Central Thalamic Contributions to Arousal Regulation and Neurological Disorders of Consciousness

14 Pages·2008·0.28 MB·English

Central Thalamic Contributions to Arousal
Regulation and Neurological Disorders
of Consciousness
NICHOLASD.SCHIFF
DepartmentofNeurologyandNeuroscience,WeillCornellMedicalCollege,
NewYork,NewYork,USA
Thisreviewfocusesonthecontributionsofthecentralthalamustonormalmechanismsofarousal
regulationandtoneurologicaldisordersofconsciousness.Forebrainarousalisregulatedbyas-
cendinginfluencesfrombrainstem/basalforebrainneuronalpopulations(“arousalsystems”)and
controlsignalsdescendingfromfrontalcorticalsystems.Thesesubcorticalandcorticalsystems
haveconvergingprojectionstothecentralthalamusthatemphasizetheirroleinmaintainingor-
ganized behavior during wakefulness. Central thalamic neurons appear to be specialized both
anatomicallyandphysiologicallytosupportdistributednetworkactivitythatmaintainsneuronal
firing patterns across long-range cortico–cortical pathways and within cortico–striatopallidal–
thalamocorticalloopconnections.Recruitmentofcentralthalamicneuronsoccursinresponse
toincreasingcognitivedemand,stress,fatigue,andotherperturbationsthatreducebehavioral
performance. In addition, the central thalamus receives projections from brainstem pathways
evolvedtorapidlygeneratebriefshiftsofarousalassociatedwiththeappearanceofsalientstimuli
acrossdifferentsensorymodalities.Throughactivationofthecentralthalamus,neuronsacross
thecerebralcortexandstriatumcanbedepolarizedandtheiractivitypatternsselectivelygatedby
descendingorascendingsignalsrelatedtopremotorattentionandalertingstimuli.Directinjury
to the central thalamus or prominent deafferentation of these neurons as a result of complex,
multifocal,braininsultsarebothassociatedwithsevereimpairmentofforebrainfunctionalinte-
grationandarousalregulation.Interventionstargetingneuronswithinthecentralthalamusmay
leadtorationaltherapeuticapproachestothetreatmentofimpairedarousalregulationfollowing
nonprogressivebraininjuries.Amodelaccountingforpresenttherapeuticstrategiesisproposed.
Keywords: intralaminarnuclei;minimallyconsciousstate;calbindin;deepbrainstimulation
The Central Thalamus and Arousal brainstem/basalforebrain“arousalsystems”thatcon-
Regulation trol overall levels of thalamic and cortical activity1,2
and supervisory frontal systems3 that organize both
Many neurons within the central thalamus (defined premotorshiftsofattention4,5andadjustmentsofvig-
here as the anterior and posterior intralaminar nu- ilanceleveloralertness.6,7 Inparallel,individualneu-
cleiandtheparalaminarportionsofrelatedthalamic rons within these cellular aggregates are targets of a
association nuclei—median dorsalis, ventral anterior, varietyofdedicatedbrainstemsensoryrelaysthathave
ventral lateral, and inferior pulvinar) share specific evolved to quickly capture attention and redirect be-
anatomicalandphysiologicalspecializationsthatsup- havior (FIG.1).8,9 Collectively, these anatomical spe-
porttheirkeyroleinthegeneralfunctionsofsustained cializationssuggestthatmanyneuronswithinthecen-
attention, working memory, and motor preparation. tral thalamus may serve a general purpose function
These neuronal populations are interposed between supporting large-scale cerebral dynamics associated
withgoal-directedbehaviorsandconsciousness.Inthis
review,thisgeneralfunctionisidentifiedasarousalreg-
ulationandthecentralthalamusisviewedascontain-
Addressforcorrespondence:NicholasD.Schiff,AssociateProfessorof ingcollectionsofcellsthatarerecruitedeither1)aspart
NeurologyandNeuroscience,Director,LaboratoryofCognitiveNeuro- ofbroadgaincontrolsystemsthatshiftandholdlevels
modulation,DepartmentofNeurologyandNeuroscience,WeillMedical of activation across large transiently established net-
CollegeofCornellUniversity,NewYork,NY10065.Voice:+1-212-746-
2372;fax:[phone]. worksor2)bytransientactivationofthesecentraltha-
[email protected] lamicneuronsthatmaybeusedtobiasactivitywithin
Ann.N.Y.Acad.Sci.1129:105–118(2008).(cid:2)C 2008NewYorkAcademyofSciences.
doi:10.1196/annals.1417.029 105
106 AnnalsoftheNewYorkAcademyofSciences
FIGURE 1. Centralthalamus(CT)andarousalregulation:connectionsofthecentralthalamus.The
connectionsofthecentralthalamussupportitsroleinarousalregulationmechanismsthatadjustactivity
levelsoverlarge-scalenetworksduringbehavior.Thecentralthalamushasstrongreciprocalconnections
withseveralsubregionsofthefrontalcortexengagedinplanningandexecutionofmovement,including
thefrontaleyefields(FEF),supplementarymotorarea(SMA),anteriorcingulatecortex(ACC),andmore
posterior cortical association areas that support polysensory integration, including posterior parietal
cortex(PPC).Bottom-upconnectionstothecentralthalamusincludeprojectionsfromthebrainstemarousal
systems,includingcholinergicfibersfromthelateraldorsaltegmentalnucleus(LDT)andpedunculopontine
nucleus (PPT), noradrenergic afferents from locus ceruleus (LC), and glutamatergic afferents from the
mesencephalic reticular formation (MRF). Parallel inputs to the central thalamus arise from a variety of
brainstemcircuitsthatredirectattentiontoeventsinthesensoryperiphery(seetextforfurtherdiscussion).
andacrossthehemispheresasrequiredduringongoing clei(centrallateral[CL]andparacentralisnuclei[Pc])
behavior. ofthecatthalamusanddemonstratedthattheseneu-
Historically, neurons within the central thalamus rons could be antidromically activated by electrically
(primarily the intralaminar and paralaminar nuclear stimulating association regions of the cerebral cortex
groupsthatproducedbroad“recruitingresponses”in and the caudate nucleus of the striatum or synapti-
the electroencephalogram (EEG) with low frequency callydrivenbystimulationoftheMRF(afterlesioning
electrical stimulation10 became identified with a pri- of all rostral pontine projections to the thalamus). In
maryroleinmaintainingwakefulness.11 Theclassical related studies, simultaneous extracellular recordings
experimental studies of Moruzzi and Magoun11 sug- from cell bodies in MRF and the anterior intralami-
gested that the intralaminar thalamic neurons were nargroup(CL,Pc)duringspontaneoussleep–wakecy-
part of an ascending pathway that originated in the clesshowedastrongcorrelationoftonicexcitationof
tegmentalmesencephalon(midbrainreticularforma- MRFneuronsandexcitabilityofintralaminarneurons
tion [MRF]). Electrical stimulation of the MRF and projectingtothecortexduringwakefulness.13Further
central thalamus in these studies desynchronized the characterization of these CL neurons demonstrated
slow large-amplitude waves of EEG activity induced thattheyshowedcharacteristicfiringpatternsduring
in anesthetized cats. Confirmation of this anatomi- wakefulness.14 These neurons generated spike bursts
cal pathway from the MRF to the central thalamus at 800–1000Hz at a firing rate in the 20–40Hz fre-
(specifically,anteriorintralaminarnuclei/mediandor- quencyrangeduringwakefulnessandrapideyemove-
salis)waslaterprovidedbydetailedelectroanatomical ment (REM) sleep. Intracellular recordings from the
studiesinthecat.SteriadeandGlenn12recordedextra- samecellsrevealedthatdepolarizingtherestingmem-
cellularlyfromhistologicallyidentifiedneuronsinthe branepotentialtriggeredfastoscillations(20–80Hz)of
largestcellpopulationsintheanteriorintralaminarnu- the short high-frequency (800–1000Hz) spike bursts.
Schiff:CentralThalamusandArousalRegulation 107
These findings can be compared to human studies RoleoftheCentralThalamusinArousal
that show increased high frequency oscillations arise RegulationwithintheWakefulState
in the EEG (or magnetoencephalogram) signal from Human imaging studies reveal that selective acti-
thecerebralcortexduringwakefulnessandREMsleep vation of central thalamus occurs both during tasks
thatsuggestoriginsinthalamocorticalsystem.15–17Al- requiring short-term shifts of attention (hundreds of
though MRF and CL neurons show clear increases milliseconds to seconds28–30) and during tasks plac-
infiringduringtransitionstowakefulness,13 thisshift ingsustaineddemandsofhighvigilanceoverextended
in firing pattern lags a marked increase in brainstem time periods of hours.31 Kinomura et al.28 identified
cholinergicneuronfiringratesthatappeartodrivethe strongactivationofboththerostral(CL,Pc)andcau-
transitiontowakefulness,18 mostlikelyinconjunction dalintralaminarnuclei(centromedian–parafasicularis
with activity shifts in several other brainstem, basal complex,Cm-Pf)duringtheshort-termshiftingofat-
forebrain, and hypothalamic populations.19–21 Thus, tentioncomponentofaforewarnedreactiontimetask
these central thalamic nuclei may play an essential (“phasic alerting”) using functional positron emission
roleinsupportingthestatechangesofcorticothalamic tomography.Inadditiontoactivationofthesethalamic
systems that underlie sleep–wake cycles18,22 but are regions,theMRFshowedaselectiveactivationconsis-
no longer considered to have a primary role in driv- tent with earlier physiological studies identifying this
ing the onset of wakefulness—a role now assigned to pathwayofascendingactivation.11,12Pausetal.31stud-
collections of nuclei in the brainstem and basal fore- iednormalvolunteerscarryingoutalong-termmon-
brain.2,19,23 itoringtask(approximately60min)anddemonstrated
thatvigilancedecrementsovertimecorrelatedwithde-
creasedbloodflowinthemedialthalamus(placedby
ConnectionsofCentralThalamuswith stereotaxiccoordinatesinthe centrallateral andme-
BrainstemandBasalForebrainArousal dial dorsalis nuclei31,32). Regression analysis showed
Systems thatthisreducedthalamicbloodflowsignificantlyco-
The central thalamus receives broad innervation variedwithparalleldecreasesintheanteriorcingulate
from both the brainstem and basal forebrain arousal cortex (ACC) and ponto-mesencephalon. The ACC
systems.9,23,24 Ascending inputs to the anterior in- hasreciprocalconnectionswiththeanteriorintralami-
tralaminar nuclei (CL, Pc) and adjacent paralaminar narnuclei33andprovideswidelayerIprojectionstothe
regionsofthalamicassociationnucleimakethempar- prefrontalcortexsuggestingitmaytransferactivation
ticularlywellpositionedtoplayaroleinarousalregula- widely throughout the prefrontal cortex.34 The ACC
tion.Theseregionsreceivetheheaviestthalamicinner- isrecruitedbyadiverserangeofcognitivedemands35
vationfrombrainstemandbasalforebraincholinergic and is activated with increasing cognitive load across
neuronalpopulations1,24 andheavyinnervationfrom widevarietiesoftasks.36TheACCmaydriveCLand
noradrenergic afferents from the locus ceruleus and othercentralthalamicregionstorecruitbroadercor-
serotoninergic afferents from the medial raphe.9,25,26 ticalactivationinresponsetodemandsoneffort.Ev-
Thebrainstemandbasalforebrainbothprovidedual idencefromratstudiesthatneuronswithintheACC
cholinergicinputstothethalamusthatactivateneurons monitor and regulate effort allocation,37 the covaria-
withintheanteriorintralaminarregion:1)Inputsarise tionofcentralthalamuswithACCdeactivationduring
from both the basal forebrain and brainstem cholin- vigilance decrements,31 and known anatomical con-
ergicgroupstothenucleusreticularis(NRT)thathy- nectionswithCL38areconsistentwiththismechanism.
perpolarize these neurons acting through muscarinic CLalsohasstrongreciprocalprojectionswiththesup-
receptors.NRTneuronsprovideagabaergicinhibitory plementary motor area (SMA) of the medial frontal
influenceonthecorticallyprojectingrelayneuronsin cortexthatisalsoshowntoactivateduringforewarned
theanteriorintralaminarnuclei;2)inputstoneurons reactiontimetasks30andgradeactivationwithrapidity
within anterior intralaminar regions that exert direct ofresponse.29 CombineduseoffunctionalMRItech-
depolarizing effects acting through nicotinic recep- niques(fMRI)andEEGtechniquesdemonstratethat
tors.1,27Inadditiontothecholinergicandmonoamin- thalamusandanteriorcingulateshowselectiveactiva-
ergicsystems,thereareatleasttwoimportantsources tion during the appearance of a characteristic direct
of inputs arising from the glutamatergic components current(DC)electricalpotentialassociatedwithantic-
of the arousal system, the parabrachical nucleus and ipatoryattentionsupportingthisgeneralmodel.30
themonosynapticexcitatorypathwayfromtheMRF Electrophysiological recordings from the central
discussedabove.12,19 thalamus in alert monkeys performing forewarned
108 AnnalsoftheNewYorkAcademyofSciences
reactiontimetasksdemonstratethatasubpopulation inargroupsare densely populatedwithneurons with
of neurons distributed throughout the central thala- wideprojectionstostriatumaswellascorticaltargets
musshowsignificantmodulationoffiringratesduring andcollectivelyprovidethelargestthalamicefference
the delay period of the task.39,40 The increased fir- to the striatum.50–52 Anatomical studies demonstrate
ingrate oftheseneuronsiscorrelatedwithincreased thatindividualintralaminarnucleiprojecttoselected
power in the 30–80Hz frequency range of the local groupsofcorticalandsubcorticaltargets.52,53–55 The
fieldpotentials,suggestingthatsynapticinputsdriving rostral intralaminar nuclei (CL, Pc, and central me-
the neurons participate in broad patterns of network dial [CeM]) tend to project to prefrontal, premotor,
activation.Otherphysiologicalstudieshaveshownthat posteriorparietal,andprimarysensoryareasandpro-
short-termalterationsofattentionalstateareidentified videadiffuseinnervationofthestriatum;52thecaudal
withincreasesin20–80Hzspectralcontentofthelo- intralaminarnucleirepresentedbythecentromedian–
calfieldpotentialinseveralcorticalregionsrecorded parafasiculariscomplex(Cm-Pf)containdifferentcell
inalertnonhumanprimates.41–43Episodicmodulation populationswithCmformingveryspatiallyrestricted
ofhighfrequencyoscillatoryactivityinthe20–80Hz connections with the striatum (Cm) and Pf neu-
rangehasbeenobservedduringattentionalcontrol,41 rons demonstrating cortical projections to cingulate,
motor preparation,42 and working memory.43 Such premotor, and anterior parietal cortices.54,56 Groe-
shifts of neuronal firing rates within the central thal- newegenandBerendse54earlierproposedthatthetha-
amusmayplayanimportantroleinfacilitatinginter- lamicintralaminarprojectionsprovideananatomical
areal cortico–cortical interactions that are crucial to substrateforinteractionsamongrelativelysegregated
the performance of many behavioral tasks.28,31,44–47 cortico–striatopallidal–thalamocorticallooppathways
Thesebriefincreasesofpowerin20–80Hzrangecan under the control of the prefrontal cortex. In a com-
be compared with the general increase of power in prehensivestudyofintralaminarthalamicconnections
this frequency range seen in cortical recordings that across the rat forebrain, van der Werf et al.53 have
correlatewiththeshiftinfiringratesduringdepolar- shownthattheintralaminarnucleicollectivelyprovide
izationofcentralthalamicneuronsduringwakefulness comprehensiveconnectionstolargecerebralnetworks
andREMstatesdiscussedabove.14,48Similarfindings roughly corresponding to the cortico–striatopallidal–
of increased power in the 35–50Hz frequency range thalamocorticalloopsystemsdescribedinnonhuman
have been shown to arise with direct electrical stim- primates57includingavisceral,motor,limbicandcog-
ulation of the brainstem cholinergic populations and nitiveloop.Theyproposethattheaccessofprefrontal
abolishedbysystemicscopolamineinjection.49 andbrainstemarousalpathwaystotheseneuronspro-
Taken together, these physiological observations vide a mechanism for linking sensory and motor ac-
suggest that central thalamic neurons participate in tivity to awareness. Consistent with the above pro-
arousal regulation (as operationalized in forewarned posedmechanismforarousalregulationandselective
reaction time tasks)6 as part of a broad network re- network activation, Shirvalkar et al.58 demonstrated
sponseseenduringwakefulstateswithdepolarization thatelectricalstimulationofCLincreasedgeneralized
of cells producing increased firing in the 20–80Hz arousal and recognition memory performance in in-
frequency band, and variations of intensity and tem- tact rats. In a series of studies, Mair and colleagues
poralshapingofthisactivityoccurringinassociation havedemonstratedthatlesionsintherostralintralam-
withspecifictaskdemands.Theadjustmentofthisdis- inarregionoftherat(centeredonCL)producebroad
tributed activation pattern across cerebral structures deficits in delayed conditional discrimination across
islikelycontrolledjointlybytoniclevelsofbrainstem sensorymodalities.59Inaddition,similarlesionsofthe
arousalsystemfiringratesandtop-downsignalsfrom ratanteriorintralaminarnucleiproducedeficitsinini-
frontalregionsinvolvedinmonitoringdemandsonef- tiatingmotorbehavior.60 Aunifyinglinkacrossthese
fortandvigilance. observations (discussed below) is provided by the re-
centobservationthatintracellularrecordingsincortex,
ContributionofConnectionsofCentral thalamus,andstriatalneuronsassociatebriefincreases
ThalamuswiththeStriatum in multi-unit firing rates in the 30–50Hz frequency
An important anatomical specialization of the in- range typically observed during attentional or mem-
tralaminar components of the central thalamus that ory delays, with shifts of input to individual neurons
supports an overall role in shifting levels of activity based on increased rates of bombardment by postsy-
acrossbroadcerebralnetworksistheirstrongefference naptic potentials (balanced excitatory and inhibitory
tothestriatum.Theanteriorandposteriorintralam- inputs61,62).
Schiff:CentralThalamusandArousalRegulation 109
RoleofSensoryInputsandPre-motor recordingsofcorticaldelayperiodactivityinwhichon-
AttentionSignals setofincreasedcorticalfiringrates(persistentactivity)
Inadditiontoshiftsoffiringratesinthecentralthal- occurredwithbriefsynchronoustransientsinterpreted
amusassociatedwithchangesofvigilancelevel,hold- inthemodelasefferencecopysignalsofsaccadesand
ingofbehavioralsets,suchasmemorydelays,andthe othermotorevents.Physiologicalstudieshavedemon-
broadstatechangesassociatedwithshiftsintowakeful stratedsuchinteractionsofpersistentactivitysupport-
or REM sleep states, electrophysiological recordings ingworkingmemoryandrepetitivepremotorsignals,
alsodemonstratethatthecentralthalamicneuronsre- e.g.,duringmemorydelaytasksatransientsignalre-
spondtospecificsensoryandpremotorsignals.Central latedtotheeyemovementsappearedtoterminatethe
thalamicneuronsshowresponsestoseveralbrainstem delayperiodactivity.66Othermodelsalsoproposethat
reflexpathwaysthatassociatepatternedinputfromthe suchtransientinputstolocalcorticalnetworksexhibit-
sensoryenvironment,suchasacousticstartle,8optoki- ingpersistentactivitymayterminatethedelayperiod
netic,andvestibularstimuli,63,64 noxioustactilestim- activity.69
uli,9 and premotor signals including an oculomotor Thus the alerting, sensory orienting, and corollary
efference copy signal.5,65,66 Among the sensory sig- dischargesignalsrecordedinthecentralthalamusmay
nals detected in the anterior intralaminar nuclei, an playanimportantroleinturningonandoffpatternsof
alertingresponserelatedtotheelementarystartlere- broadneuronalactivationacrossthecerebrumduring
sponseandorientingbehaviorhasbeencharacterized wakefulness. In support of this hypothesis, a study of
in cats identified as the central lateral elicited wave, pairrecordingsfromthecentralthalamusandregions
CL .8 This potential is similar to the PGO wave, a of extrastriate visual cortex obtained from an awake
E E
potentialmodulatedbyexternaleventsthoughttore- behavingmonkeydemonstratethatbothtransientac-
flectenvironmentalmonitoring,andbothareobserved tivation around alerting cues and saccades produce
acrossthesleep–wakecycle.BothCL andPGO re- coherent activation across these corticothalamic con-
E E
sisthabituationandpersistlongafterperipheralacous- nectionswithinthe20-to80-Hzfrequencyrange.119
ticstartleresponsesororientingbehaviorsterminate. Importantly,thisfindingwasspecificforneuronalpop-
The CL wave, like the PGO wave, likely reflects ulationsthatshowsimilarchangesinthebackground
E E
a widely broadcast signal originating from brainstem thalamiclocalfieldpotentialduringshort-termfocus-
circuitsevolvedtocaptureorganismalbehavior.Dur- ing of attention. These findings thus provide a link
ing wakefulness this signal may be used to reset pat- between the arousal regulation of the forebrain by
terns of activation and interrupt ongoing behavioral the central thalamus and the anatomical specializa-
sets. CL waves are observed as spontaneous events tions of the central thalamus that allow it to capture
E
and may be consistent with eye movements, sponta- attentionbyusingbrainstemalertingmechanismsand
neousattentionalshifts,orotherinternallyorganized corticothalamicinputsfromtheprefrontalcortex.Sim-
alertingresponses.Signalsrecordedfromtheposterior ilareffectsareseenwiththeorientingresponseinthe
intralaminar regions of the primate Cm–Pf complex EEG,whichproducesabriefincreaseinpowerinthe
similarly reflect behaviorally relevant sensory events, approximately40-Hzfrequencyrange.70
onsetofsensorycues,44orattentionalorientingperse.45
Theevidenceofanoculomotorsignalwithinthean- MicrocircuitandBiophysicalMechanisms
teriorandposteriorintralaminarregions5,65 isofpar- SupportingCorticalandStriatalActivation
ticularimportancebecauseofthecloseevolutionofthe bytheCentralThalamus
frontallobeexecutivecontrolsystemsandprimateocu- Recentstudiespointtoaspecificandverygeneral
lomotor system.5,46,67 Because these functional con- mechanismbywhichthehighfrequencyimpulsesem-
trols have co-evolved in the same brain regions in anatingfromtheintralaminarneuronstothecerebral
the human and nonhuman primate brain they share cortexandstriatummaysupportbroadnetworkacti-
manyneurophysiologicalmechanisms.Modelingstud- vations during wakefulness. Inputs from the anterior
ieshaveproposedthattransientsignals,suchascorol- intralaminarnucleihaveauniquepatternofinnerva-
lary discharges around eye movements, may initiate tion of the cortical microcircuit71 and specialization
theformationordissolutionofmaintainedelevations of contacts made within the striatum.72 Most of the
ofcorticalfiringratesasdiscussedabove,providinga neuronsfromtheanteriorintralaminarregionsynapse
potentialmechanisticlinkfortheappearanceofthese in layer I on the apical dendrites of pyramidal cells
signals within the same thalamic populations that fa- with cell bodies located in layers II–III and layer V.
cilitateincreasedlevelsofoverallactivityinresponseto Jones73 hasredefinedtheintralaminarandothertha-
taskdemands.68,69Gutkinetal.68proposedamodelof lamic subdivisions into two classes of neurons on the
110 AnnalsoftheNewYorkAcademyofSciences
basis of differential calcium-binding protein expres- contactingthedendriticspine.72 Theseexcitatoryin-
sion. One class, the “core” neurons, express parval- putstothestriatalneuronmayactasprimarydrivers
buminandsynapseinthemiddle,orgranular,layers alongwithdescendingcorticostriatalinputs.TheMSN
of the cortical microcircuit with area-specific cortical isanimportantlinkinthecontrolofanteriorforebrain
projections.Theotherclass,the“matrix”neuronsex- dynamics and its activity levels may play a key role
press calbindin D28K and project to Layer I across in many neurological disorders of consciousness (see
relatively wide cortical territories. In both humans74 discussionbelow).IntheSteriadeandGlenn12studies
andnonhumanprimates,73 intralaminarsubdivisions discussed above, inputs to the striatum from CL/Pc
aredenselypopulatedwithmatrixneurons(CL,Pc,Pf, neuronshadaslowerconductionvelocity(3m/scom-
but not Cm, which is densely parvalbumin staining). pared with 11m/s for cortically projecting neurons)
Thematrixneuronsareproposedtoactcollectivelyasa suggestingthepossibilitythatthetimingofinputsfrom
functionalsystemthatorganizesglobalpatternsofcor- these regions may be controlled to facilitate selective
ticothalamicsynchronization.73 Neuronswithinthese activationassuggestedbyearlierproposals.54
intralaminarregionsmaysynapseoncellbodieswithin Experimental studies support the view that acti-
layersVandVIaswellasLayerI71andthispatternof vation of both the cortical and striatal neurons by
dualinnervationwithinthecorticalcolumnhasbeen inputs arising from the central thalamus may facil-
proposedtosupportabiophysicalcoincidencedetec- itate the generation of a phenomenon identified in
tionmechanismthatfacilitatesinputsfromthespecific in vitro and anesthetized animal preparations as the
thalamic inputs to the granular layers.75,76 In studies “UPstate”.DuringtheUPstate,membranepotential
of the apical dendrites of Layer V and Layer II/III show relatively depolarized baselines and fast firing
corticalneurons,Larkametal.77,78havedemonstrated of the neuron. The UP state is a network-dependent
that co-activation within a narrow temporal window phenomena that reflects broad increases in excita-
oftheapicaldendrites(inLayerI)andsomaofLayer toryandinhibitorypostsynapticpotentialsbombard-
V pyramidal neurons induces burst firing through a ingthedendriticarborofneuronsacrosslargecerebral
back-propagating action potential that originates in networks linking cortex, thalamus, and basal gan-
thesomaandallowsfornormallysubthresholdinputs glia.61,62,83 From a functional point of view, the in-
in the apical dendrites to become spike generating. putstocentralthalamusandpatternsofactivationof
Similar changes in dendritic electrogenesis of Layer central thalamic neurons during attentive behaviors
II/IIIneuronscouldsupportthismechanism.78 Con- suggest that they act as gain controls for distributed
sistent with these proposals, combined stimulation of processesthroughoutthecortex,thalamus,andbasal
CLandtheventrobasalnucleus(aspecificthalamicre- ganglia. The common mechanism may be shifts in
laynucleusprojectingintocorticalLayerIV)inmouse activation across the networks increasing an overall
corticothalamicslicegeneratesasupralinearsumma- output of balanced excitatory and inhibitory synap-
tionoflocalevokedpotentials.79Depolarizationofthe ticbarrageassociatedwithanUPstate-likephenom-
supragranularlayerdendritesbyintralaminarafferents enaduringwakefulness.61,83 Firingratesofmulti-unit
hasbeenproposedtopromotesustainedcorticalactiv- activity during UP states recorded in vitro and under
ity,80,81 NMDA-mediatedlong-termpotentiation,81,46 anesthesia averages 35–50Hz, and the activity pat-
andothermechanismsofsynapticfacilitation.82Thus, tern is proposed to underlie the typical appearance
the anatomical specializations of the matrix neuron- of similar firing rates in behaving animals carrying
rich intralaminar and paralaminar regions of central out cognitive tasks as discussed above.61,62 A related
thalamicthalamusprovideauniquesubstrateforsup- common signature of these phenomena may be in-
port of distributed cortical persistent activity. Consis- creasesinlocalfieldpotentialsintheband20–80Hz
tent with these in vitro and anatomical studies, recent that could reflect increased synaptic drive of cortical
in vivo electrical stimulation studies show that electri- inhibitoryinterneuronpopulations84andsynchroniza-
calstimulationofCLgeneratebroadactivationofc-fos tion of signals in the cortico–cortical,46 corticothala-
acrossallcorticallayersandauniquepatternofupreg- mic,48,75,76corticostriatal,85andthalamostriatalpath-
ulationofzif268 (animmediateearlygeneassociated ways.85 Importantly, a recent experimental study has
withlong-termpotentiation)insupragranularandin- demonstratedthatthalamocorticalprojectionsaresig-
fragranularlayersconsistentwiththesemechanisms.58 nificantlymoreefficientinproducingcorticalUPstates
Centralthalamicinputstothestriatumarealsospe- than cortico–cortical excitatory connections;86 the
cialized and recent studies have shown that the cen- centralthalamicprojectionstobothcortexandstria-
trallateralnucleusoftheanteriorintralaminargroup tummayhavesimilarproperties,althoughthisisnot
projects to the medium spiny striatal neuron (MSN) known.
Schiff:CentralThalamusandArousalRegulation 111
The unique connectivity of central thalamic neu- the primary sources of ascending control of arousal
ronsandtheirphysiologicalspecializationssuggestthat stateperse.However,unlikebrainstemlesionsthatpro-
they may contribute to broad formation of UP state- duce coma following focal injuries,93 the recovery of
liketransitionoffiringratesseenacrosscerebralnet- consciousness in terms of goal-directed behavior and
works in vivo during organized behaviors. Facilitating communication skills is very slow following bilateral
thetransitiontoUPstatesandtheirmaintenancemay central thalamic injuries89,90 and uncertain.88 These
bethefundamentalmechanism ofarousalregulation clinicalobservationsareconsistentwithexperimental
throughthecentralthalamusthatallowsfor:1)adjust- studiesthatdemonstratethatneitherthecentraltha-
ment of gain across multiple pathways of sensorimo- lamus nor the basal forebrain are indispensable for
tor integration associated with varying levels of vigi- maintaininggeneralarousalassociatedwithsomere-
lance,interest,motivation,andotherstatefactorsand coveryofEEGcyclingandwakefulness,14,94suggesting
2) rapid capture and redirection of behavior through thatparallelbasalforebrainandthalamicmechanisms
powerfulbiascontrolsfacilitatedthroughactivationof anddirectbrainstemtocortexpathwaysarepleuripo-
the central thalamus by the frontal executive systems tent for maintaining cerebral arousal (see Ref. 23 for
usingpremotorsignalsthatdirectattentiontointended review).
movementsthroughabroadcorollarydischargemech- Thelargeandenduringbehavioraleffectsofsmall,
anism.Similarly,biasingofattentionandgoal-directed central,thalamicinjuriescanbeunderstoodinthecon-
actionmaybeachievedbytriggeringUPstatesacross textofstudiesthatdemonstratethatfocalischemicin-
cerebralnetworksthroughactivationofdedicatedre- jurieswithinthecentralthalamuscanproducemarked
flex pathways from the sensory periphery that access reductionincerebralmetabolismacrosstheentireip-
the central thalamus. Using this picture as a work- silateralhemisphereasmeasuredusingfluorodeoxglu-
ing model, it is possible to organize many disparate cose positron emission tomography.95,96 This effect
observationsassociatedwithneurologicaldisordersof reflects a crossed (trans-) synaptic downregulation of
consciousness and their phenomenology as reviewed distant neuronal populations connected to the cen-
below. tralthalamus(knownalsoasdiaschisis97).Thecrossed
synapticdownregulationresultsfromthelossofexcita-
toryinputstoremotebrainregions,andthesechanges
Contributions of the Central Thalamus
incerebralbloodflowonlymarginallyindicatemarked
to Neurological Disorders
reductions in neuronal firing rates in the distal struc-
of Consciousness
tures.98 Thelossofexcitatorydrivetoneuronalpop-
ulations in such instances produces a passive form
Itiswellestablishedthatthecentralthalamusplays
ofinhibition(disfacilitation)hyperpolarizingneuronal
an important role in neurological disorders of con-
membranepotentialsasaresultofwithdrawalofexci-
sciousness.87 The brief review below links this role
tatorysynapticinputsthatthenallowremainingleak
of the central thalamus to pathophysiological mech-
currents(principallypotassium)todominate.99
anisms that produce both persistent and paroxysmal
The profound effects of central thalamic lesions
impairments of arousal regulation after severe brain
can be understood simply as a consequence of their
injury.Aninterpretativeframeworkisthenproposedto
unique geometry; the neurons have many point to
explainunderlyingmechanismsforinterventionsthat
point connections across the corticothalamic system
improve neurological function in patients with disor-
andthroughthestriatalloopconnectionsoftheante-
dersofconsciousness.
rior forebrain (as reviewed above). A quantitative re-
FocalInjuriestotheCentralThalamus sult underscoring this point is the finding, in a com-
Direct injuries to the central thalamus can alone pletemultidimensionalscalingmodeloftheentirecat
produce global disturbances of consciousness.88–90 If thalamocorticalsystem100 thatplacestheanteriorin-
unilateral,theselesionsmayproducehemispatialun- tralaminarnuclei(CL,Pc,andcentralmedial)inone
awareness91 or altered states of consciousness simi- clustertogether,centeredamongallothersegregated
lar to acute mania or delirium.92 Restricted bilateral thalamocortical loop systems (frontal, limbic, tempo-
injuries to the central thalamus may produce acute ral,andparietal).Thispositioningcanbeinterpreted
coma indicating the important role these structures asaconsequenceoftheirrelativelyshortestpathand
playinanormalalertwakefulstate.Recoveryofcycli- multipleconnectionsacrosseachoftheotherclusters
calarousalpatternswithperiodsofeyeopeningoccurs (withatendencytobeclosertothefrontal/limbicre-
rapidlywiththeselesionsandisusuallypresentwithin gion of the cortex, which is more strongly connected
48h, again emphasizing that these neurons are not with the striatum). In this context, the broad effects
112 AnnalsoftheNewYorkAcademyofSciences
ofwithdrawalofcentralthalamicexcitationcanhelp todeath,asimilarfindingofwidespreadthalamicneu-
to explain the surprisingly long-lasting impairments ronallosswasfoundwithlessneocorticalinvolvement
of human frontal lobe executive functions correlated (only11%withdiffuseneocorticalcellloss).Inarecent
with discrete injury to CL101 and other thalamic in- follow-up study, the detailed analysis of thalamic nu-
juriesspecificallyinvolvingtherostralintralaminarre- cleirevealedthatwhenautopsystudieswerecompared
gion.88,102 withcontrols,damagetocentralthalamicstructuresin-
In addition to persistent decreases in neuronal fir- dexedbehavioraloutcomesfrommoderatedisabilityto
ingratesacrossthecerebrum,discreteinjuriestothe VS with initial involvement of the anterior intralam-
central thalamus may also lead to global functional inar structure and progressive cell loss ventrally and
impairmentthroughdifferentformsofabnormalhy- posteriorly with worsening outcome.106 These find-
persynchronous activity.47,87 Focal injuries within the ings reflect the broad effects of neuronal death and
central thalamus are also associated with production disconnectionwitharostrocaudalgradientconsistent
of epileptic seizures, typically variations of absence with the more diffuse and widespread point to point
seizures,90 andotherparoxysmalphenomenasharing connectionsoftheanteriorintralaminar/paralaminar
featuressimilartocatatonia,dystonia,andparkinson- regions.Herniationinjurieswithorwithoutevidence
ism, and responsive to pharmacologic agents used to offocalischemiclesionswithinthecentralthalamus(or
treatthosedisorders(reviewedinRefs.47,103). closely linked, subcortical, neuronal populations) can
produce profound functional downregulation across
ContributionofCentralThalamusto the entire ipsilateral cerebral hemisphere and possi-
DisordersofConsciousnessFollowing blybilateralmetabolicdysregulation.95,96,107Similarly,
MultifocalDiffuseBrainInjuries persistentglobalcerebraldysfunctioninpatientsmay
Thefarmorefrequentcauseofneurologicaldisor- be associated with abnormal capture by pathological
ders of consciousness following severe brain injury is rhythmicactivityinthecentralthalamusproducedin
widespreaddeafferentationofthecentralthalamusbe- frontalcorticalorotherareas.107
causeofwidespreadneuronaldeathordisconnection.
Consistent with the discussion above, this too is the ModulationofCentralThalamusandEffects
simpleconsequenceoftheuniquegeometryofcentral onDisordersofConsciousness
thalamic connections but is not well appreciated in Disordersofconsciousnesshavegenerallybeencon-
thecontextofpathologiesunderlyingglobaldisorders sidereduntreatableifenduringformonthsorlonger.108
ofconsciousness,103 suchasthepermanentvegetative RecentobservationsoflateimprovementinMCSpa-
state104 and enduring the minimally conscious state tientswithlong-standingbraininjuries,whetherspon-
(MCS).105 taneous,109inresponsetopharmacologicagents,110or
Threeverycommonmechanismsofinjurythatmay followingelectricalstimulation,111 suggestthatcircuit
bilaterally involve the central thalamus arise in the mechanismsmaybeavailableforimprovingfunctional
setting of multifocal head trauma, large hemispheric outcomesinsomecases.
strokes, and hemorrhages: 1) diffuse axonal injury, 2) Taking into consideration findings that some very
downward displacement of thalamus and brainstem severelybrain-injuredpatients,whononethelessshow
as a result of brain swelling (known as “herniation”), someresponsestotheirenvironment,mayhavewidely
withorwithout3)enpassant focalischemicinjuriesto preserved cerebral network activation,112 Schiff and
the brainstem, midbrain, thalamus, or basal ganglia. colleagues sought to determine whether electrical
Diffuseaxonalinjuryresultsinwidespreaddisconnec- stimulation could restore arousal regulation and pro-
tion across the cerebrum with a final common find- mote greater behavioral responsiveness in MCS pa-
ingofsecondaryneuronaldeathofthalamicneurons tients.111–113 They proposed that central thalamic
indexingoutcomes.Eveninthemostseveremultifocal deep-brainstimulation(DBS)mightsubstitutefortop-
braininjuriesassociatedwithpermanentVS,neuronal downmonitoringandregulationofarousallevelpro-
deathinthethalamusisthemostcommonpathological videdintheintactbrainbymesialfrontalcorticalre-
finding.Inastudy104 ofnontraumaticinjuriesassoci- gions and brainstem inputs (as reviewed above). Ap-
atedwithpermanentVS(mostlyanoxiafollowingcar- plication of central thalamic DBS in a 38-year-old
diacarrest),allpatientsshowedseverebilateralthala- manwhoremainedinMCSfor6yearsledtorestora-
micdamage,whichwasnotinvariablyassociatedwith tionsofspokenlanguage,oralfeeding,andmotorcon-
diffusecorticaldamage(64%ofcases).Inpathological trol of the upper limbs. These findings suggest that
studiesofbrainsfrompatientswhosufferedtraumatic electrical stimulation may approximate the normal
injuriesandremainedinVSforatleast3monthsprior role of cortical and subcortical inputs to the central
Schiff:CentralThalamusandArousalRegulation 113
FIGURE 2. (A) Potential circuit mechanisms underlying overlapping responses to dopaminergic
agents, NMDA antagonists, sedatives (Ambien, Lorazepam), and central thalamic deep-brain stimula-
tion (DBS) in severe brain injuries. A variety of pharmacologic agents have been shown to improve
responsivenessinpatientswithglobaldisordersofconsciousness.Connectionsacrosstheanteriorfore-
brain may play a key role in the response to multiple pharmacologic agents through modulation of a
commoncircuitabnormalityarisinginthesettingofmultifocalneuronalcelldeath.Thalamocorticaland
thalamostriataloutputfromthecentralthalamusmaybereducedasaresultofdiebackofconnections
acrossmultiplecorticalregionsfromneuronaldeathoraxonaldisruption.Thesethalamicafferentsappear
to have a preferential role in activating broad networks across the cortex and producing activation of
striatalneurons(seetext).(B)ProposalforcircuitmechanismunderlyingparadoxicalAmbien(zolpidem)
response.116
thalamusthatacttoadjustneuronalfiringratesinthese central thalamus as a result of the widespread loss of
neuronstoregulatecognitiveeffortandmaintainbrain incoming axonal afferents from many cerebral struc-
metabolicactivityinnormalwakefulstates.47,58,113 In tures (thus effectively overcoming the major problem
the severely injured brain, DBS of the central thala- of loss of excitatory contacts across the dendritic ar-
mus may counteract strong passive inhibition of the bor of these neurons). The observation noted above
114 AnnalsoftheNewYorkAcademyofSciences
that anterior intralaminar regions show progressive This model of altered network function that em-
neuronal loss in correlation with severity of cognitive phasizesimpairedfunctionofanteriorforebrainloop
impairmentfollowingbraininjurysupportsthisargu- systems following severe brain injury makes another
ment.106 Moreover, functional studies of changes in specific prediction.116 As shown in FIGURE2B, this
restingmetabolismafterdiffuseaxonalinjuryshowa modelcanofferanexplanationoftheveryparadoxical
specific pattern consistent with impaired function of observation that some severely brain-injured patients
theanteriorforebrain,includingmarkeddownregula- are “awakened” and show marked behavioral facili-
tionofmetabolicratesinmesialfrontalstructuresand tationwiththesedativeagentzolpidem.110 Zolpidem
thethalamusbilaterally.114 bindsselectivelytothealpha-1subunitoftheGABA-A
The results of the central thalamic DBS studies receptor,whichishighlyexpressedintheGPi,andmi-
can be considered alongside other interventions that croinfusionofzolpidemintoGPicanproducebehav-
in some patients facilitate behavioral responsiveness ioralchangesconsistentwithinactivationofthestruc-
after severe brain injury leading to MCS or severe ture.118 Most of the patients who have demonstrated
disability.110,115,116Bothclassicaldopaminergicagents theseeffectshavesufferedhypoxicinjuries,whichpro-
(L-Dopa, Bromocriptine) and the mixed dopamine ducesignificantimpairmentofMSNs.Zolpidemmay
agonist/NMDA-channelantagonistAmantidinehave acttosuppressdisinhibitedGPineuronsallowingre-
been reported to facilitate recovery of function.115 activationofthalamocorticalandthalamostriatalaffer-
TakentogetherwiththeDBSresultsdescribedabove, entsre-establishingfunctionintheanteriorforebrain
these observations are consistent with a model that network.116Reversalofmarkedhypometabolisminthe
identifiesdysfunctionacrossabroadanteriorforebrain frontal lobes and thalami in association with behav-
systemprimarilyarisingfromwidespreaddeafferenta- ioralimprovementswithzolpidemsupportsthisinfer-
tion of cortical neurons producing reduced levels of ence.110Similareffectswithlorazepam,aless-selective
global neuronal activity across the brain and caus- agent,mayariseviathesamemechanism(unpublished
ing relatively increased deafferentation of the central observations).
thalamus (resulting from the geometry of their point
topointconnections).AsillustratedinFIGURE2A,an Conclusions
important point of vulnerability within the anterior
forebrain is the medium spiny neuron (MSN) of the Asreviewedabove,theneuronsinthecentraltha-
striatum. These neurons have a high threshold UP lamusareuniquelypositionedtocontroldynamicpat-
stateandthusdonotfireeasily,requiringbothasuf- terns of activation across cerebral networks. These
ficient level of dopaminergic input and background neurons may drive both cortical and striatal neurons
synapticactivityfromcorticostriatalandthalamostri- to transition into the equivalent of an UP state dur-
atalinputs.117MSNoutputisnecessarytoopposetonic ingwakefulbehaviors,organizingverylong-rangecon-
activityoftheglobuspallidusinterna(GPi),whichacts nections in the forebrain. Transient activation of the
asastronginhibitoryinfluenceonthethalamus.Neu- samethalamicneuronsappearsinresponsetopremo-
rons in the central lateral nucleus of the anterior in- tor corollary discharge signals and bottom-up senso-
tralaminar regions that undergo significant neuronal rimotor reflexes originating in the brainstem, which
loss following multifocal brain injuries also provide likelybrieflyfacilitatebroadsynchronizationthrough
input to the dendritic spines of the MSNs and may asimilarmechanism.Damagetothisefficientsystem
specificallycontributetoreducingtheiroutputfollow- offorebrainactivationleadstoimmediateandglobal
inginjury.Thus,bothdopaminergicagentsanddirect impairments of consciousness and goal-directed be-
activation of the central thalamus may act to reverse havior.Understandingthecontributionsofthecentral
downregulation across the anterior forebrain systems thalamus to arousal regulation may aid our rethink-
producedbyseverebraininjury.Dopaminergicagents ing and reformulating of how to approach the prob-
stronglymodulatebothstriatalandmesialfrontalsys- lems posed by disorders of consciousness. Based on
tems,whereascentralthalamicneuronsprovidedirect theiruniqueanatomicalandphysiologicalproperties,
excitatory(glutamatergic)activationofthesupragran- neuronswithinthecentralthalamusaresuggestedas
ular cortical layers and MSNs. Importantly, as noted targetsofinterventionsaimedatrestoringfunctionat
above, thalamic neurons have a preferential role for thecircuitlevelforpatientswithdisordersofconscious-
generating cortical UP states.86 Reduced pallidal in- ness.Theobservationsofindividualpatients’responses
hibition with increased MSN output may allow the toDBS,sedative,andotherdrugsreviewedaboveem-
promotion of cortical UP states via release of strong phasizethekeyroleofthecentralthalamusincircuit
thalamocorticalactivation. disturbancesaffectinglarge-scaleforebraindynamics.