Fibre-specific laterality of white matter in left and right language dominant people

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NeuroImage

journalhomepage:www.elsevier.com/locate/neuroimage

Fibre-specific laterality of white matter in left and right language dominant people

Helena Verhelst

, Thijs Dhollander

, Robin Gerrits

, Guy Vingerhoets

aDepartment of Experimental Psychology, Ghent University, Belgium

bDevelopmental Imaging, Murdoch Children’s Research Institute, Melbourne, Australia

a r t i c le i n f o

Keywords:

Laterality Asymmetry Language Diffusion MR Fixel ‐based analysis White matter

a b s t r a ct

Languageisthemostcommonlydescribedlateralisedcognitivefunction,relyingmoreonthelefthemisphere comparedtotherighthemisphereinover90%ofthepopulation.Mostresearchexaminingthestructure-function relationshipoflanguagelateralisationonlyincludedpeopleshowingaleftlanguagehemispheredominance.In thiswork,weappliedastate-of-the-art"fixel-based"analysisapproach,allowingstatisticalanalysisofwhitemat- termicro-andmacrostructureonafibre-specificlevelinasampleofparticipantswithleftandrightlanguage dominance(LLDandRLD).Bothgroupsshowedasimilarextensivepatternofwhitematterlateralisationin- cludingacomparableleftwardslateralisationofthearcuatefasciculus,regardlessoftheirfunctionallanguage lateralisation.Theseresultssuggestthatlateralisationoflanguagefunctioningandthearcuatefasciculusare drivenbyindependentbiases.Finally,asignificantgroupdifferenceoflateralisationwasdetectedintheforceps minor,withaleftwardslateralisationinLLDandrightwardslateralisationfortheRLDgroup.

1. Introduction

Although the human brain mayappear to be a symmetrical or- ganatfirstsight,amplestudieshaverevealedspecificdifferencesbe- tweentheleftandrighthemispheres,bothfunctionallyandstructurally (GüntürkünandOcklenburg,2017).Regardingfunctionallateralisation, thereisbroadconsensusonwhichfunctionstypicallylateralisetowhich hemisphere(Vingerhoets,2019).Forexample,oneof thebestdocu- mentedandrobustpopulation-basedbiasesrelatestolanguagefunction, whichispredominantlydrivenbythelefthemisphereinwellover90%

ofthepopulation(Mazoyeretal.,2014;VanderHaegenetal.,2013; Westerhausenetal.,2014).Regardingstructuralasymmetry,however, theliteratureismoreambiguous.Themoststudiedwhitemattertract withrespecttolateralisationisthearcuatefasciculus,aperisylvianpath- wayconnectingimportantlanguagerelatedregions,includingBroca’s andWernicke’sareas(Catanietal.,2005).Severalstudieshaveshowna leftwardslateralisationofthiswhitematterbundle,onboththemacro- andmicroscopicscale(Bainetal.,2019;Catanietal.,2007;Slateretal., 2019).The lateralisation patterns forother tracts areless examined andreportedresultsaresometimesinconsistent.Theuncinate,forex- ample,hasbeen foundto be rightwardslateralised bysome studies (Highleyetal.,2002;Parketal.,2004),whileothersreportaleftwards lateralisation(Ocklenburgetal.,2013;Slateretal.,2019)oranabsence

∗Correspondingauthor:DepartmentofExperimentalPsychology,GhentUniversity,HenriDunantlaan2,9000Ghent,Belgium E-mailaddress:helena.verhelst@ugent.be(H.Verhelst).

1 Theseauthorscontributedequallytothiswork

ofstructuralasymmetry(Mannaertetal.,2019;ThiebautdeSchotten etal.,2011).

Whitematterstructurelikelyplaysaroleinthedevelopmentoffunc- tionallateralisationasitlinksdifferent greymatterregions responsi- bleforcognitivefunctioning(Ocklenburgetal.,2016).Severalstudies havereportedontherelationshipbetweenthedegreeoffunctionaland structurallateralisationofcognitivefunctioning.ThiebautdeSchotten andcolleagues,forexample,foundacorrelationbetweendiffusionMRI- derivedmetricsoflateralisationofthesuperiorlongitudinalfasciculus andvisuospatialfunctioning(ThiebautdeSchotten,Dell’Acqua,etal., 2011).Acorrelationbetweenbrainactivationduringlanguage-related tasks andstructural asymmetries in white matterhasbeen reported inmultiplestudies;inchildren,aswellashealthyadultsandclinical groups(forareviewseeOcklenburgetal.(2016)).However,mostof thesestudieswereperformedinright-handers,whoonlyrarelydemon- straterightwardlanguagelaterality.Assuch,thereportedcorrelations donotallowtoconcludethatthedirectionoffunctionallateralisation isrelatedtothedirectionofstructurallateralisationoflanguage.Only asinglestudy,byVernooijetal.(2007),examinedwhitematterasym- metriesinasamplewhichincludedfiveleft-handedparticipantswith a righthemisphericlanguagedominance.Regardlessof thedirection offunctionallanguagelateralisation,aleftwardsasymmetryinrelative streamlinecount(asderivedfromfibretractography)ofthearcuatefas- ciculuswasreported.TheresultsofVernooijandcolleaguessuggestthat

https://doi.org/10.1016/j.neuroimage.2021.117812

Received27October2020;Receivedinrevisedform23December2020;Accepted20January2021 Availableonline30January2021

1053-8119/© 2021PublishedbyElsevierInc.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/)

structuralasymmetryofthearcuatedoesnotnecessarilyreflectfunc- tionalhemisphericlanguagelateralisationaspreviouslyhypothesized intheotherstudies.

Mostworkon structurallateralisationtodatehasreliedondiffu- siontensorimaging(DTI) derivedmetrics, like fractionalanisotropy (FA)ormeandiffusivity(MD).IthasbeenshownthatDTI-basedmet- ricsarenot capableofcapturingmultiplefibreorientationswithin a voxel—oftenreferredtoas“crossingfibres”—whichappeartobevery prevalentacrossthewhitematter(Jeurissenetal.,2013).Additionally, whileDTImetricshaveproventobesensitivetocertainwhitematter changes,theyarenonspecifictochangesinpropertiesofindividualfi- brepopulations,oftenleadingtonon-intuitiveeffectsandmisleading interpretationinthepresenceofcrossingfibres(Mitoetal.,2018).To overcometheselimitations,thefixel-basedanalysis(FBA)framework wasrecentlyproposed.FBAenablesthequantificationof micro-and macrostructuralpropertiesthatareassociatedwithspecificfibrepop- ulationswithinavoxel(named“fixels”)(Raffeltetal.,2017).Thisap- proachthusallowstheinvestigationofdistinctorevenoppositelateral- ityeffectsofmultiplefixelswithinonevoxel,makingitespeciallyuseful instudyingwhitematterasymmetries.FBAstudiestypicallyachievethis usingthreemetrics:fibredensity(FD),fibre-bundlecross-section(FC) andfibredensityandcross-section(FDC).FDisproportionaltothetotal intra-axonalvolumeofaxonsalongtheorientationofafibrepopulation ineachvoxel(i.e.amicrostructuralmeasure,relatedtohowdenselyax- onsarepacked),whereasFCisproportionaltothecross-sectionalarea ofthewhitematterbundleintheregionofeachfixel(i.e.amacrostruc- turalmeasure).FDC,definedsimplyastheproductofFDandFC(i.e.the localdensitytimestheoverallsize),isthussensitisedtooverallchanges tothepresenceofaxonalmatterforindividualfibrepopulationsineach voxel.EventhoughFBAisarelativelyrecentlydevelopedmethod,ithas proventobeafavourabletechniquetoexaminewhitematterproperties inseveralstudies.Ithasalreadybeenusedinarangeofdifferentclinical groups(includingParkinson’sdisease(Rauetal.,2019),traumaticbrain injury(Verhelstetal.,2019),stroke(Egorovaetal.,2020),multiplescle- rosis(Gajamangeetal.,2018),depression(Lyonetal.,2019),autism spectrumdisorder(Dimondetal.,2019),andAlzheimer’sdisease(Mito etal.,2018))andinhealthycohorts(Choyetal.,2020;Dimondetal., 2020;Gencetal.,2018).

Inthecurrentstudyweaimedtoexaminestructuralwhitematter asymmetriesinanunprecedentedsampleof23left-handerswithright languagedominance(RLD),complementedwithagroupof38individu- alswithleftlanguagedominance(LLD),toextendpreviousresearchon thestructure-functionrelationshipoflanguage.Wedecidedtorecruit left-handersonly,asRLDismoreprevalentinleft-comparedtoright- handers(CareyandJohnstone,2014;Knechtetal.,2000).Weapplied astate-of-the-artFBAapproachanddefinedabespokefixel-wiseasym- metrymeasureorlateralityindex(LI)designedfortheFD,FCandFDC metrics.Thisenabledustoquantifyanddetectsignificantasymmetries inwhitemattermicro-andmacrostructureacrossallwhitematterfor participantswithleftandrightlanguagedominance,aswellastoquan- tifyanddetectsignificantrelativedifferencesoflateralisationbetween thesegroups.

2. Methods 2.1. Participants

Aspeoplewitharight(hemisphere)languagedominance(RLD)are uncommon,a specificrecruitment strategy waspursued. Individuals withsuspectedRLD(basedonabehaviouralvisualhalffieldtest)were invitedtoparticipateinthestudy.Withtheaimofincreasingthelike- lihoodofidentifyingpeoplewithRLD,welimitedtheinclusionforour studytoleft-handersonlyasithasbeenshownthatRLDismorelikely tooccurinleft-handers(15%to34%ofleft-handerscomparedtoonly 4%to14%ofright-handers(CareyandJohnstone,2014;Knechtetal., 2000)).TheclassificationoftheparticipantsasRLD orleftlanguage

dominant(LLD)wasperformedinapreviousstudy.Detailsofthere- cruitmentprocedureandtheclassificationaredocumentedelsewhere (Gerritsetal.,2020).Inshort,categorisationwasbasedonfMRIacti- vation patternsduringaletterfluencytask combinedwithanactive baseline. This approach has been well establishedand producesro- bust lateralisationpatterns(Bradshawetal., 2017).Thesamplecon- sistedof24participantswithRLDand39withLLD.OneLLDandone RLD participantwereexcluded,respectivelydue toacallosalabnor- malityvisibleontheT1wanddiffusionMRI(dMRI)scansandimag- ingartefacts. This resulted ina finalsampleof 23 RLD and38LLD participants.

TheLLDandRLDgroupsdidnotdiffersignificantlyintermsofage (LLD:20±3.98years,RLD:20±3.50years,U=463.50,p=0.69), sexdistribution(LLD:34/4,RLD:20/3females/males,𝜒²(1)=0.09, p=0.77),oryearsofformaleducation(LLD:14±1.66years,RLD:

14 ±1.56years,U=446.50,p=0.89).Allparticipantshadnormal orcorrected-to-normalvisionandreportednohistoryofbraininjuryor developmentaldisorders.Thestudywasapprovedbythemedicalethical committeeofGhentUniversityHospital.Writteninformedconsentwas obtainedfromeachparticipant.

2.2. MRIdataacquisition

MRIdatawereacquiredusinga3TSiemensPRISMAscannerwitha 64-channelheadcoil.DiffusionMRI(dMRI)datawasacquiredfor6,23, 42and70non-collineargradientdirectionsrespectivelyusingb-values of0,700,1200and2800s/mm².Additionally,anextrapairofb=0 imageswasacquiredusingoppositephaseencodings,toallowforcor- rectionofsusceptibilityinducedEPIdistortions.Otheracquisitionpa- rametersareasfollows:2mmisotropicvoxelsize,75slices,FoV=240 mmx240mm,TR/TE=3300ms/76ms.

2.3. Fixel-basedanalysesoflaterality

2.3.1. Fixel-basedanalysisprocessingpipeline

Afixel-basedanalysis(FBA)approachwasusedtoenablefixel-wise quantificationandstatisticaltestingoffibre-specificlateralityofwhite matter.FBAwasimplementedusingMRtrix3(Tournieretal.,2019)in accordancewiththerecommendedprocedures(Dhollanderetal.,2020; Raffeltetal.,2015,2017)andadaptedwherenecessarytopermitthe calculation ofbespokelaterality indices(LIs)forthe traditionalFBA metrics.

PreprocessingofthedMRIdataincludeddenoising(Veraartetal., 2016),removal of Gibbsringingartefacts(Kellneretal., 2016),and motion,eddy-current,andEPIdistortioncorrections(Anderssonetal., 2003,2016;AnderssonandSotiropoulos,2016).Afterupsamplingthe preprocessed data toa 1.5mm isotropic voxel size, the whitemat- terfibreorientationdistributions(FODs)wereestimatedbya3-tissue constrainedsphericaldeconvolutionapproach(Jeurissenetal.,2014) using thegroupaveragedtissueresponsefunctionsforwhitematter, grey matterandcerebrospinal fluid(Dhollander etal., 2016, 2019).

Multi-tissue informed log-domain intensity normalisation was per- formedtocorrectforbiasfieldsandglobalintensitydifferencesbetween participants.

Todeterminethehomologousfixelpairs(i.e.correspondingleftand righthemispherefixels),additional“mirrored” FODimageswerecre- atedforallparticipantsbyflippingtheimagedataalongtheleft-right axis(includingsimilarlyflippingtheFODineachvoxel).Next,astudy- specificunbiasedandsymmetricFODtemplatewasgeneratedbasedon asubsetoftheparticipants,usingasimilarapproachtopreviousstud- ies(HonnedevasthanaArunetal.,2021;Raffeltetal.,2017).Tothis end,30individuals(15RLDand15LLD)wererandomlyselected.The symmetric templatewas thenconstructedbyregistering the60 FOD images(both30“original” and30flipped)usinganiterativenonlinear registrationandaveragingapproach,whichincludesFODreorientation (Raffeltetal.,2011).ByregisteringboththeoriginalandflippedFOD

imagesofeachparticipanttothesymmetricgrouptemplate,FODsinthe righthemisphereoftheoriginalFODimageweremappedtothecorre- spondingFODsinthelefthemisphereoftheflippedFODimage(and viceversa).Next,afixelanalysismaskwasdefinedbysegmentingthe individualfixelsfromthesymmetricpopulationFODtemplatesubjectto anFODamplitudethresholdof0.9(Raffeltetal.,2017).Similarly,fix- elswerealsosegmentedfromtheindividualsubjectFODimages(both

“original” andflipped)intemplatespace.Finally,correspondencewas establishedbetweeneachfixelinthefixelanalysismaskandamatch- ingfixelineachindividualsubjectFODimage(“original” andflipped) intemplatespace.Theresultingcorrespondingfixelsofanindividual subjectaresubsequentlyconsideredhomologousfixelpairs.Thisthen allowstocomputelateralityindicesusingmetricsofeachfixelpair,as wellastocomparesuchlateralityindicesacrossdifferentparticipants, whosehomologousfixelpairsaresimilarlymappedtothefixelanalysis mask.

Thethreetraditionalfixel-wiseFBAmetricswerethencomputedfor allparticipants.Theapparentfibredensity(FD)wascomputedasthe integraloftheFODlobecorrespondingtoeachfixel.Thefibre-bundle cross-section(FC)metricwascomputedbasedonthewarpsthatwere generatedduringregistrationtothesymmetricFODtemplate,asthe Jacobiandeterminantin theplaneperpendiculartothefixelorienta- tion(Raffeltetal.,2017).Finally,thecombinedmeasureoffibreden- sityandcross-section(FDC)wascalculatedastheproductofFDand FC.

2.3.2. Fixel-wiselateralityindexandfixelanalysismask

Foreach homologous fixelpair (i.e.rightandcorresponding left hemispherefixel),wedefinedabespokelateralityindex(LI)foreach FBAmetric,asthe(natural)log-ratiooftherightandlefthemisphere metricvalues.Forexample,thefixel-wiseLI(FD)isdefinedas:

LI(FD)=log(FD_right/FD_left)

BothLI(FC)andLI(FDC)aredefinedanalogously.AnLIvalueof0 indicatesabsenceoflateralisation,whereasapositiveLIvaluequanti- fiesthedegreeofrightwardslateralisationandanegativeLIvaluethe degreeofleftwardslateralisation.Thelog-ratioistheonlymeasureof relativedifferencefeaturingthecombinationofthreefavourableproper- ties:itisnormed,symmetricandadditive(Tornqvistetal.,1985).This differsfromthesomewhat“traditional” indexofrelativedifferenceoften usedinlateralisationresearch(e.g.forfunctionalMRIdata),whichis computedasthedifferencedividedbythesum,sometimesmultipliedby aconstant(Seghier,2008).Thelatteris,however,boundedandthere- forelackstheadditivityproperty.InAppendixA,weprovideabrief comparisonofbothmetricsforintuitionastohowtheyrelatetoeach other.

In practice, we computed the LI value from the corresponding fixel-wise values of the “original” and flipped subject images, e.g., log(FD_original/FD_flipped).Hence,in therighthemisphereof thefixel analysismask,thisevaluatestotheLIvalueasdefinedabove.Theleft hemisphereofthefixelanalysismaskthereforeservesnoadditionalpur- posetoouranalysis(itrepresentsthenegativeLIvalue,duetosymmetry ofbothtemplateandLI).Finally,apracticalchallengeintroducedbythe FBAframeworkliesinthefactthatcorrespondencebetweensomefix- elsoftheanalysismaskandthoseofindividualparticipantssometimes cannotbeestablished.WhilethisposesnoproblemsfortheFCmetric (whichcanalwaysbederivedfromthesubject-to-templatewarpcom- binedwiththefixelsintheanalysismask),theFDvalueinthiscaseis typicallysettozero(Raffeltetal.,2017).Thismightintroducebiases inFBAingeneral,butposesauniquechallengeforthelog-ratioinour definitionofLI,whichthencannotbeevaluated.Inthiswork,wemit- igatethisproblembysetting theFDtoanon-zero lowvalueof0.01 instead(thisequals1%ofonecalibratedunitofFD).Additionally,we furtherrestrictthefixelanalysismasktoonlycontainfixelsforwhich correspondencewithatleast 90%ofallparticipanthemisphere data couldbeestablished.Partofthefinalfixelanalysismaskisshownin Fig.1.

2.3.3. Fixel-wisestatisticalanalyses

Non-parametricpermutationtesting(with5000permutations)was performedusing connectivity-basedfixelenhancement(Raffeltetal., 2015)withinMRtrix3(Tournieretal.,2019).Family-wiseerror(FWE) correctionswereappliedtocontrolforfalsepositivesforallteststhat wereperformed.

First,weseparatelytestedtheRLDgroup,theLLDgroup,aswellas bothgroupscombined(labelled“ALL”)forsignificantfixel-wiseright- wardslateralisation(LI>0) orleftwardslateralisation(LI<0),and thisalsoseparatelyforeachoftheFD,FCandFDCmetrics.Thiswas achievedwithone-samplet-tests(usingrandomsign-flipping).

Relativedifferencesinlateralisationbetweenbothgroupshowever, cannottriviallybederivedfromthoseaforementionedindividual(one- sample)tests.Tothisend,anadditionalcross-sectionalcomparisonbe- tweenRLDandLLDwasperformedtoexaminerelativegroupdifferences in lateralisationbycomparing LI(ofFD,FCandFDC)betweenboth groupsusingtwo-samplet-tests(LI_LLD<LI_RLDandLI_LLD>LI_RLD).Note thatasignificantoutcomeofsuchatestcanresultfromarangeofun- derlyingscenarios.Forexample,thescenariomightbeoneofopposite directionsoflateralisationbetweenthegroups.Butitmightalsobea caseofonegroupshowinglittletonolateralisationwhereastheother onedoes.Itcouldevenresultfrombothgroupspresentingwithlaterali- sationinthesamedirection,butwithasignificantlydifferentdegree.If asignificantresultwasfound,afurtherexplorationofaveragevaluesof bothgroupsinbothhemisphereswasperformedtodeterminetheexact cause.

3. Results

3.1. Fibre-specificasymmetriesinwhitematter

Fig.2showstheresultfortheone-samplet-testsofLI(FDC)forthe

“ALL” (combined)group,asanexampleofhowfixel-wiseresultsofthese testscanbeunderstoodaswellashowtheywillbevisualisedinthis work.Theimagein panelAandthezoomedregions inpanelsBand Cpresentthecombinedsignificant(p<0.05)fixel-wiseresultsforboth rightwardslateralisation(LI(FDC)>0,inorange)andleftwardslateral- isation(LI(FDC)<0,inblue).Thesignificantfixelsareasubsetofthe fixelanalysismask(showninFig.1).NotethattheFBAapproachallows forfixel-specificresults,wherebyfixelsrelatedtospecificwhitematter bundlescanindividuallypresentassignificantornot,eveninthesame voxel.Inourlateralityanalyses,wefoundseveralregionswherediffer- entcrossingfibrepopulationsinthesameregion(ofvoxels)evenpre- sentedwithsignificantlateralisationinoppositedirections;i.e.regions whereorangeandbluecolouredfixelscross.Thevisualisationusingfix- elsthemselves(asshowninFig.2,panelB)ishardertoinspectvisually forlargeregionsorentire3Dvolumes.Tomitigatethis,avisualisation ofthesameresultusingacroppedstreamlinestractogram(derivedfrom thepopulationFODtemplate)isused,asshowninFig.2,panelC.Note thisismerelyanalternativevisualisationofthesameresult,whichhas thebenefitofappearingvisuallydenser.

InFig.2,panelsDandE,theeffectsizeisshownforthesignifi- cantfixels(rightwardsandleftwardsrespectively).Thisrepresentsthe averageLI(FDC)withinthepopulation(whichisunbiasedduetothe additivitypropertyofthelog-ratioLImetric;seealsoAppendixA).For reference,aneffectsizeof0.5(whiteonthehotcolourscaleusedin Fig.2)representsanFDC_right/FDC_leftratioofexp(0.5)=1.65(whereas redandyellowrepresentratiosof1.18and1.40respectively).Thesame holdssymmetricallyfortheoppositedirectionoflateralisation.

Fig.3providesanoverviewoftheresultsofallone-samplet-testsfor eachgroup(ALL,LLDandRLD)andeachFBAmetric(FDC,FDandFC).

Theresultsarepresentedusingthesamestyleofvisualisationemploying acroppedstreamlinestractogram,asinFig.2,butinafull3Dglassbrain volumetricvisualisation.Asbefore,allresultsaredisplayedwithinthe righthemisphere.Adetailedslice-wiseoverviewofeachseparateresult, aswellasalleffectsizes,isprovidedinthesupplementarydocument.

Fig.1. Thefinalfixelanalysismaskusedforallstatisticalanalysesinthiswork.Itincludesonlyfixelsinasinglehemisphere,sincethelateralityindicesarecomputed fromapairofcorresponding(leftandrighthemisphere)fixelsinthebrain.Here,thisisvisualisedintherighthemisphereofthetemplate(radiologicalconvention).

Itisfurthermorerestrictedtofixelsforwhichcorrespondencewithatleast90%ofallparticipanthemispheredatacouldbeestablished.

Fig.2. Fixel-wiseresultsfortheone-sampletestsofLI(FDC)forthe“ALL” (combined)group.PanelsA-B:fixelswithsignificantlateralisationarecolour-coded.

Orangeindicatesrightwardslateralisation(LI>0)andblueindicatesleftwardslateralisation(LI<0).PanelC:astreamlinestractogramiscroppedtodisplay segmentsthatcorrespondtosignificantfixelsonly.PanelsD-E:effectsizesquantifythedegreeoflateralisationtotherightandtothelefthemisphererespectively.

Theresultsforallgroupsandallmetricsshowlargeandextended partsofseveralwhitematterfibrebundles.Interestingly,amixofright- wardsandleftwardslateralisationofdifferentstructuresisseenacross thebrainvolume.Broadly,all groupsshow averysimilarpattern of results,wherebytheresultsappearslightlymoreextendedintheLLD groupascomparedtotheRLDgroup,aswellastheALLgroupcompared

tobothothers.Thisisinlinewiththerelativenumbersofparticipants ineachgroup,wherebytheanalysesforlargersamplesizeshavemore statisticalpower.TheFDCresultshavesomefeaturesincommonwith bothFDaswellasFCresults,thoughappeartooverallresembletheFD resultsslightlymore.

Fig.3. Visualisationofacroppedstreamlinestractogramreflectingfixelswithsignificantlateralisationinfibredensity(FD),fibre-bundlecross-section(FC)and fibredensityandcross-section(FDC)withinagroupofleftlanguagedominant(LLD)andrightlanguagedominant(RLD)participantsandbothgroupscombined (ALL).Streamlinescolouredinorangeareindicativeofarightwardslateralisation(LI>0),whereassignificantleftwardslateralisationisshowninblue(LI<0).

Theareas showinglateralisation of FDC totheright hemisphere includefixelclusterslocatedintheanteriorpartofthearcuatefasci- culus,theanterior limboftheinternal capsule,theanterior andsu- periorcoronaradiata,thebody of thecorpuscallosum,theinferior- fronto-occipitalfasciculus,theuncinate,themiddlecerebralpeduncle, thegenuofthecorpuscallosumandpartofthebodyofthecorpuscal- losum.

LeftwardslateralisationofFDCwasfoundinfixelclustersbelonging tothelongsegmentofthearcuate,inferiorlongitudinalfasciculus,cin- gulum(includingthetemporalpart),fornix,externalcapsule,posterior partsofthebodyofthecorpuscallosum,inferiorandsuperiorcerebel- larpeduncles,posteriorthalamicradiation,corticospinaltract,posterior partsofthesuperiorcoronaradiata,theposteriorlimboftheinternal capsuleandthesuperiorlongitudinalfasciculus.

TheresultsfromtheFDandFCanalysesshowbothsimilaraswellas additionallateralisationpatterns.ForFC,arightwardslateralisationof theforcepsmajorwasfound.Moreover,theleftwardslateralisationof FDCintheposteriorlimboftheinternalcapsuleandtheposteriorpart ofthesuperiorcoronaradiatais mainlysupportedbyalateralisation effectinFC.Ontheotherhand,theleftwardslateralisationofFDCin thecingulumisonlysimilartoalateralisationeffectinFDinthesame structure.

3.2. Relativegroupdifferencesoffibre-specificasymmetriesinwhitematter

TheonlysignificantdifferencebetweentheLLDandRLDgroupswas foundforLI(FC)inaclusteroffixelsintheforcepsminor,awhitemat-

terfibrebundlewhichconnectsthelateralandmedialsurfacesofthe frontallobesandcrossesthemidlineviathegenuofthecorpuscallosum (Fig.4,panelA).ThedifferenceissuchthatLI(FC)issignificantlylarger fortheRLDgroupcomparedtotheLLDgroup.Hence,thiscanbeunder- stoodastheRLDgroupshowingrelativelymorerightwardslateralisation comparedtotheLLDgroup.

Asmentionedbefore,thiseffectcanresultfromdifferentkindsof underlyingscenariosandwecannottriviallyassumethelateralisation norFCvaluesthemselvesjustfromtheoutcomeofthistestalone.To betterappreciatethefullcomplexityofthepresenteffect,weplotted theaverage(acrossthesignificantregionoffixels)ofFCvaluesforboth groupsandbothhemispheres(Fig.4,panelB).Thisreveals,onaverage, thenatureoftheeffect:arightwardslateralisationin theRLDgroup andaleftwardslateralisationintheLLDgroup.Moreover,bothgroups showsimilarFCvaluesfortherightsideoftheforcepsminor,whilethe LLDgroupshowshigherFCvaluesontheleftsidecomparedtotheRLD group.

Finally,notethattheeffectsize(Fig.4,panelA)isexpressedasthe differencebetween theLIvalues fortheRLD andLLDgroups.Since thisisadifferenceoftwolog-ratios,andduetotheadditivityproperty (AppendixA),itisitselfaproperunbiasedrelativedifference(andeven alog-ratio:thelogarithmoftheratiooftheratios).

4. Discussion

Thisstudyexaminedwhitematterasymmetries,bothonamacro- andmicrostructurallevel in ahealthysample ofleft-handed partici-

Fig.4. PanelA:Significantresultsforthetwo-sampletestcomparingthelateralisationindexoffibre-bundlecross-section(LI(FC))betweentheleftlanguagedominant (LLD)andtherightlanguagedominant(RLD)group.ThegroupdifferenceissuchthatLI(FC)issignificantlylargerfortheRLDgroupcomparedtotheLLDgroup.

Fixelspresentingwithasignificantgroupdifferencearevisualisedusingacroppedstreamlinestractogramandcolouredbyeffectsize.Positivevaluesreflecta relativelystrongerrightwardslateralisationintheRLDgroupcomparedtotheLLDgroup.PanelB:AverageFCvaluesofthesignificantregionoffixelsforboth groupsandbothhemispheresshowonaveragealeftwardslateralisationofthisregionintheLLDgroupandarightwardslateralisationintheRLDgroup.Errorbars indicatethestandarderror.

pantsusingafixel-basedanalysisapproach.Extensiveareasofsignif- icantlateralisationwerefoundinbothdirections,whichwerelargely compatiblewithpreviousstudies.Thelongsegmentofthearcuatefas- ciculusforexampleshowedaleftwardslateralisation inbothmacro- andmicrostructure,as reportedbefore in avoxel-based wholebrain study(Ocklenburgetal.,2013),tractspecificDTIstudies(Bainetal., 2019; Cataniet al., 2007; Jamesetal., 2015),andin a recentFBA study(HonnedevasthanaArunetal.,2021).Similartoastudyinclud- ingleft-handersbyVernooijetal.(2007)thecorticospinaltract was lateralisedtothelefthemisphere.Otherstructuresthatshowedasym- metriestowardstheleftincludedpartofthecingulum(analogousto (Honnedevasthana Arunetal.,2021;Slater etal.,2019))andthein- feriorlongitudinalfasciculus (comparableto(HonnedevasthanaArun etal.,2021; ThiebautdeSchottenetal., 2011)).Withregardtothe uncinate,arightwardslateralisationwasfound,whichagreeswithpre- viousfindings(HonnedevasthanaArunetal.,2021;Highleyetal.,2002; Parketal.,2004).Additionally,arightwardslateralisationwasobserved forpartsoftheinferiorfronto-occipitalfasciculusandtheanteriorseg- mentofthearcuatefasciculus.

Fromthese resultsitis clearthatwhitematterdistribution, both atmicroscopicaswellasmacroscopicscales,isfarfromsymmetricin thehumanbrain. Thiswidespread structuralhemisphericasymmetry hasimportantimplicationsforclinicalstudieswherepatients’images areoftenflippedacrossthemidlinetoaligntheaffectedhemispheres, forexampleinstudieswithstrokeorepilepsy(e.g.(Baueretal.,2020; Pinteretal.,2020;Visseretal.,2019)).Withoutcaution,thispractice mightresultinfalsepositivefindingsrelatedtotypicalasymmetriessuch asthosefoundinourcurrentwork.Firstofall,itislikelyimportantto flipthesameproportionofimagesofhealthycontrolgroupsinorderto matchthedistributionsofstructuralasymmetriesortotaketheflipping intoaccountbyaddingtheflippingasacovariateofnon-interest(e.g.

(Raffeltetal.,2017;Vaughanetal.,2017)).Secondly,however,thiswill likelyincreasevariabilityinallsubjectgroupsinsuchanalyses,andthus decreasethepowertodetectsubtlegroupdifferences.Finally,effectsof lateralisedpathologiesmightthemselvesofcoursealsopresentdiffer-

entlydependingonthedirectionoflaterality.Theymighteveninteract differentlywiththeexistinglateralisedstructureofwhitematterinboth hemispheres.Takingallofthisintoaccount,itmightthusbeadvisable toevenavoidthebrainflippingstrategyaltogetherinsuchstudies,and ratheranalysebothpatientgroupsseparately.Thelatterapproachwas forexampletakenbyEgorovaetal.(2020),whocomparedleftandright sideinfarctedstrokegroupsseparatelytocontrols,toallowforgreater specificityinresults.

Studiesexaminingtherelationshipbetweenleft-rightasymmetries and language functioningto date, have almost exclusively included left languagedominant(LLD)participants(Ocklenburg etal., 2016).

They have reportedsignificantcorrelations betweenbrain activation duringlanguagetasksandstructuralasymmetries basedon diffusion MRIdata, andconcludedthatthese anatomicalasymmetriesmayre- flectorevencausefunctionallanguagelaterality.However,bynotin- cludingrightlanguagedominant(RLD)participants,thishypothesized structure-functionrelationshiphasremainedspeculative.Tofurtherun- covertherelationshipbetweenfunctionalandstructurallanguagelat- eralisation,ourpresentstudyincludedarelativelylargesampleofpar- ticipantswithRLD.Surprisinglyfewdifferenceswerefoundwhencom- paringwholebrainlateralisationpatternsofwhitematterbetweenthe LLDandRLDgroups.Moreover,nobetween-groupdifferencesofstruc- turalasymmetrywerefoundinthearcuatefasciculus.Theabsenceof a groupresultin thistract is nottheresultoflimitationsof ourap- plied methodssuchaspossible poorcorrespondencebetweensubject spaceandgrouptemplatespace,whichwouldotherwiseleadtohigh variance.Weareconvincedthatthecorrespondenceandvarianceare reasonable,becausethefinalfixelanalysismaskincludedthearcuate fasciculus(seeInlineSupplementaryFig.1)andwewereabletofind statisticallysignificantlateralisationeffectsofthearcuatefasciculusin allgroups.Thisresultregardingthearcuateisinlinewiththestudyby Vernooijetal.(2007)thatshowedaleftwardslateralisationofthearcu- ateregardlessofthedirectionoffunctionalhemisphericdominancefor language.Thissuggeststhatthelateralisationoflanguagefunctioning andthearcuatefasciculusarelargelydrivenbyindependentbiases.Fi-

Fig.5. Thetraditionallateralityindex(differencedivided bysum)infunctionofourlateralityindex(alog-ratio).Be- causebotharemeasuresofrelativedifference,theirvalues canberelatedtoeachotherindependentlyoftheabsolute valuesofRandL.

nally,asignificantbetween-groupdifferenceinlateralityoffibre-bundle cross-section(FC)wasfoundintheforcepsminor.Interestingly,FCof therighthemisphereinthisregionwas,onaverage,actuallyverysimilar inbothgroups,whileadifferencewasobservedinthelefthemisphere, leadingtooppositedirectionsoflaterality(i.e.leftwardsintheLLDand rightwardsintheRLDgroup).Theforcepsminor,alsoknownasthean- teriorforceps,isawhitematterfibrebundlewhichcrossesthemidline viathegenuofthecorpuscallosumandconnectsthelateralandme- dialsurfacesofthefrontallobes.Contralateralconnectionstravelvia thecorpuscallosumwiththeforcepsminortoendinBrodmannareas 9and10.These areasareinvolvedinexecutivecontrolandworking memory(area9) andinabstractcognitivefunctioning, episodicand workingmemory(area10)(Bakeretal.,2018).AlargeDTItwinstudy foundnogeneticinfluenceforitsleftwardlaterality,butsharedenvi- ronmentalfactorsaccountforabout10%ofitsvarianceinasymmetry (Jahanshadetal.,2010).Theexactfunctionoftheforcepsminoritself remainselusive.Fractionalanisotropy(derivedfromDTI)showsaposi- tivecorrelationwithexpressivelanguageandcognitivecontrolabilities inchildreninthistract(Farahetal.,2020).OtherDTI-basedfindings inadultssuggestarelationwithindicesofgeneralandcrystallisedin- telligence(Coxetal.,2019;Góngoraetal.,2020).Inagreementwith thesefindings,recentclinicalresearchalsoreportsthatwhitematterhy- perintensitiesintheforcepsminorpredictglobalcognitiveimpairment (Biesbroeketal., 2020).Theestablishmentofacompleteandformal accountoftherelationbetweenforcepsminorasymmetryandlanguage dominancerequiresfurtherinvestigation.Aslanguageencompassesdif- ferentaspects(e.g.phonology,syntax,semantics,...),itwouldbeofin- terestforfutureresearchtoinvestigatetherelationshipbetweenlater- alityofdistinctlanguagefunctionsandtheasymmetriesfoundinthe forcepsminortofurtherunravelitsexactrole.Thiscouldbedonefor examplebylookingatcorrelationsbetweenlateralityindicesbasedon fMRIparadigmsprobingdifferentlanguagerelatedfunctionsandstruc- turallateralityindicesoftheforcepsminor.

SeveraldiffusionMRIstudieshavepreviouslyreportedonstructural whitematterasymmetriesusingmetricsderivedfromtheDTImodel (GüntürkünandOcklenburg,2017;Ocklenburgetal.,2016).Byusing theFBAapproachinourcurrentstudy,importantlimitationsinherent totheDTImodelwereresolved,leadingtomorereliableandinforma- tiveresults.FBAallowsforstatisticalanalysisoffibre-specificmeasures (Raffeltetal.,2017).Inthiswork,wecombinedtheFBAframeworkwith abespokelateralityindex,computedforthe3traditionalFBAmetrics (FD,FCandFDC).Asaresult,wewereabletodeterminelateralisa- tionofmultiple fibrepopulationswithin avoxelindividually.Inour work,thisspecificityoftheFBAframeworkshowsinseveralregions of theresults,includingforexample fixelswithin thearcuate show- ingoppositeasymmetry(Fig.2).Thelongsegmentwaslateralisedto theleftsideofthebrain,whereasfixelsbelongingtotheanteriorpart andcrossingthelongsegmentshowedarightwardslateralisation.These

opposingfibre-specificresultsareinlinewithanotherrecentstudyby HonnedevasthanaArunetal.(2021),whoappliedFBAtoexaminewhite matterasymmetriesinagroupofhealthyadults.Theseresultsempha- sizetheaddedvalueofusingFBAinlateralityresearch,asthisapproach can uncoverdistinctlateralityeffectswithin largerfibrebundles.Fi- breswithdirectionallyoppositeasymmetry mayin turnreflectinde- pendentcontributionsof thesefibres todifferent cognitivefunctions.

Voxel-averagedDTImeasuresmighthavefailedtodetectandexplain thelateralisation patternwithinthese andsimilar regionscontaining multiplecrossingfibrepopulations,underscoringtheaddedvalueofus- ingFBAforlateralityresearchofwhitematter.ThankstotheFBAmet- ricsitwasfurthermorepossibletodistinguishbetweenmacroscopicand microscopicasymmetriesofwhitematterproperties.Forexample,the cingulumshowedaclearleftwardslateralisationoffibredensity,sensi- tisedtoaxonalvolumeatamicroscopicscale.Thisasymmetrywasnot presentforthefibre-bundlecross-sectionatthemacroscopicscale.Such aresultis forexamplecompatiblewiththeleftward lateralisationof FAforthecingulum,whichwasfoundbypreviousstudies(Gongetal., 2005;Parketal.,2004),whileThiebautdeSchottenetal.,2011also failedtofindvolumedifferencesintheleftandrightcinguluminmost subjectsoftheirstudy.ItishoweverimportanttonotethattheFDmet- ric,whichreflectsaxonalvolume,isnotabletodisentangleeffectsof axonal countandaxon diameter.Additionally,FDis notsensitiveto myelin,sonodirectinterpretationscanbemadeaboutasymmetryef- fectsinmyelinationfromourfindings,eventhoughconcomitanteffects mightbe plausible(Dhollanderetal.,2020).Finally,FBAisawhole braindata-drivenanalysisapproachallowingtodetectstructuralasym- metriesinsubpartsofwhitemattertractswithoutanyapriorihypothe- ses.Thisisincontrasttoseveralstudiesexaminingwhitematterlateral- isationviadelineationoftractsofinterestandextractionofregion-wise averagedmetrics,whichlackregionallyvaryingspecificitytodetectsub- tleeffects.

TheFBAstatisticalframeworkhasbeenusedinmanydifferentstud- ies overthepastfewyears.Wholebrainwhitematterasymmetryin a healthyadult sample has beenexamined using the FBAapproach by Honnedevasthana Arun et al. (2021). While they employedone- sampletestingoftheabsolutedifferencebetweenleftandrighthemi- sphereFBAmeasures,weoptedforabespokerelativelateralityindex tomoredirectlyquantifyasymmetriesspecifically.Thisrepresentsan approachcommonlyusedinthebroaderfieldoflateralisationresearch (Seghier,2008).Italsoallowedustocomparetherelativedegreeof lateralitydirectlyandinanintuitivemannerbetweendifferentpopula- tions.However,ratherthandirectlyadoptingthemostcommondefi- nitionofarelativelateralityindex—thedifferencedividedbythesum (Seghier,2008)—wedefinedourlateralityindexasalog-ratio.While thetraditionallateralityindexissymmetric,itisalsobounded(between valuesof-1and1),andthereforelackstheadditivityproperty.Thelog- ratio,ontheotherhand,istheonlymeasureofrelativedifferencethat

Table1

Correspondingvaluesofothermeasuresofrelativedifference,fortherangeofvaluesofour log-ratioLIasusedtodescribeeffectsizesintheFig.sinthisworkandthesupplementary document(from0.5downto-0.5).

LI = log(R / L) R / L (R-L) / L (R-L) / R (R-L) / ((R + L) / 2) LI trad= (R-L) / (R + L)

0.5 1.649 0.649 0.393 0.490 0.245

0.4 1.492 0.492 0.330 0.395 0197

0.3 1.350 0.350 0.259 0.298 0.149

0.2 1.221 0.221 0.181 0.199 0.100

0.1 1.105 0.105 0.095 0.100 0.050

0.0 1.000 0.000 0.000 0.000 0.000

− 0.1 0.905 − 0.095 − 0.105 − 0.100 − 0.050

− 0.2 0.819 − 0.181 − 0.221 − 0.199 − 0.100

− 0.3 0.741 − 0.259 − 0.350 − 0.298 − 0.149

− 0.4 0.670 − 0.330 − 0.492 − 0.395 − 0.197

− 0.5 0.607 − 0.393 − 0.649 − 0.490 − 0.245

isnotonlysymmetric,butalsonormedandadditive(Tornqvistetal., 1985).Despiteitsdefinitionpotentiallyappearingquitedifferentatfirst sight,a directandintuitiverelationship existsbetween both indices (AppendixA).Ourlog-ratiolateralityindexcanbecalculateddirectly onafixel-specificlevel,thoughparticularcarehastobetakeninimple- mentingstrategiestodealwith“absent” fibredensities(however,thisis notunlikethestrategytoassigntheseavalueofzerointraditionalFBA studies).

Oneofthelimitationsofthepresentstudyistheinclusionofleft- handedparticipantsonly.Toincreasetheprobability offindingright languagedominant participants,we focused on left-handersbecause RLDisrareandoccursmoreofteninthispopulation(CareyandJohn- stone,2014).Asaresultofthisapproach,anunprecedentedsampleof RLDparticipantswasrecruited.Thequestionhoweverremainswhether structuralasymmetriesarecomparableinright-handedLLDandRLD.

5. Conclusion

Wefoundthatwhitematterasymmetriesareubiquitousthrough- outthebrain,whichholdsimportantconsequencesforclinicalresearch.

Fixel-basedanalysespresentapromisingavenuetostudytheasymmetry ofwhitematterusingafibre-specificlateralityindexdefinedformicro- andmacrostructuralmetrics.Thedirection of languagelateralisation appearedtobeunrelatedtothestructuralasymmetryofwhitematter tractsknowntobetypicallyinvolvedinlanguage.Finally,asignificant differenceinrelative lateralisationwas foundfor partof theforceps minorwhencomparingparticipantswithleftandrightlanguagedom- inance.Theexactrelationshipbetweenforcepsminorasymmetryand languagedominancecouldbeaninterestingsubjectoffuturestudies.

Dataandcodeavailabilitystatement

AllanonymisedrawdiffusionMRIdata(inBIDSformat)andcode filesusedfordataanalysisareavailableonOpenScienceFramework https://osf.io/jg6hb.

Creditauthorshipcontributionstatement

Helena Verhelst: Investigation, Methodology, Formal analysis, Writing-originaldraft,Visualization.ThijsDhollander:Methodology, Formalanalysis,Writing-originaldraft,Visualization.RobinGerrits:

Investigation,Datacuration,Writing-review&editing.GuyVinger- hoets:Conceptualization,Investigation,Writing-review&editing,Su- pervision,Fundingacquisition.

Acknowledgements

Wewouldlike tothank alltheparticipantswhotook partinthe studyandDr.BenJeurissenforhisassistancewiththeoptimizationof

thediffusionMRIscanprotocol.ThisstudywasfundedbytheFonds WetenschappelijkOnderzoekVlaanderen(GrantG.0114.16N,toG.V.).

Supplementarymaterials

Supplementarymaterialassociatedwiththisarticlecanbefound,in theonlineversion,atdoi:10.1016/j.neuroimage.2021.117812. AppendixA

Inlateralisationresearch,traditionallyameasureofrelativediffer- enceisusedtorepresentthedirectionanddegreeoflateralityindepen- dentlyoftheabsolutemagnitudeofrelevantmeasurements(e.g.corti- calvolumeandothers).Thishasthebenefitofintuitivelyquantifying asymmetriesspecifically,andallowsfordirectcomparisonofthesebe- tween differentstructuresor populations.The “traditional” laterality index(LI_trad) usedforthispurposeiscalculatedasthedifferencedi- videdbythesum,sometimesmultipliedbyaconstant(Seghier,2008).

Inthemostcommonlyappearingvariant,thisconstantissimplysetto 1,resultingin

LI_trad=(R-L)/(R+L)

withRandLhererepresentingtherelevantrightandleftsidemeasure- ments.Thisisasymmetricversionofthetypicaldefinitionofarelative difference, whichwouldotherwisedividebyjust oneof bothvalues (i.e.RorL),resultinginanasymmetricdefinitionwhichisobviously undesirableforexpressinglateralityinanintuitiveandunbiasedman- ner.Interestingly,theaboveLI_tradisnotproperlynormed;itwouldbeif thesuminthedenominatorwereameaninstead,i.e.byintroducinga factor2(Tornqvistetal.,1985).Thiswouldrenderitmoreintuitivein particularforsmallervalues,whichcanthenbethoughtofdirectlyasa

“percentage” difference,yetwithoutsacrificingthevaluablesymmetry property.

However,inthisworkwedefinedourlateralityindex(LI)asalog- ratioinstead,i.e.,

LI=log(R/L)

where“log” referstothenaturallogarithm.Thismeasureofrelativedif- ferenceisalsosymmetric,aswellasproperlynormed(Tornqvistetal., 1985).However,it’salsoadditive:log-ratioscanbeaddeddirectlytocal- culateunbiasedtotalchanges(i.e.sumsofchanges),whichthemselves alsorepresentaproperlog-ratio.TheaforementionedLI_tradlacksaddi- tivity:thiscanbeeasilyseenbythefactthatitisbounded(between-1 and1).

WhilethedefinitionsofLI_tradandLImayappearquitedifferentat firstsight,theydofeatureadirectrelationshipduetothefactthatthey arebothmeasuresofrelativedifference.Allrelativedifferencemeasures

canultimatelybewritteninfunctionoftheratiobetweenbothvalues (e.g.RandL),independentlyofthemagnitudeofthosevaluesthem- selves.ThisallowsustoexpressLI_traddirectlyinfunctionofLI:

LI_trad=(exp(LI)-1)/(exp(LI)+1)

Toaidintuition,thisrelationshipisplottedinFig.5.Thisreveals that,forsmallmagnitudes,bothindicesarealmostlinearlyrelated(via theaforementionedfactor2).Whileouraverageeffectsizesareonly inan(LI)rangeof-0.5to0.5,notethattheoriginalsubject-wisevalues willvarymore.Hence,theadditivitypropertyiskeyincalculatingthese veryaveragesinanunbiasedmanner.Similarly,relativecomparisonsof lateralitybetweenpopulationsrelyoncomputingdifferences,whichcan alsoonlybedoneinanunbiasedwaywhentheadditivitypropertyis satisfied.

MoredetailsareprovidedinTornqvistetal.(1985).Acomparisonof thevaluesofLIandotherrelativemeasures,fortherangeof(average) effectsizesinthiswork,isprovidedinTable1.

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