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BasalGanglia:func.onalcircuitries,neurotransmi9ers

andearlymotordevelopment

GabriellaHorvathCNSF,ChildNeurologyDayVictoria,June24,2017

Objec.ves

•  Overviewofbasalgangliaanatomy•  Basalgangliafunc.onalcircuitries•  Neurotransmi9ersinthebasalganglia•  Developmentalaspectsofmovement•  Cogni.ve-motorinterac.onsofthebasalgangliaindevelopment

Disclosures

•  Nothingtodisclose

Basalganglia:orchestraformovementBasalgangliacircuitry:dancefloorNeurotransmi9ers:musicofthemind

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Itallstartshere:

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Dopaminergicmodula.onofdirectandindirectpathways Cholinergicmodula.on

ofdirectandindirectpathways

TheRateModel

•  Developedinthe1980searly1990s•  Describestheconnec.vity,neurochemistryandphysiologyoftheBG(Albinetal,DeLong)

TheRateModel•  Keycomponents:–  interconnectednetwork–  involvedinmotorandcogni.vefunc.ons– cortexgeneratesmotordemands,BGexecuteswithposi.vefeedbacksystem

– dopamineactsdifferen.allyinstriatum– compe.ngac.onssuppressed– networkoutputisintegratedatthelevelofGpiandSNr,whichinhibitordisinhibitthalamocor.caland/orbrainstem

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TheRateModel•  Keyconcepts:

–  Dopaminehasopposingeffectsonthedirectandindirectpathways

–  Abla.onorinac.va.onofindirectpathwayneuronsleadstoincreasedorexcessivemovement

–  Abla.onofindirectpathwayleadstodecreasedmovement

–  Ac.va.onofindirectpathwayleadstodecreasedmovement

–  Ac.va.onofdirectpathwayleadstoincreasedmovement–  DecreasesinBGoutputcorrelateswithincreasedmovement

–  IncreasesinBGoutputcorrelateswithdecreasedmovement

InconsistenciesoftheRateModel

•  Lesioningors.mula.onoftheGpiistherapeu.cinbothhypokine.candhyperkine.cmovementdisorders

•  Furtherstudieshaveshownthatdifferentgroupsofneuronswithinpar.cularnucleusmaybeac.vatedorsuppressedatthesame.meinordertoreleasedifferentmotorprograms

Neurotransmi9ers

•  Neuromodulatoryprojec.onsystems:– Dopamine– Serotonin– Norepinephrine

•  Classicalneurotransmi9ersystems:– Glutamate– GABA– acetylcholine

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Developmentalaspectsofmovement

•  Developingsenseofself•  Uprightposi.onneedspriorfaileda9emptsassociatedwithpain

•  Thediscomfortresultsinself-pacedmovements

•  Usingthecorrectcombina.ontotakethefirstsuccessfulstep

•  Thiswillconsolidatelaterintoamorecomplexmotorpa9ern

Developmentalaspectsofmovement

•  TheBGarekeyelementsinthecontrolofreward-basedlearning,sequencing,discreteelementsthatcons.tuteacompletemotoractandcogni.vefunc.on

•  Connec.onsbetweenBGandcortexareorganizedintocircuits–loopsreciprocallyinterconnectalargeanddiversesetofcor.calareaswithBG– Neuronalac.vitywithinBGassociatedwithmotorcortexcorrelateswithmovement

– Neuronalac.vitywithintheBGandcerebellarloopsassociatedwiththeprefrontalcortexisrealtedtocogni.vefunc.on

Earlydevelopment•  Needtounderstand:–  Phylogeny(evolu.on)andontogeny(development)ofthemotorsystem

•  Movementormo.onisessen.alforthedevelopmentofafunc.onalmusculoskeletalsysteminafetusorinfant

•  Humanfetushas11separatemovementpa9ernsofincreasingcomplexityasgesta.onprogresses:–  Twitching,independentlimb,isolatedheadmovement,combina.onmovements,quazi-startle,hand-facemovements,isolatedbodyextension,thumbsucking,breathing

Earlydevelopment

•  Post-delivery:–  remodelingoftheinnerva.onofagonist-antagonistmusclepairsoftheperipheralneuromuscularsystem

– Centrallydriventruncal,armandlegflexorandextensorposturalstages

•  Newborn:Dystonic-ThalamicMan– Persistentflexedtrunkandlimbposturesasscoiatedwiththalamicandbrainstemac.vity

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Earlydevelopment

•  3-4months:ChoreiformMan(Riverdance)–  Trunksymmetricallystraightposture,armsandlegshyperac.ve(physiologicalchorea)

•  6-8months:Kung-FuMan– Directedandtargetedswagngandkickingofarmsandlegs(prelocomotorequipoten.alphaseofallfourlimbs)–striataltoes

•  6-10months:Ballerina– Holdinglegsstraightplayingwiththefeet–dissipateswhenlegsarecommi9edtolocomotortask

Earlydevelopment

•  24months:maturegait– Firsthallmark:heel-strike– Secondhallmark:asynchronoushipflexion-knee-extension-ankledorsiflec.on

– Thirdhallmark:contralateralarmswing

Earlydevelopment

•  Ini.alclumsy,goal-directedmotorbehavioursandmovementstransi.ontohabitualmovements(internalized,semi-automa.c)

•  Ini.alco-contrac.onofmosttrunkandlimbmusclegroupsarerequired

•  Willgraduallydevelopmorefluentandeconomicalmovementsreplacingco-contrac.onwithagracefulinterplayofagonist-antagonistmuscles

Developmentofpathology

•  Lackofselec.vecontrolandsurroundinhibi.onproducesunwantedsynergies(CP)

•  Lackofselec.vemotorcontrol,excessiveplas.city(dystonia)

•  Knowledgeofdiversepathwaysandcircuitsadvantageouswhenassessingneonatalbraininjury

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JPLin,NNardocci,2016

Summary

•  Understandingbasalgangliaanatomy,circuitry,neurotransmi9ers,developmentofmovementininfancy,helpsin:– diagnosisandtreatmentof

•  developmentalmovementdisorders,suchasCP•  primarygene.cmovementdisordersinchildren

References•  www.neuroanatomy.wisc.edu/coursebook/motor2.pdf•  ANelson,AKreitzer.Reassessingmodelsofbasalgangliafunc.onand

dysfunc.on.AnnuRevNeurosci.2014;37:117•  LBrichta,PGreengard,MFlajolet.Advancesinthepharmacological

treatmentofParkinson’sdisease:targe.ngneurotransmi9ersystems.TrendsinNeurosci.2013:36;9

•  GLeisman,OBraun-Benjamin,RMelillo.Cogni.ve-motorinterac.onsofthebasalgangliaindevelopment.FrontSystNeurosci.2014;8:16

•  JPLin,NNardocci.Recognizingthecommonoriginsofdystoniaandthedevelopmentofhumanmovement:Amanifestoofunmetneedsinisolatedchildhooddystonias