Primary motor cortex activation and lateralization in patients with tumors of the central region☆.

0.87 MB·English

by  Tozakidou, Magdalini

NeuroImage:Clinical2(2013)221–228
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NeuroImage: Clinical
journal homepage: www.elsevier.com/locate/ynicl
Primary motor cortex activation and lateralization in patients with
☆
tumors of the central region
Magdalini Tozakidou a,⁎, Holger Wenz b, Julia Reinhardt a,b, Ernst Nennig b, Katharina Riffel b,
Maria Blatow a,b, Christoph Stippich a,b
aDivisionofDiagnosticandInterventionalNeuroradiology,DepartmentofRadiologyandNuclearMedicine,UniversityHospitalofBasel,Basel,Switzerland
bDivisionofNeuroradiology,DepartmentofNeurology,UniversityofHeidelberg,Heidelberg,Germany
a r t i c l e i n f o a b s t r a c t
Articlehistory: Hemisphericlateralizationisafrequentlyencounteredphenomenonofcorticalfunction.Itdescribesthefunc-
Received7November2012 tionalspecializationofaregionononesideofthebrainforagiventask.Itiswellcharacterizedinmotorandsen-
Receivedinrevisedform23December2012 sory,aswellaslanguagesystemsandbecomesmoreandmoreknownforvariouscognitivedomains.Whilein
Accepted8January2013
theadulthealthybrainhemisphericlateralizationismostlyset,pathologicalprocessesmayleadtocorticalreor-
Availableonline14January2013
ganization.Inthesecasesneuroplasticityofthecorrespondingregioninthenon-dominanthemisphereseemsto
playanimportantrole.Inapreviousstudyweinvestigatedlanguageassociatedregionsinright-handedpatients
Keywords:
withfrontalandtemporaltumorsofthelefthemisphere.Weobservedamarkedchangeoflanguagelateraliza-
FunctionalMRI
M1 tioninthesepatientstowardsthenon-dominanthemisphereasmeasuredbyfunctionalMRI(Partovietal.,
Plasticity 2012).
Functionalreorganization Inthepresentstudyweevaluatedactivationandlateralizationofcorticalmotorareasinpatientswithtumors
Ipsilateralcoactivation ofthecentralregion.BOLDfMRIwasperformedduringunilateralvoluntarymovementsofthecontralesional
handin87patients.IndividualcorrelationsofmeasuredBOLD-signalswiththemodelhemodynamicrefer-
encefunctionweredeterminedonaROIbasisinsinglesubjectsandcomparedtothoseof16healthyvolunteers.
InvolunteersthestrongestactivationisusuallyfoundintheM1handrepresentationcontralateraltothemove-
ment,whileaweakerhomotopicco-activationisobservedinipsilateralM1(Stippichetal.,2007a).Inthepatient
groupourresultsshowsignificantchangesofmotoractivations,rangingfromareductionofM1lateralizationto
equalizationofM1activationsoreveninversionofM1lateralizationduringcontralesionalmovements.This
studycorroboratesinalargepatientgrouptheideathatlesionsaffectingM1mayleadtofunctionalreor-
ganizationofcorticalmotorsystemsandinparticularequalizehemisphericlateralization.However,itis
notyetclearwhetherthesechangesareonlyanepiphenomenonorindeedreflectanattemptofrecovery
ofbrainfunction.
©2013TheAuthors.PublishedbyElsevierInc.Allrightsreserved.
1.Introduction Within this network strongest activation during unilateral
handmovementsisusuallyfoundintheM1motorhandrepresentation
The primary motor cortex (M1) plays an important role in the contralateraltotheexecutedmovement(M1)asdemonstratedinvar-
c
controlandexecutionofvoluntarymovements.Increasingevidence iousstudiesusingbloodoxygenleveldependent(BOLD)functionalMRI
attributesthisfunctiontoitsconnectiontoawiderangeofcortical (fMRI)(KleinschmidtandToni,2005).However,eventhoughM1acti-
motorcontrolareasincludingthepremotorarea(PMA),thesupple- vationisstronglylateralizedtoM1 alsoM1coactivationipsilateralto
c
mentarymotorarea(SMA)aswellastheparietalcorticesthatarein- the executed movement (M1-CoA) is present in healthy volunteers
i
volved in different aspects of a motor task e.g. motor execution, (Stippichetal.,2007a),andisespeciallythoughttobepresentinpa-
planningandcoordination(Lotzeetal.,1999). tients with lesions in the primary motor cortex of the contralateral
hemisphere(StoeckelandBinkofski,2010).
Evidenceofenhancedipsilateralactivationunderpathologicalcon-
ditions arouse from studies in patients with congenital hemiparesis
☆ Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommons due to intrauterine lesions of the periventricular white matter (Cao
Attribution-NonCommercial-ShareAlikeLicense,whichpermitsnon-commercialuse, et al., 1994;Staudtet al.,2002).Especially those patients with large
distribution,andreproductioninanymedium,providedtheoriginalauthorandsource
lesionsshowedabnormalactivationofthehandmotorrepresentation
arecredited.
⁎ Correspondingauthor.Tel.:[phone]. intheipsilateralprimarymotorcortexasrevealedbyTMSandfMRI
E-mailaddress:[email protected](M.Tozakidou). (Staudtetal.,2002).Notonlyduringearlyinjurybutalsoduringinjury
2213-1582/$–seefrontmatter©2013TheAuthors.PublishedbyElsevierInc.Allrightsreserved.
http://dx.doi.org/10.1016/j.nicl.2013.01.002
222 M.Tozakidouetal./NeuroImage:Clinical2(2013)221–228
inadulthoodplasticityofM1activationhasbeendemonstrated.Forex- study protocol was approved by the local ethics committee of the
ampleinpatientssufferingfrommotordeficitsduetoischemicstroke UniversityofHeidelberg,MedicalSchoolandisinlinewiththeDec-
TMSandfMRIrevealedchangesinM1lateralizationwithpresenceof larationofHumanRights,Helsinki,2002.Thepatients'resultswere
prominentipsilateralM1-CoA(StoeckelandBinkofski,2010).Astudy compared to the normative data obtained from 16 healthy right
i
conductedbyCrameretal.couldshowthatactivationvolumewasin- handedvolunteers(Blatowetal.,2011).
creasedintheunaffectedhemisphereinstrokepatients(Crameretal.,
1997).SimilarlyLotzeetal.demonstratedthatTMSstimulationover
contralesionalM1resultedininterferencewithrecoveredperformance 2.2.FunctionalandmorphologicalMRI
instrokepatients(Lotzeetal.,2006).
In patients with brain tumors so far only little is known about After intensive individual training of the movement tasks
ipsilateral M1 activation. A study in a heterogeneous patient group performedunderinstructionanddirectsupervisionoftheinvestiga-
withdifferenttypesofneoplasmsandmalformationscouldshowthat tor, each patient was positioned in a clinical 1.5-Tesla (T) imager
ispilateralM1activationismorepronouncedinpatientswithcortical (SymphonySiemensAG,Erlangen,GermanyorEdge,Picker/Marconi,
malformations than in patients with neoplasms (Carpentier et al., Cleveland,OH,USA)or3.0-Timager(MagnetomTRIO,SiemensAG,
2001).InadditionAlkadhietal.examined9patientswitharteriovenous Erlangen, Germany). The healthy controls were measured on the
malformations(AVMs)andcouldshowenhancedactivityinipsilateral 3.0-TMR-imager(Blatowetal.,2011).Forallanatomicalandfunc-
M1 in 3 patients. In a larger study on patients with neoplasmsonly tional MR measurements standard birdcage head-coils were used.
Kringsetal.couldshowsignificantdecreasesofactivationincontralat- Movementartifactswerereducedbyrelaxedpositioningoftheextrem-
eralM1,butdidnotassessipsilateralM1Co-activationandthusdidnot ities, by fixing the head with preformed foam cushions and by
addresstheroleofM1lateralization(Kringsetal.,2002). instructing each patient to gaze at a fixation point. During the fMRI
Hemispheric lateralization of cortical function has not only been measurements, all patients performed complex finger opposition in-
describedforthemotorsystem,buthasbeenshowninvarioussystems. volvingdigits1–5ofthecontralesionalhandasastandard.Patientsun-
In a previous study we investigated language associated regions in able to perform the complex finger opposition due to contralesional
right-handed patients with frontal and temporal tumors of the left motor deficits performed repeated opening and closing of the hand.
hemisphere(Partovietal.,2012;Stippichetal.,2007b)andobserved Allpatientswereaskedtoperformthemostdemandinghandmotor
amarkedchangeoflanguagelateralizationinthesepatientstowards task possible in order to achieve maximum BOLD-activation. Tasks
the non-dominant hemisphere as measured by fMRI. In the present wereperformeduponcommandoftheinvestigator.Taskperformance
studyweevaluatedipsilateralactivationofmotorcontrolareasin87 was monitored directly by inspection during execution. Incorrectly
patientswithtumorsaffectingthecentralregioncomparedtohealthy performed measurements were excluded from the evaluation and
controls. repeated immediately. A standardized block-designed whole brain
BOLD-fMRIwascarriedoutineachpatientorvolunteerusingasingle-
shot blipped gradient echo-planar imaging sequence (GE-EPI: 1.5-T
2.Materialsandmethods Edge:, TR=3000ms, TE=80ms, FOV=256×256mm2, Matrix=
128×128voxels,flipangle=90°,22axialslices,slicethickness5mm,
2.1.Studypopulation gap 1mm; 1.5-T Symphony:, TR=2860ms, TE=65ms, FOV=256×
256mm2,Matrix=64×64voxels,flipangle=90°,22axialslices,slice
Over a period of 6years 301 patients with brain tumors were thickness 5mm, gap 1mm; 3.0-T TRIO:, TR=2500ms, TE=30ms,
investigatedpresurgicallyinaprospectivestudydesignusingBOLD- FOV=256×256mm2, Matrix=64×64 voxels, flip angle=90°, 36
functional MRI (fMRI) of motor and/or language function. Of those axialslices,slicethickness3mm,gap1mm).
the87consecutivepatientswithtumorsaffectingthecentralregion IndividualT1-weightedstructural3DMRIdatasetswereacquiredto
only–accordingtoestablishedanatomicallandmarks–wereinclud- superimposefunctionalonstructuralimages,inpatientsthefollowing
edinthisstudy.Exceptforonepatientwithmultiplemanifestations sequenceswereused:Edge:RF-spoiledFLASHsequence,TR=30ms,
of a glioblastoma all patients suffered from single lesions. Tumor TE=4.4ms, flip angle=15° FOV=256×256mm2, Matrix=256×
types were confirmed histologically as summarized in Table 1. The 256voxels,68sagittalslicethickness2.5mmor135transversalslices,
slice thickness 1.3mm. Symphony: 3D turbo FLASH sequence, TR=
2180ms, TE=3.49ms, flip angle=15°, FOV=256×256mm2,
Matrix=300×300voxels,88sagittalslices,slicethickness2.0mmor
Table1 FOV=256×256mm2,Matrix=512×512voxels,144or128transver-
Typesoftumorsaffectingthecentralregion.
sal slices, slice thickness 1.3mm; TRIO: Magnetization-Prepared
Tumor type No. of patients Rapid-Acquisition-Gradient-Echo sequence (MPRAGE) sequence,
Grade IV/ metastasis GMGlleiiootasbaslatracsstooimsmaa 12180 MoFTOrRaV=tMr=i1Px6R2=8A5065G1×Em22s×s5,e65qT1Eum2e=mnvc4o2e.,x3,e8MTlsRm,a=1tsr,2i1x8fl5=ips7a02ga5mint6tgsa×l,le2T=s5lEi6c1=e5sv°3,,o.s0xFl5iOecleVms,=tsh,1i2cfl45k4i6pn×etasr2sna5gn16ls.e3vm=emrms9ma2°l,,
slices,slicethickness1.3mm.TheaxialT1weighted3D-datasetswere
Oligodendroglioma 9
acquiredinallpatientsundergoingfunctionalneuronavigationafterad-
mors Astrozytoma 21 mwhinoiswtrearteionnootfsci.hve.dguadleodlifnoirufmun.Actlilopnaatliennetusrowniathvignaotnio-nenrheacenicviendgsleagsiiottnasl
de I-III tu OGalinggolaisotgrloiozymtoama 81 TtMh1PisRwaAelsGiogEh,rteeTddRu=c3iDn1g-6dm8a0toavmseesm,tseTnaEts=aar4tsi.f3taa8cntmds.asVr,dofllutionptseaaenfregsliwem=earge1i5nm°g,etaFisOmuVree=dan2ud5si6nb×yg
Gra Meningeoma 6 256mm2,matrix=512×512voxels,128sagittalslices,slicethickness
Dysembryoplastic neuroepithelial tumor (DNET) 1 1.3mm.
Chondrosarcoma 2 TumorvolumewasmeasuredonT1weighted3D-datasetsusing
thefollowingformula:volume=0.52∗x∗y∗zaccordingtoPasqualin
Total 87
etal.(1991).
M.Tozakidouetal./NeuroImage:Clinical2(2013)221–228 223
2.3.StandardizedanalysisofindividualfMRIdata indicate statistical significance. Analyses were performed using
GraphPadPrism5.0(GraphPad,LaJolla,USA).
BrainVoyager® (BrainInnovations, Maastricht, The Netherlands)
wasusedforstandardizedprocessingandevaluationofbothstructur- 3.Results
alandfunctionalMRIdataonanindividualbasisinallpatientsandall
volunteers. Data processing including motion correction, temporal 3.1.M1activationinpatientswithcentralbraintumors
andspatialsmoothing,andavoxel-wisecalculationofBOLDactiva-
tion using the general linear model (GLM) was fully standardized In patients BOLD fMRI was performed during unilateral move-
andsemi-automated.Functionalimageswereoverlaidonstructural ments of the contralesional hand (Fig. 1D, right panel). Statistical
imagesmanuallyandineachpatient,thestructuralandallfunctional comparison of activations between patients and controls (Fig. 1D)
datasetsweretransformedtoTalairachspace(Talairach,1988).The showedonaverageasimilarpatterninbothgroupswiththehighest
methodhasbeendescribedelsewhere(Blatowetal.,2011;Stippich r-valuebeingfoundinM1 butahighervariabilityofr-valuesofacti-
c
et al., 2000, 2007a, 2007b). Ten different regions of interest (ROIs) vationsinallevaluatedregionsofinterest(ROI)inpatients.However,
weredefined,namelytheprimarysensorimotorcortex(M1c,M1i), meanr-valueofM1 activationoftheentirepatientgroupwaslower
c
thepremotorcortex(PMAc,PMAi),thesupplementarymotorcortex than in controls (Fig. 1D). Comparison of r-values in patients mea-
(SMAc,SMAi),thesuperiorparietallobulus(SPLc,SPLi)andtheinfe- sured at 1.5T and at 3T showed no significant difference (Suppl.
riorparietallobulus(IPLc,IPLi)inbothhemispheres.Thesuffix“c”re- Table1).
ferstocontralateraltotheexecutedmovementsandthesuffix“i”to
ipsilateraltotheexecutedmovements. 3.2.Corticalmotornetworkactivationinpatientsandvolunteers
The precentral gyrus was identified according to morphological
landmarks as established by Yousry et al. (1997) and Naidich et al. Themotornetworkincludingtheprimarymotorcortex(M1),pre-
(2001).The“handknob”wasusedontransversesectionstoidentify andsupplementarymotorareasinthefrontallobe(PMA/SMA)and
theprimarymotorhandrepresentation(M1),whichwasthenverified the superior and inferior parietal lobule of both hemispheres is
onsagittalimagesusingthe“hooksign”.SMAwasdefinedasthecorti- shownschematicallyinFig.1A.ExamplefMRIactivationpatterndur-
calareaonthemedialsurfaceofeitherthesuperiorfrontalgyrusorthe ingmovementoftherightfingersispresentedinFig.1B.Statistical
cingulatedgyrusposteriortotheanteriorcommissure.PMAwaslocal- comparisonof r-values in volunteersshowedthat during unilateral
izedincontinuationoftheSMAonthelateralsurfaceoftheconvexity movementsinvolunteershighestr-valueisfoundinM1contralateral
rostraltotheprecentralsulcusandcaudaltothesuperiorfrontalsulcus totheexecutedmovement(M1)(Fig.1C).Ipsilateralco-activationin
c
(Gordonetal.,1998).SPLwasidentifiedintheparietallobeposteriorto M1 (M1 CoA) is also present with a significantly lower r-value
i-
the postcentral sulcus and superior to the parietooccipital sulcus (Fig.1C).Similarly,r-valuesofactivationsinpre-orsupplementary
(Kringsetal.,2000),whereasIPLwasdefinedintheparietallobeinferi- motor areas (PMA/SMA) or the superior and inferior parietal lobe
ortotheparietooccipitalsulcus.IneachROI,theexactanatomicalcorre- (SPL/IPL) on the ipsilateral side (Fig. 1C) were significantly lower
latesofthecentersofgravityofeachBOLDactivationwereassessedon thanr-valuesofM1 activations,butshowednosignificantdifference
c
transverse, sagittal, and coronal sections (3D-view). An independent comparedtor-valuesofactivationsinM1.Sincemotornetworkacti-
i
second reading was performed by an experienced neuroradiologist vationinrighthandedvolunteerswassimilarformovementsofthe
(CS)toconfirmallanatomo-functionalcorrelations.Correlation(r)of right and left fingers (Fig. 1C) data of both sides were pooled
themeasuredBOLDsignaltotheappliedhemodynamicresponsefunc- (Fig.1D,leftpanel).
tion(hrf)andtherelativeBOLD-signalchange(ΔS%)wasmeasuredfor Occurrence probability of activations was 100% in M1 in both
c
eachBOLDcluster.Topreciselyanalyzeeachindividualfunctionaldata groups (Fig. 1E). Interestingly in volunteers activation in M1 was
i
set,astandardizedevaluationroutinewasemployedinwhichadynam- present in 69% of volunteers and was increased in patients to 91%.
icstatisticalthresholdwasapplied(Stippichetal.,2000,2002,2004, In volunteers occurrence probabilities of SMA/PMA and SPL/IPL
2005, 2007a). The empirically proven cluster size of 36mm3 was were100%and 88%respectively;in patientsoccurrenceprobability
takenasthestandardfordataevaluationsoastomostpreciselydeter- ofSMA/PMAandSPL/IPLwas99%(Fig.1E).
minetheanatomicalcorrelatesofthedifferentfunctionalactivationsby
alsoeliminatingverysmallclustersintheactivationmaps.Atfirst,a 3.3.DifferenttypesofM1lateralizationinbraintumorpatients
very high statistical threshold value for the correlation (r) between
themeasuredBOLDsignalandthehrfwasselectedsothatnofunctional For a more detailed analysis of primary motor cortex activation
activationwasdisplayed(emptymap).Thisthresholdwasthencontin- andinparticularinterhemisphericlateralizationbetweencontralat-
uallyreduced.Asaresult,theactivationwiththehighestcorrelationto eralandipsilateral M1activation wenormalizedr-valuesofactiva-
thehrfthatexceededtheclustersizeof36mm3wasdisplayedfirst tions in M1 to r-values of activations in M1 in each individual
i c
(Suppl.Fig.1).Byfurtherreducingthethreshold,activationinother patient and volunteer. The mean calculated relative r-values (r-
functionalareaswithalowercorrelationbetweenthemeasuredBOLD -values)showednosignificantdifferencebetweenvolunteersand
rel
signalandthehrfwasdisplayedinahierarchicalorder.Thisprocedure patients(Fig.2A,Table2).However,r -valuesofactivationsinvol-
rel
wascontinueduntiltheactivationwasidentifiedinallROIs.Aminimal unteersrangedfrom0.80to0.98,whereasr -valuesofactivations
rel
threshold of r=0.4 with a false discovery rate (FDR) of 0.05 was in patients were widely scattered from 0.67 to 1.14, indicating a
established as the lower limit. BOLD-responses with relative signal higher interindividual variability in the patient group ranging from
changes>5%wereexcludedfromevaluationandconsideredasartifacts normalvaluestoinversionofM1lateralizationduringcontralesional
mostlikelyreflectingvenouscontribution. movements.
InordertofurtherexaminethisvariabilityofM1lateralizationpa-
tientsweredividedinthreegroupsaccordingtothedeviationfrom
2.4.Statisticalanalysis thenormalactivationpatternofM1lateralization.Thefirstgroupin-
cludedpatientswithactivationinM1 butnoactivationinM1 and
c i
Results are presented as means±SD or individual data points patients with r -values comparable to those of M1-CoA in volun-
rel i
to show the distribution of the r-values for cases and controls. To teers (M1 >>M1; n=56). The upper inclusion limit for the first
c i
detect possible significant differences in the distribution of coordi- group was the 75% percentile of r -values of activations in volun-
rel
nates Wilcoxon-U-tests were calculated. P≤0.05 was considered to teers (r =0.94). The second group (M1 >M1; n=16) included
rel c i
224 M.Tozakidouetal./NeuroImage:Clinical2(2013)221–228
M.Tozakidouetal./NeuroImage:Clinical2(2013)221–228 225
patients with a small upward deviation of r -values (r -values of
rel rel
M1-CoA>0.94,butb1).Finally,thethirdgroupshowedmarkedabnor-
i
malM1activationswithaninversionofM1lateralization(M1 ≤M1;
c i
r ≥1; n=15) including those in which contralateral M1 activation
rel
haddisappeared.Individualandgroupdataofr -valuesofM1-CoA
rel i
areshowninFig.2BandTable2.Fig.3Ashowsschematically3types
of M1activation patterns. Representative fMRIof activationpatterns
areshowninFig.3B.
3.4.InfluenceoftumorcharacteristicsonM1activationpatterns
InordertobetterexplaintheunderlyingmechanismsofM1later-
alizationweexamineddifferentpotentiallyinfluencingfactorsinthe
three groups of M1 lateralization. However, only trends could be
identified.Despitethelargepatientpopulation,subgroupsweretoo
smallforproperstatisticalanalysis.Analysisofdistributionoftumor
typewithinthethreegroupsofM1lateralizationshowedthetrend
thatthemoreM1lateralizationwasaffectedthelargerthepercent-
ageofpatientswithmalignanttumorsandthelowerthepercentage
ofpatientswithgradeI-IIItumors(Fig.4A,Table3).Inordertoexam-
inetheinfluenceoflesionlocalizationweanalyzedthenumberoftu-
morsaffectingtheprecentralgyrus,thepostcentralgyrusand/orthe
superiororinferiorparietallobe(Fig.4B).Theprecentralgyruswas
affected in 73 patients, the postcentral gyrus in 63 patients and in
39 patients the superior or inferior parietal lobe was involved. In
totalwithinthethreegroupsthepre-andpostcentralgyruswassim-
ilarlyaffectedinalldegreesofM1lateralization(Fig.4B).However,
involvementoftheparietallobewasfoundin60%ofthepatientsin
thegroupwithinversionofM1lateralization,whereasonlyapproxi-
mately40%ofthegroup1patientsshowedparietalaffection.Clinical
dataconcerningmotordeficitswereavailablein73patients.Within
those patients more patients without deficits were found in the
group1patientspresentingwith“normal”M1lateralization,whereas
relativelymorepatientswithmotordeficitscouldbeidentifiedwhen
M1lateralizationwasaffected(Fig.4C).Regressionanalysisshowed Fig.2.M1lateralizationinvolunteersandpatientsbasedontheanalysisofr-values.
neither correlation between tumor volume and relative r-values (A)r-ValuesofactivationinipsilateralM1arepresentedasfractionofr-valueincon-
(Spearmanr=0.105;p=0.361)norcorrelationbetweenthepatients tralateralM1(rrel-values);volunteerspooleddataofrightandlefthand(n=22,outof
32measurements),patientmovementofthecontralesionalhand(n=79,in87pa-
ageandrelativer-values(Spearmanr=−0.033;p=0.774). tients).(B)ThreedegreesofM1lateralizationcouldbeidentified.The75%percentile
ofhealthyvolunteers(rrel=0.94)andtheinversionoflateralization(rrel=1)were
4.Discussion usedascriteriaforgroupseparation.
InthepresentstudyweusedBOLD-fMRItoassessthefunctionalor- arteriovenousmalformations(AVMs)(Alkadhietal.,2000),cerebral
ganizationofthemotorcorticalnetworkinpatientswithrolandicbrain hemorrhageorischemicstroke(StoeckelandBinkofski,2010).Simi-
tumors.Whenfocussingontheprimarymotorcortexactivation,theoc- lartoourresultsastudyon11patientswithAVMsshowedchanges
currenceprobabilityofipsilateralM1-co-activationwashigherthanin in primary motor cortex activations with prominent ispilateral
healthy controls, indicating tumor induced functional reorganization M1-co-activationin5cases,outofwhich3casesshowednoactiva-
inM1towardstheunaffectedside.TheobservedchangesinM1activa- tioninM1 (Alkadhietal.,2000).However,itisstillamatterofde-
c
tion ranged from slight reduction to complete abolishment or even bate whether increased ipsilateral M1 CoA is functionally relevant
inversion of M1 lateralization during contralesional movements. Pa- orratherrepresentsa maladaptiveprocess(Boroojerdietal.,1996;
tients with inversion of M1 lateralization showedthe trendto more StoeckelandBinkofski,2010).
likely suffer from grade IV tumors/metastasis and more frequently Evidence of functional relevance of ipsilateral activation arouse
displayed affection of the parietal lobe. Only in about 50% of our from TMS and fMRI studies in young patients with congenital
tumor patients the activation pattern in M1 remained physiological hemiparesesinwhichpatientswithlargeunilateralcerebrallesions
withapredominantM1activationofthehemispherecontralateralto ofvariousetiology(Staudtetal.,2002)aswellasinpatientssuffering
theperformedmovement. frommotor deficitsduetoischemicstroke(Stoeckeland Binkofski,
2010) displayed increased hand motor activation in the ipsilateral
4.1.M1lateralizationinpatientswithbraintumors primarymotorcortexofthenonlesionedhemisphere.Itwashypoth-
esized that this was due to enhanced connectivity of motor areas
Changes in M1 lateralization under pathological circumstances in the contralesional hemisphere (Gerloff et al., 2006) and altered
have been described previously, for example in patients with transcortical interactions (Nair et al., 2007; Stoeckel and Binkofski,
Fig.1.AnalysisofactivationofthemotorcorticalnetworkinhealthyvolunteersandpatientswithtumorsofthecentralregionusingBOLDfMRI.(A)Schematicdrawingofactiva-
tionsinM1,PMA,SMA,IPLandSPLand(B)exampleofnormalmotornetworkactivationinahealthyvolunteerduringmovementoftherighthand.Volunteers:(C)Comparisonof
rightandlefthandactivationshowednodifference.Meanr-valuesofactivationsinM1contralateraltotheperformedmovementorinipsilateralM1i,SMAi/PMAiorSPLi/IPLiduring
movementoftheleft(n=16)orright(n=16)hand.Comparisonsofvolunteersandpatients:(D)Pooledmeanr-valuesinvolunteers(n=32,leftpanel)comparedtopatients
(n=87,rightpanel).(E)Occurrenceprobabilitiesofthedifferentcorticalactivationsinvolunteers(n=32,leftpanel)andpatients(n=87,rightpanel).
226 M.Tozakidouetal./NeuroImage:Clinical2(2013)221–228
Table2 However,plasticchangesafterstrokearedrivenbysuddenonset
Relativer-valuesofM1activationsinvolunteersandpatients. irreversibledamage,whereasinpatientswithbraintumorschanges
Volunteers Patients are continuously induced by the neoplasm now allowing or even
askingforcontinuousadaptationalprocessesandmaythusdifferin
Total M1c>>M1i M1c>M1i M1c≤M1i clinicaloutcomeaswellasincorticalactivations.
No.ofindividualsa 16 87 56 16 15 Sofaronlyfewstudiesonbraintumorpatientsexaminedclinical
No.ofrrel-valuesb 22 79 48 16 15 deficits and functional cerebral changes. For example, in a recent
Mean 0.90 0.91 0.85 0.97 1.04
Std.deviation 0.06 0.10 0.07 0.01 0.05 studyOttenetal.usedrestingstatefMRIin22patientswithcerebral
Minimum 0.80 0.67 0.67 0.95 1.00 neoplasmsandcouldshowdecreasedmotornetworkconnectivityin
25%Percentile 0.84 0.85 0.81 0.95 1.00 patientswithmotorweakness,particularlyinterhemisphericconnec-
Median 0.91 0.92 0.87 0.97 1.01
tionsinM1wereaffected(Ottenetal.,2012).Furthermore,Shinoura
75%Percentile 0.94 0.98 0.91 0.98 1.09
etal.reportedacoincidenceofdiffusiontensorimaging(DTI)find-
Maximum 0.98 1.15 0.946 0.99 1.14
ings, motor reorganization and clinical deficits in a case series of
a Involunteersmeasurementswereperformedforleftandrighthand(32measure-
braintumorpatients(Shinouraetal.,2006).Therefore,thecharacter-
ments).
b Notethatrrelvalueswereonlycalculatedinvolunteers/patientswithactivationsin izationofstructuralchangesinwhitematterconnectionsunderlying
ipsi-andcontralateralM1. motor plasticity DTI combined with different fMRI techniques may
furtherimprovetheinsightsinfunctionalreorganizationinpatients
2010).However,whilesomestudiesreportedenhancedcontralesional withbraintumors.
M1activationespeciallyinwellrecoveredpatients(Nairetal.,2007),
anotherstudyconductedbyTakeuchietal.couldshowthatinparetic 4.2.Influenceoftumorcharacteristicsonactivationpatterns
strokepatientsinhibitedcontralesionalM1(TMS)generallyimproved
performance(Takeuchietal.,2005),indicatingthatcontralesionalM1 InthepatientgroupwithinversionofM1lateralizationmorelikely
activation in thosepatientsismaladaptiveandratherhindersmotor gradeIVlesionsormetastasiswasfound,indicatingthatfastgrowing,
performance. invasive lesions more likely induce plastic changes. In contrast the
Fig.3.ExamplesoffMRimagesdemonstratingdifferenttypesofM1lateralizationinpatients.(A)Schematicdrawingsand(B)examplefMRIofdifferentdegreesofM1lateralization:
Type1(leftcolumn)“NormalM1lateralization”representedbyCase11showingrobustM1activationcontralateraltotheperformedmovement.Type2(middlecolumn):Moderately
changedM1lateralizationrepresentedbyCase64.r-ValueofM1activationisstillhigherinM1cbutpronouncedipsilateralM1iactivationispresent.Type3(rightcolumn):Inversionof
M1lateralizationrepresentedbyCase85.r-ValueinM1iishigherthaninM1c.
M.Tozakidouetal./NeuroImage:Clinical2(2013)221–228 227
acquired in adulthood. Considerable experimental evidence suggests
thatrecoveryoffunctionafterCNSdamagedependsonthematurity
of the brain at the moment the damage occurred (Carr, 1996;
Passinghametal.,1983),implyingthatthebrainpossessesagreater
abilitytocompensatefunctionallossinitsimmaturethaninitsmature
state(Alkadhietal.,2000).
SofarinpatientswithbrainneoplasmsplasticchangesinM1have
mainly been examined using BOLD fMRI during a bimanual motor
task(Liuetal.,2005;Schreiberetal.,2000)oramotortaskwithalter-
nating movements of left and right hand (Carpentier et al., 2001),
without addressing the role of ipsilateral M1 Co activation and are
thusdifficulttocomparetoourfindings.Asfarascomparableourre-
sultsconcerninglessplasticchangesinpatientswithgradeI-IIIglio-
masareinlinewithastudybyCarpentieretal.(2001)thatshowed
onlyminimalplasticity(16patientswithgradeI-IIIgliomas,onepa-
tient with a glioblastoma). A study conducted by Schreiber et al.
(2000)showedthattheBOLDsignalisreducedneargliomasbutis
notaffectedbynonglialtumors.Thisfindingwaspartiallyexplained
previouslybydirecteffectsoftumormassonhemodynamics,asana-
lyzed with infrared imaging during cranial surgery (Gorbach et al.,
2004). Thus, lesion induced neurovascular uncoupling causing re-
duced fMRI signal in perilesional eloquent cortex, in conjunction
with normal or increased activity in the homologous brain region,
may simulate hemispheric dominance of the other hemisphere
and lesion induced cortical reorganization (Ulmer et al., 2004). In
thiscontextHouetal.examinedBOLDfMRIsignalsincorrelationto
cerebral blood flow during a bilateral finger task in patients with
intra-andextraaxiallesionsandfoundacorrelationbetweenactiva-
tionvolumeandregionalcerebralbloodvolumeingradeIVtumors
(Hou et al., 2006). This result could partially explain our finding
concerningmorepronouncedchangesinpatientswithgradeIVtumors.
InpatientswithinversionofM1lateralizationtheposteriorparie-
tal cortex was more likely affected. The posterior parietal cortex is
essentialforplanningofmovements.Itisimportantfortheintegration
ofvisual,acousticandsensoryinformationandthusplaysaroleinspace
Fig.4.Lesiontype,lesionlocalizationandmotordeficits.(A)Lesiontype:Distribution perceptionandguidingactions(CulhamandValyear,2006).Further-
of lesion type within different groups of M1 lateralization. Strongest effect on M1 more, it is connected to premotor cortical areas (Gharbawie et al.,
lateralization is found in high grade tumors and metastasis (B) Lesion localization: 2011;Wiseetal.,1997).Ourresultsimplythattumorinducedinterrup-
Percentageofpatientsinwhichthepre/postcentralortheparietallobewasaffected.Effect tionoftheparieto-frontalconnectionsisinvolvedinremodelingwithin
on M1 lateralization increases with parietal lobe involvement. Note that in various
M1.
patientsmorethanonegyruscouldbeaffected.(C)Motordeficit:Percentageofpatients
without(black)orwith(white)motordeficitsineachgroupofM1lateralization.Atypical InourpatientstumorvolumedidnotcorrelatewiththedegreeofM1
M1lateralizationismorepronouncedinpatientswithmotordeficits. lateralization.ThisfindingdiffersfromresultsofStaudtetal.(2002),who
couldshowthatlargelesionmorelikelyinduceplasticchanges.Howev-
resultsoftheabovementionedstudyonpatientswithAVMswhichare er,theseauthorsexaminedahomogeneousgroupofpatientswithwell
regarded as non-invasive/slow growing lesions point to prominent definedbraindefectsresultingfromintrauterineperiventricularwhite
reorganization in contralesionalM1 in thosepatients (Alkadhi et al., matterlesions,whereasinmanyofourtumorpatientstheprecisedeter-
2000).Hence,onecouldexpectthatslowgrowinglesionsinourstudy minationoftumorvolumeswasdifficult,sincetumorborderswereoften
suchaslow grade gliomas would inducemore prominentipsilateral illdefined(asingliomasorotherinvasivemalignancies).Thetumorex-
M1 activation.Thosedifferencesmightbeexplainedbythefactthat tentvisibleonMRdependsontheMR-sequencesapplied(T2,T2-FLAIR,
AVMs represent vascular lesions acquired in infancy or perinatally T1with/withouti.v.contrast,etc.).MRisnotcapabletovisualizetumor
whereas the brain neoplasms in our patient group are still mainly cellsandthereforetodeterminethecorrectextentoftumorinvading
brain parenchyma including white matter tracts, which is driving
motorreorganization.
Table3
CharacteristicsofpatientgroupsofM1lateralization.
Noofpatients 4.3.Limitationsofthestudy
Total M1c>>M1i M1c>M1i M1cbM1i
Althoughweincludedatotalof87patientsinthisstudy,which
87 56 16 15
GradeI–IIItumors 48 32 11 5 is a large group compared to other studies on the topic so far, the
GradeIVtumors/metastasis 39 24 5 10 observedplasticityeffectsweredifficulttoquantifystatistically.We
Precentralgyrusaffected 74 47 12 13 observed not only changes in M1 lateralization but also increased
Postcentralgyrusaffected 62 38 11 13
occurrenceprobabilityofipsilateralM1activation,whichcannotbe
IPL/SPLaffected 39 22 8 9
Nomotordeficits 28 19 7 2 attributedtodirectlesioninducedhemodynamiceffects.Eventhough
Motordeficits 43 25 8 10 corticalplasticityappearstobeinfluencedbylesiontypeandlesion
Age±std 41.7±14.7 46.3±15.4 49.2±14.5 49.2±13.1 location,thereisnoconsistentpatterninourpatientgroup.Also,it
Tumorvolume(cm3) 41.2±36.6 37.7±31.0 52.9±36.8 45.5±47.0
isnotyetclearwhetherthesechangesareonlyanepiphenomenon
228 M.Tozakidouetal./NeuroImage:Clinical2(2013)221–228
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