Beruflich Dokumente
Kultur Dokumente
NCBIBookshelf.AserviceoftheNationalLibraryofMedicine,NationalInstitutesofHealth.
LaskowitzD,GrantG,editors.TranslationalResearchinTraumaticBrainInjury.BocaRaton(FL):CRC
Press/TaylorandFrancisGroup2016.
Chapter8 NeuroplasticityafterTraumaticBrainInjury
YouRongSophieSu,AnandVeeravagu,andGeraldGrant.
Traumaticbraininjury(TBI)isachallengingdiseaseprocess,bothtotreatandinvestigate.Broadly
speaking,TBIconsistsofstructuralinjuriesorphysiologicchangesinbrainfunctionsecondaryto
externalforces.1Suchinjuriesmayresultincelldeath,glioticscarformation,and/ordamagefrom
reactiveoxygenspeciesandinflammation.1
PriorTBIpopulationstudiesrevealedthattheprevalenceofTBIinadultsover18was8.5%.2In
2010,2.5millionemergencydepartmentvisits,hospitalizations,anddeathswereassociatedwith
TBIwithdatafromtheCentersforDiseaseControlandPrevention3suggestingthatTBIwas
relatedto30%ofmortalities.PediatricTBI,whilelargelyunderstudied,isalsoanimportant
concern,asitcanreachanannualincidenceof100,000200,000withchildrenbetweentheages
of0and4yearshavingthehighestpercentageofincidenceandmortality.4,5Theeconomicimpact
ofbraininjuryisdifficulttodeterminewhenconsideringcompensationforworkloss,qualityof
life,rehabilitation,andhomeservicesinadditiontomedicalcosts.Nonetheless,estimatesoftotal
lifetimecostsrangefrom$147billionforfatalTBIto$18billionfornonhospitalizedTBI.2
Althoughbraininjuriesareasignificantportionoftrauma,theseverityofTBIrangesfrommild,
definedasamomentarychangeinconsciousness,tosevere,whichinvolvessustainedperiodsof
unconsciousnessand/oramnesia.Fortunately,morethan85%ofTBIthatismedicallytreatedis
consideredmildandmostpatientsareabletorecoverfromtheirinjuries.2
NEUROPLASTICITY
Thecentralnervoussystem(CNS)retainsaninnovativeabilitytorecoverandadaptsecondary
compensatorymechanismstoinjury.Thebasisofrecoverystemsfromneuroplasticity,definedas
theabilityforneuronalcircuitstomakeadaptivechangesonbothastructuralandfunctionallevel,
rangingfrommolecular,synaptic,andcellularchangestomoreglobalnetworkchanges.Theadult
brainwastraditionallythoughttobestagnant,withneuroplasticityconfinedtocortical
development.
Now,however,neuronalplasticityoccursafteraninjuryinasequenceofthreephases.6
Immediatelyafterinjury,celldeathoccursalongwithdecreaseincorticalinhibitorypathwaysfor1
to2daysthatisthoughttorecruitorunmasknewandsecondaryneuronalnetworks.7Eventually,
theactivityofcorticalpathwaysshiftfrominhibitorytoexcitatoryfollowedbyneuronal
proliferationandsynaptogenesis.Bothneuronalandnonneuronalcells(i.e.,endothelial
progenitors,glialcells,andinflammatorycells)arerecruitedtoreplacethedamagedcells,facilitate
glioticscartissue,andrevascularize.6Weeksafterinjury,newsynapticmarkersandaxonal
sproutingareupregulated,8allowingforremodelingandcorticalchangesforrecovery.Chronic
changeshavebeenstudiedinseveralmouseinjurymodels,althoughoutcomesvaryandare
affectedbytheageofthemouseattimeofinjury.4Preliminaryworkdoessuggestthatlonglasting
morphologicchangesoccurinthehippocampusafterTBI,includinggrowthofcellsomaand
recruitmentofneuronstothehippocampus.4,9
Directevidenceforneurogenesisandplasticityhaveexistedfordecades,sincethediscoveryof
labelingagentssuchasBrdU,3Hthymidine,and14C,1012allowingforthedirectvisualizationof
celldivisionandturnover.Mappingstudies,usingthesesameagentsonnonhumanprimatesafter
injury,demonstratedthattheoriginalinjuredcorticalregioninmonkeysafterbehavioralrecovery
wouldlocalizetoanadjacentterritory.13Studiesinthesomatosensoryandmotorcortex,in
particular,haveimplicatedtheseregionstobecapableandreceptivetoneuroplasticity,although
littleworkhaslookedattheentirecorticalcircuitry.Earlyevidenceforneuroplasticitywas
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determinedinthehealthybraininthesomatosensoryandmotorcortex.Bothsomatosensoryand
motormapsofthebodysurfacecouldberetrainedsothatadjacentbodypartscometorepresenta
largercorticalregion.14,15Clarketal.16suturedtwoadjacentdigitstogetherinprimatesandfound
that,overtime,thereceptivefieldsofcertainneurons,especiallyatthejunctionofthetwofingers,
wouldspanacrossbothdigits.Nudo14trainedprimatestomovemultiplejointsinareachand
retrievaltaskthatsimilarlyincreasedcorticalrepresentationsofadjacentmuscles.Intheinjured
brain,withworkfocusingonstrokerelatedinjuries,researchershavefoundthattheoutcomeof
neuroplasticityultimatelydependsonpostinjurybehaviors.Furthermore,imagingstudiesusing
diffusiontensorimaginghavefoundthatplasticitycanoccurinareasthatwereinitiallysparedfrom
strokerelateddamage,suchaschangesinthearcuatefasciculusthatoccursecondarytochronic
Brocasaphasia.17Plasticityfurthermorecorrelateswithchangesinthefunctionalperformanceof
patients.Fraseretal.,15inlookingatcorticobulbarexcitabilityinstrokepatientssufferingfrom
dysphagia,foundthatstimulustothecorticobulbarnucleuspromptedreorganizationofthecortex,
asgaugedbyfunctionalMRI(fMRI),andyieldedimprovementsinswallowing.Evidencefor
whetherneuroplasticityoccursonamoreglobal,corticallevelislimitedasmoststudieshave
focusedoneitherthesomatosensoryormotorcortexthroughelectrophysiologyorfMRI.
Nonetheless,workbySchlaugetal.17inpatientswithdysphagiaraisesthepossibilitythatthe
entirecortexmaybeindirectlyshapedbyneuroplasticchanges,althoughmoreimagingstudieswill
beneeded.Thesestudiessetthegroundworkthatneuroplasticityexistsforcertainregionsofthe
cortexandoccursthroughoutlifeandthatinjuries,suchasstrokeortrauma,serveasstimulito
promptfurtherregenerativeevents.
Studiesontheresponseofthepediatricbraintoinjuryhaveyieldedinterestingfindingsand
differingviewsontheeffectofageonrecoveryafterinjuryanditsfunctionaleffect.Oneview,first
proposedbyMargaretKennard,latertobenamedtheKennardprinciple,proposedthatthe
developingbrainiscapableofmoresignificantreorganizationandrecoveryafterinjury.18
Furthermore,theyoungerbrain,incontrasttotheelderlybrain,islesslikelytodevelopprogressive
cognitivedecline,andtheongoingdevelopmentmayinactualitypromoterecovery.19The
opposingperspective,however,seesthedevelopingbrainasmorevulnerabletodamagegiventhat
itisundergoingsignificantgrowthandcircuitryformationduringcriticalperiods,whichmaylead
tomoresevereormorepermanentphysiologicchangesinthepresenceofinjury.Animalworkby
Casellaetal.4injuvenile(postnatalday17)andimmature(postnatalday7)ratswhounderwent
focalTBIwithcontusionrevealedthattheageofthemiceattimeofinjuryaffectstheplasticityand
recoveryofthebrainpostinjury.Intheirwork,theresearchersfindthatjuvenileratshaveboth
memoryandlearningdeficitsintheMorriswatermazethatlastuntilpostinjuryday17(PID17).
Juvenilemicehavelongerlastingsomaticandemotionaldysfunction,upuntilPID60,astestedby
behaviorsdisplayinganxietyandsensorimotorfunction.4Thepoorfunctionaloutcomesinjuvenile
micewerefoundtocorrelatewithanatomicalchangesspecificallyinthehippocampus,including
increasesinthesomasize,dendriticlengthandbranchingpointsincellsofthedentategyrusafter
injury.SomasizeofcellsinCA3alsoincreased,whereasthedendriticlengthandbranchpointsof
cellsinCA1decreasedafterinjury.Interestingly,immaturemicewerefoundtohaveno
morphologicalchangesincellsofthedentategyrus,CA1,orCA3afterinjury.4Casellareportshis
workasevidencefordependencyonnotonlyage,butalsotheregionofthebraininregardsto
responseafterinjury.Unfortunately,hisworkdoesnotcorrelatethemorphologicalfindingsin
PND7micewithanycognitive,motor,orsensorimotoroutcomes.Otherworkinmicereportthat
outcomesafteragerelatedinjuriesisassociatedmorewiththeparticularstageofcortical
developmentatacertainageratherthantheageitself.18
Inhumanstudies,contradictoryevidenceexistsregardingtheeffectofageontheresponseof
childrenafterinjury.Theconsistencyacrossthestudies,however,suggeststhatthetypeofinjury
playsalargefactorinthefinalresponse.Severalstudiessupportthetheorythatyoungerageisa
protectivefactor.Bergeretal.20reviewedtheirseriesof37childrenunder17yearsofagewith
traumaticbraininjuryandfoundthatthechildrenhadbetterfunctionalrecoverythanadults.
Anothergroupshowsthatpatientsinjuredatayoungerage(lessthan26years)werelessdisabled
comparedtoolderpatients(greaterthan40years)despitehavingmoresevereinjuries.19In
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contrast,otherstudiesreportthatchildrenlessthan4yearsoldhaveaworsemotorandcognitive
outcomecomparedwitholderchildrenwhosufferfromTBI.21Morerecentworkfoundthat
youngeragehadmoreadverseimpactsonlanguageinworkdonebyLevinetal.22whotested
wordgeneration,repetition,receptivevocabulary,narration,andrecallinbothyoungandolder
childrenwithvaryingdegreesofcloseheadinjuries(CHI).YoungchildrenwithsevereCHItook
longertorecoverwordfluencywhencomparedtosameagedchildrenwithmildCHIandolder
childrenwithanydegreeofheadinjury.Thisfindingisthoughttobeexplainedbythedisruption
ofwhitematterdevelopmentandtracksbythediffuseaxonalinjurythattypicallyoccurssecondary
toseveretrauma.22Furthermore,itisthoughtthatolderageallowsfornotonlymoreneuronal
trackstobeincorporatedintotheappropriatecircuitry,butalsonormalbraindevelopment,thus
improvingoverallfunctions.22Stillotherstudiesseemtosuggestthatageisnotacriticalfactorin
determiningfunctionaloutcomesandcapacityforrecovery,aswasthecaseforSchuettandZihl23
intheirstudyofagerelatedeffectsonvisualfielddisorders.Botholderandyoungerpatientshad
nodifferenceintheseverityofimpairments,functionaloutcomes,andresponsetotreatments.
Althoughstudieshaveyieldedvaryingresults,theydidestablishtheuseofneuroimagingin
trackingandinvestigatingneuroplasticity.
FUNCTIONALIMAGINGOFTRAUMATICBRAININJURYAND
NEUROPLASTICITY
Untilveryrecently,noninvasiveneuroimaginghadlimitedpowertodetectwhitematterstructural
changes.Thedevelopmentoftechniquessuchaspositronemissiontomography(PET),functional
MRI(fMRI),diffusiontensorimaging(DTI),andtranscranialmagneticstimulation(TMS)have
changedthedetectionofresponseafterbraininjury(seeTable8.1).
TABLE8.1
ComparisonofVariousImagingModalitiesforNeuroplasticity
POSITRONEMISSIONTOMOGRAPHYANDFUNCTIONAL MRI
PETandfMRIaretwotechniquesthatdonotassessneuronalactivitydirectlyrather,theyuse
vascularandmetabolicchanges,respectively,asindicationsofneuronalactivity.PETisamore
invasiveimagingtechniquethatinvolveseitherinhalationorinjectionofradioactivetracersthat
accumulateinactivatedbrainregions.PETreliesonthepremisethatcerebralbloodflowincreases
toregionsofneuronalactivity.SignalchangesarethenmappedontoastandardMRIscanofthe
braintoallowforanatomicalcorrelation.WhilePEToffershighspatialresolutionupto510mm,
ithaspoortemporalresolutiongiventhetimeneededtorecordbloodflow.24
Similarly,fMRIoperatesontheassumptionthatneuronalactivityincreasesoxygenconsumption
andglucosemetabolism.Aparticularsequencecalledbloodoxygenationleveldependent(BOLD)
issensitivetothepresenceofdeoxyhemoglobinintheblood,whichdistortsthemagneticfields
andusestheratioofdeoxytooxyhemoglobintocreatesignals.BOLDfMRIallowsformultiple
acquisitionsthatofferusefultemporalresolutiontodetectdifferencesbetweenbrainregions.24,25
PreliminaryfMRIstudiesinpatientswithTBIshowdifferentialactivationpatternsforexample,in
apatientwithrighttemporoparietalcontusionnowexperiencingdyscalculiaandreadingdisability,
fMRIrevealsconsiderablelefthemisphereactivationandminimalrighthemisphereactivationin
contrasttothebilateralactivationdetectedinneurologicallyintactpatients.26Unfortunately,given
thatPETandfMRIdependonbloodflowandmetabolicactivities,thereadoutcanbeaffectedby
ageandcerebrovasculardiseasessuchasatherosclerosis.
DIFFUSIONTENSORIMAGING
Diffusiontensorimaging(DTI)hashighsensitivityformicroscopicinjuryandisincreasinglyused
todetectearliersignsofinjury.DTIanalyzesthemicrostructureofwhitematterbasedonvector
mapscreatedfromdiffusionpatternsofwatermolecules.Algorithmsthatanalyzepropertiesof
27
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waterdiffusioncandeterminefibertracts27andcanconferinformationonfiberorientationand
damagethatarenotdetectablethroughconventionalMRI.28,29Preliminaryworkindicatesthat
DTIcandetectmicroscopicinjuryinmoderatetosevereTBI,whereasimagingonpatientswith
mildTBIhavethusfarnotshownanysignificantdifferencecomparedtoneurologicallyintact
patients.29,30Unfortunately,therearelimitedstudiesonpatientswithmildTBI,makingitdifficult
todeterminetheeffectoftimelapseafterinjuryonthelackofchanges.Nonetheless,DTIdoes
provideinformationontheamountandseverityofbraininjurywithpromisingfindingsonthe
structuraldisorganizationassociatedwithdiffuseaxonalinjury.26,30Diffuseaxonalinjuryhas
neverbeendirectlydetectedbutratherinferredatalatertimepointwhenwhitematterinjuryleads
todegenerativechangescontributingtoventriculomegaly.26Assuch,thereisinterestinusingDTI
tonotonlyquantifythedegreeofwhitematterinjury,butalsoprognosticateseveritybasedonthe
abnormalitiesdiscovered.Futureworkwillalsofocusontheeffectsofinterventionsonthe
trajectoriesandconnectionsofwhitemattertracts.26
TRANSCRANIAL MAGNETICSTIMULATION
Transcranialmagneticstimulation(TMS)usesmagneticfieldsandelectricalcurrentstostimulate
corticalregionsofthebraininanoninvasivemanner.Primarilyusedtotriggerbrainplasticityinthe
motorsystem,TMSinvolvesapplyingacurrentoverthescalpcorrespondingtoamotorregionthat
thentriggersanelectrographicresponseinitstargetmusclescalledmotorevokedpotentials
(MEP).31ComparingMEPsbeforeandafterinjuryoracrossinjuredanduninjuredhemispheres
determinesresidualandchangingcorticalfunction.Preliminaryworkthusfardemonstratesthat
corticalmapschangeinresponsetoinjurythroughtwomechanisms:(1)theregionofexcitationfor
acorticalmapwilleitherenlargeorshrinkand(2)theregioncorrespondingtoacorticalmapmay
migratetoadjacentregions.32,33TheapplicabilityofTMSinstudyingplasticitywasshownby
Liepertetal.,whoimagedpatientstrainedinnewfinemotorskillsusingbothhandsandfeetand
foundshiftsincorticalrepresentationsforthemusclegroups.Theshiftsincorticalrepresentations
detectedbyTMSrecapitulatedtheearlymappingstudiesdonebyGleesandColeandwasthought
tobesecondarytocorticalmodulations.TMScanalsodetectasymmetrybetweenhemispheresin
motormapstimulationafterahemisphericstrokethatislikelyrelatedtodisuseontheinjuredside
andcompensatorychangesontheuninjuredside.
ImagingmodalitiessuchasfMRI,PET,andDTIareexcitingfortheirpotentialuseinmonitoring
ongoingneuroplasticity.DTI,however,islimitedtomonitoringonlysinglewhitemattertracksas
itssensitivityisdecreasedwiththepresenceofmultiplewhitemattertracksintersectingor
degeneratingincomplexorinjuredregions.Whilelongtermneuroplasticityandimprovementhas
notbeenfullymonitoredafterinjury,stimulationandtrainingseemstopromoteneuralchangesthat
arelonglasting,suggestingthatneuroplasticityshouldgenerallybeachronicprocess.Onegroup
reviewedfMRIacrossmultiplestudiestodeterminethatpoststroketreatmentpromotedcortical
changesinthemotorregionbeyondtherecoveryplateautypicallyseenafterstroke.34Limited
longitudinalstudiesareavailableonthepresenceofchronicneuroplasticityinotherdomains,such
asthesensorycortexorlanguage.
PROMISINGTHERAPEUTICSAFTERTBI
Traumaticbraininjurycausesbothdirectdamage,throughshearinjuryofneuronsandblood
vessels,andindirectdamagefromsecondaryischemia,edema,orinflammation.Through
destructionofthebloodbrainbarrier(BBB),TBIallowsimmunecellstoentertheinjuredregion
toactivateinflammatoryresponses.TBIalsoactivatesmicrogliaandastrocytestorelease
inflammatorycytokines,chemokines,andprostaglandinsthatfurtherincreasethepermeabilityof
theBBB.35
AcutetreatmentalgorithmsforTBIincludeminimizingintracranialpressureandoptimizing
cerebralperfusionpressuretolimitsecondarydamage.Longtermtherapiesfocusonimproving
motor,cognitive,andbehavioraloutcomes.However,therapiesforTBIandintrinsicrepair
mechanismsinthebrainareoftenconstrainedbytheextentandseverityofinjury,ageofthe
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patient,priororpolytrauma,andtimelapsetomedicalmanagement.Thus,newertherapiestarget
preventionofsecondarysequelaetoenhanceneuroprotection.Inparticular,mountingevidencefor
neuroplasticityandneuralregenerationintheadultCNShasencouragedthedevelopmentof
pharmacologictherapiestoenhancetheregenerativeprocess.Manyofthepharmacological
therapiesdescribedbelowarestillintheirearlystagesofinvestigation,buttargetprocessessuchas
neurogenesis,inflammation,angiogenesis,andsynapticremodelingandformation(seeTable8.2).
TABLE8.2
SummaryofPromisingNewTherapies
STEMCELLS
Animalstudieshaveshownpromisingresultsintheuseofstemcellstoamelioratethesequelaeof
TBI.Becausestemcellsarecapableofselfrenewalanddifferentiationintomultiplecelltypes,
exogenousstemcelltransplantationintoinjuredbraincancounteractmultipledamaging
mechanisms,fromdirectneuronallosstosecondaryinflammatorysequelaeandevenprovide
trophicfactorsforanurturingmicroenvironment.36Bycompensatingformanyaspectsof
recovery,stemcellsareprotectiveevenforchronicphasesofrecovery.Typesofstemcellsunder
investigationforTBIincludeneuralstemcells(NSCs),bonemarrowderivedmesenchymalstem
cells(BMMSCs),andumbilicalcordderivedmesenchymalstemcells(UCMSCs).
TheexistenceofNSCswerefirstdiscoveredfromadultmicestriataltissue,37buthavesincebeen
isolatedfromdiversepartsoftheadultbrain,includingthecortex,subventricularzone,and
ventricularzone.12,38NSCscandifferentiateintofunctionalneurons,astrocytes,and
oligodendrocytesandintegrateintoexistingneuronalcircuitry.39Theargumentforusingadult
neuralstemcellsratherthanembryonicandothermultipotentstemcellsisrelatedtopossible
tumorigenicitywiththelattercells.Incontrast,othersarguethatNSCsislimitedinthatitprovides
onlytheneuralcellsandtrophicfactors,whileignoringtheroleofthesurrounding
microenvironment,vasculature,andimmunesystemonrepair.However,perhapsbecauseoftheir
abilitytorespondtoandsecretetrophicfactors,NSCshaveanadvantageoverothertypesofstem
cellsinmigratingtoregionsofinjury.NSCsexpresscelladhesionproteins,integrins,and
chemokinereceptorsthathoneontoinflammatoryregionsofthebrain.38Onceatthesiteofinjury,
NSCscanconfercertainfunctionalbenefits.Inmicesubjectedtocontrolledcorticalimpact(CCI)
injuries,transplantedNSCscanreturnmotorbutnotcognitivefunction.40,41ThebenefitsofNSCs
arelikelyderivedfromincreasedexpressionofneurotrophicfactorsandreleaseofchemokines.
Neurotrophicfactors,suchasbrainderivedneurotrophicfactor(BDNF),nervegrowthfactor
(NGF),andfibroblastgrowthfactor(FGF)promotecellsurvival,growth,anddifferentiation
throughactivationofsignalingpathways,whereaschemokineshelptomodulatetheinflammatory
response.38TheutilityofNSCsunfortunatelymaybelimitedbytheseverityofTBI,improving
functiononlyincasesofmildTBI42andforyoungerpopulationsexperiencingTBI.43Inmice
subjectedtoCCI,Shindoetal.42foundthattransplantedNSCssurvivedinmildTBIinjuriesin
contrasttosevereTBIthoughttobeduetodifferencesinthesurroundingmicroenvironment
promptingdifferentialexpressionofneurotrophicfactors.Furthermore,intrinsicNSCs,detectable
inTBIinjuredbrain,ispresentinhigherquantitiesandhaveincreasedsurvivalratesinyounger
micecomparedtooldermice,andalsothoughttoberelatedtoincreasedexpressionof
neurotrophicfactorsanddecreasedexpressionofproinflammatorycytokinessuchastumor
necrosisfactora(TNF)andinterleukins(IL)1/.43
Mesenchymalstemcells(MSCs)aremultipotentnonhematopoieticcellsthathavebeenshownto
haveaprotectiveroleinTBI.WhiletheexactprotectivemechanismoftransplantedMSCsstill
needstobeelucidatedandlikelymultifactorial,initialworksuggeststhatthepromiseofMSCslies
withmodulatingtheimmunesystemandalteringtheinflammatoryresponsescommonlytriggered
byTBI.AspartoftheimmuneresponsetoTBI,astrocytesbecomereactiveandtriggeraglialscar
responsesurroundingthebraininjury.Theglialscarservestolimittheexcitotoxicitythatoccurs
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withneuronaldeathandwillalsorecruitmicrogliaandmacrophagestodigestdeadneurons.
However,thepresenceoftheglialscaritselfofteninhibitssynapticreformationandrepair.
TransplantedMSCsmodulatethisresponsebymigratingtositesofinjuryanddecreasingthe
thicknessoftheglialscar,allowingforenhancedregenerationandimprovedfunctionalrecovery.44
Furthermore,MSCsdifferentiateintoneurons,glialcells,andvascularendothelialcells,andsecrete
factorsandcytokinestopromoteneurogenesisandangiogenesis.36,45TheabilityofMSCsto
influencethesurroundingmicroenvironmentandtheirlowimmunogenicitywhenallogenicalso
conferadvantagesoverothertypesofstemcells.35,45Inaddition,MSCsareeasilyobtainedand
willrapidlyproliferateexvivo.MSCsderivedfrombonemarrow(BMMSCs)andumbilicalcord
blood(UCBMSCs)havebothbeeninvestigated.Functionalrecoveryimproveswitheither
intravenousorintraarterialinfusionofBMMSCsasdoesintracisternalMSCs.46,47Tianetal.48
alsofoundthatasubpopulationofpatientswithTBIhadfunctionalimprovementsafter
transplantationwithBMMSCsthroughlumbarpuncture.Outcomes,however,canbeconfounded
byanumberoffactors,suchasageofpatients,timeafterinjury,modeofdelivery,andMSC
isolationandculturetechniques.Nonetheless,thebenefitsofMSCsareconferredthroughBDNF
andNGF49aswellasdifferentialexpressionsofproinflammatorycytokinesdependingonthe
timeperiodafterTBI.MSCsinitiallydecreaselevelsofIL6intheacuteperiod,butsubsequently
upregulateIL6levelstopromoterevascularizationandscarformation.35
Despitethesuccesswithcellsfromthebonemarrow,umbilicalcordblood(UCB)isdesirablefor
multiplereasons:(1)UCBoffersarichsourceofmultipletypesofstemcells,fromhematopoietic
andmesenchymalstemcellstoembryonicstemcells(2)iseasilyandreadilyobtainedcomparedto
bonemarrowaspiration,and(3)ethicallyaccepted.49UCMSCsalsohavemoreproliferative
activitythanBMMSCswheninitiallycultured,whichmayconfergreaterbenefitsin
transplantationtoaninjuredbrain.50,51UCMSCshavebeeninvestigatedinbothischemicand
traumaticbraininjuries.Zanieretal.44showthatthatUCMSCsbehavesimilarlytoBMMSCs
whenplacedintracerebroventricularly,UCMSCssurviveatahighrate,migratetotheinjurysite,
andsecreteBDNF,whichthenalterstheresponseofmicrogliaandmacrophagestoinflammation
todecreasethesizeofthebrainscar.InmicewithCCIinjuries,UCMSCswereabletoclinically
improvesensorimotorfunctions.52LimitedstudieswithUCMSCsexistinhumans,butinpatients
withdistantTBI,UCMSCsimprovedmotorscoresandfunctionalindependencemeasures.51
ANTIOXIDANT THERAPY
Reactiveoxygenspecies(ROS)areacommonsourceofdamagesecondarytoischemicrelated
injury.Ischemiainducesexcitotoxicitywhenneuronsreleaseglutamatethatthensetsoffcascades
forfreeradicalproduction.FreeradicalproductionafterTBIhasbeenshowntoinduceNSC
degenerationanddeath,53,54preventingtheneuronalregenerationneededforultimaterepair.ROS
alsointerferewithautoregulatorymechanismsinthevasculatureandinducelipidperoxidation,
whichdamagesneuronalmembranes.Assuch,antioxidanttherapiesseektoinhibittheformation
ofROS,neutralizetheROS,orantagonizetheenzymesthatactupontheROS.Assuch,
antioxidanttherapiesseektoinhibittheformationofROS,neutralizetheROS,orantagonizethe
enzymesthatactupontheROS.Thepresenceofantioxidativeenzymesdecreasewithage,leading
tomoreradicalinduceddamageandcelldeathwhenTBIoccursamongtheelderly.Thisgives
antioxidativeagentsaspecialnicheinfunctionalrecoveryfortheelderly.55ExamplesofROS
scavengingcompoundsincludepolyethyleneglycolconjugatedsuperoxidedismutase(PEG
SOD),the2methylaminochromancompound,U83836E,andedaravone.PEGSODprevents
posttraumaticmicrovasculardysfunctionbyisolatingthe radicalsresponsibleforthe
56
damage. AlthoughphaseIItrialsstudyingPEGSODshowedinitialpromise,subsequentphase
IIIstudiesdidnotproduceanysignificantclinicalbenefit,relatedtoeitherpoorpenetrationthrough
thebloodbrainbarrierordegreeofTBIstudied.57U83836E,consideredtobethemosteffective
lipidperoxidationinhibitorduetohighaffinityformembranephospholipids,hasreducedlipid
peroxidationandproteinnitrationandpreservedmitochondrialfunctioninmouseinjurymodels.56
ClinicaltrialsonU83836E,however,arestillneededtodemonstrateclinicalefficacy.Edavarone,
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alsoknownas3methyl1phenylpyrazoline5one,hastheabilitytopenetratethroughtheBBB
andhasalreadyshownremarkableneuroprotectiveeffectsinischemicmousemodelsandpatients
withstroke.InTBI,edavaroneattenuatesischemicdamagethroughinteractionswith and
OH,whichreducebrainedema.Edavaronealsohastheabilitytoblockapoptoticpathways
throughinhibitionofcytochromecandcaspase3andupregulationofphosphatidylinositol3
kinaseAktpathway.Combined,theseeffectspreventneuronalandglialdeathandallowforNSCs
toappearandsurviveatthesiteofTBI.54Functionally,edavaroneadministrationallowedmice
withTBItoperformtheMorriswatermazefasterthancontrolmice,suggestingitspotentialin
amelioratingTBI.58
CyclosporinA(CsA)preservesmitochondrialfunctionbyinhibitingpermeabilityofthetransition
poreandreducingtheamountofreactiveoxygenspecies.59Combinedwithitsabilitytoinhibit
calcineurin,CsAreducestheamountofaxonalinjuryandsizeoflesionafterTBI.60Functionally,
CsAimprovesmotoroutcomesasgaugedbytheMorriswatermazewhentestedinmiceafter
lateralfluidpercussioninjuries(FPI).61However,dependingonthetypeofmouseinjurymodel
studied,CsAcanyieldconflictingresults.IntheCCIinjurymodel,CsAhadnoeffectoncognitive
outcomes.62Inhumans,initialclinicaltrialscomparingCsAtoaplaceboinadultswithsevereTBI
havebeenpromisingCsAbothimprovesGlasgowComaScores(GCS)at6monthsandincreases
meanarterialpressure(MAP)andcerebralperfusionpressure(CPP).63Unfortunately,many
studieswithCsAhavesmallsamplesizesandlacklongtermfollowupforevaluationoftoxicity.
PHARMACOLOGICTREATMENT
Erythropoietin(EPO)isacytokine,knownforitsroleinerythropoiesis,butalsocapableof
counteractingamultitudeofapoptotic,oxidative,andinflammatoryreactions.64EPOcameunder
studywhenmicewithoutEPOreceptorwerefoundtohaveworseoutcomesafterCCIcompared
towildtypemice.65EPOconfersbenefitsacrossmultiplemouseinjurymodels,suchasCCI,FPI,
impactacceleration,andcombinedinjuries.64Forexample,carbamylatedEPO,whichdoesnot
affecthematocrit,reduceslesionsizeinCCIandpromotesbothneurogenesisandangiogenesis.66
WorkwithEPOinhumanTBIhasmostlyfocusedondeterminingtiminganddosing,but
preliminarydatarevealsthatEPOdecreaseshospitalmortality.67,68
Thesteroidprogesterone,enrichedinthebrain,isanotheragentwithmultiplemechanismsfor
neuroprotection.ItsmetabolicderivativesandactiononGABAAreceptorsproduceananti
inflammatorystatebyreducingbrainedema,apoptosis,andneuronalcelldeath.6971Limited
randomizedcontrolledtrialscurrentlyexistontheeffectsofprogesteroneinTBI,butrevealthat
progesteronedecreasesthemortalityrate,comparedtoplacebo,followingacuteTBIandalso
increasesscoresmeasuringfunctionaloutcomes(Wrightetal.,2007).72
Aspartofthemechanicaldamagetobraintissueandtheensuinginflammatoryresponse,the
bloodbrainbarrieroftenbecomesdisrupted.Priorworkdemonstratedthatanonhistonechromatin
DNAbindingprotein,calledhighmobilitygroupbox1(HMGB1),isreleasedfromdamagedcells
particularlyinischemicregions,whichsetsofftheinflammatoryeventsresponsibleforBBB
disruption.73Assuch,therapiessuchasaneutralizingmonoclonalantibodyagainstHMGB1
(mABHMGB1)havebeeninvestigated,discoveringthatmABHMGB1isabletoreducethe
extentofbraininjuryandedemafromfluidpercussionbyreducingtheextentofBBB
permeability.74,75Furthermore,antiHMGB1reducestheamountofinflammatoryproteins
expressed,thuslimitingthedegreeofsecondaryinsults.74
CONCLUSION
Therecoveryprocessaftertraumaticbraininjuryislong,butwithemergingevidencefor
neuroplasticity,theprospectsforrecoveryarenolongersogrim.Theexactmechanismremains
unknown,however,manyhypothesesarecurrentlybeinginvestigated.Manypotentialtherapeutic
opportunitiesarebeingexploredtotargetknownchangeswithneuroplasticity,fromdifferential
https://www.ncbi.nlm.nih.gov/books/NBK326735/ 7/11
201763 NeuroplasticityafterTraumaticBrainInjuryTranslationalResearchinTraumaticBrainInjuryNCBIBookshelf
geneexpressionandcellularproliferation,totheupregulationofsynapticproteinsandjunctionsfor
newnetworkconnections,tothemodulationofinflammatoryreactionsandtherecruitmentof
immunecellstolimitthesizeandvolumeofdamage.Futuretherapiesmayfindbenefitintargeting
multiplemechanismsofrecoveryandassuch,stemcelltherapiesoracombinationofdifferent
pharmacologictherapiesareofutmostinterestandcurrentlyunderheavyinvestigation.
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