AnnalsoftheNewYorkAcademyofSciencesofwithdrawalofcentralthalamicexcita - PDF document

AnnalsoftheNewYorkAcademyofSciencesofwithdrawalofcentralthalamicexcitationcanhelptoexplainthesurprisinglylong-lastingimpairmentsofhumanfrontallobeexecutivefunctionscorrelatedwithdiscreteinjurytoCLandotherthalamicin-juriesspeciÞcallyinvolvingtherostralintralaminarre-InadditiontopersistentdecreasesinneuronalÞr-ingratesacrossthecerebrum,discreteinjuriestothecentralthalamusmayalsoleadtoglobalfunctionalimpairmentthroughdifferentformsofabnormalhy-persynchronousactivity.Focalinjurieswithinthecentralthalamusarealsoassociatedwithproductionofepilepticseizures,typicallyvariationsofabsenceseizures,andotherparoxysmalphenomenasharingfeaturessimilartocatatonia,dystonia,andparkinson-ism,andresponsivetopharmacologicagentsusedtotreatthosedisorders(reviewedinRefs.47,103).ContributionofCentralThalamustoDisordersofConsciousnessFollowingMultifocalDiffuseBrainInjuriesThefarmorefrequentcauseofneurologicaldisor-dersofconsciousnessfollowingseverebraininjuryiswidespreaddeafferentationofthecentralthalamusbe-causeofwidespreadneuronaldeathordisconnection.Consistentwiththediscussionabove,thistooisthesimpleconsequenceoftheuniquegeometryofcentralthalamicconnectionsbutisnotwellappreciatedinthecontextofpathologiesunderlyingglobaldisordersofconsciousness,suchasthepermanentvegetativestateandenduringtheminimallyconsciousstateThreeverycommonmechanismsofinjurythatmaybilaterallyinvolvethecentralthalamusariseinthesettingofmultifocalheadtrauma,largehemisphericstrokes,andhemorrhages:1)diffuseaxonalinjury,2)downwarddisplacementofthalamusandbrainstemasaresultofbrainswelling(knownasÒherniationÓ),withorwithout3)enpassantfocalischemicinjuriestothebrainstem,midbrain,thalamus,orbasalganglia.Diffuseaxonalinjuryresultsinwidespreaddisconnec-tionacrossthecerebrumwithaÞnalcommonÞnd-ingofsecondaryneuronaldeathofthalamicneuronsindexingoutcomes.EveninthemostseveremultifocalbraininjuriesassociatedwithpermanentVS,neuronaldeathinthethalamusisthemostcommonpathologicalÞnding.Inastudyofnontraumaticinjuriesassoci-atedwithpermanentVS(mostlyanoxiafollowingcar-diacarrest),allpatientsshowedseverebilateralthala-micdamage,whichwasnotinvariablyassociatedwithdiffusecorticaldamage(64%ofcases).InpathologicalstudiesofbrainsfrompatientswhosufferedtraumaticinjuriesandremainedinVSforatleast3monthspriortodeath,asimilarÞndingofwidespreadthalamicneu-ronallosswasfoundwithlessneocorticalinvolvement(only11%withdiffuseneocorticalcellloss).Inarecentfollow-upstudy,thedetailedanalysisofthalamicnu-cleirevealedthatwhenautopsystudieswerecomparedwithcontrols,damagetocentralthalamicstructuresin-dexedbehavioraloutcomesfrommoderatedisabilitytoVSwithinitialinvolvementoftheanteriorintralam-inarstructureandprogressivecelllossventrallyandposteriorlywithworseningoutcome.TheseÞnd-ingsreßectthebroadeffectsofneuronaldeathanddisconnectionwitharostrocaudalgradientconsistentwiththemorediffuseandwidespreadpointtopointconnectionsoftheanteriorintralaminar/paralaminarregions.Herniationinjurieswithorwithoutevidenceoffocalischemiclesionswithinthecentralthalamus(orcloselylinked,subcortical,neuronalpopulations)canproduceprofoundfunctionaldownregulationacrosstheentireipsilateralcerebralhemisphereandpossi-blybilateralmetabolicdysregulation.Similarly,persistentglobalcerebraldysfunctioninpatientsmaybeassociatedwithabnormalcapturebypathologicalrhythmicactivityinthecentralthalamusproducedinfrontalcorticalorotherareas.ModulationofCentralThalamusandEffectsonDisordersofConsciousnessDisordersofconsciousnesshavegenerallybeencon-sidereduntreatableifenduringformonthsorlonger.RecentobservationsoflateimprovementinMCSpa-tientswithlong-standingbraininjuries,whetherspon-taneous,inresponsetopharmacologicagents,followingelectricalstimulation,suggestthatcircuitmechanismsmaybeavailableforimprovingfunctionaloutcomesinsomecases.TakingintoconsiderationÞndingsthatsomeveryseverelybrain-injuredpatients,whononethelessshowsomeresponsestotheirenvironment,mayhavewidelypreservedcerebralnetworkactivation,Schiffandcolleaguessoughttodeterminewhetherelectricalstimulationcouldrestorearousalregulationandpro-motegreaterbehavioralresponsivenessinMCSpa-tients.Theyproposedthatcentralthalamicdeep-brainstimulation(DBS)mightsubstitutefortop-downmonitoringandregulationofarousallevelpro-videdintheintactbrainbymesialfrontalcorticalre-gionsandbrainsteminputs(asreviewedabove).Ap-plicationofcentralthalamicDBSina38-year-oldmanwhoremainedinMCSfor6yearsledtorestora-tionsofspokenlanguage,oralfeeding,andmotorcon-troloftheupperlimbs.TheseÞndingssuggestthatelectricalstimulationmayapproximatethenormalroleofcorticalandsubcorticalinputstothecentral 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Schiff:CentralThalamusandArousalRegulationTheuniqueconnectivityofcentralthalamicneu-ronsandtheirphysiologicalspecializationssuggestthattheymaycontributetobroadformationofUPstate-liketransitionofÞringratesseenacrosscerebralnet-worksinvivoduringorganizedbehaviors.FacilitatingthetransitiontoUPstatesandtheirmaintenancemaybethefundamentalmechanismofarousalregulationthroughthecentralthalamusthatallowsfor:1)adjust-mentofgainacrossmultiplepathwaysofsensorimo-torintegrationassociatedwithvaryinglevelsofvigi-lance,interest,motivation,andotherstatefactorsand2)rapidcaptureandredirectionofbehaviorthroughpowerfulbiascontrolsfacilitatedthroughactivationofthecentralthalamusbythefrontalexecutivesystemsusingpremotorsignalsthatdirectattentiontointendedmovementsthroughabroadcorollarydischargemech-anism.Similarly,biasingofattentionandgoal-directedactionmaybeachievedbytriggeringUPstatesacrosscerebralnetworksthroughactivationofdedicatedre-ßexpathwaysfromthesensoryperipherythataccessthecentralthalamus.Usingthispictureasawork-ingmodel,itispossibletoorganizemanydisparateobservationsassociatedwithneurologicaldisordersofconsciousnessandtheirphenomenologyasreviewedbelow.ContributionsoftheCentralThalamustoNeurologicalDisordersofConsciousnessItiswellestablishedthatthecentralthalamusplaysanimportantroleinneurologicaldisordersofcon-sciousness.Thebriefreviewbelowlinksthisroleofthecentralthalamustopathophysiologicalmech-anismsthatproducebothpersistentandparoxysmalimpairmentsofarousalregulationafterseverebraininjury.Aninterpretativeframeworkisthenproposedtoexplainunderlyingmechanismsforinterventionsthatimproveneurologicalfunctioninpatientswithdisor-dersofconsciousness.FocalInjuriestotheCentralThalamusDirectinjuriestothecentralthalamuscanaloneproduceglobaldisturbancesofconsciousness.unilateral,theselesionsmayproducehemispatialun-awarenessoralteredstatesofconsciousnesssimi-lartoacutemaniaordelirium.Restrictedbilateralinjuriestothecentralthalamusmayproduceacutecomaindicatingtheimportantrolethesestructuresplayinanormalalertwakefulstate.Recoveryofcycli-calarousalpatternswithperiodsofeyeopeningoccursrapidlywiththeselesionsandisusuallypresentwithin48h,againemphasizingthattheseneuronsarenottheprimarysourcesofascendingcontrolofarousalstateperse.However,unlikebrainstemlesionsthatpro-ducecomafollowingfocalinjuries,therecoveryofconsciousnessintermsofgoal-directedbehaviorandcommunicationskillsisveryslowfollowingbilateralcentralthalamicinjuriesanduncertain.Theseclinicalobservationsareconsistentwithexperimentalstudiesthatdemonstratethatneitherthecentraltha-lamusnorthebasalforebrainareindispensableformaintaininggeneralarousalassociatedwithsomere-coveryofEEGcyclingandwakefulness,suggestingthatparallelbasalforebrainandthalamicmechanismsanddirectbrainstemtocortexpathwaysarepleuripo-tentformaintainingcerebralarousal(seeRef.23forreview).Thelargeandenduringbehavioraleffectsofsmall,central,thalamicinjuriescanbeunderstoodinthecon-textofstudiesthatdemonstratethatfocalischemicin-jurieswithinthecentralthalamuscanproducemarkedreductionincerebralmetabolismacrosstheentireip-silateralhemisphereasmeasuredusingßuorodeoxglu-cosepositronemissiontomography.Thiseffectreßectsacrossed(trans-)synapticdownregulationofdistantneuronalpopulationsconnectedtothecen-tralthalamus(knownalsoasdiaschisis).Thecrossedsynapticdownregulationresultsfromthelossofexcita-toryinputstoremotebrainregions,andthesechangesincerebralbloodßowonlymarginallyindicatemarkedreductionsinneuronalÞringratesinthedistalstruc-tures.Thelossofexcitatorydrivetoneuronalpop-ulationsinsuchinstancesproducesapassiveformofinhibition(disfacilitation)hyperpolarizingneuronalmembranepotentialsasaresultofwithdrawalofexci-tatorysynapticinputsthatthenallowremainingleakcurrents(principallypotassium)todominate.Theprofoundeffectsofcentralthalamiclesionscanbeunderstoodsimplyasaconsequenceoftheiruniquegeometry;theneuronshavemanypointtopointconnectionsacrossthecorticothalamicsystemandthroughthestriatalloopconnectionsoftheante-riorforebrain(asreviewedabove).Aquantitativere-sultunderscoringthispointistheÞnding,inacom-pletemultidimensionalscalingmodeloftheentirecatthalamocorticalsystemthatplacestheanteriorin-tralaminarnuclei(CL,Pc,andcentralmedial)inoneclustertogether,centeredamongallothersegregatedthalamocorticalloopsystems(frontal,limbic,tempo-ral,andparietal).Thispositioningcanbeinterpretedasaconsequenceoftheirrelativelyshortestpathandmultipleconnectionsacrosseachoftheotherclusters(withatendencytobeclosertothefrontal/limbicre-gionofthecortex,whichismorestronglyconnectedwiththestriatum).Inthiscontext,thebroadeffects 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AnnalsoftheNewYorkAcademyofSciencesbasisofdifferentialcalcium-bindingproteinexpres-sion.Oneclass,theÒcoreÓneurons,expressparval-buminandsynapseinthemiddle,orgranular,layersofthecorticalmicrocircuitwitharea-speciÞccorticalprojections.Theotherclass,theÒmatrixÓneuronsex-presscalbindinDandprojecttoLayerIacrossrelativelywidecorticalterritories.Inbothhumansandnonhumanprimates,intralaminarsubdivisionsaredenselypopulatedwithmatrixneurons(CL,Pc,Pf,butnotCm,whichisdenselyparvalbuminstaining).Thematrixneuronsareproposedtoactcollectivelyasafunctionalsystemthatorganizesglobalpatternsofcor-ticothalamicsynchronization.NeuronswithintheseintralaminarregionsmaysynapseoncellbodieswithinlayersVandVIaswellasLayerIandthispatternofdualinnervationwithinthecorticalcolumnhasbeenproposedtosupportabiophysicalcoincidencedetec-tionmechanismthatfacilitatesinputsfromthespeciÞcthalamicinputstothegranularlayers.InstudiesoftheapicaldendritesofLayerVandLayerII/IIIcorticalneurons,Larkametal.havedemonstratedthatco-activationwithinanarrowtemporalwindowoftheapicaldendrites(inLayerI)andsomaofLayerVpyramidalneuronsinducesburstÞringthroughaback-propagatingactionpotentialthatoriginatesinthesomaandallowsfornormallysubthresholdinputsintheapicaldendritestobecomespikegenerating.SimilarchangesindendriticelectrogenesisofLayerII/IIIneuronscouldsupportthismechanism.sistentwiththeseproposals,combinedstimulationofCLandtheventrobasalnucleus(aspeciÞcthalamicre-laynucleusprojectingintocorticalLayerIV)inmousecorticothalamicslicegeneratesasupralinearsumma-tionoflocalevokedpotentials.Depolarizationofthesupragranularlayerdendritesbyintralaminarafferentshasbeenproposedtopromotesustainedcorticalactiv-ity,NMDA-mediatedlong-termpotentiation,andothermechanismsofsynapticfacilitation.Thus,theanatomicalspecializationsofthematrixneuron-richintralaminarandparalaminarregionsofcentralthalamicthalamusprovideauniquesubstrateforsup-portofdistributedcorticalpersistentactivity.Consis-tentwiththeseinvitroandanatomicalstudies,recentinvivoelectricalstimulationstudiesshowthatelectri-calstimulationofCLgeneratebroadactivationofc-fosacrossallcorticallayersandauniquepatternofupreg-ulationof(animmediateearlygeneassociatedwithlong-termpotentiation)insupragranularandin-fragranularlayersconsistentwiththesemechanisms.Centralthalamicinputstothestriatumarealsospe-cializedandrecentstudieshaveshownthatthecen-trallateralnucleusoftheanteriorintralaminargroupprojectstothemediumspinystriatalneuron(MSN)contactingthedendriticspine.Theseexcitatoryin-putstothestriatalneuronmayactasprimarydriversalongwithdescendingcorticostriatalinputs.TheMSNisanimportantlinkinthecontrolofanteriorforebraindynamicsanditsactivitylevelsmayplayakeyroleinmanyneurologicaldisordersofconsciousness(seediscussionbelow).IntheSteriadeandGlenndiscussedabove,inputstothestriatumfromCL/Pcneuronshadaslowerconductionvelocity(3m/scom-paredwith11m/sforcorticallyprojectingneurons)suggestingthepossibilitythatthetimingofinputsfromtheseregionsmaybecontrolledtofacilitateselectiveactivationassuggestedbyearlierproposals.Experimentalstudiessupporttheviewthatacti-vationofboththecorticalandstriatalneuronsbyinputsarisingfromthecentralthalamusmayfacil-itatethegenerationofaphenomenonidentiÞedininvitroandanesthetizedanimalpreparationsastheÒUPstateÓ.DuringtheUPstate,membranepotentialshowrelativelydepolarizedbaselinesandfastÞringoftheneuron.TheUPstateisanetwork-dependentphenomenathatreßectsbroadincreasesinexcita-toryandinhibitorypostsynapticpotentialsbombard-ingthedendriticarborofneuronsacrosslargecerebralnetworkslinkingcortex,thalamus,andbasalgan-glia.Fromafunctionalpointofview,thein-putstocentralthalamusandpatternsofactivationofcentralthalamicneuronsduringattentivebehaviorssuggestthattheyactasgaincontrolsfordistributedprocessesthroughoutthecortex,thalamus,andbasalganglia.Thecommonmechanismmaybeshiftsinactivationacrossthenetworksincreasinganoveralloutputofbalancedexcitatoryandinhibitorysynap-ticbarrageassociatedwithanUPstate-likephenom-enaduringwakefulness.Firingratesofmulti-unitactivityduringUPstatesrecordedinvitroandunderanesthesiaaverages35Ð50Hz,andtheactivitypat-ternisproposedtounderliethetypicalappearanceofsimilarÞringratesinbehavinganimalscarryingoutcognitivetasksasdiscussedabove.Arelatedcommonsignatureofthesephenomenamaybein-creasesinlocalÞeldpotentialsintheband20Ð80Hzthatcouldreßectincreasedsynapticdriveofcorticalinhibitoryinterneuronpopulationsandsynchroniza-tionofsignalsinthecorticoÐcortical,corticostriatal,andthalamostriatalpath-ways.Importantly,arecentexperimentalstudyhasdemonstratedthatthalamocorticalprojectionsaresig-niÞcantlymoreefÞcientinproducingcorticalUPstatesthancorticoÐcorticalexcitatoryconnections;centralthalamicprojectionstobothcortexandstria-tummayhavesimilarproperties,althoughthisisnotknown. 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Schiff:CentralThalamusandArousalRegulationRoleofSensoryInputsandPre-motorAttentionSignalsInadditiontoshiftsofÞringratesinthecentralthal-amusassociatedwithchangesofvigilancelevel,hold-ingofbehavioralsets,suchasmemorydelays,andthebroadstatechangesassociatedwithshiftsintowakefulorREMsleepstates,electrophysiologicalrecordingsalsodemonstratethatthecentralthalamicneuronsre-spondtospeciÞcsensoryandpremotorsignals.Centralthalamicneuronsshowresponsestoseveralbrainstemreßexpathwaysthatassociatepatternedinputfromthesensoryenvironment,suchasacousticstartle,netic,andvestibularstimuli,noxioustactilestim-andpremotorsignalsincludinganoculomotorefferencecopysignal.Amongthesensorysig-nalsdetectedintheanteriorintralaminarnuclei,analertingresponserelatedtotheelementarystartlere-sponseandorientingbehaviorhasbeencharacterizedincatsidentiÞedasthecentrallateralelicitedwave,ThispotentialissimilartothePGOwave,apotentialmodulatedbyexternaleventsthoughttore-ßectenvironmentalmonitoring,andbothareobservedacrossthesleepÐwakecycle.BothCLandPGOre-sisthabituationandpersistlongafterperipheralacous-ticstartleresponsesororientingbehaviorsterminate.TheCLwave,likethePGOwave,likelyreßectsawidelybroadcastsignaloriginatingfrombrainstemcircuitsevolvedtocaptureorganismalbehavior.Dur-ingwakefulnessthissignalmaybeusedtoresetpat-ternsofactivationandinterruptongoingbehavioralsets.CLwavesareobservedasspontaneouseventsandmaybeconsistentwitheyemovements,sponta-neousattentionalshifts,orotherinternallyorganizedalertingresponses.SignalsrecordedfromtheposteriorintralaminarregionsoftheprimateCmÐPfcomplexsimilarlyreßectbehaviorallyrelevantsensoryevents,onsetofsensorycues,orattentionalorientingperseTheevidenceofanoculomotorsignalwithinthean-teriorandposteriorintralaminarregionsisofpar-ticularimportancebecauseofthecloseevolutionofthefrontallobeexecutivecontrolsystemsandprimateocu-lomotorsystem.Becausethesefunctionalcon-trolshaveco-evolvedinthesamebrainregionsinthehumanandnonhumanprimatebraintheysharemanyneurophysiologicalmechanisms.Modelingstud-ieshaveproposedthattransientsignals,suchascorol-larydischargesaroundeyemovements,mayinitiatetheformationordissolutionofmaintainedelevationsofcorticalÞringratesasdiscussedabove,providingapotentialmechanisticlinkfortheappearanceofthesesignalswithinthesamethalamicpopulationsthatfa-cilitateincreasedlevelsofoverallactivityinresponsetotaskdemands.etal.proposedamodelofrecordingsofcorticaldelayperiodactivityinwhichon-setofincreasedcorticalÞringrates(persistentactivity)occurredwithbriefsynchronoustransientsinterpretedinthemodelasefferencecopysignalsofsaccadesandothermotorevents.Physiologicalstudieshavedemon-stratedsuchinteractionsofpersistentactivitysupport-ingworkingmemoryandrepetitivepremotorsignals,e.g.,duringmemorydelaytasksatransientsignalre-latedtotheeyemovementsappearedtoterminatethedelayperiodactivity.Othermodelsalsoproposethatsuchtransientinputstolocalcorticalnetworksexhibit-ingpersistentactivitymayterminatethedelayperiodactivity.Thusthealerting,sensoryorienting,andcorollarydischargesignalsrecordedinthecentralthalamusmayplayanimportantroleinturningonandoffpatternsofbroadneuronalactivationacrossthecerebrumduringwakefulness.Insupportofthishypothesis,astudyofpairrecordingsfromthecentralthalamusandregionsofextrastriatevisualcortexobtainedfromanawakebehavingmonkeydemonstratethatbothtransientac-tivationaroundalertingcuesandsaccadesproducecoherentactivationacrossthesecorticothalamiccon-nectionswithinthe20-to80-Hzfrequencyrange.Importantly,thisÞndingwasspeciÞcforneuronalpop-ulationsthatshowsimilarchangesinthebackgroundthalamiclocalÞeldpotentialduringshort-termfocus-ingofattention.TheseÞndingsthusprovidealinkbetweenthearousalregulationoftheforebrainbythecentralthalamusandtheanatomicalspecializa-tionsofthecentralthalamusthatallowittocaptureattentionbyusingbrainstemalertingmechanismsandcorticothalamicinputsfromtheprefrontalcortex.Sim-ilareffectsareseenwiththeorientingresponseintheEEG,whichproducesabriefincreaseinpowerintheapproximately40-Hzfrequencyrange.MicrocircuitandBiophysicalMechanismsSupportingCorticalandStriatalActivationbytheCentralThalamusRecentstudiespointtoaspeciÞcandverygeneralmechanismbywhichthehighfrequencyimpulsesem-anatingfromtheintralaminarneuronstothecerebralcortexandstriatummaysupportbroadnetworkacti-vationsduringwakefulness.Inputsfromtheanteriorintralaminarnucleihaveauniquepatternofinnerva-tionofthecorticalmicrocircuitandspecializationofcontactsmadewithinthestriatum.MostoftheneuronsfromtheanteriorintralaminarregionsynapseinlayerIontheapicaldendritesofpyramidalcellswithcellbodieslocatedinlayersIIÐIIIandlayerV.JoneshasredeÞnedtheintralaminarandothertha-lamicsubdivisionsintotwoclassesofneuronsonthe 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AnnalsoftheNewYorkAcademyofSciencesreactiontimetasksdemonstratethatasubpopulationofneuronsdistributedthroughoutthecentralthala-musshowsigniÞcantmodulationofÞringratesduringthedelayperiodofthetask.TheincreasedÞr-ingrateoftheseneuronsiscorrelatedwithincreasedpowerinthe30Ð80HzfrequencyrangeofthelocalÞeldpotentials,suggestingthatsynapticinputsdrivingtheneuronsparticipateinbroadpatternsofnetworkactivation.Otherphysiologicalstudieshaveshownthatshort-termalterationsofattentionalstateareidentiÞedwithincreasesin20Ð80Hzspectralcontentofthelo-calÞeldpotentialinseveralcorticalregionsrecordedinalertnonhumanprimates.Episodicmodulationofhighfrequencyoscillatoryactivityinthe20Ð80Hzrangehasbeenobservedduringattentionalcontrol,motorpreparation,andworkingmemory.SuchshiftsofneuronalÞringrateswithinthecentralthal-amusmayplayanimportantroleinfacilitatinginter-arealcorticoÐcorticalinteractionsthatarecrucialtotheperformanceofmanybehavioraltasks.Thesebriefincreasesofpowerin20Ð80HzrangecanbecomparedwiththegeneralincreaseofpowerinthisfrequencyrangeseenincorticalrecordingsthatcorrelatewiththeshiftinÞringratesduringdepolar-izationofcentralthalamicneuronsduringwakefulnessandREMstatesdiscussedabove.SimilarÞndingsofincreasedpowerinthe35Ð50Hzfrequencyrangehavebeenshowntoarisewithdirectelectricalstim-ulationofthebrainstemcholinergicpopulationsandabolishedbysystemicscopolamineinjection.Takentogether,thesephysiologicalobservationssuggestthatcentralthalamicneuronsparticipateinarousalregulation(asoperationalizedinforewarnedreactiontimetasks)aspartofabroadnetworkre-sponseseenduringwakefulstateswithdepolarizationofcellsproducingincreasedÞringinthe20Ð80Hzfrequencyband,andvariationsofintensityandtem-poralshapingofthisactivityoccurringinassociationwithspeciÞctaskdemands.Theadjustmentofthisdis-tributedactivationpatternacrosscerebralstructuresislikelycontrolledjointlybytoniclevelsofbrainstemarousalsystemÞringratesandtop-downsignalsfromfrontalregionsinvolvedinmonitoringdemandsonef-fortandvigilance.ContributionofConnectionsofCentralThalamuswiththeStriatumAnimportantanatomicalspecializationofthein-tralaminarcomponentsofthecentralthalamusthatsupportsanoverallroleinshiftinglevelsofactivityacrossbroadcerebralnetworksistheirstrongefferencetothestriatum.Theanteriorandposteriorintralam-inargroupsaredenselypopulatedwithneuronswithwideprojectionstostriatumaswellascorticaltargetsandcollectivelyprovidethelargestthalamicefferencetothestriatum.Anatomicalstudiesdemonstratethatindividualintralaminarnucleiprojecttoselectedgroupsofcorticalandsubcorticaltargets.Therostralintralaminarnuclei(CL,Pc,andcentralme-dial[CeM])tendtoprojecttoprefrontal,premotor,posteriorparietal,andprimarysensoryareasandpro-videadiffuseinnervationofthestriatum;thecaudalintralaminarnucleirepresentedbythecentromedianÐparafasiculariscomplex(Cm-Pf)containdifferentcellpopulationswithCmformingveryspatiallyrestrictedconnectionswiththestriatum(Cm)andPfneu-ronsdemonstratingcorticalprojectionstocingulate,premotor,andanteriorparietalcortices.Groe-newegenandBerendseearlierproposedthatthetha-lamicintralaminarprojectionsprovideananatomicalsubstrateforinteractionsamongrelativelysegregatedcorticoÐstriatopallidalÐthalamocorticallooppathwaysunderthecontroloftheprefrontalcortex.Inacom-prehensivestudyofintralaminarthalamicconnectionsacrosstheratforebrain,vanderWerfetal.haveshownthattheintralaminarnucleicollectivelyprovidecomprehensiveconnectionstolargecerebralnetworksroughlycorrespondingtothecorticoÐstriatopallidalÐthalamocorticalloopsystemsdescribedinnonhumanprimatesincludingavisceral,motor,limbicandcog-nitiveloop.Theyproposethattheaccessofprefrontalandbrainstemarousalpathwaystotheseneuronspro-videamechanismforlinkingsensoryandmotorac-tivitytoawareness.Consistentwiththeabovepro-posedmechanismforarousalregulationandselectivenetworkactivation,Shirvalkaretal.demonstratedthatelectricalstimulationofCLincreasedgeneralizedarousalandrecognitionmemoryperformanceinin-tactrats.Inaseriesofstudies,Mairandcolleagueshavedemonstratedthatlesionsintherostralintralam-inarregionoftherat(centeredonCL)producebroaddeÞcitsindelayedconditionaldiscriminationacrosssensorymodalities.Inaddition,similarlesionsoftheratanteriorintralaminarnucleiproducedeÞcitsinini-tiatingmotorbehavior.Aunifyinglinkacrosstheseobservations(discussedbelow)isprovidedbythere-centobservationthatintracellularrecordingsincortex,thalamus,andstriatalneuronsassociatebriefincreasesinmulti-unitÞringratesinthe30Ð50Hzfrequencyrangetypicallyobservedduringattentionalormem-orydelays,withshiftsofinputtoindividualneuronsbasedonincreasedratesofbombardmentbypostsy-napticpotentials(balancedexcitatoryandinhibitory AnnalsoftheNewYorkAcademyofSciencesthatanteriorintralaminarregionsshowprogressiveneuronallossincorrelationwithseverityofcognitiveimpairmentfollowingbraininjurysupportsthisargu-Moreover,functionalstudiesofchangesinrestingmetabolismafterdiffuseaxonalinjuryshowaspeciÞcpatternconsistentwithimpairedfunctionoftheanteriorforebrain,includingmarkeddownregula-tionofmetabolicratesinmesialfrontalstructuresandthethalamusbilaterally.TheresultsofthecentralthalamicDBSstudiescanbeconsideredalongsideotherinterventionsthatinsomepatientsfacilitatebehavioralresponsivenessafterseverebraininjuryleadingtoMCSorseveredisability.Bothclassicaldopaminergicagents(L-Dopa,Bromocriptine)andthemixeddopamineagonist/NMDA-channelantagonistAmantidinehavebeenreportedtofacilitaterecoveryoffunction.TakentogetherwiththeDBSresultsdescribedabove,theseobservationsareconsistentwithamodelthatidentiÞesdysfunctionacrossabroadanteriorforebrainsystemprimarilyarisingfromwidespreaddeafferenta-tionofcorticalneuronsproducingreducedlevelsofglobalneuronalactivityacrossthebrainandcaus-ingrelativelyincreaseddeafferentationofthecentralthalamus(resultingfromthegeometryoftheirpointtopointconnections).AsillustratedinF2A,animportantpointofvulnerabilitywithintheanteriorforebrainisthemediumspinyneuron(MSN)ofthestriatum.TheseneuronshaveahighthresholdUPstateandthusdonotÞreeasily,requiringbothasuf-Þcientlevelofdopaminergicinputandbackgroundsynapticactivityfromcorticostriatalandthalamostri-atalinputs.MSNoutputisnecessarytoopposetonicactivityoftheglobuspallidusinterna(GPi),whichactsasastronginhibitoryinßuenceonthethalamus.Neu-ronsinthecentrallateralnucleusoftheanteriorin-tralaminarregionsthatundergosigniÞcantneuronallossfollowingmultifocalbraininjuriesalsoprovideinputtothedendriticspinesoftheMSNsandmayspeciÞcallycontributetoreducingtheiroutputfollow-inginjury.Thus,bothdopaminergicagentsanddirectactivationofthecentralthalamusmayacttoreversedownregulationacrosstheanteriorforebrainsystemsproducedbyseverebraininjury.Dopaminergicagentsstronglymodulatebothstriatalandmesialfrontalsys-tems,whereascentralthalamicneuronsprovidedirectexcitatory(glutamatergic)activationofthesupragran-ularcorticallayersandMSNs.Importantly,asnotedabove,thalamicneuronshaveapreferentialroleforgeneratingcorticalUPstates.Reducedpallidalin-hibitionwithincreasedMSNoutputmayallowthepromotionofcorticalUPstatesviareleaseofstrongthalamocorticalactivation.Thismodelofalterednetworkfunctionthatem-phasizesimpairedfunctionofanteriorforebrainloopsystemsfollowingseverebraininjurymakesanotherspeciÞcprediction.AsshowninF2B,thismodelcanofferanexplanationoftheveryparadoxicalobservationthatsomeseverelybrain-injuredpatientsareÒawakenedÓandshowmarkedbehavioralfacili-tationwiththesedativeagentzolpidem.bindsselectivelytothealpha-1subunitoftheGABA-Areceptor,whichishighlyexpressedintheGPi,andmi-croinfusionofzolpidemintoGPicanproducebehav-ioralchangesconsistentwithinactivationofthestruc-ture.Mostofthepatientswhohavedemonstratedtheseeffectshavesufferedhypoxicinjuries,whichpro-ducesigniÞcantimpairmentofMSNs.ZolpidemmayacttosuppressdisinhibitedGPineuronsallowingre-activationofthalamocorticalandthalamostriatalaffer-entsre-establishingfunctionintheanteriorforebrainnetwork.Reversalofmarkedhypometabolisminthefrontallobesandthalamiinassociationwithbehav-ioralimprovementswithzolpidemsupportsthisinfer-ence.Similareffectswithlorazepam,aless-selectiveagent,mayariseviathesamemechanism(unpublishedobservations).Asreviewedabove,theneuronsinthecentraltha-lamusareuniquelypositionedtocontroldynamicpat-ternsofactivationacrosscerebralnetworks.TheseneuronsmaydrivebothcorticalandstriatalneuronstotransitionintotheequivalentofanUPstatedur-ingwakefulbehaviors,organizingverylong-rangecon-nectionsintheforebrain.Transientactivationofthesamethalamicneuronsappearsinresponsetopremo-torcorollarydischargesignalsandbottom-upsenso-rimotorreßexesoriginatinginthebrainstem,whichlikelybrießyfacilitatebroadsynchronizationthroughasimilarmechanism.DamagetothisefÞcientsystemofforebrainactivationleadstoimmediateandglobalimpairmentsofconsciousnessandgoal-directedbe-havior.Understandingthecontributionsofthecentralthalamustoarousalregulationmayaidourrethink-ingandreformulatingofhowtoapproachtheprob-lemsposedbydisordersofconsciousness.Basedontheiruniqueanatomicalandphysiologicalproperties,neuronswithinthecentralthalamusaresuggestedastargetsofinterventionsaimedatrestoringfunctionatthecircuitlevelforpatientswithdisordersofconscious-ness.TheobservationsofindividualpatientsÕresponsestoDBS,sedative,andotherdrugsreviewedaboveem-phasizethekeyroleofthecentralthalamusincircuitdisturbancesaffectinglarge-scaleforebraindynamics. Schiff:CentralThalamusandArousalRegulationTheseÞndingscanbecomparedtohumanstudiesthatshowincreasedhighfrequencyoscillationsariseintheEEG(ormagnetoencephalogram)signalfromthecerebralcortexduringwakefulnessandREMsleepthatsuggestoriginsinthalamocorticalsystem.thoughMRFandCLneuronsshowclearincreasesinÞringduringtransitionstowakefulness,thisshiftinÞringpatternlagsamarkedincreaseinbrainstemcholinergicneuronÞringratesthatappeartodrivethetransitiontowakefulness,mostlikelyinconjunctionwithactivityshiftsinseveralotherbrainstem,basalforebrain,andhypothalamicpopulations.Thus,thesecentralthalamicnucleimayplayanessentialroleinsupportingthestatechangesofcorticothalamicsystemsthatunderliesleepÐwakecyclesbutarenolongerconsideredtohaveaprimaryroleindriv-ingtheonsetofwakefulnessÑarolenowassignedtocollectionsofnucleiinthebrainstemandbasalfore-ConnectionsofCentralThalamuswithBrainstemandBasalForebrainArousalThecentralthalamusreceivesbroadinnervationfromboththebrainstemandbasalforebrainarousalsystems.Ascendinginputstotheanteriorin-tralaminarnuclei(CL,Pc)andadjacentparalaminarregionsofthalamicassociationnucleimakethempar-ticularlywellpositionedtoplayaroleinarousalregula-tion.Theseregionsreceivetheheaviestthalamicinner-vationfrombrainstemandbasalforebraincholinergicneuronalpopulationsandheavyinnervationfromnoradrenergicafferentsfromthelocusceruleusandserotoninergicafferentsfromthemedialraphe.Thebrainstemandbasalforebrainbothprovidedualcholinergicinputstothethalamusthatactivateneuronswithintheanteriorintralaminarregion:1)Inputsarisefromboththebasalforebrainandbrainstemcholin-ergicgroupstothenucleusreticularis(NRT)thathy-perpolarizetheseneuronsactingthroughmuscarinicreceptors.NRTneuronsprovideagabaergicinhibitoryinßuenceonthecorticallyprojectingrelayneuronsintheanteriorintralaminarnuclei;2)inputstoneuronswithinanteriorintralaminarregionsthatexertdirectdepolarizingeffectsactingthroughnicotinicrecep-tors.Inadditiontothecholinergicandmonoamin-ergicsystems,thereareatleasttwoimportantsourcesofinputsarisingfromtheglutamatergiccomponentsofthearousalsystem,theparabrachicalnucleusandthemonosynapticexcitatorypathwayfromtheMRFdiscussedabove.RoleoftheCentralThalamusinArousalRegulationwithintheWakefulStateHumanimagingstudiesrevealthatselectiveacti-vationofcentralthalamusoccursbothduringtasksrequiringshort-termshiftsofattention(hundredsofmillisecondstoseconds)andduringtasksplac-ingsustaineddemandsofhighvigilanceoverextendedtimeperiodsofhours.Kinomuraetal.strongactivationofboththerostral(CL,Pc)andcau-dalintralaminarnuclei(centromedianÐparafasiculariscomplex,Cm-Pf)duringtheshort-termshiftingofat-tentioncomponentofaforewarnedreactiontimetask(ÒphasicalertingÓ)usingfunctionalpositronemissiontomography.Inadditiontoactivationofthesethalamicregions,theMRFshowedaselectiveactivationconsis-tentwithearlierphysiologicalstudiesidentifyingthispathwayofascendingactivation.Pausetal.iednormalvolunteerscarryingoutalong-termmon-itoringtask(approximately60min)anddemonstratedthatvigilancedecrementsovertimecorrelatedwithde-creasedbloodßowinthemedialthalamus(placedbystereotaxiccoordinatesinthecentrallateralandme-dialdorsalisnuclei).RegressionanalysisshowedthatthisreducedthalamicbloodßowsigniÞcantlyco-variedwithparalleldecreasesintheanteriorcingulatecortex(ACC)andponto-mesencephalon.TheACChasreciprocalconnectionswiththeanteriorintralami-narnucleiandprovideswidelayerIprojectionstotheprefrontalcortexsuggestingitmaytransferactivationwidelythroughouttheprefrontalcortex.TheACCisrecruitedbyadiverserangeofcognitivedemandsandisactivatedwithincreasingcognitiveloadacrosswidevarietiesoftasks.TheACCmaydriveCLandothercentralthalamicregionstorecruitbroadercor-ticalactivationinresponsetodemandsoneffort.Ev-idencefromratstudiesthatneuronswithintheACCmonitorandregulateeffortallocation,thecovaria-tionofcentralthalamuswithACCdeactivationduringvigilancedecrements,andknownanatomicalcon-nectionswithCLareconsistentwiththismechanism.CLalsohasstrongreciprocalprojectionswiththesup-plementarymotorarea(SMA)ofthemedialfrontalcortexthatisalsoshowntoactivateduringforewarnedreactiontimetasksandgradeactivationwithrapidityofresponse.CombineduseoffunctionalMRItech-niques(fMRI)andEEGtechniquesdemonstratethatthalamusandanteriorcingulateshowselectiveactiva-tionduringtheappearanceofacharacteristicdirectcurrent(DC)electricalpotentialassociatedwithantic-ipatoryattentionsupportingthisgeneralmodel.Electrophysiologicalrecordingsfromthecentralthalamusinalertmonkeysperformingforewarned Addressforcorrespondence:NicholasD.Schiff,AssociateProfessorofNeurologyandNeuroscience,Director,LaboratoryofCognitiveNeuro-modulation,DepartmentofNeurologyandNeuroscience,WeillMedicalCollegeofCornellUniversity,NewYork,NY10065.Voice:2372;fax:nds2001@med.cornell.edu AnnalsoftheNewYorkAcademyofSciences FIGURE1.Centralthalamus(CT)andarousalregulation:connectionsofthecentralthalamus.Theconnectionsofthecentralthalamussupportitsroleinarousalregulationmechanismsthatadjustactivitylevelsoverlarge-scalenetworksduringbehavior.Thecentralthalamushasstrongreciprocalconnectionswithseveralsubregionsofthefrontalcortexengagedinplanningandexecutionofmovement,includingthefrontaleyeÞelds(FEF),supplementarymotorarea(SMA),anteriorcingulatecortex(ACC),andmoreposteriorcorticalassociationareasthatsupportpolysensoryintegration,includingposteriorparietalcortex(PPC).Bottom-upconnectionstothecentralthalamusincludeprojectionsfromthebrainstemarousalsystems,includingcholinergicÞbersfromthelateraldorsaltegmentalnucleus(LDT)andpedunculopontinenucleus(PPT),noradrenergicafferentsfromlocusceruleus(LC),andglutamatergicafferentsfromthemesencephalicreticularformation(MRF).Parallelinputstothecentralthalamusarisefromavarietyofbrainstemcircuitsthatredirectattentiontoeventsinthesensoryperiphery(seetextforfurtherdiscussion).andacrossthehemispheresasrequiredduringongoingbehavior.Historically,neuronswithinthecentralthalamus(primarilytheintralaminarandparalaminarnucleargroupsthatproducedbroadÒrecruitingresponsesÓintheelectroencephalogram(EEG)withlowfrequencyelectricalstimulationbecameidentiÞedwithapri-maryroleinmaintainingwakefulness.TheclassicalexperimentalstudiesofMoruzziandMagoungestedthattheintralaminarthalamicneuronswerepartofanascendingpathwaythatoriginatedinthetegmentalmesencephalon(midbrainreticularforma-tion[MRF]).ElectricalstimulationoftheMRFandcentralthalamusinthesestudiesdesynchronizedtheslowlarge-amplitudewavesofEEGactivityinducedinanesthetizedcats.ConÞrmationofthisanatomi-calpathwayfromtheMRFtothecentralthalamus(speciÞcally,anteriorintralaminarnuclei/mediandor-salis)waslaterprovidedbydetailedelectroanatomicalstudiesinthecat.SteriadeandGlennrecordedextra-cellularlyfromhistologicallyidentiÞedneuronsinthelargestcellpopulationsintheanteriorintralaminarnu-clei(centrallateral[CL]andparacentralisnuclei[Pc])ofthecatthalamusanddemonstratedthattheseneu-ronscouldbeantidromicallyactivatedbyelectricallystimulatingassociationregionsofthecerebralcortexandthecaudatenucleusofthestriatumorsynapti-callydrivenbystimulationoftheMRF(afterlesioningofallrostralpontineprojectionstothethalamus).Inrelatedstudies,simultaneousextracellularrecordingsfromcellbodiesinMRFandtheanteriorintralami-nargroup(CL,Pc)duringspontaneoussleepÐwakecy-clesshowedastrongcorrelationoftonicexcitationofMRFneuronsandexcitabilityofintralaminarneuronsprojectingtothecortexduringwakefulness.characterizationoftheseCLneuronsdemonstratedthattheyshowedcharacteristicÞringpatternsduringwakefulness.Theseneuronsgeneratedspikeburstsat800Ð1000HzataÞringrateinthe20Ð40Hzfre-quencyrangeduringwakefulnessandrapideyemove-ment(REM)sleep.Intracellularrecordingsfromthesamecellsrevealedthatdepolarizingtherestingmem-branepotentialtriggeredfastoscillations(20Ð80Hz)oftheshorthigh-frequency(800Ð1000Hz)spikebursts. Schiff:CentralThalamusandArousalRegulation FIGURE2.)Potentialcircuitmechanismsunderlyingoverlappingresponsestodopaminergicagents,NMDAantagonists,sedatives(Ambien,Lorazepam),andcentralthalamicdeep-brainstimula-tion(DBS)inseverebraininjuries.Avarietyofpharmacologicagentshavebeenshowntoimproveresponsivenessinpatientswithglobaldisordersofconsciousness.Connectionsacrosstheanteriorfore-brainmayplayakeyroleintheresponsetomultiplepharmacologicagentsthroughmodulationofacommoncircuitabnormalityarisinginthesettingofmultifocalneuronalcelldeath.Thalamocorticalandthalamostriataloutputfromthecentralthalamusmaybereducedasaresultofdiebackofconnectionsacrossmultiplecorticalregionsfromneuronaldeathoraxonaldisruption.Thesethalamicafferentsappeartohaveapreferentialroleinactivatingbroadnetworksacrossthecortexandproducingactivationofstriatalneurons(seetext).()ProposalforcircuitmechanismunderlyingparadoxicalAmbien(zolpidem)thalamusthatacttoadjustneuronalÞringratesintheseneuronstoregulatecognitiveeffortandmaintainbrainmetabolicactivityinnormalwakefulstates.theseverelyinjuredbrain,DBSofthecentralthala-musmaycounteractstrongpassiveinhibitionofthecentralthalamusasaresultofthewidespreadlossofincomingaxonalafferentsfrommanycerebralstruc-tures(thuseffectivelyovercomingthemajorproblemoflossofexcitatorycontactsacrossthedendriticar-boroftheseneurons).Theobservationnotedabove