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Consciousness

supporting

networks

Athena

Demertzi,

Andrea

Soddu

and

Steven

Laureys

consciousnessexhibitdisruptedsystem-levelfunctional connectivity.Unresponsive/’’vegetativestate’’patients preservewakefulnessnetworksofbrainstemandbasal forebrainbutthecerebralnetworksaccountingforexternal perceptualawarenessandinternalself-relatedmentationare disrupted.Specifically,the‘externalawareness’network encompassinglateralfronto-temporo-parietalcortices bilaterally,andthe‘internalawareness’networkincluding midlineanteriorcingulate/mesiofrontalandposteriorcingulate/ precunealcortices,arefunctionallydisconnected.Bycontrast, patientsinminimallyconsciousstate‘minus’,whoshow non-reflexbehaviors,arecharacterizedbyright-lateralizedrecovery oftheexternalawarenessnetwork.Similarly,patientswho evolvetominimallyconsciousstate‘plus’andrespondto commandsrecoverthedominantleft-lateralizedlanguage network.Now,theuseofactiveexperimentalparadigms targetingatdetectingmotor-independentsignsofawareness orevenestablishingcommunicationwiththesepatients, challengethesetwoclinicalboundaries.Suchadvancesare naturallyaccompaniedbylegitimateneuroscientificandethical queriesdemandingourattentiononthemedical

implementationsofthisnewknowledge.

Address

ComaScienceGroup,CyclotronResearchCenter&CHUNeurology Department,Alle´edu6aouˆtn88,SartTilmanB30,UniversityofLie`ge, 4000Lie`ge,Belgium

Correspondingauthor:Demertzi,Athena(a.demertzi@ulg.ac.be)

CurrentOpinioninNeurobiology2013,23:239–244 ThisreviewcomesfromathemedissueonMacrocircuits EditedbyStevePetersenandWolfSinger

ForacompleteoverviewseetheIssueandtheEditorial

Availableonline27thDecember2012

0959-4388/$–seefrontmatter,#2012ElsevierLtd.Allrightsreserved.

http://dx.doi.org/10.1016/j.conb.2012.12.003

Whatis‘minimally conscious’?

Atpresent there is no generally accepted definition of consciousness[1].Asclinicians,wewillreducethe com-plexityofthistermanddefineconsciousness operation-ally,separating twomaincomponents:wakefulness and awareness[2].Wakefulnesshasbeenshowntocritically dependuponthefunctionalintegrityofsubcortical arou-salsystemsover50yearsago[(e.g.,see3)].Thelevelof wakefulness can be estimated by simple behavioral criteriabasedoneyeopeningrangingfromabsent,over stimulus-inducedtospontaneoussustainedeyeopening.

Forinstance,everynightwhenfallingasleep,we experi-enceadecreaseofthelevelofwakefulnessuptothepoint weloseawarenessofourenvironment.Awarenessismore difficult todefineandmorechallenging toassess beha-viorally [4]. We have recently proposed to reduce the phenomenological complexity of awareness into two further components: external awareness, namely every-thingweperceivethroughoursenses(whatwesee,hear, feel,smellandtaste),andinternalawarenessor stimulus-independentthoughts.Interestingly,theswitchbetween the external andinternal milieu wasfound not only to characterize overt behavioral reports but also had a cerebral correlate [5]. In particular, it was shown that behavioral reportsof internal awareness werelinked to the activity of midline anterior cingulate/mesiofrontal areas as well as posterior cingulate/precuneal cortices. Conversely, subjective ratings for external awareness seem tocorrelatewith theactivity of lateral fronto-par-ieto-temporalregions(Figure1).Thesefindingshighlight thattheanticorrelatedpatternbetweentheinternaland external awareness systemis of functional relevance to consciouscognition.Indeed,inanalteredconsciousstate likehypnosis,wheresubjectsreportawarenessalterations butremainfullyresponsive,hypnosis-relatedreductions in functional connectivity were shown in the external awareness system parallel to subjective ratings of increased sense of dissociation from the environment and reduced intensity of external thoughts [6]. Similar reductionsinexternalawarenesssystemshavebeenalso shownfornon-responsiveconditions,suchasdeepsleep and anesthesia [(for a review see 7)]. Taken together these studiesindicate that thetwo awarenessnetworks mediate(atleastpartially)consciousongoing mentation underthefunctionsofawide‘globalneuronalworkspace’ [1,8].Anincreasinglistofevidencefavorsthishypothesis. Studiesinhealthyvolunteersonperceptioninthevisual, somatosensory and auditory domains confirm that the subtractionbetweenperceivedandunperceivedstimuli identifiesthelateralfrontoparietalassociativecortices[8].

Over the past fifteen years we have increased our un-derstandingoftheneuralcorrelatesofawareness[9].The studyofpatientswithdisordersofconsciousnessprovides unique opportunities to determine the sufficient and possiblythenecessaryconditionsforconsciouscognition tohappen.Patientsincomaareunconsciousbecause,by definition,theycannotbeawakenedevenwhenintensely stimulated.Patientswillnotremainincomaformonthsor years in contrast to what is sometimes reported in the media[10].Inanumberofcases,patientswillshowsucha massivebraindamagethatallbrainstemfunctionwillbe irreversibly lost and evolve to brain death [11]. Those

patientswhowillshowagoodrecoveryaftercoma classi-cally will doso withinthe first days or weeksafter the insult.Asubstantialfractionofcomapatientswillrecover near-normalfunctionofthesubcortical‘wakefulness net-work’(locatedinthebrainstem)whileremainingwithout externalsignsofawareness.Thisconditionofeyes-open wakefulness was coined ‘persistent vegetative state’ in the1970s[12]andmorerecentlyithasbeendescribedin moreneutraldescriptivetermsas‘unresponsive wakeful-nesssyndrome’[13].Vegetative/unresponsive(VS/UWS) patientsclassicallybreathespontaneouslyandcanmakea wider range of movements than can be seen in coma. Depending onthe partialorfullrecoveryofsubcortical wakefulness networks andbrainstem function they can show spontaneous or stimulus-induced eye opening, blinkingtovisualthreat;haveauditorystartleresponses or orient theeyes or head tostimuli;show stereotyped posturing, normal flexion withdrawal to noxious stimu-lationorgrasping;showgag,deglutition,oralreflexesor vocalizations.Forcliniciansdealingwithacuteorchronic disordersofconsciousness,themainchallengeisto dis-entanglethese‘reflex’orautomaticmovementsfromany ‘voluntary’or‘willed’behavior.Therecoveryofminimal, inconsistent butreproduciblesignsofawareness,in the absenceoffunctionalcommunicationorobjectuse,coins the diagnosis of minimally conscious state (MCS).

Dependingonthe complexityof thesebehaviorsitwas recently proposed that MCS patients be categorizedas MCS when only showing simple non-reflex move-ments, such as visual pursuit, orientation to pain or non-contingent behavior (e.g. smiling to the presence ofafamilymemberandnottoothers)andMCS+when patients recover the ability to respond to simple com-mands(e.g.moveyour hand)[14,15].

Itis importantto stressthat whenaimingto say mean-ingfulthings aboutpatients’ consciousness,weare lim-itedtomakeinferencesbasedonpatients’motorbehavior [16].Mostofthetimethisworksfinebut,aswewillseein somecases,consciousnesscanbepresentintheabsence ofconsistentmotorresponsiveness.

Trackingthe recoveryof consciousness

networks

Withtheadventoffunctional neuroimaging(functional MRIandPET)andelectrophysiology (EEG andevent relatedpotentials)thestudyofresidualbrainfunctionin patients with consciousness alterations has provided unique insights on the underlying brain mechanisms accountingforthepresenceofconsciousness[17].Based onthislesionparadigm,itisthoughtthatconsciousness doesnotrequirethewholebrain’sactivity,butratherthat

240 Macrocircuits Figure1 PCC Pr ACC MPFC PPC Th DLPFC

Internal awareness network

External awareness network

Current Opinion in Neurobiology

Anoversimplifieddistinctionofhumanawarenessintoawarenessoftheenvironmentandofself-relatedmentation.Experimentalworkssuggeststhat thesetwocomponentshavetwodistinctfunctionallyalternatingcerebralcorrelates.Theexternalawarenessnetwork(areasinred)encompasses mainlylateralbilateraldorsolateralprefrontalcortices(DLPFC)andposteriorparietalcortices(PPC).Theinternalawarenessnetwork(areasinblue) includesmainlymidlineposteriorcingulatecortex(PCC)/precuneus(Pr)andanteriorcingulate(ACC)/medialprefrontalcortices(MPFC).Apartfrom cortico-corticalconnectivity,connectivitywithsubcorticalstructures,suchaswiththethalamus(Th)isconsideredtobeessentialtosupport wakefulnessandongoingconsciousprocessing.

someareasaremore criticalthan otherstosupport con-sciousness. FDG-PET studies have demonstrated that when patients recover from coma to VS/UWS, they recover the wakefulness network (encompassing brain-stemandbasalforebrain)whichexplainstherestoration ofsustainedspontaneousorstimulus-inducedeye open-ing and of autonomic functions including spontaneous breathing [18]. However, recovery from VS/UWS does notcoincidewithnear-normalmetabolicactivityin over-allbrain function. Voxel-based analyses between brain metabolicscansobtainedinawakeyetunawareVS/UWS patientscomparedtohealthycontrols(between-subject) orcomparisonswith recoveryof awareness (within-sub-ject)havehighlightedthecriticalroleofthewidespread fronto-temporo-parietalassociativecorticalnetwork[19]. Recently,FDG-PETdataindicatethatrecoveryof MCS-patientsseemstobeaccompaniedby aright-lateralized recoveryoftheexternalawarenessnetworkwhereasthe presenceofcommandfollowing,definingMCS+, classi-cally parallels the recovery of the dominant left-latera-lized language network [20]. Similar results have been observedinslowwavesleepandgeneralanesthesia[(for review see 21)]. Interestingly, these findings were also confirmedintransientdissociativestatesofunresponsive wakefulness such as absence seizures, complex partial seizuresorsleepwalking–allcharacterizedbypreserved automatic reflex motor behavior in the absence of responseto commands andshowing transient impaired activityinthefronto-temporo-parietalassociativecortical network[2,22].

The study of coma and related states has shown that consciousness is not an emergent property of sensory corticalactivationinisolation.Auditorystimulationwith simple clicks in MCS patients activated widespread temporal auditory areas and most importantly lead to functionalconnectivitychangeswiththeexternal aware-ness network [23]. Similar activation and connectivity changes were observed in normal conscious controls butnotinVS/UWSpatientswereactivationwaslimited to isolatedlow-level auditory cortices, functionally dis-connectedfromtheexternalawarenessnetwork[24].By contrast,emotionally salient stimuli, suchas baby cries and the patient’s own name, led to much more wide-spread temporal activation also recruiting anterior and posterior midline cortices [25,26]. Similarly, in MCS patients,presentationofastorytoldbytheirmotherlead tomorewidespreadactivation[27].Noveltechnological developmentsnowpermittoassessthedirectionalityof this long-range cortico-cortical connectivity. Using dynamic causal modeling on auditory oddball evoked potential data obtained with high-density EEG, it was shownthatonlyMCSpatients(butnotVS/UWSpatients) showedfeedbackortop-downconnectionsfrom higher-orderfrontalassociativeareastohierarchicallylower-level auditory regions [28]. A study combining transcranial magnetic stimulation with simultaneously recorded

EEG confirmed the importance of long-range connec-tivityfromtheposteriorparietalassociativecortex.Only MCSandnotVS/UWSpatientsshowedsuchlong-range connectivity changes.This technique alsopermitted to longitudinally follow connectivity changes in patients who recovered (or failed to recover) from VS/UWS [29]. Theseearlyfunctionalconnectivitystudies high-lighttheimportanceofconnectivitymeasurementsinthe emergenceofhumanconsciousawareness.Inparticular, global yet specific cerebral functional identification of thalamo-cortical connectivity has lead to the develop-ment of thalamic deep brain stimulation paradigms for thetreatmentofpost-traumaticMCSpatients[30].

Within‘globalworkspace’,theposteriormidlineregions encompassingprecuneusandadjacentposteriorcingulate cortexseemtoformacriticalhub.Indeed,theseareasare themost metabolicallyactive corticalregionsin normal consciouswaking,aremostlyimpairedinpatientsincoma or VS/UWSwhereas they areminimally active inMCS patients.Itscriticalrole inconsciousnesswasconfirmed by a much mediatized case of ‘miracle recovery from coma’namedTerryWallis[30].Nineteenyearsafterhis traumatic brain injury this patient was still considered ‘vegetative’andstartedtospeak.Whencarefully exam-iningthepatient’smedicalfilesitbecameclearhewasin aMCSalreadymonthsafterthetrauma.UsingMRIand diffusiontensorimaginginMr.Wallis,Schiffand collab-oratorsreportedaxonalregrowth,nearlytwodecadesafter theacuteinsult,intheaforementionedposteriormidline structures[31].Thiscasenotonlyillustratestheproblem of misdiagnosing disorders of consciousness if merely based on behavioral unstandardized tools [32] but also thepossibilityofneuralplasticityevenmanyyearsafter the acute insult [33]. More recent fMRI studies have confirmedthesefindingsanddemonstrateda conscious-ness-dependentnon-linearbreakdowninfunctional con-nectivity of the so-called default mode ‘midline core’ network when comparing normal consciousness to MCS,VS/UWSandcomatosestates[34].

Conclusions

Studying VS/UWS patients has shown that awareness seems an emergent property of collective critical cor-tico-thalamo-cortical network dynamics, involving the frontoparietal global workspace[35]. Atthe moment, it remains controversialwhether consciousness should be considered asabinary all-or-nonephenomenon or con-tinuous[36].Basedonclinicalexperienceandonrecent evidencefrom careful studies in normalhealthy volun-teers [(e.g., 37)] we here consider consciousness on a continuousnon-linearscale.

Despitethebestclinicalassessment,wearestilllimited tomakeinferencesaboutconsciousnessbasedonmotor responsiveness,possiblyleadingtoanunderestimationof conscious awareness. Recently, the so-called ‘active’

functionalneuroimagingorevent-relatedpotential para-digmshavebeendevelopedtoassessmotor-independent responsestocommands.Thefirstofsuch‘active’mental imageryparadigmshavebeendevelopedusingfMRI.Ina collaborative effort between Cambridge and Lie`ge, healthyvolunteerswereaskedtoperformaseriesoftasks (e.g.,imaginesingingasonginyourheadorimagineyour mother’s face). The most robustand reproducible pat-ternsofbrainactivationwereobtainedusingmotor ima-gery(i.e.,imagine playingtennis)andspatialnavigation (i.e.,imaging walkingaroundinyourhouse),leading to the predictedactivation ofsupplementary motor cortex andparahippocampalareasrespectively [38]. Usingthis tool,both teamstogetherwith CornellUniversity, have identifiedaseriesofseverelybraindamagedpatientswho wereclinicallydiagnosedasbeingVS/UWSorMCS-and who yet showed robust fMRI evidence of response to command, and consequently conscious awareness [39,40,41].Inoneofthesecases,functional communi-cation could even be established by explaining to the patienttodothemotorimagerytasktocommunicate‘yes’ andthespatialnavigationtasktocommunicate‘no’.This patient, a22-year-oldmanwhowassent toLie`ge fora one-weekdiagnostic assessment,is anotherexample of clinicalmisdiagnosis.Indeed,thispatienthadtheclinical diagnosis of VS/UWS while standardized behavioral assessments showed that he was actually in a MCS [40]. To a series of simple questions (e.g., is your father’s name Alexander) the automated user-indepen-dent analysis of the acquired fMRI data classified the brain’sresponsesasa‘yes’or‘no’answer.Correctanswers wereobtainedandreportedbytheblindedexaminersfor fiveconsecutivequestions.Onlyforthelastquestionno answercouldbeelicited merelycausedbyabsentbrain activation.Asaconsequence,thispatientcouldbe con-sideredasbeinginafunctionallocked-insyndrome,givenit wasonlyfunctionalneuroimagingthatpermittedto estab-lish the yes–no communication to closed questions (in contrasttoclassicallocked-insyndromewhereaneye-coded yes–nocommunicationcanbeestablished) [15].

Evidently,thestudybyMontietal.[40]shouldbeseenas aproofofconceptratherthanapracticalcommunication tool. As soon as the patient wastaken out of the MRI machine, no communication whatsoever was possible. Hence, portable and cheaper EEG-based equivalents [(e.g.,42,43,44)]havebeendevelopedformoreroutine clinicaluse[(forrecentreviewsee45)].Suchbraincomputer interfaces(BCI)havealreadybeenusedsuccessfullyinreal clinicalsettings.Itisimportanttostressthattheabsenceof brainactivationtocommandscannotbetakenasproofof absence of consciousness and frequently false negative resultshavebeenreportedinMCS+patients[(e.g.,44)]. Repeated fMRI and EEG BCI assessments would be needed to increase the confidence for true negative findings.Inaddition,wealsoneedtotackletheproblem offalsepositives,namelythefactthatunconsciouspatients

mayshowartifactornoise-relatedactivation[46].Future studiesshoulddealwiththeseissuesinlargepatientcohort andalsoassesstest–retestvariabilityofthesenovel tech-nologiesinthisspecificcontext.

In conclusion, our clinical boundaries are increasingly beingchallenged by neuroimagingor electrophysiology studies in patientswith disorders ofconsciousness who showmotor-independentsignsofawarenessor communi-cation. Such advances are naturally accompanied by legitimate neuroscientific and ethical queries, such as on painperception andmanagementas wellas end-of-lifeoptions[47–50].Inthefuture,effortsshouldbemade towardsconsciousnessclassificationmetrics,where system-levelfunctionalneuroimagingandelectrophysiologywill provide an objective means to better characterize the underlyingmechanismsaccounting forconscious cogni-tionanditsrecoveryaftersevereacquiredbrain injury.

Acknowledgements

ThisworkwassupportedbytheBelgianNationalFundsforScientific Research(FNRS),theEuropeanCommission,theJamesMcDonnell Foundation,theEuropeanSpaceAgency,MindScienceFoundation,the FrenchSpeakingCommunityConcertedResearchAction,thePublic UtilityFoundation‘Universite´ Europe´enneduTravail’,‘Fondazione EuropeadiRicercaBiomedica’andtheUniversityandUniversityHospital ofLie`ge.Theauthorshavenoconflictsofinterestandnodisclosuresof financialinteresttoreport.

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