov).Allparticipantssignedanethicalcommittee-
approved,informedconsentformpriortoscans.
2.1.Participants
Twenty-sevenneurologicallyintactmorbidlyobesesubjects(M =41.4,SD =3.9)were
BMI BMI
recruitedforthestudy(Table1).Fourteenneurologicallyintactandage-matchednormal-
weightvolunteersubjects(M =22.6,SD =2.7)wererecruitedasacontrolgroup
BMI BMI
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Table1.Thecharacteristicsofstudyparticipants.
MorbidlyObesen=27 Mean SD HealthyControlsn=14 Mean SD Independentsamplet-test
females females p-values
Age(years) 42.1 9.3 44.9 11.9 0.47
Height(cm) 165.2 6.3 165.5 6.4 0.89
Weight(kg) 113.5 14.4 61.8 6.9 <0.001
BMI(kg/m2) 41.4 3.9 22.6 2.7 <0.001
Subjectivehungerratingbeforethe 4.3 2.4 3.9 2.3 0.63
MRIscan(1–9)
doi:10.1371/journal.pone.0116640.t001
(Table1).Eatingdisorders,severementaldisordersandsubstanceabusewereexclusioncriteria
forallparticipants.InFinlandca.85%ofpatientsundergoingbariatricsurgeryarefemale.
Consequently,thestudywasconductedwithfemaleparticipantswhomatchedthecharacteris-
ticsofthenationaltargetpopulation.
2.2.ExperimentalDesignforfMRI
Participantswereinstructedtorefrainfromeatingandtodrinkonlywaterfor3–4hourspriorto
scanning.BeforetheMRIscans,participantsratedtheirfeelingsofhunger(usingascaleranging
from1=I’mnotfeelinghungryatallto9=I’mstarving)toassessthenutritionalstate[15].
StimulianddesignaresummarizedinFig.1.Thestimuliwere80digitizedfull-colorimages
offoods[2].DuringfMRIacquisition,foodstimuliwerepresentedatthecenterofthescreen
in16sblocksintermixedwith1.75srestperiodsbetweenblocks.Duringeachblock,
Fig1.Experimentaldesignandtrialstructure.
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participantssawfourfoodpicturesshownfor4seach.Acoloredrectanglearoundthepicture
denotedthetasktheparticipanthadtoperformthroughouteachblock.Duringinhibitioncon-
dition,theyhadtoinhibiturgestoeatthefood,duringpassiveviewingconditiontheyhadto
viewthefoodspassively,andduringimaginaryeatingconditiontheyhadtoimagineeatingthe
foods.Theblockswerepresentedinafixed,pseudo-randomizedorder,whichwascounterbal-
ancedacrossparticipants.Altogetherthereweretwentyblocksofeachcondition,andtotal
scanningtimewasapproximately19minutes.Participantsweregivenwrittenandspokenin-
structionsbeforeenteringthescanner,andtheypracticedthetaskinthescannerbeforetheex-
perimentbegan.Theparticipantswerealsointerviewedaftertheexperimenttoassurethatthey
hadfinishedthetaskasinstructed.
ThestimuluspresentationandbehavioraldatacollectionwerecontrolledwithPresentation
software(NeurobehavioralSystems,Inc.).StimuliwereprojectedfromanLCDprojectoronto
anon-magneticscreenmountedatthefootofthebore,andanangledmirrorreflectedimages
ontothescreenintotheparticipants’fieldofvision.
2.3.fMRIAcquisitionandAnalysis
MRimagingwasperformedwithPhilipsGyroscanIntera1.5TCVNovaDualscannerat
TurkuPETcentre.Whole-brainfunctionaldatawereacquiredwithT2(cid:1)weightedecho-planar
imaging(EPI)sequence,sensitivetotheblood-oxygen-level-dependent(BOLD)signalcon-
trast(TR=2987ms,TE=50ms,90°flipangle,192mmFOV,64×64reconstructionmatrix,
62.5kHzbandwidth,4.0mmslicethickness,withnogapsbetweenslices,30interleavedslices
acquiredinascendingorder).High-resolutionanatomicalimages(1mm3resolution)were
acquiredusingaT1-weightedsequence(TR25ms,TE4.6ms,flipangle30°,280mmFOV,
256x256reconstructionmatrix).
Altogether380functionalvolumeswereacquired.Furthermore,four‘dummy’volumes
wereacquiredanddiscardedatthebeginningtoallowforequilibrationeffects.Thedummy
volumeswerenotincludedintheanalysis.Datawerepre-processedandanalyzedusingSPM8
software(http://www.fil.ion.ucl.ac.uk/spm/)runningonMatlab2011b.TheEPIimageswere
realignedtothefirstscanimagebyrigidbodytransformationstocorrectforheadmovements.
Echoplanarandstructuralimageswereco-registeredandnormalizedtotheT1standardtem-
plateinMNIspace(MontrealNeurologicalInstitute–InternationalConsortiumforBrain
Mapping)usinglinearandnon-lineartransformations,andsmoothedwithaGaussiankernel
of8mmfullwidthathalfmaximum—FWHM8mm.
2.4.Analysisofregionaleffects
Awhole-brainrandomeffectsmodelwasused.Thistwo-stageprocess(firstandsecondlevel)
assesseseffectsonthebasisofinter-subjectvarianceandthusallowsinferencesaboutthepopu-
lationthattheparticipantsaredrawnfrom.Foreachparticipant,weusedagenerallinear
model(GLM)toassessregionaleffectsoftaskparametersonbrainactivation.Thefirstlevel
modelincludedallthreeexperimentalconditions(inhibition,passiveviewingandimaginary
eating)aswellasthesixrealignmentparametersaseffectsofnointerest.Low-frequencysignal
driftwasremovedusingahigh-passfilter(cut-off128s)andweappliedautoregressiveAR(1)
modelingoftemporalautocorrelations.Theindividualcontrastimagesweregeneratedusing
thet-contrastsi)inhibitionminusviewing,ii)imaginaryeatingminusviewing,andiii)inhibi-
tionminusimaginaryeating,aswellastheoppositecontrasts.Thecontrastimagesofthe
voxel-wisedifferenceinbetaestimatesforthecontrastsofinterest.Thesecond-levelanalysis
usedthesecontrastimagesinanewGLMfromwhichgeneratedstatisticalimages,thatis,SPM
t-mapsacrossallsubjectsandbetweensubjectgroups.Whenthesecond-levelanalysishas
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balanceddesignsatfirstlevelwithsimilarnumbersofsimilareventsforeachsubjectitclosely
approximatesatruemixed-effectsdesign,exhibitingwithin-andbetween-subjectvariance.In
addition,second-levelanalysisinSPMisconsideredtoberobustagainstunequalgroupsizes,
whenunequalvariancesareassumed.Theinhibitionminuspassiveviewingandimaginaryeat-
ingversuspassiveviewingcontrastswereusedtodelineatethebrainregionsinvolvedincogni-
tivecontrolofappetiteandmentalprocessingofthehedonicvalueofthefoods.Theappetite
controlcontrast(inhibitionminusimaginaryeating)wasconsideredthemaincontrastofin-
terestforrevealingtheneuralbasisofappetitecontrol,asthisenabledcontrastingthetwoac-
tivefood-relatedtasksdirectlyagainsteachother,thusaccountingforeffectsofincreasing
taskcomplexityintheactiveversuspassiveviewingconditions[11].Datawerethresholdedat
p<0.05,falsediscoveryrate(FDR)correctedattheclusterlevel.
2.5.Psychophysiologicalinteractions(PPI)inthegenerallinearmodel
(GLM)
Theconnectivitybetweenbrainregionscanvaryasafunctionofthepsychologicalcontext
[16].ThisisknownasaPsychophysiologicalInteraction(PPI).PPIsdonotrequireaspecific
anatomicalmodel.Rather,theyrevealcontext-dependentconnectivityofthesourceregion
withanypossibletargetregion(s).ThismeansthatPPIsindicatetask-dependentinteractions
betweenregionalbrainsystems;thusthePPIrevealswhichregionshavemoreorlesssimilar
activitypattern(‘connectivity’)withthesourceregionasafunctionofaspecificcontrast.Asis
trueforotherconnectivitymethodssuchasdynamiccausalmodeling,PPIsdonotindicatethe
directionofcausalinfluencesbetweensourceandtargetregions,norwhethertheconnectivity
ismediatedbymono-orpoly-synapticconnections,norchangesinstructuralneuroplasticity
fromepochtoepoch[17].
Sourceregionsforthebrain’sinhibitionnetworkwereselectedfromapreviousmeta-analy-
sisoninhibitoryprocessinginGo/No-Gotasks[10,11]andcaudatenucleus,givenitskeyrole
inanticipatoryfoodreward[2](seeTable2forMNIcoordinates).Aspherical8-mmregionof
interest(ROI)wasdrawnattheselocationsininhibitionminuspassiveviewingcontrasttofur-
therdelineateconnectivitychangesinthecognitivecontrolnetwork.Thetime-seriesforeach
participantwascomputedbyusingthefirsteigenvariatefromallvoxeltimeseriesinthede-
finedROI,andde-convolvedusingthePPI-deconvolutionparameterdefaultsinSPM8[18].
ThePPItermwasthencalculatedastheelement-by-elementproductoftheROIin“neuronal
time-series”andavectorcodingfortheselectedcontrast(1forinhibitionand-1forpassive
viewing).Thisproductwasthenre-convolvedbythecanonicalhemodynamicresponsefunc-
tion(hrf).First-levelPPIswereruntogenerateSPMcontrastimagessimilartothefirstlevel
Table2.SeedregionsusedinthePPIanalysis.
Region Hemisphere X Y Z
MiddleCingulum R 6 21 38
Precuneus R 11 -72 58
preSMA R 4 25 38
preSMA L -2 16 67
Insula R 36 19 -7
Caudatenucleus R 15 22 13
Middle(lateral)frontalcortex L -42 14 42
Orbitofrontalcortex R 40 40 -2
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GLMmodel,andthesecontrastimageswereanalyzedandthresholdedinthesecond-level
modelasdescribedabove.
Results
3.1.Task-evokedBOLDresponsesacrossallsubjects
Contrastingtheinhibitionconditionwithpassiveviewingrevealedwidespreadactivationin
fronto-corticalregions(Fig.2A,Table3).Theseincludedbilateralsuperior,superiormedial-
andmiddlefrontalgyri,middlecingulatecortexandprecentralgyrusbilaterally.Increasedacti-
vationwasalsoobservedintheleftinferiorfrontalgyrusandtemporalpole.Supplemental
motorarea(SMA),thalamusandcerebellumwereactivatedbilaterally.Additionalactivations
wereobservedintheearlyvisualareasintheoccipitalcortex.Whenimaginaryeatingwascon-
trastedwithpassiveviewing,similarbrainareaswereactivated,suchasintheinhibitionminus
passiveviewingcontrast(Fig.2B,Table3).Viewingversusinhibitionandviewingversusimag-
inaryeatingconditionsalsobothactivatedasimilarpatternofbrainregions:superior/middle
frontalgyri,superiormiddletemporalgyriandprecuneus(Table4).Finally,wecontrastedthe
inhibitionandimaginaryeatingconditionsdirectlywitheachother(appetitecontrol).The
areasshowingincreasedactivationduringinhibitionversusimaginaryeatingincludedrightin-
feriorfrontalgyrus,bilateralmiddlefrontalcortices,middlecingulatecortex,precuneus,
cuneus,righthippocampusandparietallobes(Fig.2C,Table3).Thereversecomparison
(imaginaryeating>inhibition)showedincreasedactivationininferiortemporalandsuperior
parietallobes(Table3).
3.2.Comparisonsbetweennormal-weightandmorbidlyobesesubjects
Ininhibitionminusimaginaryeatingcomparison,normal-weightsubjectsshowedstrongerac-
tivationsthanobesesubjectsinbilateraldorsalcaudatenucleiandanteriorcingulatecortex
(Fig.3C,Table5).Correspondingly,obesesubjectshadgreateractivationsinthebilateralpos-
teriorcingulum(Table5).Othercontrastsofinterestrevealednosignificantactivationsatour
aprioristatisticalthreshold.Usingaslightlymorelenientstatisticalthreshold(p<0.005,un-
correctedascomparedtoapriorithresholdofp<0.05,FDRcorrected),wefoundthatininhi-
bitionvs.passiveviewingcomparison,normal-weightsubjectshadstrongerresponsesinthe
leftmiddleandinferiorfrontalgyri,andrightorbitofrontalcortex(OFC),andobesesubjects
hadgreateractivationofbilateralposteriorcingulum(Fig.3A,Table5).Whencontrasting
imaginaryeatingminuspassiveviewing,healthysubjectsshowedstrongerright-hemispheric
insularactivation(Fig.3B,Table5).
3.3.Psychophysiologicalinteractions
Acrossallsubjects,therightcaudatenucleusshowedincreasedtask-driven(inhibitionversus
passiveviewing)connectivitywithbilateralprecuneiandcuneiandparietalcortices(Fig.4).In-
feriorparietalgyruswasthepeakareaofactivation(Table6).TheleftpreSMAshowedde-
creasedconnectivityacrossallsubjectswithbilateralcerebellum,leftsuperiorparietalgyrus
(Table6).Theclusterextendedtoleftinsula,thalamusandcaudate(Fig.4).Therightinsula
showeddecreasedconnectivityacrossallsubjectswiththeleftpre-centralgyrusandparacen-
trallobule(Table6),withanextendingclustertopreSMA(Fig.4).
Between-groupcomparisonsrevealedthatobesesubjectshadstrongerfunctionalconnectiv-
itybetweenmiddlefrontalcortexandbilateralsupplementalmotorarea(SMA),rightputamen
andrightmiddletemporalgyrus(Fig.5,Table6).Obeseversusnormal-weightsubjectsalso
showedstrongerconnectivitybetweentherightprecuneusandbilateralsupplementalmotor
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Fig2.Regionalbrainactivationsacrossallsubjects.Brainregionsshowingstrongerresponsesduringinhibitionminuspassiveviewingcondition(A),
imaginaryeatingminuspassiveviewingcondition(B)andinhibitionconditionminusimaginaryeating(C).Thedataarethresholdedatp<0.05,FDR
correctedatclusterlevel.
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area,bilateralthalamus,bilateralpre-centralgyriandrightinferiorfrontalgyrus(Table6)ex-
tendingtorightinsula(Fig.5).Inaddition,obeseversusnormal-weightsubjectsshowedstron-
gerconnectivitybetweenpreSMAandbilateralmiddlecingulatecortex,bilateralmedialand
lateralsuperiorfrontalcortices,thalamus,rightinferiorparietallobuleandrightangulargyrus
(Fig.5,Table6).
Hungerratings(Table1)didnotdifferbetweengroups.Nevertheless,allsecond-levelmod-
elswererunseparatelywithhungerratingasaregressorofnointerest.Thisrevealedthathun-
gerdidnotsignificantlyinfluencetheresultsoftheanalysesreportedinthemanuscript.
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Table3.Brainregionsshowingincreasedresponsesinallsubjectsduringinhibitionandimaginaryeatingversuspassiveviewingand
inhibitionversusimaginaryeating.
Peaklocation Hemisphere X Y Z T
Inhibition>Passiveviewing
Superiorfrontalgyrus L -18 52 32 6.59
Supplementalmotorarea L -2 6 60 6.40
-8 2 74 6.28
Inhibition>Imaginaryeating
Inferiorfrontalgyrus(p.Triangularis) R 50 24 6 5.54
Superiortemporalgyrus L -46 -36 18 4.84
Superiortemporalgyrus R 64 -32 18 4.25
Cuneus R 8 -74 32 4.50
Hippocampus R 40 -16 -10 3.97
Angulargyrus R 48 -62 40 3.93
ImaginaryEating>Passiveviewing
Cerebellum R 27 -72 -24 5.39
Supplementalmotorarea L -12 4 72 6.02
ImaginaryEating>Inhibition
Inferiortemporallobe L -50 -34 48 3.96
Superiorparietallobe L -24 -72 42 3.55
Dataarethresholdedatp<0.05,FDRcorrectedatclusterlevel.
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Table4.Brainregionsshowingincreasedresponsesinallsubjectsduringpassiveviewingversusinhibitionandimaginaryeating.
Peaklocation Hemisphere X Y Z T
Passiveviewing>Inhibition
Middlecingulatecortex R 6 -38 40 5.61
Middletemporalgyrus R 44 -74 26 5.45
Middlefrontalgyrus R 40 8 46 4.08
36 14 62 4.06
Superiorfrontalgyrus R 30 20 62 4.05
Passiveviewing>ImaginaryEating Hemisphere X Y Z T
Superiortemporalgyrus R 56 -52 24 8.57
Middletemporalgyrus R 52 -62 22 6.87
Precuneus R 6 -76 38 6.47
Superiorfrontalgyrus R 24 16 48 6.19
R 38 52 24 5.25
R 30 20 62 4.76
Superiortemporalgyrus L -50 28 8 4.40
Middletemporalgyrus L -66 -28 8 3.72
L -60 -16 -2 3.69
Dataarethresholdedatp<0.05,FDRcorrectedatclusterlevel.
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Fig3.Regionaldifferencesinbrainactivationsbetweennormal-weightandobesesubjects.Brainregionsshowingstrongeractivationinnormal-
weightversusmorbidlyobesesubjectsininhibitionminuspassiveviewing(A),imaginaryeatingminuspassiveviewing(B)andinhibitionminusversus
imaginaryeating(C)contrasts.ThedatainCarethresholdedatp<0.05,FDRcorrectedatclusterlevel(p<0.005,uncorrectedatAandB).
doi:10.1371/journal.pone.0116640.g003
Discussion
Hereweshowthatvolitionalappetitecontrolwhileviewingvisualfoodcuesactivatesanet-
workofprefrontal,frontalandparietalandinferiorcerebellarcorticalregions.Thisconfirms
thatthefrontocorticalcontrolsystem–wellknownforinhibitionanderrormonitoring[8,9]
isalsoengagedduringvolitionalappetitecontrol.Moreover,regionalresponsesandconnectiv-
ityprofilesofthisnetworkwasinfluencedbyobesity.Duringappetitecontrol,obeseindividu-
alsshoweddiminishedresponsesinthefrontalcorticesaswellasinthedorsalstriatum,
whereasduringimaginaryeatingtheirresponseswerediminishedintheinsularcortex.Func-
tionalconnectivityanalysisfurtherrevealeddissociationbetweentheregionalresponsiveness
andinterconnectivityofthecognitivecontrolnetworkinobeseversusnormal-weightindividu-
als:connectivityofthecontrolnetwork,particularlyofpreSMAandprecuneus,withregions
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Table5.Brainregionsshowingsignificantbetween-groupdifferencesinthetask-evokedBOLDresponses.
Contrastsandcomparisons Hemisphere X Y Z T
Inhibition>Passiveviewing*
Healthy>Obese
Middleorbitalgyrus R 28 32 -6 4.18
Inferiorfrontalgyrus(p.Orbitalis) R 44 38 -2 3.26
Inferiorfrontalgyrus(p.Triangularis) R 44 22 26 3.30
Obese>Healthy
Posteriorcingulatecortex R 6 -38 12 5.16
L -4 -32 12 4.52
ImaginaryEating>Passiveviewing*
Healthy>Obese
Insula R 38 14 -10 3.74
Inhibition>ImaginaryEating
Healthy>Obese
Anteriorcingulatecortex L -14 16 30 3.74
Caudatenucleus R 20 6 22 2.99
Dataarethresholdedatp<0.05,FDR-correctedattheclusterlevel.Note:*p<0.005andclusterleveluncorrected.
doi:10.1371/journal.pone.0116640.t005
involvedinconflictmonitoring(anteriorcingulatecortex)andarousalcontrol(thalamus)was
strongerinobeseversusnormal-weightindividuals.
4.1.Brainbasisofcognitiveappetitecontrol
Eatingandappetitearecontrolledbycomplexhomeostaticmechanisms[1].Inreal-lifesitua-
tions,asuddenurgetoeatmaybetriggeredbymerepicturesoffoodsinadvertisements,super-
marketsandonTV;thustheseimpulsesneedtobeinhibitedtopreventexcessivefoodintake.
Wefoundthatfrontalandprefrontalregionsarereliablyactivatedwhenindividualsengage
volitionallyinsuchinhibition.Theseareasarelikelythekeycomponentsresponsibleforvoli-
tionalappetitecontrol,andarealsoimpliedinpreviousstudiesonresponseinhibition[8–11,
19–21].However,asubsetoftheseregionssuchasBroca’sareaandleftlateralfrontalcortices
werealsoengagedduringimaginaryeating.Bothvolitionalinhibitionofappetiteandimagi-
naryeatingtasksrequireworkingmemoryinretrievingthetaskandsomeverbalinstructions
aswell,soactivationintheseregionscanbeexpectedinbothtasks[10].Observedcerebellar
activationcouldreflectengagementofafronto-cerebellarnetwork,whichconstantlyupdates
anticipatorycontrolmechanisms[22].
Thesefindingsfromthetask-evokedBOLDresponsestocognitiveappetitecontrolaccord
withthosemadebyYokumetal.Theycomparedtheneuralresponsesofthreecognitivereap-
praisalstrategieswhenadolescentsubjectsviewedvisualfoodcuesandthoughtofthelong-term
costsorbenefitsofnoteatingthefoodandsuppressingcravingsforthefood.Theyfoundin-
creasedactivationininhibitoryprefrontalandsuperiorfrontalregionsduringthesementaltasks,
yetinthatstudyparticipants’BMIdidnotmodulatetheintensityofbrainactivation[12].Fur-
thermore,Yokumetalreporteddecreasedactivationoftheprecuneusandposteriorcingulate
gyrusduringtaskperformanceandmoresoduringthinkingofthelong-termbenefitsfornot
eatingthefoodascomparedtoothertasks[12].Inanotherrecentstudyparticipantshadtoeither
increaseordecreaseappetitewhileviewingfoodpictures[13].Intheappetitedecreasecondition
thesubjectswereaskedtoreappraisethepresentedstimulii.e.givenewmeaningtothefood
PLOSONE|DOI:10.1371/journal.pone.0116640 February6,2015 10/16