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Neuroscience
Research
j ou rn a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / n e u r e s
Rapid
communication
Role
of
the
supplementary
motor
area
in
the
automatic
activation
of
motor
plans
in
de
novo
Parkinson’s
disease
patients
Kevin
D’Ostilio
a,∗,
Benjamin
Deville
a,
Julien
Cremers
a,b,
Julien
Grandjean
c,
Eva
Skawiniak
b,
Valérie
Delvaux
b,
Gaëtan
Garraux
a,baMoVeReGroup,CyclotronResearchCenter,UniversityofLiege,Liege,Belgium bDepartmentofNeurology,UniversityHospitalCenter,SartTilman,Liege,Belgium cCyclotronResearchCenter,UniversityofLiege,Liege,Belgium
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received18December2012 Receivedinrevisedform3April2013 Accepted15April2013
Availableonline1May2013
Keywords: Subliminal Parkinson’sdisease Priming Reactiontime Neuroimaging
Supplementarymotorarea
a
b
s
t
r
a
c
t
Theroleofthebasalganglia-corticalmotorloopinautomaticandunconsciousmotorprocessesispoorly understood.Here,weusedevent-relatedfunctionalmagneticresonanceimagingin11denovo Parkin-son’sdiseasepatientsastheyperformedavisuomotormaskedprimingtask.Thestrongersubliminal primingeffectforthenon-dominantsideofmotorsymptomsthanforthedominantsidewasparalleled bystrongersupplementarymotorareaproperactivityinresponsetolateralizedvisualstimulipresented belowthethresholdofawareness.Thisnovelresultsupportsthepredictionthatthisareaisinvolvedin theautomaticactivationofmotorplansasafunctionofstriataldopaminelevels.
©2013ElsevierIrelandLtdandtheJapanNeuroscienceSociety.Allrightsreserved.
ThepathologicalhallmarkofParkinson’sdisease(PD)isa pro-gressivelossofneuronsinthelateralventraltiersofthesubstantia nigraparscompacta(FearnleyandLees,1991),leadingtoadecrease ofdopaminergicnigrostriatalterminalsthatistypicallymore pro-nouncedintheposterioraspectsofthestriatuminthehemisphere contralateraltothemostclinicallyaffectedbodyside(Kishetal., 1988).Sincetheposteriorputamenisthemaininputstructureof themotorloopinthemodelproposedbyAlexanderetal.(1990),the lossofstriataldopaminergicterminalsisexpectedtohaveremote influencesonothercomponentsofthemotorloopduringvoluntary movements.Accordingtothismodel,themajorprobleminmotor slownessisadeficiencyintheactivationofcorticalareasinvolved inthemotorloop,notablythemoreposteriorpartofthemedial pre-motorcortex,thesupplementarymotorareaproper(SMA),which isconsideredtobeakeystructureofthecortico-basalgangliamotor loop(Nachevetal.,2008;Aronetal.,2009).Thispredictionhasbeen supportedbymanyexperimentalresultsinPDpatients.Afailureto activatetheSMAduringtheexecutionofupperlimbmovements isaconsistentobservationinPDpatientsstudiedintheoffstate ascompared withcontrols(Jenkinset al.,1992; Playfordetal., 1992;Jahanshahietal.,1995).Apomorphine,anon-selectiveD1/D2
∗ Correspondingauthor.Tel.:+3243665475;fax:+3243662946. E-mailaddress:Kevin.dostilio@ulg.ac.be(K.D’Ostilio).
agonist(Albinetal.,1989;DeLong,1990;Jenkinsetal.,1992;Rascol etal.,1992),fetalmesencephalicdopaminergictransplantsintothe striatum(Piccinietal.,2000), pallidotomy(Graftonetal.,1995; Samueletal.,1997),pallidalandsubthalamicelectricstimulation (Limousinetal.,1997),allincreasethelevelofSMAactivityalong withresolutionofakinesia(i.e.delayedmovementinitiation).
Inhealthysubjects,weandothershaveshownthatSMA activ-itychangescanbeelicitedbythepresentationofvisualstimuliif thesehavebeenassociatedwithaspecificmotorresponse regard-lessofwhether(i)stimuliarepresentedbeloworabovethelevelof awarenessand(ii)thecorrespondingmotorresponseisexecuted ornot(Boyetal.,2010;D’OstilioandGarraux,2011;D’Ostilioetal., 2012).Moreprecisely,weprovidedfunctionalmagneticresonance imaging(fMRI)evidencesuggestingthatSMAactivityisinvolved intheprocessingofmotorplansautomaticallyelicitedby uncon-sciouslyperceivedvisualstimuli,evenifthecorrespondingplan isnotexecuted(D’OstilioandGarraux,2011).Inpatients,afocal lesionoftheposteriorpartoftheSMAhasbeenassociatedwitha deficitintheautomaticandunconsciousinhibitionofmovements (Sumneretal.,2007).
Here, we hypothesized that this SMA activity pattern is dependentonstriatal dopaminelevels.Thiswastested usinga within-subjectdesignin11denovo,drug-naïve,PDpatientsunder theassumptionthatstriataldopaminedeficiencyisasymmetrical, i.e.lesspronouncedinthemotorloopconcernedwiththecontrol
0168-0102/$–seefrontmatter©2013ElsevierIrelandLtdandtheJapanNeuroscienceSociety.Allrightsreserved.
maskandthetarget)inordertostudythepositivecompatibility effect(PCE)thatreflectstheautomaticactivationofmovements. Wedidnotexaminethenegativecompatibilityeffect(NCE) reflect-inganinhibitionprocessatlongerISIs(Sumneretal.,2007).To minimizeanybiasinmotorperformancebetweenleftandright handresponses,werestrictedfMRIdataanalysistotrialsthatdid notrequireanymotorresponse.
ElevendenovodrugnaïvePDpatients(3women/8men) par-ticipatedinthefMRIexperiment.Denovopatientswerepreferred asitisknownthatasymmetryismorepronouncedearlyoninthe disease(RiedererandSian-Hülsmann,2012).Agerangedfrom59 to80years,withamean±SDof68±7years.Allwererighthanded andhadnormalorcorrected-to-normalvisionandhearing.Global motorimpairmentwasassessedusingthemotorpart(partIII)of theUPDRS(Fahnetal.,1987)andtheHoehnandYahrscale(Hoehn andYahr,1967;Goetzetal.,2004).Thegroupmeanscoreonthese scaleswas15±6and1.4±0.5,respectively(Table1).Asexpected, compositeUPDRSIIIscores(sumofUPDRSIIIscoresfromitem22: rigidity+item 23:fingertaps+item 24:handmovements+item 25:pronation–supination movementsof hands)showed higher impairmentonthedominantside(median=8)ascomparedwith thenon-dominantside(median=2)ofmotorsymptoms(Wilcoxon test:Z=2.93,p=0.003).Allsubjectsprovidedinformedwritten con-sentinthisstudythatwasapprovedbytheethicscommitteeofthe UniversityofLiège.
Thevisuo-motortaskduringfMRIwassimilartothatpreviously reported(D’OstilioandGarraux,2011)(Fig.1).Briefly,eachtrial startedwithafixationdotdisplayedonthecenterofthescreen foradurationthatwaspseudo-randomlyjitteredbetween1500 and3000msacrosstrials.Thiswasfollowedbyablankscreen,a primestimulusand amaskstimulusalongwithtargetstimulus sequentiallydisplayedfor300ms,33ms,and100ms,respectively. Theprime stimulus waseither a double arrow pointing tothe leftor therightora plussign. The maskstimulusconsisted in
motorresponsefacilitationwasformallyassessedbycomparing behavioral performance between compatible and incompatible conditions(i.e.responsetrials).Reactiontimedataanalysisshowed aPCEforthenon-dominantsideofmotorsymptoms[PCE:19ms; t(10)=2.54, p=0.03] but notfor the dominantside [PCE=3ms; t(10)=0.14,p>0.05].Inaddition,asexpected,thepatientsmade moreerrorswhentheno-responseconditionswereprecededby anarrow prime (error ratefor primearrow no-response trials: 6.8%>neutralno-responsetrials:3.6%;p=0.045).
FunctionalMRItimeserieswereacquiredona3Thead-only scanner(MagnetomAllegra,SiemensMedicalSolutions,Erlangen, Germany) operatedwiththestandard transmit-receive quadra-turehead coil. MultisliceT2*-weighted functional imageswere acquiredwithagradient-echoecho-planarimagingsequenceusing axialsliceorientationandcoveringmostofthebrain(20slices, FoV=220mm×220mm,voxelsize3.4mm×3.4mm×5mm,25% interslicegap,matrixsize64×64×20,TR=1170ms,TE=30ms, FA=90◦). For each session, the first eight volumes acquired before the first trial onset were discarded to allow for T1 saturationeffects. Headmovementwas minimizedby restrain-ing the subject’s head using a vacuum cushion. Stimuli were displayed on a screen positioned at the rear of the scan-ner,which the subjectcould comfortablyseethrough a mirror mountedonthestandard headcoil.Foranatomical reference,a high-resolution T1-weightedimage wasacquired for each sub-ject (3D MDEFT, TR=7.92ms, TE=2.4ms, TI=910ms, FA=15◦, FoV=256mm×224mm×176mm,1mmisotropicspatial resolu-tion).
Data were preprocessed and analyzed using SPM8 (Wellcome Department of Imaging Neuroscience,
http://www.fil.ion.ucl.ac.uk/spm) implemented in MATLAB 7.4.0(MathworksInc.,Sherbom,MA).Imagesofeachindividual subjectwerefirstcorrectedforslicetimingandrealigned(motion corrected).ThemeanEPIimagewasspatiallycoregisteredtothe
Table1
Demographicandclinicalpatients’data.
Patients Age(years) Gender GlobalRT DS NDSscore DSscore UPDRSpartIIIa HoehnandYahrscaleb
1 59 M 470.75 Right 2 8 11 1 2 66 M 479.09 Left 4 10 23 2 3 80 F 686.75 Left 3 9 23 2 4 66 M 483.43 Right 1 7 10 2 5 72 F 542.50 Left 1 3 9 1 6 59 M 502.29 Right 3 9 19 1 7 65 M 397.88 Left 4 12 22 2 8 63 M 552.03 Right 4 7 16 1 9 75 M 611.72 Left 1 3 4 1 10 78 F 961.87 Right 2 9 17 1.5 11 70 M 476.30 Right 1 7 15 1.5
DS=dominantsideofmotorsymptoms;NDS=non-dominantsideofmotorsymptoms.
aUPDRS:minimumscore=0,maximumscore=108.
b HoehnandYahrscale:stage0:nosignsofdisease;stage1.0:unilateraldisease;stage1.5:unilateralandaxialinvolvement;stage2.0:bilateralinvolvementwithout
impairmentofbalance;stage2.5:mildbilateraldiseasewithrecoveryonpulltest;stage3.0:mildtomoderatebilateraldisease;someposturalinstability;physically independent;stage4.0:severedisability;stillabletowalkorstandunassisted;stage5.0:wheelchairboundorbedriddenunlessaided.
Fig.1.Subliminalmaskedprimetask.Thetargetsstimuliweredisplayedtogetherwiththemask,directlyafterthesubliminalprimestimulus(apointingarroworaneutral stimulus),andwereeithercomposedofdoublepointingarrows(=responsetrials)ordouble“0”signs(=no-responsetrials).
anatomicalMRIimageandcoregistrationparameterswereapplied to the realignedBOLD time series. Individual anatomical MRIs werespatiallynormalizedintoMNIspace(MontrealNeurological Institute, http://www.bic.mni.mcgill.ca) and the normalization parametersweresubsequentlyappliedtotheindividually coreg-isteredBOLDtimesseries,whichwasthenreslicedtoavoxelsize of 2mm×2mm×2mm, and smoothed using an 6mm FWHM Gaussian kernel. In first level analyses, the six experimental conditionsweremodeledseparately.Eacheventwastime-locked tothetargetstimulusofeachtrialandconvolvedwithacanonical hemodynamic response function and its time and dispersion derivatives.Weusedthegeneralized linearmodeltomodelthe intensity level of each voxel as a linear combination, for each subjectandevent.
Theneuralcorrelatesofthedifferencein thelevel of prime-induced activation of motor plans between the dominant and non-dominantsideofmotorsymptomswasexaminedusing no-response trials. Since we postulated that the priming effect is asymmetricallyaffected,wecontrastedprime-inducedactivation
ofthemotorplanfor thenon-dominantand thedominantside ofmotorsymptoms(Fig.2).Contrastimagesfromallparticipants wereenteredinasecond-level randomeffectone-sample t-test analysis.Bycomparingthe11contrastimagesrelatedtothe non-dominantside(rightorleft)tothoseofthedominantsideofmotor symptoms(rightorleft),weexpectedastrongerbilateralactivity intheSMA.Resultsarereportedinthisregionatp<0.005, uncor-rectedwitha20voxelextentthresholdofactivation.Thepredicted activationsintheSMAwerefurthertestedusingaspherical small-volumecorrection(SVC)witharadiusof10mm(cut-offvalue:0.05, familywiseerror[FWE]corrected),centeredonthepeak coordi-natesfromourprevioussubliminalprimingstudies(rightSMA, MNI:8,−2,62)(D’OstilioandGarraux,2011,2012).
Asexpected,we foundstrongerbilateralSMA activitywhen the motor plan for the non-dominant side of motor symp-toms was subliminally activated (i.e. when the prime arrow pointed to the same side as this hand) compared with that for thedominantside[leftSMA-proper: (−10,−6,58), Z=3.93, p(unc.)=0.00004; right SMA-proper: (14, −12, 58), Z=3.50,
Fig.2.fMRIresults.ThefigureillustratesstrongerSMAactivitywhentheprimetriggeredanautomaticandunconsciousmotoractivationofthenon-dominantsideofmotor symptoms(NDS)incomparisontothedominantside(DS)forno-responsetrials.Resultsaredisplayedatapeakthresholdofp<0.005anda20voxelextentthresholdof activation.
effect.
AfterthefMRIsession,threepatientsintheexperimentalgroup performed a prime identification task consisting in 180 trials. Resultsshowedthattheycorrectlyidentifiedthesubliminal33 ms-stimulusinonly33%ofalltrials.Theidentificationperformance wasvery low because patientsdid not respondto some trials despiteclearinstructions.Resultsobtainedinaseparategroupof 15PDpatientsconfirmedthata33ms-primeisunlikelytobe con-sciouslyperceivedbyparticipants.Thiswasformallyassessedusing anidentificationtaskcontaining60trials. Thetaskdisplaywas exactlythesameasinthefMRIexperimentbutparticipantswere askedtoguessthedirectionoftheprimearrowstimulipresented beforethemask.Thepercentageofcorrectresponseswas calcu-latedand comparedtochancelevels.Participantsidentifiedthe primein47%ofalltrials(i.e.atchancelevels),supportingthe state-mentthattheprimestimuliwerenotconsciouslyperceivedinour task.
TheaimofthisstudywastoexamineSMAactivityrelatedtothe automaticandunconsciousmotoractivationprocessinearlystages PDpatientswhileadministeringasubliminalvisuomotorpriming task(EimerandSchlaghecken,1998).fMRIdataanalysisrevealed strongeractivationsintheposteriorpartoftheSMA,bilaterally, when theprime stimulustriggered a motor response withthe non-dominantsideascomparedwiththedominantsideofmotor symptoms.Thisresultisnotconfoundedbydifferenceinmotor performancebetweentheformerandthelattersincethefMRIdata analysiswasrestrictedtotrialsinwhichnomotorresponsewas required.Thisextendspreviousfindingsonimpaired-movement relatedSMAactivityinPDtounconsciousandautomaticmotor processes.Thisresult corroboratespreviousfindings suggesting thatthisregionparticipatesinautomaticactivationofmotorplans unconsciouslyelicitedbyvisualstimuli(GrezesandDecety,2002; D’OstilioandGarraux,2011).Ourdatadonotallowustoinvestigate therelativecontributionofothercomponentsofthe cortico-basal-corticalmotorloop.Sincethemedialfrontalcortexhypoactivation mayaccountforthepatients’difficultiesininitiatingmovements (Jenkinsetal.,1992;Playfordetal.,1992)andbecause sensorimo-torintegrationatthelevelofthemotorpreparationisimpaired inPDpatients(AbbruzzeseandBerardelli,2003),weproposethat lateralizedmotordeficitsofautomaticandunconsciousmotor acti-vationmightpartiallyexplaintheearlymotorsymptomsofthe diseasesuchastheslownessinselectingtheappropriatemotor response.
Authors’contributions
KevinD’Ostiliowasimpliedinconception,organizationand exe-cutionoftheresearchproject,designandexecutionofthestatistical analysis,aswellasindraftingthemanuscript.BenjaminDeville, JulienCremers,JulienGrandjean,EvaSkawiniak,andValérie Del-vauxwereimpliedintheexecutionof theresearchprojectand gaverevisionofthemanuscript.GaëtanGarrauxwasimpliedin
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