NEURALPLASTICITYVOLUME10NO122003TheBasalGangliaandMotorControlHenk - PDF document

NEURALPLASTICITYVOLUME10,NO.1-2,2003TheBasalGangliaandMotorControlHenkJ.GroenewegenDepartmentofAnatomy,ResearchInstituteNeurosciencesVrijeUniversiteit,VUUniversityMedicalCenter,Amsterdam,TheNetherlandsABSTRACTThispaperbrieflyreviewsthefunctionalanatomyofthebasalgangliaandtheirrelationshipswiththethalamocorticalsystem.Thebasalganglia,includingthestriatum,pallidum,subthalamicnucleus,andsubstantianigra,areinvolvedinanumberofparallel,functionallysegregatedcortical-subcorticalcircuits.Thesecircuitssupportawiderangeofsensorimotor,cognitiveandemotional-motivationalbrainfunctions.Amainroleofthebasalgangliaisthelearningandselectionofthemostappropriatemotororbehavioralprograms.Theinternalfunctionalorganizationofthebasalgangliaisverywellsuitedforsuchselectionmechanisms,bothindevelopmentandinadulthood.Thequestionofwhetherclumsinessmaybe,atleastinpart,attributedtodysfunctionofthebasalgangliaisdiscussedinthecontextofthedifferential,comple-mentary,orinteractiverolesofthebasalgangliaandthecerebelluminthedevelopmentofmotorcontrol.KEYWORDScerebellum,dopamine,developmentReprintrequeststo:H.J.GroenewegenMDPhD,DepartmentofAnatomy,VUUniversityMedicalCenter(VUmc),VanderBoechorststraat7,1081BTAmsterdam,TheNetherlands;e-mail:hj.groenewegen@vumc.nlINTRODUCTIONVoluntary(intended)movementsaswellasunintentionalmovementsarebasedonspatialandtemporalpatternsofmusclecontractionsthatareinitiatedandcoordinatedbydifferentstructuresinthecentralnervoussystem.Thefine-tuningofthesestructuresandtheneuronalnetworksthatareinvolvedinmotorexecutionareessentialfortheexpressionofadequatemotorbehavior.Mostofourskilledmovements,aswellasourcomplexbehaviors,havebeenlearnedinthecourseofdevelopmentandhavetobe'maintained'duringadultlife.Althoughinthisextended,lifelonglearningprocessextensivepartsofthebrainareimportant,inthecaseofskilledmovementsinparticularthecerebralcortex,thecerebellum,andthebasalgangliahaveacrucialrole.Clumsinessisatermassociatedinchildhoodwithproblemsinthelearningandexecutionofskillfulmovements,theneuronalbasisofwhichis,however,poorlyunderstood(Hadders-Algra,2003).Theknowledgeofnormalstructuralandfunctionalrelationsamongthebrainstructuresinvolvedinmotorfunctionsisessentialforinsightintotheetiologyandpatho-genesisofvariousmovementdisorders,includingclumsiness.Theexecutionofwilled,intentionalmovementsoftenrequiresthesubtle,concertedactionofthemotorandsensorysystems.Consider,forexample,eye-handcoordinationduringtheexecutionoffinemanipulationswiththehandandfing

ers.Complexmovementshavetobelearnedandtheyhavetobepracticedfrequently.Thecorrectexecutionofsuch(C)2003Freund&Pettman,U.K.107 108H.J.GROENEWEGENmovementsisdependentupontheexacttimingintheactivationandswitchingofmotorprogramsthathavebeenimprintedinthebrainduringthecourseofmotorlearningprocesses(motormemory).Indailylife,onceamovementhasbeeninitiated,theexecutionofmostofourwilled,intentionalmovementsoccursvirtuallyautomatically.Intentionalmovementsareinessenceinitiatedbythecerebralmotorcortexthatdirectly,orindirectlyvialocalpremotorcircuits,reachesthebrainstemorspinalmotorneuronsthatprojecttothemuscles.Beforeamotorsignaldescendsfromthemotorcortextothebrainstemandspinalcord,however,severalcorticalandsubcorticalcenters,includingthebasalgangliaandthecerebellum,haveposedtheirinfluenceonthemotorcortexto'shape'thefinal,descendingsignal.Thebasalgangliaandthecerebellumexerttheirinfluenceonthefinalmotoroutputpathwayslargelyviathethalamusonthedescending,corticobulbarandcorticospinalmotorpathwaysthatoriginateinthemotorandpremotorareasofthecerebralcortex.Inthisway,boththebasalgangliaandthecerebellumhaveanessentialanddistinctiveroleintheorganization(coordination,timing,andsequencing)ofanormalmotoroutput.Finally,thebasalganglia,aswellasthecerebellum,playanimportantroleinmotorlearningprocesses,albeitindifferentaspectsandphases.Thepresentaccountbrieflyreviewsthefunctional-anatomicalaspectsofthebasalgangliainrelationtothebraincircuitsinwhichtheyareinvolved.Thearrangement(describedbelow)of'intrinsic'connectionsbetweenbasalgangliastructuresandtheirfunctional-anatomicalrelationswiththe(frontal)thalamocorticalsystem,aswellaswithanumberofcentersinthemesencephalon,lendsupporttothehypothesisthatthebasalgangliaplayaroleinthefacilitationofintended,desiredmotorprogramsandinthesuppressionofunintendedorcompetingones.Thebasalgangliamightalsoplayaroleinthelearningofskillfulmovementsand(complex)behavioralprograms,bothinearlydevelopmentaswellasduringlaterlife.Towhatextent,ifatall,clumsinesscanbeattributedtoamalfunctioningofthebasalgangliaortodisturbancesthatarerelatedtoaroleofthebasalgangliainthedevelopmentofnormalmotorbehavior,remainsanopenquestion.STRUCTUREANDFIBERCONNECTIONSOFTHEBASALGANGLIAWhichstructuresbelongtothebasalganglia?Thebrainstructuresthatareincludedinthe'basalganglia'consistofthestriatum,thepallidum,thesubthalamicnucleus,andthesubstantianigra.Eachindividualstructureis,inthehumanbrain,constitutedbymacroscopicallydifferentsubnuclei.Thus,thestriatu

mincludesthecaudatenucleus,putamen,andnucleusaccumbens,thepallidumconsistsofaninternalandanexternalsegment,andtheventralpallidum.Thesubthalamicnucleusappears,macroscopically,asanundividedmorphologicalunity,butthesubstantianigrahasaclearlydistinguishableparscompactaandparsreticulata.Theventraltegmentalarea(VTA),situatedmediallytothesubstantianigraintherostralmesencephalon,canalsobeconsideredapartofthebasalganglia'family'.Thereasonforincludingthecaudatenucleus,putamen,andnucleusaccumbenscollectivelyinthestriatumisthatallthreenucleihavesimilarhistological,neurochemical,andconnectionalcharacteristics.Thepredominantstriatalneuronalelementisthemedium-sized,denselyspinyneuronthatreceivesandintegratesthebulkofstriatalinputsfromthecerebralcortexandthalamusandthatprojectstothepallidumandthesubstantianigra(Fig.1;Smith&Bolam,1990;Gerfen&Wilson,1996).Medium-sizedspinyneuronscontaintheneurotransmittergamma-aminobutyricacid BASALGANGLIAANDMOTORCONTROL109(GABA)andco-localizedifferentneuropeptides.Aminorityofstriatalneuronsisformedbyvarioustypesofinterneurons,amongwhicharecholinergicandparvalbuminergic,aswellasavarietyofpeptidergicneurons(Bolametal,2000).Althoughthevariouspartsofthestriammmaytransferdifferenttypesofinformation(onthebasisofinputsfromfunctionallydistinctareasofthecerebralcortex;seebelow),asaresultofitsrelativehistologicalandneurochemicaluniformity,thewayinwhichthesedifferenttypesofinformationare'processed'inthestriatumisprobablyverysimilar.Likewise,distinctpartsofthepallidalcomplexcantransferdifferenttypesofinformation,butthemorphologicalcharacteristicsofthevariotssubnucleiofthepallidalcomplexarecomparable.MostofthepallidumconsistsofrelativelylargeaspinyneuronsthatcontaintheneurotransmitterGABA;theneuronaldensityofthepallidumismuchlowerthanthatofthestriatum.Pallidalneuronsreceivemostoftheirinputfromthestriatumandthesubthalamicnucleus,andtheyprojecteithertootherbasalgangliastructuresortothethalamusorthebrainstemoutsidethebasalgangliacircuitry(Gerfen&Wilson,1996).Incontrasttothestriatumandthepallidumthehistologicalandconnectionalcharacteristicsofthetwopartsofthesubstantianigraareverydiftrent.Initshistological,neurochemical,andMSNCerebralcortexAmygdalaSNCVTACholinergicinterneuronsMSNFig.1"Schematicrepresentationofamedium-sizedspinyneuron(MSN)inthestriatum.Thepositionofdifferentinputsontheneuronareindicated:excitatorycorticaloramygdaloidinputsendontheheadofspines,dopaminergicterminalsfromthesubstantianigraparscompacta(SNC)andventr

altegmentalarea(VTA)terminateincloseassociationwiththecorticostriatalinputsonthespinenecksordendriticshafts.Inputsfromneighboringmedium-sizedspinyneuronsandstriatalinterneuronsterminateontheproximalpartsofthedendrites.AdaptedfromSmithandBolam(1990). 110H.J.GROENEWEGENconnectionalcharacteristics,theparsreticulatamostresemblestheinternalsegmentofthepallidum,whiletheparscompactacontainsthedopaminergicneuronsthatprojecttoboththestriatumandthe(pre)frontalcortex.TheVTAcontainsbothdopaminergicandGABAergicneuronsinaboutequalquantitiesandcanbeconsideredamixtureofelementscomparablewiththeparscompactaandparsreticulataofthesubstantianigra.Thesubthalamicnucleus,situatedatthejunctionbetweentheventraldiencephalonandthemesencephalon,isacompacthomogeneousgroupofneuronsthatuseglutamateasneuro-transmitter.Thesubthalamicnucleusisstronglyinfluencedbyinputsfromthepallidum,aswellasbyextrinsiccorticalandthalamicinputs.Itsendsglutamatergicprojectionstothepallidumandtotheparsreticulataofthesubstantianigra,excitingtheoutputneuronsofthebasalganglia(Gerfen&Wilson,1996;Wiseetal.,1996).'Position'ofthebasalgangliainforebraincircuitsThestriatumcanbeconsideredthemaininputstructureofthebasalgangliainthattheentirecerebralcortex,inatopographicalmanner,projectstothestriatumwhilealsothemidlineandintralaminarthalamicnuclei,thehippocampusandamygdalasendfiberstothestriatum.Allthesestriatalinputsareexcitatory(Parent&Hazrati,1995;Wiseetal.,1996).Thetransferofcorticalandthalamicinformationthroughthestriatumismodulatedbydopaminergicandserotonergicinputsfromtheparscompactaofthesubstantianigraandthemesencephalicraphenuclei,respectively.ThestriatumisrichindopamineD1andD2receptors,whereasvarioustypesofsero-tonergicreceptorsareexpressed,amongwhichthe5HT-2receptorsaremostprominent(Gerfen&Wilson,1996).Theventralpartsofthestriatum,includingthenucleusaccumbens,aswellasventralpartsofthecaudatenucleusandputamen,receive'limbic'inputsfromthehippocampusandtheamygdala;thispartofthestriatumcontainsthehighestdensityofserotonergicreceptorsandexpresses,inadditiontotheD1andD2receptors,thedopamineD3receptor(Groenewegenetal.,1996;Diazetal.,1995).Theelectrophysiologicalpropertiesofmedium-sizedspinyoutputneuronsofthestriatumaresuchthattheydependonconvergentexcitatoryinputs(fromthecerebralcortexandthethalamus)tobecome'active'.Inviewoftheveryintricatepatternsofoverlapandsegregationofinputsfrom(functionally)differentcorticalareas,thisdependencemostprobablyallowsforahighlyselectivemechanismofactiv

ationofspecificstriatalregionsorpopulations(ensembles)ofstriatalneurons,whichisimportantforanunderstandingofthefunctionsofthebasalganglia(Pennartzetal.,1994;Gerfen&Wilson,1996;seealsobelow).Themainoutputofthebasalgangliaisderivedfromtheinternalsegmentoftheg|obuspallidus,theparsreticulataofthesubstantianigra,andtheventralpallidum.Thesestructurespredominantlyprojecttotheventralanteriorandmediodorsalthalamicnucleiandreachinthiswaythecerebralcorticalareasintheentirefrontallobe.Also,thecentromedian-parafascicularthalamicnucleusisreachedbypallidalinputs,andthisthalamicstructureprojectstothemotorcortexaswellastothestriatum.Inaddition,pallidalandnigraloutputsreachthesuperiorcolliculus,themesencephalicreticularformation,andthepedunculopontineregion,inthiswayinfluencingdescendingbrainstemprojectionstothespinalmotorapparatus(Parent&Hazrati,1995;Gerfen&Wilson,1996).Theexternalsegmentoftheglobuspallidusandthesubthalamicnucleushaveverylimited,ifany,projectionsoutsidethebasalgangliacircuitrybutareintensivelyinterconnectedwitheachother,aswellaswithothersubnucleiofthepallidalandnigralcomplex.Thesestructuresformpartofthe BASALGANGLIAANDMOTORCONTROLlllso-called'indirectpathway',orrather'indirectnetwork'(Bolametal.,2000),thatisinterposedbetweenthestriatumasthebasalgangliainputstructureandtheoutputstructures,namelytheinternalpallidalsegment,ventralpallidum,andparsreticulataofthesubstantianigra.A'directpathway'alsoexistsbetweenthebasalgangliainputandoutputstructures,whichcomprisethedirectstriatopallidalandstriatonigralprojections(Fig.2;Gerfen&Wilson,1996).TheprevailingCEREBRALCORTEX/,"/;outputdopapineSPYNFig.2:Schematicrepresentationoftheorganizationofbasalganglia-thalamocorticalcircuits.Directandindirectpathwaysbetweenthestriatumandtheinternalsegmentoftheglobuspallidus(GPi)andthesubstantianigraparsreticulata(SNr)areoutlined.InthedirectpathwaythepeptidessubstanceP(SP)anddynorphin(DYN)areexpressed,togetherwiththedopamineDreceptor.Intheindirectpathway,theprojectionfromthestriatumtotheexternalsegmentoftheglobuspallidus(GPe)containsthepeptideenkephalin(ENK)andthedopamineD2receptor.ThisindirectpathwayisfurtherconstitutedbytheGABAergicprojectionfromGPetothesubthalamicnucleus(STN)andtheglutamatergicSTNprojectionstoGPi/SNr.Inthethalamustheventralanterior(VA)andmediodorsal(MD)nucleiarereachedbythebasalgangliaoutputs.SolidlinesrepresentingprojectionscodeforGABAergicpathways,dashedlinesforglutamatergicpathways,unlessotherwiseindicated. 112It.JoGROENEWEGENno

tionisthatthedirectandindirectpathwaysarisefromtwodifferentpopulationsofstriatalmedium-sized,spinyprojectionneurons.ThedirectpathwayarisesfromstriatalneuronsthatcontainGABA,substancePanddynorphinasneurotransmitter/neuromodulatorandthatexpressthedopamineDreceptor.Thestriatalneuronsthatgiverisetotheindirectpathway,whichreachestheexternalpallidalsegmentasafirstwaystationinthismultisynapticpathway,containGABAandenkephalin,andtheseneuronsexpressthedopamineD2receptor(Fig.2;Gerfen&Wilson,1996).SubsequentprojectionsinthisindirectpathwayincludetheGABAergicprojectionsfromtheexternalsegmentoftheglobuspallidustothesubthalamicnucleusand,subsequently,thegluta-matergicprojectionsfromthesubthalamicnucleustotheinternalsegmentoftheglobuspallidusandtheparsreticulataofthesubstantianigra(Fig.2;Gerfen&Wilson,1996;Parent&Hazrati,1995).Theprojectionneuronsinthebasalgangliaoutputstructureshavetheelectrophysiologicalcharacteristicofbeingtonicallyactiveandinthiswayexertatonicinhibitoryinfluenceonthethalamusandthemesencephalon.Interestingly,thedirectandindirectstriataloutputpathwayshaveopposingeffectsontheoutputneuronsinthepallidumandthesubstantianigra.Thus,activityinthedirectstriataloutputpathwayproducesaninhibitionofthetonicallyactivepallidaland/ornigraloutputneurons,resultinginadisinhibitionoftheirtargetareas(Chevalier&Deniau,1990).Bycontrast,ahigheractivi.tyinthe'indirectnetwork',tbrexamplethroughtheactivityoftheindirectstriataloutputpathway,is'translated'intoanincreasedactivityoftheexcitatorysubthalamicprojectionstothebasalgangliaoutputneurons,leadingtoastrongerinhibitionofthebasalgangliatargets.Ifahigheractivityinthe(we)frontalthalamocoicalsystemsisconsideredtobeassociatedwithincreasedmotororcognitive/behavioraloutputofthebrain,wecanconcludethatthedirectpathwayfacilitates,whereastheindirectpathwayornetworksuppressessuchoutput.Noteworthyisthatthesubthalamicnucleusnotonlyreceivesa(tonic)inhibitoryinputfromtheexternalpallidalsegment.(andinthiswayisdisinhibitedduringstriatalactivity)butalsoisprojectedupondirectlybyexcitatorycorticalandthalamicfibers(Gerfen&Wilson,1996;Fegeretal.,1994).Thecorticalfibersoriginatemostlyinthefrontalcortex,whereasthethalamicfibersarederivedfromthecentromedian-parafascicularcomplex.Thismeansthat(partsof)thecerebralcortex,aswellasthecaudalintra|aminarthalamusplayaroleinastrongerinhibitionofthebasalgangliatargetareasand,thereby,thesuppressionofmotorand/orcognitiveoutputs.Viadifferenttypesofdopaminereceptorsinthetwopopulation

sofstriataloutputneurons,dopaminehasanopposingroleontheseoutputpathwaysofthestriatum.ViathedopamineD1receptor,theactivityofthedirectpathwayisfacilitated,whereasthedopamineD2receptorsuppressestheactivityoftheindirectpathwayatthelevelofthebasalgangliaoutputneurons(Gerfen&Wilson,1996).Therefore,higherstriataldopaminelevelsresultinadisinhibitionofthebasalgangliatargetareas,whereaslowerdopamineconcentrationsatthestriatallevelleadtoastrongerinhibitionofthebasalgangliatargets.ThelattersituationoccursinParkinson'sdiseaseandisassociatedwithbradykinesiaandhypokinesia.Asindicatedabove,theprojectionsfrownfunctionallydifferentpartsofthecerebralcortextothestriatumaretopographicallyorganized.Theresultofthisorganizationisthatthestriatumcanbesubdividedintofunctionallydifferentsectors,namelyasensorimotorsectorreceivingconvergentinputsfrommotor,premotor,andsensorycorticalareas;anassociativesectorreceivinginputsfrown(pre)frontal,temporal,andparietalassociationcorticalareas;and,finally,a'limbicsectorthatisprojecteduponbythehippocampus,amygdala, BASALGANGLIAANDMOTORCONTROL113andparahippocampalandorbitofrontalcortices(Fig.3).Ofcourse,nosharpboundariesexistbetweenthesefunctionallydifferentstriatalsectors.Thesensorimotorsectorislocateddorso-laterallyinthestriatum(includingdorsalpartsofboththecaudateandputamen),whereasinventromedialdirection,thereisagradualtransitionintotheassociative(includingmainlythecaudatenucleus,butalsoventralpartsoftheputamen)and,subsequently,the'limbic'sectorofthestriatum(includingthenucleusaccumbensandthemostventralpartsofbothcaudateandputamen).TheSensory-motorcorticesAssociationcorticesLimbiccorticesAmygdalaFig.3"Schematicrepresentationofthetopographicarrangementoftheprojectionsfromfunctionallydifferentcorticalareastothestriatum,i.e.,thecaudatenucleus(Caud),putamen(Put),andthenucleusaccumbens(Acb).Thecorticostriatalprojectionsglobally'dictate'thefunctionalsubdivisionofthestriatuminadorsolateral'sensorimotor'part,anintermediateandmedial'cognitive'partandaventrolateral'emotional/motivational'part.Notethatthefunctionalzonationofthestriatumwhichfollowsthecorticostriatalorganizationdoesnotcomplywiththemacroscopicsubdivisionofthestriatumincaudatenucleus,putamenandnucleusaccumbens. 114H.J.GROENEWEGENsubsequentprojectionsfromthestriatumtothepallidumandsubstantianigra,aswellasthebasalgangliaoutputstothethalamus,arealsotopo-graphicallyorganized.Onthebasisofthesepoint-to-pointrelationsintheprojectionsfromthecerebralcortextothebasalgang

lia,theintrinsicbasalgangliaconnectionsandtheoutputfromthebasalgangliatothethalamocorticalsystem,theexistenceofparallel,functionallysegregatedbasalganglia-thalamocorticalcircuitshasbeenputforward(Alexanderetal.,1986;Groenewegenetal.,1990).Allthalamocorticalcircuits,viadifferentthalamicnuclei,aredirectedtodifferentareasofthefrontallobe,inthiswayemphasizingtheimportanceofthebasalgangliaforthewidearrayofmotor,executive,andemotional-motivationalfunctionssubservedbythefrontallobe,whichincludesprimarymotor,premotor,andassociative(cognitive)and'limbic'prefrontalcorticalareas.ConvergenceandsegregationofinformationNexttoaparallelarrangementofconnectionswithinthebasalgangliaandthebasalganglia-thalamocorticalcircuitry,convergenceofinfor-mationatseverallevelsislikewisecharacteristicfortheorganizationofbasalgangliacircuitsandessentialfortheunderstandingofbasalgangliafunctioning.Forexample,atthelevelofthestriatum,intricatepatternsofoverlapandsegre-gationexistbetweentheafferentsfromdifferentcorticalandsubcorticalsources.Becausethemedium-sizedstriataloutputneurons,duetotheirelectrophysiologicalmembraneproperties(seeabove),aredifficulttoexciteandneedstrongconvergentinputfromexcitatoryinputstobecomeactive,theyareexcellent'coincidentdetectors'(Fig.1;Houketal.,1995).Thus,primarilyonthebasisof'coincident'activityofdifferentexcitatoryinputswhichmaybederivedfromdifferentcerebralcorticalareas,midline-orintralaminarthalamicnuclei,theamygdala,orhippocampusspecificstriatalneuronalpopulationscanbecomeactiveandproduceaspecificpatternofoutputthroughdirectand/orindirectpathways.Thespatialandtemporalaspectsofthiscoincidentafferentactivitydeterminesthelocationandtheidentityofthestriatalpopulation('ensemble';Pennartzetal.,1994)thatbecomesactiveataparticularmoment.Atthelevelofthestriatum,individualcorticalareascanhavemultiple(small)areasofterminationandprovideinthiswayamechanismthroughwhichvariousdifferentcombinationsbetweenafferentinputscanbeestablished(Flaherty&Graybiel,1991).Inmoregeneralfunctionalterms,sucharrangementsarepre-eminentlysuitedfortheactivationofaparticularoutputonthebasisofaspecificsetofinputs,namely,thedetectionofaparticularsensory,motor,cognitive,oremotionalcontext.Theintegrationofdifferentstreamsofinfor-mationcanplayarolenotonlyinthestriatumbutalsoinotherbasalgangliastructuresnamely,thepallidum,thesubstantianigra,andthesubtha|amicnucleus.Inparticularthesubstantianigrahasbeenproposedtoplayanimportantroleinintegratingfunctionallydifferentstr

eamsofinformationthatinfluencemotorandbehavioraloutput(Haberetal.,2000).Nevertheless,thestriatumcanbeconsideredthemainlocusofintegrativeaspectsofbasalgangliafunctioning.FUNCTIONALASPECTSOFTHEBASALGANGLIAIntheprecedingparagraphs,haveemphasized,basedonthefunctional-anatomicalorganizationofthebasalganglia,thatthesebrainstructuresplayaroleinawidearrayoffrontallobefunctions,rangingfromsensorimotorandcognitivetoemotional-motivationalbehavioralfunctions.Yet,thespecificcontributionofthe BASALGANGLIAANDMOTORCONTROL115basalgangliatothesefunctionshasnotbeendiscussed.Mostconsiderationsonthefunctionalroleofthebasalgangliarefertothefunctionaldeficitsthatarecausedbylesionsofthesestructures,either'natural'inthecourseofadiseaseorexperimentallyinduced.Fromtheextensivebodyofliteratureonthissubject,wecanconcludethatsuchlesionsleadeithertoapaucityand/orslownessofmovements(hypo-andbradykineticmovementdisorders)ortothereleaseofunintentionalmovements,includingchoreatic,athetotic,dyskinetic,anddystonicmovements(hyperkineticmovementdisorders)(DeLong,1990;Marsden&Obeso,1994).Globallyconsidered,thehypo-andhyperactivityintheexpressionofbasalgangliadisordersmightbeunderstandablefromtheabove-discussedarrangementofdirectandindirectpathwayswithinthebasalgangliacircuitry.Anoveractivityofthedirectpathwayrelativetotheindirectpathwaywouldleadtoadisinhibitionofthethalamocorticalsystemandtherebytheuncoordinatedorunsupervisedreleaseofmotoroutputorcognitiveprocessing.Bycontrast,therelativeoveractivityoftheindirectpathwayornetworkwouldultimatelyleadtoanoverinhibitionofthethalamocorticalsystem,inthiswaypreventingorimpedingmotoroutputorcognitiveprocessing(DeLong,1990;Gerfen&Wilson,1996).Alsowidelyaccepted,however,isthatthebasalgangliaarenotcrucialfortheinitiationofmovements.Thisconclusionisbasedmainlyontheobservationsthattheelectrophysio-logicalactivityofbasalgangliastructuresoccursrelativelylateintheinitiationphaseofamovement(Mink,1996).Thus,whileintentionalmovementscanstillbeexecuted,evenwhenthefunctionsofthebasalgangliaareimpaired,thesestructuresappeartobeimportantforthequalityandcorrectnessofamovementorabehavioralact.Therefore,thequestionofwhatthebasalgangliaexactlycontributetotheexecutionofmovementsandbehavioralactsstillremainsopen.Interpretationsbasedonlesionsorinterferenceswith,usuallyextensivepartsofbasalgangliastructures,mightnotrevealtherealfunctionalroleofthebasalgangliaunderphysiologicalconditions.Severalhypotheseshavebeenput.forward,noneofwhichhasbeendefi

nitelyestablished.Thus,earlierhypotheseshaveentertainedtheideathatthebasalgangliaareresponsiblefortheautomaticexecutionoflearnedmovementsequences(Marsden,1987;Marsden&Obeso,1994).Whetherthebasalgangliaarethesiteof'storage'ofmotorprogramsorwhethertheseprogramsarelaiddowninthecerebralcortexremainedopen,whereasthebasalgangliaareconsideredcrucialfor'callingup'theseprogramsandtheswitchingbetweenthem.Hikosaka(1994)suggestedthatthebasalgangliaareresponsibleforthesuppressionandreleasemechanismsonsuchinnatemovementsasloco-motion,mastication,andsoonviadescendingprojectionstothebrainstem,aswellasforsimilarmechanismsoncomplex,learnedmovementsviatheprojectionstothethalamocorticalsystem.Hikosaka(1994)alsoproposedaroleforthebasalgangliainthelearningphaseofcomplexmove-ments,specificallyalsoforthedopaminergicsystemandinhisproposal,motorprogramsare'stored'inthecerebralcortex.Followingthephaseoflearningofmotorprograms,thebasalgangliawouldhavearoleonlyinthe'activation'oftheseprograms,orinelementsofthose,inaparticularcontext.Arecenthypothesis(Mink,1996),takingintoaccountthedetailedknowledgeofthebasalgangliacircuitryoutlinedabove,ismorespecificabouttheroleofthebasalgangliainmotorbehavior.Thishypothesisstatesthatthebasalgangliaarecrucialforthefacilitationofdesiredmovementsandthesuppressionofunwanted,competingmovements(Mink,1996).Thebasalganglia,withtheirstrongandtonicinhibitoryinputonthethalamicandmes-encephalictargetareas,actasageneralbrakeontheexpressionofmotorandbehavioraloutput.Atthemomentthatitis'decided'intheprefrontaland 116H.J.GROENEWEGENpremotorcorticestoexecuteamotorprogram,thisinformationissenttothestriamm,aswellasinacorollarymannertothesubthalamicnucleus.Theactivationofstriatalneuronsthatgiverisetothedirectoutputpathwaytoeithertheinternalsegmentoftheglobuspallidusortothesubstantianigraparsreticulataleadstoadisinhibitionofthethalamocorticalsystemthat,inram,providesthefinaloutputforthedesiredmovement(Fig.4).The'parallel'corticalexcitationofthesubthalamicnucleusleadstoahigheractivityofthebasalgangliaoutputneuronsnotconcernedwiththeintendedmovementorcomplexofmovements,resultinginthesuppressionofpotentiallycompetingmotoroutput(Mink,1996).Futureexperimentswillhavetotestthisattractivehypothesisforitsvalidity.StriatumGPi/SNrCerebralCortexThalamusMidbrainOthermotorOthermotorprogramsprogramsDesiredmotorprogramsFig.4:Schematicrepresentationoftheinteractionsbetweenthecortexcerebri,thestriatum,theinternalsegmentoftheglobuspallidus(GPi)orthereticula

rpartofthesubstantianigra(SNr)andthesubthalamicnucleus(STN)thatarehypothesizedtoleadtotheselectionofdesiredmotorprogramswhilesuppressingothermotorprograms.LinesrepresentingGABAergicprojectionshavesolidarrowheads,thoseusingexcitatoryneurotransmittershaveopenarrowheads.Slightlyadaptedfromfigure14inMink(1996). BASALGANGIIAANDMOTORCONTROL117Possible,differentrolesfordopamineAsindicatedabove,levelsofdopamineinthestriatumdetermine,viatheiractionsondopamineD1andD2receptors,theoutputactivityofthebasalganglia.Ingeneralterms,lowlevelsofdopaminecauseastronginhibitoryoutputofthebasalgangliatothethalamocorticalsystemandtothebrainstem.Lowstriataldopaminelevelsare,therefore,associatedwithapaucityofmovementsaswellaswithcognitiveandemotional/motivationalbehavior.Bycontrast,highlevelsofstriataldopamineresultinalowactivityoftheinhibitorybasalgangliaoutputsand,consequently,a'disinhibition'ofitstargets.Thissituationiscorrelatedwithafacilitationofmovementsandcognitive/behavioralacts.Inthisway,dopamineappearstohavea'gatingrole'atthelevelofthestriatum.Thisaspectoftheroleofdopamineinthebasalgangliaismostprobablycorrelatedwithvariationsinthetonic,relativelylowrateoffiringofdopamineneurons(Gerfen&Wilson,1996;Schultz,2002).Another,moredifferentiatedrolefordopaminehasbeenhypothesizedintherealmofthelearningofmovementsandbehavioralacts.Onthebasisofbehavioralstudiescombinedwithinvivoelectrophysiologyofthedopaminergicsystem,Schultzandcolleagues(forreview,seeSchultz,2002)elucidatedimportantaspectsoftheroleofdopamineinguidingbehaviorinprimates.Dopaminergicneuronsintheventralmesen-cephalonshowphasicactivationsfollowingtheencounteroftheanimalwithnovelstimuli,particularlyinrelationtothepresentationofprimaryreward.Thephasicactivationsoccurbetween100and300rnsecfollowingthestimulusandareshort-lasting.NeuronsinthemedialsubstantianigraparscompactaandtheVTA,projectingtoventralstriatalregions,tendtoshowastrongeractivationthanthoseinmorelateralpartsofthesubstantianigra.Furthermore,inwell-controlledexperimentaltasksofbehaviorallearning,suchasPavlovianorinstrumentallearning,thephasicactivityofthedopaminergicneuronsgraduallyshiftsfromtheprimaryrewardtoconditionedstimulithatpredicttheprimaryreward.Interestingly,dopamineneuronsshowadepressionintheiractivityifanexpectedreward,predictiveonthebasisofthepreviouslearningprocess,doesnotappear(Schultz,1998).Noteworthyisthattheactivationsofthedopamineneuronsarenotrelatedtoanyaspectofthemovementsthatanimalshavetomakeduringthetasksund

erlyingthebehaviorallearning(Schultz,2002).Theeffectofabrief,phasicactivationofthedopaminergicsystem,whichatthestriatallevelleadstoaspatiallyrathergeneralreleaseofdopamine,canbeinterpretedasfollows.Dopamineterminalsarepresentonstriatalmedium-sizedspinyneuronsand,attheultrastructurallevel,terminateveryclosetothecorticostriatalterminalsonthespinesoftheseneurons(Fig.1;Smith&Bolam,1990).Asdiscussedabove,thecortico-striatalsystemisverypreciselyorganized,andfibersfromdifferentalthoughfunctionallyrelatedcorticalareasconvergeonthesameneuron,oronsmallgroupsofneurons('ensembles').Theseneuronswillbeactivatedonlyunderspecificcircumstances,namelywhenasufficientnumberoftheirexcitatorycorticostriatalafferentsareactive.Striatalmedium-sizedspinyneuronsarethereforethoughttobeideal'contextdetectors'(Houketal.,1995).Theeffectofthereleaseofdopamineunderthesecircumstancesmightbetwofold.First,dopaminereleasemighthaveanimmediatefocusingorattentionaleffectthatcouldenableorfacilitatetheoutputofaparticularensembleofstriatalneuronsattheexpenseofotherstriataloutputs.Inthisway,dopamine,onthebasisofrewardingorerrorsignals,couldhaveagatingor'instructional'role.Suchprocessescouldcontributetothe 118H.J.GROENEWEGENselectionmechanismsthatarethoughttoplayaroleatthelevelofthestriatum(Pennartzetal.,1994;Redgraveetal.,1999).Second,dopaminemayleadtoplasticsynapticchanges,buildingandshapingstriataloutputmodulesthat,onthebasisofalearningprocess,willbeselectivelyandpreferentiallyactiveinaparticularcontext.Inthisway,dopaminewouldhaveatransientroleintheprocessofreward-basedmotorandbehaviorallearning(Hikosaka,1994;Houketal.,1995;Schultz,2002).CONCLUSIONSAsdiscussedabove,thebasalgangliaappeartohavearoleinawiderangeofsensorimotor,cognitive,andbehavioralprocessesthatarecloselyassociatedwiththeexecutiveandmotorfunctionsofthe(pre)frontalcortex.Theselectionofmotororbehavioralprograms,orelementsthereof,appropriateforaparticularcontext,mightbeoneoftheprimaryfunctionsofthebasalganglia(Mink,1996;Redgraveetal.,1999).Plasticityinthebasalgangliacircuitryandlearningprocessesareimportantfundamentsforthesefunctions.Inparticular,theventralstriatummightbecrucialforthelearningandexecutionofreward-relatedbehavior,whereasthedorsalstriatumisimportantforstimulus-responsebehavior(habits).Thedevelopmentofthehumanbasalganglia,inparticularthedopaminergicsystem,takesplaceoveranextendedperiodoftimeandmostprobablyincludesatleastthefirstthreedecadesoflife(Segawa,2000).Theactivityoftyrosinehydroxylase,

asamarkerforthedopaminergicsystem,andtheexpressionofdopaminereceptorsvarysignificantlyinthisextendedageperiod.Certainvariablesmayreach'adult'levelsonlyinthefourthdecade.Theeffectsoflesionsofthebasalgangliaarealsodependentupontheageatwhichtheyoccur.Thus,whereaslesionsofthedopaminergicsysteminearlylifeleadtodystonicsymptoms,afterthethirddecadesuchlesionsratherresultinparkinsonisticsymptoms(Segawa,2000).Anotherdiseaseinwhichthebasalgangliaaremostlikelyaffectedandwithonsetinchild-hoodisTourette'ssyndrome.Thissyndromeischaracterizedbymultiplechronicticsthatmaybeconsideredastheexpressionofunwanted,stereotypedmovementsor(fragmentsof)behavioralacts.WithinthecontextofthehypothesisofMink(1996),namely,thatthebasalgangliaplayanimportantroleinthereleaseofdesiredandinthesuppressionofunwantedmovements,thesymptomsinTourette'ssyndromecanbeinterpretedastheresultofadefectivesuppressionmechanisminthebasalganglia(Mink,2001).Thesetwoexamplesofbasalgangliadisordersoccurringinchildhoodillustratedifferentaspectsoftheroleofthebasalgangliainthecontrolofmovements.Indystonianamely,focalormoregeneralizedprolongedcontractionof(groupsof)musclesleadingtoadisturbedposturenormalskillfulmovementsarehamperedbytheunwantedcontractions.InTourette'ssyndrome,fragmentsofinprincipalnormalmovementsareexpressedbeyondthecontrolofthepatient.Inbothcases,however,themechanismtoselectamovementoramotorprogramisdefective.Thequestionwhetherclumsiness,atleastinpart,maybeattributedtoadefectiveroleofthebasalgangliaintheprocessofthelearningandexecutionofskillfulmovementsisatpresentdifficulttoanswer.Itseemsverylikelythatdisturbancesinthedevelopmentofthecerebellumplayanimportantroleinclumsiness(Gramsbergen,2003).Clumsiness,however,isaveryheterogeneousconceptinwhichvariousdifferentaspectsofmotorcontrol,includingsensoryfeedback,canbeinvolved.Asfarasdeficientmotorprogrammingisinvolved,thebasalgangliaprobablyplayarole(seeabove).When BASALGANGLIAANDMOTORCONTROL119inappropriatetimingofcontractions'within'amoreglobalmotorprogramisaffected,thecerebellumcanbemoreinvolved.Boththebasalgang|iaandthecerebellumundergoanextendedperiodofpostnataldevelopment,inhumansspanningalmosttwodecades.Factorsthataffectthenormaldevelopmentofthebraininthisextendeddevelopmentalperiodcanaffectthefunctionsofbothstructures.Animportantissueforfutureresearchmightbethemoreprecisedeterminationoftherelativecontributionofthebasalgangliaandthecerebellumtothelearningofskillfulmovements.Clearlybothstructurescontributetomotorsk

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