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ContentslistsavailableatGait&Posturejournalhomepage:www.elsevier.com/locate/gaitpost Balanceandthebrain:AreviewofstructuralbraincorrelatesofposturalbalanceandbalancetraininginhumansOliviaJ.Surgent,OlgaI.Dadalko Correspondingauthorat:WaismanCenter,UniversityofWisconsin-Madison,1500HighlandAvenue,Room435Madison,WI53705,UnitedStates.E-mailaddress:(B.G.Travers). populations.Indoingso,weexpecttoidentifypossiblebiomarkerstofacilitateearlydetectionofbalancechallengesandtolaytheground-workforecaciousinterventions.Apreviousreviewoftheeectsofbalancetrainingonspinalandsupraspinalexcitability[]suggestedthatbalancetrainingreducesspinalreexexcitabilityandcorticalinvolvementduringbalance-re-latedtasks,therebytheoreticallyincreasingtherelianceonsubcorticalstructures.However,thisreviewconcludedthatadvancedelectro-physiologicalandneuroimagingtechniqueswouldneedtobeim-plementedbeforewecouldfullytestthistheoreticalmodel.Ad-vantageously,suchadvancedtechniqueshavebeenutilizedinanumberofstudiesinthetenyearssincepublicationofthisreviewandhaveledtoabetterunderstandingofthebraincorrelatesofbalanceandbalancetraining.Specically,magneticresonanceimaging(MRI)hasexaminedbalanceinrelationtobothvolumeandmicrostructureofbrainregionsusingstructuralanddiusiontensorimaging(DTI),respectively.Structuralimaginghasallowedforcomparisonofbalancetovolumetricmeasuresofgrayandwhitematter,whileDTI-derivedmicrostructuralpropertiesquantifywhitematterintegrityusingmeasuresoffractionalanisotropy(FA),mediandiusivity(MD),axialdiusivity(AD),andradialdiusivity(RD).Together,thesetechniquespromoteacom-plementaryunderstandingofthecircuitsthatmayplayaroleinbal-ance.StructuralandDTIbrainimagingusedincombinationwithclinicalandlaboratorybasedbalanceassessment,provideaclearerpictureofthebrainregionsthataremostcriticallyimplicatedinpos-turalbalanceandaremostaectedbybalancetraining.Structuralneuroimagingprovidestwogeneralmechanismsbywhichwecanapproachresearchquestionsaboutneuroanatomicalre-gions.Therstoptionallowsourpriorassumptionsandpreviousndingsfromtheliteraturetodrivetheimagingquestionthatisasked.Inthesestudies,predeterminedregionsofinterest(ROIs)areestab-lishedandobservationsarelimitedtowithintheduciallinesofthoseregion.Thesecondoptiondoesnotlimittheanatomicalexplorationtoagivenlocationorregion,butratherallowsforexaminationoftheentirebrainthroughvoxelbasedanalysis.Eachmethodhasitsstrengthsandlimitations.AnROIbasedanalysismayresultinthecollectionandanalysisofdatathathasthepotentialtodemonstrateasignicantvo-lumetricrelationshipbetweentheamygdala(forexample)andperfor-manceonastandardizedclinicalbalanceassessment,butiftheamyg-dalaisnotincludedasanROI,therelationshipmayneverbeobserved.Thatsaid,ROIstudiesallowfortheexaminationofvastsumsofima-gingdatabasedonapriorihypothesisthatservetolimitthenumberofnecessarymultiplecomparisoncorrectionsandincreasethepowerofthestudy.Incontrast,wholebrainvoxelbasedstudiesallowfortheexaminationoftheentirebrainbutatthecostofnumerouscomparisonsandtherequiredmultiplecomparisoncorrections,whichmaylimitthepowerofthestudy.LookingacrossbothROI-andvoxel-basedstudiesislikelytoprovideamorecompleteunderstandingofwhichneuralstructuresareassociatedwithbalance.Previousworkinrodentssuggestsacomplicatedpatternofcorticalandsubcorticalchangesassociatedwithchangesinbalance[].Spe-cally,inresponsetoan8-dayrotarodtraining,thevolumeofsomebrainareasincreased(i.e.,theinsular,piriform,andorbito-frontalcortices,hippocampallayer7,anteriorthalamus,amygdala,andthecerebellum),whereasthevolumeofotherareasdecreased(i.e.,corpuscallosumnearthesomatosensorycortex,corticospinaltract,ventralspinocerebellartract,centrallobuleofthecerebellum,medial/superiornuclei,andretrosplenialcortex).Inaddition,betterperformance(i.e.,betterbalance)wascorrelatedwithlargervolumeoftheprimaryandsecondarymotorcortices,olfactorybulb,medulla,andfrontalasso-ciationcortex,butsmallervolumeofthethalamusandlobuleIIIofthecerebellum.Betterrotarodperformancewasalsoassociatedwithin-creasedFAofthehippocampus,hypothalamus,thalamus,mediallongitudinalfasciculus,lobule8ofthecerebellum,thestriatum,andolfactorybulbs.Inall,theresultsofthisstudysuggestthattheeectsofbalancetrainingarewidespreadbutparticularlyprominentinthecerebellum,theprimaryandsecondarymotorregions,frontalregions,andthehippocampus.Suchresearchinrodentsmayprovidepre-liminaryevidenceforbrainstructuresinvolvedinhumanposturalthepatternofresultsinrodentsdoesnotcleanlyalignwithpre-existingsuggestionsthatbalancetrainingreducescorticalin-volvementbutincreasessubcorticalinvolvement,asmicethatde-monstratedimprovedbalancehadsmallersubcorticalvolume.Thisdiscrepancyraisesthequestionsofwhetherhumansdemonstratethesamebrainbasisofbalanceasmiceandwhichregionsofthebrainaremostimplicatedinbothbalanceperformanceandbalancetraining,whicharekeygapsintheliterature.Therefore,theaimofthepresentstudywastocharacterizebrainstructuresthatsubserveposturalbal-anceinhumans,takingintoaccountdierentclinicalpopulations,structuralimagingmethodologies,dataanalysisstrategies,andstudydesigns.Weapproachthisaimbyexaminingevidenceforbrainmetricsrelatedto

2 balanceinpopulationswithtypical,exceptio
balanceinpopulationswithtypical,exceptional,orimpairedbalance,andbyexaminingchangestothebrainthatcoincidewithin-tensivebalancetraining.Further,weusedescriptivestatisticstoex-aminewhetherbrainstructuresassociatedwithbalancevariedasafunctionofbalanceassessmentversusintervention,staticversusdy-namicbalance,clinicalversusnon-clinicalpopulations,orROIversusvoxel-basedanalysis.2.MethodsThepresentreviewwasconductedtoidentifykeybrainstructuresinvolvedinposturalbalanceandbalancetraining.Whiletherearestudiesthatexaminebalanceinrelationtofunctionalmagneticre-sonanceimaging(fMRI)measures,weonlyincludedstructuralimagingndingsinordertobetterreectthelastingstructuralchangesasso-ciatedwithbalanceperformanceandbalancetraining.TolocatestudiesthatusedMRIanalysistoimplicatespecicbrainregionswithbalance,weperformedadatabasesearchduringSeptember2017usingaPubMedsearchwithkeyterms:postur[AllFields]ORpostura[AllFields]ORpostural[AllFields]ORpostural[AllFields]AND(("Balance"[Journal]OR"balance"[AllFields])AND("brain"[MeSHTerms]OR"brain"[AllFields])AND("magneticresonanceimaging"[MeSHTerms]OR("magnetic"[AllFields]AND"resonance"[AllFields]AND"imaging"[AllFields])OR"magneticresonanceimaging"[AllFields]OR"mri"[AllFields]))NOT("JMolCatalAChem"[Journal]OR"chemical"[AllFields]).termsweredevelopedtocapturerelevantarticlesandtoensurethatthetermsrelevanttothespecicthesaurusofthedatabasewereincluded.Thesearchyieldedatotalof285articles,whichwerethenscreenedforPredeterminedexclusionarycriteriaforstudiesincludedthesoleuseofnon-humansubjects,functionalimaging,theuseofanMRIscannerwithstrengthbelow1.5T(duetoreducedresolution),casestudiesin-volvingfewerthaneightparticipants,orstudiesthatdidnotinvolvetheuseofbothstructuralbrainandbehavioralbalanceassessmentsortraining.Articleswerescreenedbyasinglepersonandthenvettedforinclusionbyasecondindividual.Ultimatelyatotalof37studieswereincludedforreview.Imaging,participantsummaries,andstudydesignparametersforthese37studiesaredepictedinTable1.DetailsofthestudiescanbefoundinSupplementaryTable1.Studiesvariedinsamplesize(=113.6,range:141387),averagesubjectage,MRIscannerstrength,andimagingparameters,butallstudiesassessedstructuralmeasuresofthebraininrelationtobalance.AscanbeseeninTable1,themajorityofthestudiesincludedparticipantsovertheageof40years,useda3Tscanner,andassessedgraymattervolume.Themajorityalsoimplementedabalanceassessment,lookedatstaticbal-ance,usedanROIanalysisapproach,andinvestigatedaclinicalpo-Brainstructuresweredistinguishedbasedonthenamingconven-tionsusedineachstudy.Inordertosummarizekeyresultsacrossndingsweregroupedintoninegeneralanatomicalregions:O.J.Surgent,etal. brainstem/cerebellarregions,frontalregions,subcorticalregions,temporalregions,occipitalregions,parietalregions,insularregions,ventricles/paraventricularregions,andcorpuscallosum.Thehippo-campuswasincludedwithtemporalregionsbasedonthedevelop-mentalnatureofthehippocampus,whichultimatelyisconstructedfromaninfoldingofthetemporalcorticalregions[].Theinsularregionsweresingledoutduetotheiranatomicallocationandversatilefunction.Whitemattertractsthatcrossedmultipleregionsofthebrainweregroupedintotheregionswheretheirassociatedstudiesfoundthemostchange.Theexceptiontothiswasthecorpuscallosum,whichremaineditsowngroupduetoitsexpansiveandextensiveconnectionsthroughoutthebrain.Frequencyofregionalinvolvementinbalancewasdenedasthenumberoftimeseachregionwasimplicatedinbalanceacrossthepa-persreviewed.OneconcernwehadwithrawfrequencywasthebiasinherenttocombiningndingsacrossROIstudies(thatcanonlydetectndingsinpre-speciedareasofthebrain)andVBMstudies(thatareabletodetectndingsacrossthebrain).Totrytoaccountforthisbias,wecalculatedafrequency-of-ndings-per-paperproportion,dividingthenumberoftimeseachregionwasimplicatedinbalancebythenumberofpapersthatweredesignedtopotentiallydetectawithinthatregion.PapersweredeemedtobeabletodetectawithinaregionifthestudyusedanROIdenedwithinthatregionorifastudyusedaVBMapproachingeneral.Averysimilarpatternofre-sultsoccurredacrossboththerawfrequency(Fig.1)andproportion(SupplementaryFig.1)measures,whichiswhyrawfrequencyisre-portedhere.Findingswerefurtheranalyzedonthebasisofexperimentaldesign(BalanceAssessment/Intervention),balanceparadigm(Static/Dynamic),population(Clinical/Non-clinical),andregionalanalysismethod(ROI/VBM).Findingsthatinvestigatedstructuralbrainprop-ertiesinrelationtobalanceabilityatasingletimepointwereclassindingsthatinvestigatedthechangeinneuralstructureoverthecourseofbalancetraininginterventionwereclassi-edasFindingsthatquantiedbalancebasedonabilitytoremainstillwereconsideredtohaveusedmeasureswhereasthosethatrequiredtheparticipanttobalancewhileinmotionwereconsideredtohaveusedmeasuresofbalance.Findingsbasedonthespecicpopulationswithimpairedbalanceweredesig-natedaswhilethosethatwerebasedontypicallydevelopingpopulationsorpopulationswithenhancedbalanceweredesignatedasFindingswerealsoclassiedbasedontheregionalanalysismethodused(i.e.,ROIorVBManalysisapproaches).Allstu-diesthatusedVBMincludedafamily-wiseerrorcorrectioninthesta-tisticalassessmentoftheirndings.Findingspermajorbrainregionw

3 ereclassionanindependentlevelaswellasona
ereclassionanindependentlevelaswellasonastudylevelandshowedverysimilarresults(SupplementaryFig.2).3.ResultsAcrossthe37studies,atotalof234ndingsin71brainstructureswereevaluated.Fig.1Ashowsthatthebrainstem/cerebellarregionplayedthelargestroleinbalanceacrossbothassessmentandinter-ventionparadigms,with79signindingsintheregioncomingfrom22studies(59%ofstudies;Fig.2).Withinthisregion,ndingsinthecerebellargraymatteraccountedforoverhalfofthetotalbrain-ndings(58%;Fig.1B).Findingswererelativelyevenlydistributedacrossthecerebellarlobes(whenthelobeswerespecibythestudy),howeverthedirectionalitiesofthecerebellarweremixed(seeSupplementaryTable1).Forexample,balanceas-sessmentstudiesgenerallyshowedthatlargercerebellargraymattervolumewasassociatedwithbetterbalanceacrossclinicalpopulations.However,individualswithADHDshowedanoppositepattern,ascer-ebellargraymattercorrelatednegativelywithbetterbalance.Thecerebellumwasalsoheavilyimplicatedinbalancetrainingstudies,al-thoughdirectionalityofthevolumechangevariedaccordingtothepopulationofstudy(seeSupplementaryTable1).Thesuperiorcere-bellarpeduncle(SCP)accountedfor10.1%ofthebrainstem/cerebellarndings(Fig.1B)withhigherwhitematterintegrity(asindexedbyDTImeasuresofhigherFAandlowerMD)beingassociatedwithbetterbalanceinassessmentstudies[].InterventionstudiesshowedasimilarpatternofincreasedFAbeingassociatedwithbetterbalanceinbalance-impairedpopulations[Fig.2depictsthedegreetowhichthesendingswereassociatedwithspecicstudyparameters.ndingsinthebrainstemandcerebellarregion,weremorecommonininterventionstudies(46ndings;58%ofndings),clinicalpopulations(57ndings;72%ofndings),andmeasurementsofdy-namicbalance(49ndings;62%ofndings).Interestingly,46%ofndings(37ndings)inthebrainstemandcerebellarregionwerebasedonROIanalysis(Fig.2B).ThisisproportionofROIbasedinasingleregionwasatypicallyhighcomparedtootherbrainstruc-tures.Additionally,34ofthe37ROIbasedndingsinvolvedclinicalFollowingthebrainstem/cerebellarregion,thefrontalregionhadthemostwithatotalof44ndingsfrom13studies(35%ofFig.1C).Theinferiororbitofrontalcortex,primarymotorcortex,superiorfrontalgyrus,andsupplementarymotorareaseachaccountedfor11.9%ofthendingsinthefrontalregion.Structuralchangesinthesebrainareaswerehighlyvariableacrosspopulationsandnotconsistentacrossstudies(seeSupplementaryTable1Fig.2showsthatndingsinthefrontalregionweredisproportionatelyfromVBManalysistechniques(40ndings;90%ofndings)andinvolvedmoredynamicbalancemeasurementsthanstaticbalance(3681%ofTemporalregionswereimplicatedinoverhalfofthebalancestudieswith28ndingsfrom11studies(33%ofpapers;Fig.1D).Thiswaslargelyduetothehippocampus,whichaccountedfor46.4%ofthetemporalregionndings.Increasedhippocampalgraymattervolumewasassociatedwithbetterbalanceinthecaseofpeoplewithexpertbalance[]butpoorerbalanceinthecaseofindividuals40yearsorolder[].Graymattervolumeinthehippocampusduringbalancetrainingstudiesanddirectionalityofthesechangeswas Table1Imagingtechniqueandparticipantsummariesacrossthe37studiesreviewed.StudyParameterParticipantAge(years)�4025012ScannerMagneticFieldStrength231.5TImagingTechniqueGrayMatterVolumeusionTensorImagingLesionVolumeWhiteMatterHyperintensityCorticalThicknessWhiteMatterVolumeVentricularVolumeStudyDesignAnalysisMethodBalanceMetricDynamicandStaticNeither(professionalvestibulo-visuallytrainedsubjects)ClinicalandNon-ClinicalO.J.Surgent,etal. inconsistentacrosspopulationsandtime.Themiddletemporalgyrusaccountedforanadditional17.8%ofthendingsinthetemporallobe.Graymattervolumeinthemiddletemporalgyrusvariedwithpopu-lationandability.Individualswithexpertbalanceshowedincreasedgraymattervolumeinthemiddletemporalgyrus,whiletypicallyde-velopingindividualsshowedgraymattervolumedecreasesduringbalancetrainingthatcorrelatedpositivelywithbalanceimprovement.Changesingraymattervolumeoverthecourseofbalancetrainingwereshowntocorrelatewithbalanceimprovement;howeverthedirection-alityofsuchchangewasinconsistentacrossstudies.Whileseveralofndingsinthetemporalregionwerefromasinglestudythatdidnotmeasurebalancedirectly,ndingsalsocamefromstudiesthatim-plementedbothstaticanddynamicmeasures(Fig.2Subcorticalregionswereimplicatedin9studiesincludedinthisreview(24%ofstudies;1E)with24ndings(Fig.1E).Thebasalgangliaandthalamuseachaccountedforover20%ofthesubcorticalndingsandthenucleusaccumbenseachaccountedfor12.5%.Themajorityofndingsinthebasalgangliacamefrombalanceassessmentstudies(Fig.2).Thesendingswerealsoinpopulationsover40yearsold,allconcludingthatreducedsizeandthepresenceofwhitematterhyperintensitiesinthebasalgangliawereassociatedwithpoorerbal-anceability.Interestingly,thegraymattervolumeinthebasalganglia,callytheputamen,wasseentodecreaseoverthecourseofbal-ancetrainingintypicallydevelopingindividuals[].However,ase-paratestudyreportedanincreaseinputamensizefollowingbalancetraining[].Lowergraymattervolumeineithertheputamenorthecaudatewasalsoassociatedwithworsebalanceinindividualswithmultiplesclerosis[]andAlzheimersDisease[],respectively.Findingsinthethalamusaccountedfor20.8%ofthetotalndingsinthesubcorticalregionsandallstemmedfrombalanceassessmentstu-dies.Graymatterv

4 olumeinthethalamuswasincreasedinindividu
olumeinthethalamuswasincreasedinindividualswithexceptionalbalanceandconverselydecreasedinindividualswithbalanceimpairments.Noneofthestudiesthatimplementedbalanceinterventionnotedsignicantchangesinthethalamus.Thedistributionndingsamongthestudyparametersinthesubcorticalregionswasrelativelyconsistentwithwhatwastobeexpected(Fig.2ndingsacrossninestudies(24%ofstudies)wereattrib-utedtostructureswithintheoccipitalregion(Fig.1F).Likethatofthefrontalregions,therewerenostructureswithintheoccipitalregionthatshowedsignicantanddistinctcontributionstobalanceabilityorim-provement.Severalstructureswithintheoccipitalregions,includingtheinferioroccipitalgyrusandthelingualgyrusmayplayaroleinbalancebuthavenotbeenimplicatedacrossstudiesfrequentlyenoughtodrawconclusionsabouttheirdistinctrolesinbalance.Themajorityndingsintheoccipitalregionwereimplicatedindynamicbalancendings;68%ofndings)ratherthanstaticbalancemeasuresFig.2Theparietalregionshadonly18ndingsin7studies(18%ofstu-Howevertheinferiorparietalcortexaccountedfor33.3%ofthendingsintheparietalregions,potentiallymakingitacriticalregionforunderstandingtheneuralmechanismsassociatedwithbalance.Typicallydevelopingindividualsshowdecreasedwhitematterintegrity(increasedMDanddecreasedFA)inthisregionoverthecourseofbalancetraining.Further,graymattervolumeintheinferiorparietalcortexinpeoplewithParkinsondiseasewasfoundtochangeoverthecourseofbalancetrainingwithaninitialincreaseandsubsequent Fig.1.Structuralinvolvementinbalanceasindexedbytotalnumberofndingsperregion.A)Frequencyofndingsimplicatingeachbrainregioninbalance.BFrequencyofndingsperstructurewithineachregionthathad15ormoretotalndings.Structuresthatcontributedto10%ormoreofthatregionstotalnumberofndingsarereported.Remainingstructuresthatcontributedtolessthan10%oftheregionstotalnumberofndingsarenotlistedbutcanbefoundinTable1.GM,GrayMatter;WM,WhiteMatter.O.J.Surgent,etal. decreaseinvolumeovertime.Thesechanges,regardlessofdirection-ality,wereassociatedwithimprovedbalanceatalltimepoints.Themajorityofndingsintheparietalregionsinvolveddynamicmeasuresofbalance(16ndings;88%ofndings)andVBManalysismethodsndings;17%ofFig.2Thecorpuscallosum,insularregionsandventricles/paraventricularregionswereallimplicatedinbalancelessthansixtimesandinfewervestudiesindicatingthatwhiletheymayplayasupportiveroleinbalance,theylikelyarenotthemostcriticalunderlyingcomponentsofbalanceinthebrain.Findingsintheventricles/paraventricularre-gionswereexclusivelyfromstudiesinvolvingbalanceassessment(5ndings)andROIanalysis(5ndings),andndingsinthecorpuscallosumwereexclusivelyfromstudiesinvolvingstaticbalanceas-sessment(6Fig.24.DiscussionThepurposeofthepresentreviewwastobetterunderstandstruc-turesofthebrainthataremosthighlyassociatedwithbalanceandbalanceimprovementacrossavarietyofmethodologicalapproaches.Thepresentndingssuggestthatbalanceisawhole-brainphenomenonthatisnotisolatedtoafewspecicregionsbutrathercanbeinandimpactedbynearlyeveryregionofthebrain.Nevertheless,certainstructures,suchasthecerebellum,thebasalganglia,thethalamus,thehippocampus,theinferiorparietalcortex,andfrontallobe(broadlyned)maybeparticularlycentraltobalanceskills,regardlessofwhetherbalanceisbeingtrainedorassessed.4.1.CerebellumWhilethepresentresultssuggestthatnearlyeveryregionofthe Fig.2.Frequencyofspecicparametersusedtoproduceregionalndings.A)Frequencyofndingsperregionthatusedassessmentversusinterventionstudydesigns.B)FrequencyofndingsperregionthatusedROIversusVBManalysistechniques.C)Frequencyofndingsperregionthatusedstaticversusdynamicmeasuresofbalance.Studiesthatassessedbalanceusingbothstaticanddynamicmetricsoracompositescoreofbothstaticanddynamicbalancearenoted.D)Frequencyofndingsperregionthatlookedatbalanceinclinicalversusnon-clinicalpopulations.Studiesthatpresentedndingsinbothclinicalandnon-clinicalpopulationsarenoted.O.J.Surgent,etal. brainisinvolvedinbalance,cerebellargrayandwhitematterhadthehighestcountofndings,suggestingthekeyroleofthecerebelluminbalanceacquisitionandability.Althoughitisunsurprisinggiventhewidelyacceptedroleofthecerebelluminmotorcoordinationandplanning,thedegreetowhichthecerebellumwasimplicatedinbalanceaboveallotherstructuresclearlydemonstratesitsimportanceinbal-ance.Inmostcases,lowergraymattervolumeorlesionsinthecere-bellarlobeswereassociatedwithpoorerbalance[],andhighervolumewasassociatedwithbetterbalance[].How-ever,inthecaseofADHD,highergraymattervolumeinthecerebellumwasassociatedwithpoorerbalance[].ThisuniquepatternfoundintheADHDpopulationmaybeduetothedevelopmentalaspectofADHD,whichisnotpresentintypicallydevelopingorotherpopula-tionsthatencounterbalancedecitslaterinlifeafterthebrainhasdeveloped(i.e.MS,TBI,alcoholism,stroke,spinalcordinjury).Giventhedevelopmentalcourseofbalance,itispossiblethatbrain-behaviorrelationsmaybedistinctinyouthwithdevelopmentaldisorderscom-paredtootherpopulations,whichshouldbeconsideredinfutureex-aminationsofbalanceandthebrain.Thestudypopulationalsoseemstoplayasignicantroleincere-bellargraymatteradaptationtobalancetraining.Specically,typicallydevelopingindividualstendedtoshowvolumedecreasesacrosscere-bellarlobulesas

5 balanceimprovedovertime[],whereasin-divi
balanceimprovedovertime[],whereasin-dividualswithbalanceimpairmentshowedincreasesincerebellarlo-bulevolumeasbalanceimprovedovertime[].Interestingly,peoplewithexpertbalancealsoshowedincreasedgraymattervolumeinthecerebellumcomparedtoindividualswithaveragebalancebalance19,32],thusparallelingtheeectsofbalancetraininginbalanceim-pairedpopulationsandcontradictingtheeectsofbalancetraininginthetypicallydevelopingpopulation.Onepotentialexplanationisthatshorter-termtraining(i.e.,amatterofweeks)mayberelatedtore-ductionsincerebellarvolume,whereaslonger-termtraining(i.e.,yearsofactivitieslikeprofessionaldancing,gureskating,orslack-lining)maybeindicativeofincreasesincerebellarvolume.Speculatively,thepre-trainingvolumeofthecerebellummayalsobeakeyfactor,suchthatbalancetrainingmaybeabletonormalizethecerebellumsvolume(i.e.,cerebellaratrophyinindividualsfromclinicalpopulationsmaybecorrectedwithbalancetraining).However,futureresearchisneededtoexaminethesepossibilities.Thepresentresultsalsosuggestthatndingswithinthecerebellum(andbrainstem)wereoverrepresentedinstudiesthatusedROImeth-odologiesandstudiesthatusedclinicalpopulations.Itispossiblethatthecerebellumandbrainstemregionsmaybemoreimplicatedinclinicalpopulationthaninnon-clinicalpopulations.However,thisndingmayalsobeanartifactstemmingfromtheoverrepresentationofstudieswithclinicalpopulationsusingROImethods(presumablyduetosmallersamplesizesorgreaterapriorievidencemakingitmorelikelyforscientiststoselectivelyexaminethecerebelluminclinicalpopula-tions).Futureresearchisneededtodeterminewhetherthecerebellumisindeedmorecommonlyimplicatedinclinicalpopulationswithbal-ancechallengesoriftheoverrepresentationofthecerebelluminbal-ancestudiesisanartifactofnarrowingthesearchspacetothecere-belluminROIstudies.relativelyhighimplicationofthesuperiorcerebellarpeduncle(SCP)isalsounsurprising,asitisknowntotransmitmotorcoordinationinformationfromthecerebellumtocorticalareas.Therefore,itislo-gicalthatreducedwhitematterintegrity,intheformoflowFAandhighMD,wasconsistentlyassociatedwithpoorerbalanceinindividualswithbalancedisorders[].WhilenotmanystudieshavefoundchangesintheSCPfollowingbalanceintervention,astudyconductedwithparticipantswithMSshowedasustainedincreaseofFAintheSCPwithbalancetraining[].ThisndingmayindicatethatwhitematterchangesintheSCPcouldcorrespondtograymatterchangesinthecerebellum,althoughthistheorythiswillneedtobeaddressedinfuture4.2.HippocampusThetemporalregionalndingswerelargelydrivenbythehippo-campalregion(i.e.,thehippocampusandparahippocampalgyri),whichaccountedfor46.4%ofthetemporallobendings.Unlikere-gionssuchasthecerebellum,thehippocampusisnotoftenthoughttobeattheforefrontofbalanceormotorfunctions.However,thepresentresultssuggestthatthehippocampusmayplayakeyroleinbalance.Importantly,therewasnodierenceintherepresentationoftemporallobestructuresinstudiesthatassessedbalanceversusstudiesthatsoughttoimprovebalanceskills.Therefore,itisunlikelythatthehip-pocampusisonlyinvolvedinthelearningofnewbalanceskills.Instead,thehippocampusandparahippocampusmaybeinvolvedintheen-codingorretrievalofspatialinformation,likelyneededforsuccessfulbalance(forareviewsee[]).Speculatively,theroleofthehippo-campusinspatialandconguralreasoningskillsmayberelatedtoitsroleinbalanceability[Whilethendingsinthehippocampalandparahippocampalstructureswithinthetemporalregionmaysuggestthatthetemporalgraymatterismorecriticaltobalancethanwhitematter,theyalsomaypointtoalackofexplorationoftemporalwhitematterinneuroimagingstudiesinvolvingbalance.Itispossiblethattractsleadingtowardandawayfromthehippocampalregionsarealsoinvolvedinbalanceandhaveyettobeexploredorreported.Regardless,thepresentresultssuggestthatthehippocampusmaybeakeyareainvolvedinbothbalanceandbalancetraining,althoughfutureresearchisneededtobetterunderstandthespecicrolethatthehippocampusplaysinbal-anceoverthecourseofthelifespan.4.3.BasalGanglia&ThalamusFindingsinthesubcorticalregionsweremainlydrivenbythebasalgangliaandthalamusthushighlightingtheirimportanceinbalance.Thebasalgangliaareanotherknownhubofmotorfunctionandthereforearehighlyimplicatedinbalancedisorders.Althoughtherewasnospecictrendofchangeswithinthesub-structuresofthebasalganglia,graymattervolumereductioninanypartofthebasalgangliastructurecommonlyhadnegativeeectsonbalance,andvolumein-creaseswerecommonlyassociatedwithimprovedbalancebalance12,18,22,23,25,37].Similartothebasalganglia,thethalamusisthoughttoplayakeyroleinbalanceaswellasseveralothersensory-motorfunctions.Itsroleinmotorabilityhasbeendocumentedthroughlesionstudiesoftha-lamicnucleiandcorrespondencewithmovementdecits[].Detobalancewerealsoassociatedwithatypicalthalamicpre-sentationsuchaswhitematterhyperintensities[],impairedwhitematterintegrity[],andreducedgraymattervolumevolume.Thecriticalnatureofthethalamusinbalanceiscorroboratedbytheingsthatindividualswithexpertbalancehadincreasedthalamicgraymattervolume[4.4.InferiorparietalcortexFindingsintheparietalregionweredrivenheavilybytheinferiorparietalcortex,whichmadeupalmosthalfofthendingsinthepar-ietalregionandhadmorendingsthanthebasalgangliaorthalamus.Unlikemanyoft

6 heotherregionsimplicatedinbalance,theinf
heotherregionsimplicatedinbalance,theinferiorparietalcortexwasmostcommonlyimplicatedinbalanceinterventionstudies.Inindividualswithtypicaldevelopment,decreasedwhitematterintegrity(higherMDandlowerFA)occurredoverthecourseofasix-weekdynamicbalanceintervention[].Graymattervolumeintheinferiorparietalcortexalsochangedwithbalancetraininginin-dividualswithParkinsondiseaseinthatgraymattervolumetionswerepositivelyassociatedwithbalanceimprovement[However,theseuctuationswerenotalwaysinthesamedirectionbutlikelyreectagrowthandsubsequentpruningoftheregionoccurringO.J.Surgent,etal. overthecourseofbalancetraining.Specically,graymattervolumeoftheinferiorparietalcortexincreasedovertwobalancetrainingsessionsbutthendecreasedafterthreeweeks,whilebehavioralassessmentsshowedonlyimprovementofbalanceovertime[Astheinferiorparietalcortexisinvolvedinawiderangeoffunc-tionsincludingperception,planning,andinterpretationofsensoryin-formation[],itsroleinbalanceislikelyoneofhigherordermotorintegrationandplanningratherthanmotorexecution[].Thistheorymayhelpexplainthegeneraltrendofdecreasinggraymatterandwhitematterintegrityasbalanceimproves.Becausethebrainworkstoau-tomatetasksovertime,renedperception,integration,andplanningisneededtoexecuteanovelordiculttaskascomparedtothatwhichisneededtoexecuteafamiliartasktask.Therefore,thepatternofinferiorparietalcortexgraymatterincreasefollowedbydecreaseoverthecourseofshort-termbalancetrainingmayreectapatternoflearningandautomatizationofthebalancetask.4.5.FrontallobeUnlikethemajorityofotherregions,thendingsinthefrontalre-gionswerenotdrivenbyaparticularstructurebutrathercomprisedofrelativelyfewndingsinseveraldierentstructureswithinthefrontalregion.Thisvariabilityinfrontalstructuresledustoconcludethatwhilethefrontalregionsmayplayapartinbalance,theirspecicroleinbalanceisnotaswelldenedormightvaryaccordingtothetypeofbalancebeingtrainedorassessed.Thisspeculationisinpartsupportedbyoverrepresentationoffrontalareasindynamiccomparedtostaticbalance.Gainingamorenuancedunderstandingoffrontalcontribu-tionstobalancewillbeakeyavenueofinquiryforfutureresearch.However,duetothelackofinformationinthecurrentliteratureim-plicatingspecicstructureswithinthefrontalregionsinbalance,con-clusionsregardingtheiruniquerolesinbalancecannotbedrawnatthis4.6.ConclusionsandfuturedirectionsAcrossclinicalandnon-clinicalpopulationsandacrossdistructuralimagingmodalities,theresultsofthisreviewsuggestthatthemostheavilyimplicatedbrainstructuresinstudiesofbalancearethecerebellargraymatter,superiorcerebellarpeduncle,basalganglia,thalamus,hippocampus,andinferiorparietalcortex.Theconvergenceofsuchdiversestudiesontheseparticularregionsanddemonstrationthatthispatternofresultswassimilaracrossdierentpopulations,imagingmodalities/techniques,andassessment/manipulationofbal-ancefurtheraddstotheirsignicanceasbeinginvolvedinbalance.Theseresultssuggestthatwhenbalanceimpairmentsarepresent,itisprobablethatatleastoneoftheseareasofthebrainisinvolved.Theseresultscorroboraterodentdata[]thathaveindicatedstructuralchangesincerebellar,subcortical,andhippocampalregionsasafunc-tionoftraining.Thiscorroborationgivesvaliditytotherodentmodelofbalanceandmayprovidereasonforitscontinuedusetotrackbrainplasticityasitpertainstobalance.Theserodentmodelsalsomaybeusedtoexplorenewmethodsofbalanceinterventiontargetedtowardplasticityinspecicregions.Despitethehighimplicationofthecerebellar,subcortical,hippo-campal,andinferiorparietalregionsinbalance,theresultsofthisre-viewsuggestthatbalanceisawhole-brainphenomenonthatisnotisolatedtoahandfulofregions.Althoughthespecicregionscom-monlyappeartobeassociatedwithbalanceacrosspopulationsandmayprovideinsightintotheunderlyingneurobiologyofbalanceimpair-mentsattheglobalscale,theseregionsareunlikelytobetheonlyonesthatcanaectorbeabybalanceabilityandtraining.Assuch,aVBMapproachinfuturebalancestudiesmaybeadvisabletomostac-curatelyrepresentthecomplexpatternofstructuresinvolvedinbalanceacrossthebrain.Further,acrossdierentpopulationsthereislikelyvariabilityintheregionsassociatedwithbalanceimpairments.Indeed,alimitationofthisreviewisthatthecurrentliteratureisnotrobustenoughforareliableexaminationofbrain-balancerelationshipsuniquetospecicclinicalpopulations.Moreresearchisneededtodeterminewhichbrainregionsmaybeuniquelyassociatedwiththespecicbal-ancechallengesofdierentpopulations.Anotherlimitationofthepresentreviewistheinconsistencyinthedirectionalityoftheeectsforthebrainregionsassociatedwithbal-ance.Futureresearchintotheeectsofbalanceonthebrainmayconsideremployinglongitudinaldesignswithmultipleimagingtimepointstoexaminethetime-sensitiveeectsofbalancetraining.Indeed,studiesthathaveemployedsuchadesignduringmotortraining(i.e.(i.e.12,42])havefoundcomplexpatternsoflargerandsmallervolumesaterentstagesofmotorlearning.Similarly,instudiesofbalanceim-pairments,longitudinaldesignswouldenableabetterunderstandingofwhichbrainstructuresareinvolvedintheearlystagesofbalancechallengesandhowthosemightchangeovertimeandcontributetomoreseverelyimpactedbalanceatlaterstages.Althoughthescopeofthepresentreviewdidnotincludestudiesthatfocusedonfunctio

7 nalimaging,itisalsolikelythatfunctionoft
nalimaging,itisalsolikelythatfunctionofthesespecicregionschangeswithtime.Futurestudiesmayconsidermultimodalimagingtechniquesthatincludestructuralaswellasfunctionalimagingcomponents(i.e.,functionalmagneticresonanceimaging[fMRI],positronemissiontomography[PET],functionalnear-infraredspectroscopy[fNIRS]).Suchstudiesmayilluminatealterationsinfunctioneitherwithorwithoutthepresenceofstructuralplasticity.Convergenceoffunctionalneuroimagingndingswiththestructuralndingsinthepresentreviewmayexposeapatternofchangesinthebrainthatcanbeattributedtobalance.Inall,thepresentreviewprovidesevidenceoftheimportantroleofthecerebellum,basalganglia,thalamus,hippocampus,andinferiorparietalcortexinbalanceandbalancetraining.Whilemoreresearchisneededtodisentanglehowtheseareaschangeovertimeandimpactbalanceacrossdierentclinicalpopulations,theseregionsmayserveasimportantbiomarkersthatcanbeusedtoisolatethecauseofthebal-anceimpairmentandmonitortreatmentprogress.Further,theroleoftheseregionsinbalancetrainingmaybegintoshedlightondipatternsofbalance-training-inducedneuroplasticityacrossdistructuresofthebrain.Anumberofindividualsareimpactedbybal-ancechallenges[],andthepresentreviewmayhelpcliniciansandresearchersprioritizewhichbrainregionstoexaminewhenbalancechallengesarepresent.DeclarationofinterestsCRediTauthorshipcontributionstatementOliviaJ.Surgent:Conceptualization,Methodology,Formalana-lysis,Investigation,Datacuration,Writing-originaldraft,OlgaI.Dadalko:Conceptualization,Writing-review&KristenA.Pickett:Conceptualization,Writing-review&BrittanyG.Travers:Conceptualization,Methodology,Formalanalysis,Writing-review&editing,Supervision,Fundingacquisition.ThisworkwassupportedbytheBrainandBehaviorResearchNARSADYoungInvestigatorAward[toBGT];theHartwellFoundationIndividualBiomedicalAward[toBGT];theEuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelopment[P30HD003352andU54HD090256totheWaismanCenterandR01HD094715toBGT];andtheNeuroscienceTrainingProgramTrainingGrant[T32GM007507].ThecontentissolelytheresponsibilityoftheauthorsanddoesnotnecessarilyrepresentthecialviewsoftheNationalInstituteofChildHealth&DevelopmentO.J.Surgent,etal. 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