Hemispatial neglect - Journal of Neurology, Neurosurgery and ...

The syndrome of hemispatial neglect is characterised by reduced awareness of stimuli on one side of space, even though there may be no sensory loss. Skiptomaincontent YouarehereHome Archive Volume75, Issue1 Hemispatialneglect Emailalerts ArticleText Articlemenu ArticleText Articleinfo CitationTools Share RapidResponses Articlemetrics Alerts PDF Review HemispatialneglectFree AParton,PMalhotra,MHusainDivisionofNeuroscienceandPsychologicalMedicine,ImperialCollegeLondon,LondonW6,UK;InstituteofCognitiveNeurology,UCL,London,UKCorrespondenceto:
DrMasudHusain
DivisionofNeuroscienceandPsychologicalMedicine,ImperialCollegeLondon,CharingCrossHospitalCampus,LondonW68RF,UK;m.husainimperial.ac.uk Abstract Thesyndromeofhemispatialneglectischaracterisedbyreducedawarenessofstimuliononesideofspace,eventhoughtheremaybenosensoryloss.Althoughitisextremelycommon,ithasproventobeachallengingconditiontounderstand,andtotreat.Newinsightsfromdetailedbehaviouralandanatomicalstudiesinpatients,aswellasfunctionalimaginginhealthyindividuals,havebeguntorevealsomeofthecomponentdeficitsunderlyingthedisorder.Thisreviewfocusesonimportantclinicalissuesinneglect,includingbedsidediagnostictestsandemergingtherapeuticandrehabilitationmethods,involvingbothbehaviouralanddrugtreatments. anosognosiaextinctionneglectBIT,behaviouralinattentiontestfMRI,functionalmagneticresonanceimagingSPECT,singlephotonemissioncomputedtomographySTG,superiortemporalgyrus StatisticsfromAltmetric.com anosognosiaextinctionneglectBIT,behaviouralinattentiontestfMRI,functionalmagneticresonanceimagingSPECT,singlephotonemissioncomputedtomographySTG,superiortemporalgyrusHemispatialneglectisacommondisablingconditionfollowingunilateralbraindamage,particularlyoftherighthemisphere.Althoughitcanbecausedbyvariousdifferentpathologicalconditions,itismostoftenobservedaftercerebralinfarctionorhaemorrhageandaffectsuptotwothirdsofrighthemispherestrokepatientsacutely.12Patientswithneglectoftenfailtobeawareoforacknowledgeitemsontheircontralesionalside(theleftsideforpatientswithrightbraindamage)andattendinsteadtoitemstowardsthesamesideastheirbraindamage—theiripsilesionalside.Theirneglectmaybesoprofoundthattheyareunawareoflargeobjects,orevenpeople,inextrapersonalspace.Neglectmayalsoextendorbeconfinedtopersonalspace,withpatientsfailingtoacknowledgetheirowncontralesionalbodypartsindailylife.3–5Moreover,somepatientsfailtousetheircontralesionallimbseveniftheyhavelittleornoweakness—socalled“motorneglect.”67Importantly,manyneglectpatientsmaybeunawarethattheyhaveanyoftheseproblems(anosognosia),sometimesdenyingthatthereisanythingwrongwiththeirperceptionorcontrolofmovement.78Perhapsitisnotsurprising,therefore,tofindthatenduringneglectisapoorprognosticindicatorforfunctionalindependencefollowingstroke.9–13Inthisselectivereview,wefocusonsomeimportantclinicalaspectsoftheneglectsyndrome.First,weconsiderhowbedsideexaminationmaybestrevealandquantifythedegreeofneglect.Second,wediscussthepotentialmechanismsunderlyingneglect.Mostcontemporaryviewsoftheneglectsyndromeconsiderittobeaheterogeneouscondition14–26consistentwiththeheterogeneousnatureoftheassociatedlesionsites152728(seeVallar29foroneproposedtaxonomy).Here,wearguethatneglectemergesasaresultofacombinationofcomponentcognitivedeficitsthatmayvaryacrosspatientsandneednotbeneglectspecific.1824Finally,wediscusstreatments,focusingparticularlyonrecentresearchusingprismtherapy,3031whichhasshownpromisingbeneficialeffectsandmaywellhaveanimpactonclinicalpractice. BEDSIDEEXAMINATION Doesthepatienthaveneglect? Patientswiththemostsevereunilateralneglectareobvious“fromtheendofthebed”—thatis,thediagnosismaybemadebysimpleobservationfromadistance.Thepatientwithalargeinfarctintherightmiddlecerebralarteryterritorymayhavetheirheadandeyesturnedtotheextremerightandnevergazetotheleft.Whenpresentedwithfoodoranewspapertoread,theymayshowinterestinitemsonlytotheirright,ignoringthosetotheirleft.Similarly,whenapproachedbywardstafffromtheirlefttheymayfailtoacknowledgethemor,iftheyarespokento,theymayorientatethemselvestotherightandreplywiththeirgazedirectedawayfromthepersontheyareaddressing.Notethatsuchbehaviourwouldbeveryunusualforahemianopicpatientwhodoesnotsufferfromneglectaswell,although,aswediscussbelow,thedistinctionbetweenpureneglectandneglectplushemianopiaisnotalwaysstraightforward. Mostpatientswithneglectarenotnecessarilysoeasytoidentifyasthis.Moreover,itisincreasinglybecomingimportanttomeasuretheseverityofneglect.Justlikemoreconventionalneurologicalexaminationmeasures,suchasthedegreeoflimbweakness,thishelpsthecliniciantotracktheprogressofthepatient.Manypatientswithneglectfollowingstrokeimprovewithinafewweeks,butsomecontinuetoshowpersistentneglectanditistheseindividualswhoarelikelytorequirerehabilitationinput.Earlyidentificationofpatientswhoshowlittleornosignofimprovementmayfacilitatetheirreferraltospecialisedrehabilitationunitsoridentifythosewhomayneedmoreintensiveoccupationaltherapyorphysiotherapy. Severalsimplebedsidescreeningtestshavebeendevelopedfortheassessmentofneglect.Althoughmanycliniciansarefamiliarwithobjectcopying(fig1A)andclockdrawingtests(fig1B),thesearenotverysensitiveontheirown,32andarealsonotalwayseasytoscoreinagradedmanner.Furthermore,patientswithconstructionalapraxiamayperformpoorlyonsuchtasks,showingcopyingerrorsonboththeleftandtherightsideofspace,eventhoughtheydonotshowanyspatialneglect.Fortunately,therearevariousotherrelativelysimpletestsavailablethatareoftenusedbyneuropsychologistsandtherapistsassessingpatientsontheward,althoughperhapsnotsofamiliartomanypractisingneurologistsorphysicians.Batteriesofsuchtestshavebeendeveloped,33–36largelybecausenosingletestaloneisabletodetectneglectinallpatients.323537Moreover,therearemanyreportsofcleardissociations,withsomepatientsshowingneglectoncertaintasksbutnotonothers.353839Herewefocusononlyafewoftheavailabletests,concentratingonsomeofthecommononesthatareusedatthebedside.Downloadfigure Openinnewtab Downloadpowerpoint Figure1 Typically,righthemispherepatientswithleftneglectomitelementstotheirleftwhencopyingsimpleobjects(A),drawingaclockface(B),andcancellingtargetsamongdistractors(C).Theyalsotendtoerrtotherightwhenaskedtobisectahorizontalline(D).Whenaskedtonameobjectsintheirsurroundings,theywilltendtonameonlythoseontheright.Crossesin(E)markthelocationsofreportedobjectswithrespecttothepatient. Oneofthemostusefultypesoftestforneglectisthecancellationtask.Thereareseveraldifferentversionsavailable;allofthemrequirethepatienttofindandcancel(markwithapen)targetitemsdistributedonanA4sizedsheetofpaperplaceddirectlyinfrontofthem.Somecancellationtaskshaveonlytargetitems—forexample,theAlbert’stask40orlinecancellationfromthebehaviouralinattentiontest(BIT)battery,33butmostofthemhavetargetsembeddedwithinanarrayofmanydifferenttypesofdistractoritems—forexample,thebellstest,41starcancellationfromtheBIT,33andtheMesulamshapecancellationtest.42Manyrighthemispherepatientswithleftneglectcancelitemsononlytherightsideofcancellationtasks,omittingtargetstotheleft(fig1).Animportantcluetothepresenceofneglectisthatmostsuchpatientsalsostarttosearchfromtherightofthearray,32whereasmostcontrolsubjectswhoreadlefttorightstartontheleft.Inourexperience,densecancellationtaskswithdistractorsareusuallybetterandmoresensitiveindetectingneglectthanthesimplercancellationtasksthathavenodistractoritems(seealsoHalliganetal37).Moreover,theydetectneglectmorefrequentlythananyothersingletest,353739althoughthereareafewpatientswhoperformwelloncancellationbutshowneglectonothertasks43—hencetheneedtousemorethanonescreeningmeasureforneglect. Anothersimplepenandpapertaskthathasbeenextensivelyusedislinebisection.AlonghorizontallinemarkedonanA4sheetofpaperisplacedinfrontofthepatient,whoisaskedtomarktheapparentmidpointoftheline.Manyrighthemispherepatientswithleftneglect,particularlythosewithposteriorlesions,3238tendtomarktheapparentmiddleofthelinewelltotherightofthetruemidline(fig1D).Patientswithalefthemianopiabutwithoutneglecttendtobisectthelineslightlytotheleft,perhapsbecausetheyareawareoftheirvisualdeficitandattempttocompensateforit.44Asimilarcontralesionalbiasinperformancecanalsobeseeninleftneglectpatientsifthelinetobebisectedissmall(thesocalled“crossover”effect45)butinnormalclinicalpracticelargehorizontallines(18–20cmlong)arenormallyused,sothisisnotaconfoundingfactor. Askingthepatienttoreport10objectsintheroomaroundthemprovidesanotherrapidandusefulmeasure.146Providedthatthepatientisnotsituatedtotheextremeleftorrightofaroom,thistestmayrevealaspatialbias,withneglectpatientsoftenreportingitemsonlyormostlytotheiripsilesionalside(fig1E),whereaspatientswithpurehemianopiawilltendtocompensatebymovingtheirheadandeyestowardscontralesionalspace.Moreover,patientswithpurehemianopiaaretypicallyawareoftheirdeficit. Alltheteststhatwehavediscussedsofardependheavilyonvisionorvisuomotorcontrol.Somepatientswithneglectmayperformnormallyonsuchtasks,butshowpersonalneglect(ignoringthecontralesionalsideoftheirbody)ormotorneglect(failingtousetheircontralesionallimbsdespitethefactthatstrengthinthesemaybeintactoronlymildlyreduced).Personalneglectmaybedetectedformallybyaskingthepatienttogesturehowtheywouldgroomthemselves—forexample,combtheirhair,shave,orputonmakeup.547Moreoften,however,suchneglectisobservedbycarers.Inourexperiencemotorneglect67isalsomostoftendetectedbytherapistsorcarers,whoremarkonthelackofuseofacontralesionallimbeventhoughitisstrong.Finally,manypatientswithneglectalsoshowlateralisedspatialdeficitsontestsofrepresentationalneglect—forexample,iftheyareaskedtorecallafamiliarscenefrommemory,righthemisphereneglectpatientsmayignoretheleftside,4849andsimilarlywithclockdrawingfrommemory. Intheclinicalsetting,iftheavailabletimeislimitedtoabriefassessment,thecombinationofadensecancellationtaskwithclockdrawingandfigurecopyingmaybesufficienttopickupover70%ofneglectpatients.32However,ifmoretimeisavailable,behaviouralassessmentsofneglectindailylifeusuallyaremoresensitive.3235 Doesthepatientsufferfromhemianopiaaswellasneglect? Manyneglectpatientssufferfromhemianopiaaswellasneglect.50Inaddition,therearealsotwoothertypesofpatient:first,thereareindividualswhosufferfromhemianopiabutdonotshowneglect;second,therearepatientswhoshowneglectonbedsidetestingoronclinicalobservationbutwhoneverthelesshavefullvisualfieldstoconfrontation.51Itisusuallyoperationallystraightforwardtoconfirmthepresenceofneglectbyusingthetestswedescribeabove.Intheabsenceofneglect,thepresenceofacontralesionalfielddefectwhichshowsastrictdemarcationattheverticalmeridianinbotheyesisreferredtoashomonymoushemianopia.Therealproblemisdecidingwhetherafailurebyapatienttoreportacontralesionalstimulusisduetoneglectalone,orneglectplushemianopia.Disentangling“absolute”fielddefectsfromneglectisnotalwayseasyandsomequestionthevalidityofmakingsuchadistinction.52 Thefactthattwodistinctsyndromesmayco-occurwithinthesamepatientisperhapsbestillustratedbyindividualswhohavecompletelossofvisioninthelowercontralesionalquadrant(regardlessofthesizeorilluminationoftheteststimulus),butwhoneverthelesscanreportasalientstimulusintheupperquadrantandalsoshowneglectonstandardtests.Weconsidersuchapatienttohaveanabsolutesensorydefect(manifestasaninferiorquadrantanopia),plusneglect.Inourexperience,assessmentofsuchfielddefectsisbestdonebycarefulclinicalexaminationatthebedsideratherthanbytheuseofautomatedperimetry,whichtendstooverestimatetheapparent“absolute”fielddefect.53Ifthereisevidenceofafielddefectoninitialtestingwithsmalltargets(forexample,ahatpin)werepeattestingwithlargertargets(suchasfingers)beforewearefullysatisfiedofan“absolute”fielddefect.Evenunderthesecircumstances,weagreethatitissometimesdifficulttodistinguishclinicallybetweendenseneglectandneglectplushemianopia.52 Markersofneuralactivityevokedbyavisualstimulusthatthepatientfailstobeawareofmaybeausefulwayofdistinguishingbetweenneglectandabsolutesensoryloss.ThusevokedresponsesandfMRIhavebothbeenusedtoshowthatstimuliwhichfailtobereportedbyapatientmayneverthelessproducebrainresponses.54–56Moreover,behaviouralstudieshavedemonstratedthatsuchstimulimaybe(implicitly)processedtorelativelyhighlevels.5758 Doesthepatienthaveextinction? Ifapatienthasfullvisualfieldsbutneverthelessfailstoreportthecontralesionalstimuluswhenitispresentedsimultaneouslywithanipsilesionalstimulus,heissaidtoshow“extinction.”5960Manypatientshaveextinctionbutnotneglectonstandardtests,andsomeconsiderextinctiontobeamildtypeofneglectorasignof“inattention.”Inaddition,manypatientswithneglectalsoshowextinction,whichmaybeconsideredonecomponentoftheneglectsyndrome,althoughweemphasisethatitmaynotbepresentinallneglectpatients.Ifthepatientappearstohaveafielddefectinadditiontoneglect,itmaystillbepossibletodetectextinctionbypresentingtwostimuliintheintactfield.61Finally,itisalsoworthnotingthatextinctionmayalsooccurinothermodes—forexample,tactileandauditory—aswellasbeingcrossmodal,aswhenavisualstimulustotheright“extinguishes”atactilestimulusontheleft.62Thesignificanceofextinctionforunderstandingthepossiblecompetitiveattentionalmechanismsunderlyingneglectisdiscussedbelow. Isthepatientanosognosic? Althoughpatientswithsevereanosognosiaareoftenidentifiedthroughconversationatthebedside,manymaynotrevealunawarenessofoneormoreoftheirneurologicaldeficitssoeasily.Therearevariousrelativelysimplestructuredinstruments863thatcanbehelpfulinscreeningforsuchdeficits,whichmayhaveanimportantimpactonfunctionalrecoveryorrehabilitationpotential.Neglect,asdefinedbythebedsidetestswehavediscussed,mayoccurwithoutanosognosiaandviceversa,butmanypatientssufferfrombothconditions.763 MECHANISMSUNDERLYINGNEGLECT Damagetomanydifferentbrainregionscausesneglect Lesionsoftherighthemispherearefarmorelikelytoleadtosevereandenduringneglectthanlefthemispheredamage,264perhapsbecauseofthespecialisationofthelatterforlanguage.Corticaldamageinvolvingtherightinferiorparietallobeornearbytemporo-parietaljunctionhasclassicallybeenimplicatedincausingneglect.50Ithasbecomeapparent,however,thatthesyndromemayalsofollowfocallesionsoftheinferiorfrontallobe2865(fig2),althoughlesionsconfinedtothefrontallobemayleadtoamoretransientneglect(see,forexample,thecasedescribedbyWalkeretal66).Morecommonly,however,largemiddlecerebralarterystrokesspanboththecriticalparietalandfrontalregions,resultinginasevereandpersistentneglectsyndromethathasaprofoundimpactonthedailybehaviourofpatients.Downloadfigure Openinnewtab Downloadpowerpoint Figure2 Corticalrighthemispherebrainregionsthathavebeenassociatedwithneglectincludetheangular(ang)andsupramarginal(smg)gyrioftheinferiorparietallobe(IPL),thetemporo-parietaljunction(TPJ),thesuperiortemporalgyrus(STG),andtheinferior(IFG)andmiddlefrontal(MFG)gyri. Recently,aprovocativeanatomicalstudyhaschallengedtheconventionalviewthatinferiorparietallobeortemporo-parietaljunctionlesionsarethecriticalposteriorcorticallocationsassociatedwithneglect.Karnathandcolleagues67haveinsteadproposedthatthekeyregionthatmustbedamagedisthemid-superiortemporalgyrus(STG).However,asubsequentinvestigation,usinghigherresolutionlesionmappingmethods,showedthat,althoughtheSTGmaywellbeinvolvedinmanyneglectpatients(50%inthesample),damagetothisregionisnotinvariablyassociatedwiththecondition.68Rather,thecriticalbrainregioninvolvedineverycaseofneglectfollowingmiddlecerebralarterystrokewasfoundtobetheangulargyrusoftheparietallobe. Inadditiontocorticaldamage,subcorticalischaemiclesionsintheterritoryofthemiddlecerebralarteryinvolvingtherightbasalgangliaorthalamusmayalsoproduceneglect,2869butthismayreflectdiaschisisorhypoperfusioninoverlyingparietalandfrontalregions,asdemonstratedbybothSPECTandmagneticresonanceperfusion.7071Finally,somepatientswithposteriorcerebralarteryterritorystrokealsosufferfromneglect,althoughtheseindividualshavebeenlesswellstudied.Somegroupshaveobservedthatwhilesmalllesionsinvolvingtheoccipitallobeleadtohemianopia,largerstrokesextendingintothemedialtemporallobealsoleadtoneglect.506872Specifically,Mortetalhaverecentlyshown68thatthekeymedialtemporalareathatisdamagedinthesepatientsistheparahippocampalregion,anareathathasstrongconnectionswiththeparietalcortex,7374andmaybeconsideredanimportantgatewayforparietalinformationtothehippocampus.Althoughlesionsoftherightparahippocampalregionaretraditionallyassociatedwithtopographicaldisorientation,therearereportsofpatientswhoalsoshowneglect.75Whatremainstobedeterminediswhetherneglectfollowingextensiveposteriorcerebralarteryinfarctionisinfactcausedbydiaschisisintheparietalcortexorisaseparatedisorderdistinguishedbyuniqueunderlyingcomponentdeficits. Manydifferentmechanismsmaycontributetoneglect Giventhevarietyandwidespreadnatureofthelesions—bothcorticalandsubcortical—thathavebeenimplicatedinneglect,itisperhapsnotsurprisingthatmanydifferentmechanismsarenowconsideredtocontributetothesyndrome.Moreover,functionalimagingstudiesinhealthyindividualshaveshownthatmanydifferentfunctionsmightbesubservedbysubregionswithineventheinferiorparietallobe.18242676Increasingly,neglectisconsideredtoconsistofanumberofcomponentdeficits,withtheprecisecombinationvaryingfrompatienttopatient,andpresumablydeterminedbytheexactlocationandextentofbraindamage.Asecondcriticalconceptthatisemergingisthatthemechanismsunderlyingneglectneednotbeneglectspecific:theymayoccurseparatelyontheirowninpatientswithoutneglect.1824Whencombinedwithothercomponentdeficits,however,theymayleadtoneglect.Theseperspectiveshaveimportantimplicationsnotonlyforunderstandingtheneglectsyndromebutalsofortreatingit. Becauseofspaceconstraints,itisnotpossibleheretodetailallthecomponentdeficitsthathavebeenconsideredtoplayaroleinneglectorrelateddisorderssuchasanosognosia.714–2023–2577Rather,ourobjectivehereistoprovideabriefoverviewanduseafewexamplestoillustratethekeyconceptsthatwehaveoutlinedabove. Variousimportantspatiallylateralisedcomponentdeficitshavebeenproposedtounderlieneglect.Adisorderofdirectingattentiontotheleftisconsideredtobea“core”problembymanyinvestigators.Itisdebatablewhetherthisreflectsanintrinsicgradedbiastodirectattentionrightwardsfollowingrighthemispheredamage7879orbecauseitemsontherightinvariably“win”overobjectstotheleftinthecompetitionforselection,assomehavearguedtobethecaseinextinction8081;orbecauseofdifficultyindisengagingattentionandshiftingitleftward,198283asothersclaimalsoforextinction.Severalinvestigatorshavealsoraisedthepossibilitythatneglectmayresultfromanimpairedrepresentationofspace,4884whichcanbeinmultipleframesofreference(forexample,retinotopic,headcentred,trunkcentred)orbespecifictonearorfarspace.85–87Stillothershaveconsideredthatneglectmayalsoreflectadirectionalmotorimpairment,withpatientsexperiencingdifficultyininitiatingorprogrammingcontralesionaleyeorlimbmovements.8889Ofcourse,theseproposedlateralisedcomponentdeficitsarenotmutuallyincompatible90andseveralmaycoexistwithinthesameindividual—forexample,directionalmotorandattentionaldeficitshavebeenshowntobepresentinbothparietalandfrontalneglectpatients.91 Inadditiontothesedirectionaldeficits,itisincreasinglybecomingapparentthatnon-spatiallylateralisedmechanismsmayalsocontributetoneglect.1824Forexample,impairmentsinsustainedattention,92selectiveattentionatcentralfixation93orinbothvisualfields,9495abiastolocalfeaturesinthevisualscene,229697aswellasadeficitinspatialworkingmemory98—evenwithinaverticalarray99—haveallbeenimplicatedintheneglectsyndrome.Importantly,noneofthesedeficitshastraditionallybeenconsideredtobeneglectspecific.Instead,theyhavebeenviewedascoexistingdeficits,astheymayoccurindependentlyinpatientswithoutneglect—thatis,theyare“doublydissociable”fromtheneglectsyndrome.However,severalinvestigatorsarguethatwhensuchnon-spatiallylateraliseddeficitscombinewithspatiallylateralisedones,theyexacerbateanydirectionaldeficitandtherebyhaveasignificantimpactontheneglectsyndrome,reducingthepotentialforrecovery.1824100 Suchaviewofneglecthastwoimportantconsequences.First,itbringstobearinsightsfromotherbranchesofcognitiveneuroscience—suchasspatialworkingmemoryandsustainedattention—thathavehithertonotbeenconsideredtobeimportantforunderstandingneglect.Second,itraisesthepossibilityoftargetingtreatmentstowardsspecificcomponentdeficitsthatmaynotbeneglectspecificbutneverthelessareimportantindeterminingtheseverityofneglect.Thefullpotentialforsuchtreatmentshasyettobetested,butrecentworksuggeststhismaybeapromisingavenueinthenearfuture. TREATMENTANDREHABILITATION Scanningtherapyandhemianopicpatching Initialattemptstorehabilitateneglectoftenattemptedtoencouragepatientstodirecttheirgazetowardscontralesionalspace,101–103andfunctionalimaginghassuggestedthismaybeassociatedwithincreasedactivationofintactrighthemisphereregionsthatareinvolvedinvisualsearch.104Althoughtheseapproachesshowedsomesuccessinreducingneglectwithinaparticulartask(forexample,inreadingbycueingpatientstofindaredlinemarkedbytheinvestigatorsontheleftmargin102),patientsshowedlittleornogeneralisationoftheirimprovedscanningbehaviourtotasksoutsideofthetrainingenvironment.12Thisfailuretogeneralisemaypartlybeattributabletothedependenceoftheseparadigmsonthepatientsbeingawareoftheirdeficitanddeliberatelymodifyingtheirbehaviour(“top-down”)asaconsequence.Unfortunately,asmanypatientswithneglectareoftenunawareoftheirdeficit,theymayrequirefrequentreminderstoscanleft,andincomplexrealworldenvironments,cues(suchastheredlineusedtoimprovereadingofwordsontheleft)arenotreadilyavailable. Arecentalternativeapproachconsistsofusingspectaclesthatoccludethegood(ipsilesional)sideofvisionineacheye,effectivelyforcingneglectpatientstodirecttheirgazetotheircontralesionalside,105whateverthevisualenvironment.Althoughsuch“hemianopicpatching”seemspromising,thereportedbenefitshavebeenmodest,106perhapsbecausepatientswhomightbenefitneedtobeselectedcarefully.Manypatientsdonottoleratethesespectacleswell,presumablybecausetheirnaturalinclinationistogazetowardsthenowoccludedipsilesionalvisualfield,and,inourlimitedexperiencewiththistechnique,complianceisnotoptimal. Inducingshiftsinspatialrepresentations Severalgroupshaveattemptedtoinvolveamoredirectapproachtoalteringtheimpairedrepresentationofspaceinneglect.Themethodstheyhaveusedincludecaloric,orvestibular,stimulation,107108contralesionallimbactivation,109trunkrotation,110neckmusclevibration,111112andelectricalstimulationoftheneck.113Althoughthemechanismsinvolvedinthesedifferenttechniquesvarytheyhaveallbeenshowntoproduceanimprovementinsomeaspectsofneglect.Furthermore,theyallproduceanautomatic(“bottom-up”)changeinbehaviour,orrecalibrationofthesensorimotormechanismsrecruited,thatdoesnotdependuponpatientsadopting(“top-down”)anewcontrolstrategytolookleftwards.Perhapsasaresult,improvementsinperformancehavebeenshown—atleastinsomecases—togeneralisetotasksthatwerenotusedintraining. Rubens107wasthefirsttodemonstratethepotentialofthesetechniquesusingcaloricstimulation,whichinvolvestheapplicationofcoldwatertothecontralesionalear(orwarmwatertotheipsilesionalear),causingavestibularinducedcontralesionalshiftingaze.Thisproducesatransientameliorationinthepatient’sneglectduringandafterapplication(for10to15minutes)acrossarangeoftasks.However,whilethistechniqueisoftheoreticalinterest,theshortdurationofitseffects,togetherwiththediscomfortofapplication,rendersitimpracticalasabasisforrehabilitation. Becauseofthepossibleroleofanimpairedrepresentationofspaceanchoredtothemidlineofthetrunk,Karnathandcolleaguesproposedthatshiftingtheperceivedlocationofthebodymidlineintothecontralesionalfieldmightalsoameliorateneglect.110112114Theyfoundthatiftheorientationofapatient’strunkwasrotatedleftwards,whiletheykepttheirheadandeyesfixedstraightahead,performanceforstimuliontheleftimprovedsignificantly.110Asimilareffectaftervibrationofthecontralesionalneckmuscles—whichproducesthesameproprioceptivefeedbackfromtheneckmusclesasacontralesionaltrunkrotation—hasalsobeenreported.114Moreover,whenpatientsweretreatedwithneckmusclevibrationincombinationwithscanningtraining,alonglastingimprovement(discernibleevenaftertwomonths)wasobservedonvisuomotortasksthathadnotbeenusedininitialtraining.112 Robertsonandcolleagueshavefoundthatactivemovementsofpartofthecontralesionalhalfofapatient’sbody(afinger)canproduceimprovementsonanumberoftestsofneglect,109115116particularlyinnearcomparedtofarspace115(seealsoFrassinettietal117).Althoughthisspatiomotorcueingtechniquehasalsobeenshowntobeeffectiveinpatientswithcontralesionallimbweakness,117theprevalenceofseverehemiparesisandsensorylossinneglectpatientsmaylimitthenumberofindividualswhomightbenefitfromthistechnique.Nevertheless,onetrialhasshownthatsuchtreatmentmayreducethelengthofhospitalstayinpatientswithneglectsignificantly.118 Prismadaptation Anewtypeoftreatmentwhichischeap,simpletoapply,apparentlyfreeofsideeffects,andwhichgeneralisesacrossarangeoftasksformanyweeksafterwardshasattractedagreatdealofinterestrecently.ThebenefitsofprismadaptationwerefirstreportedbyRossettietal,30whoexaminedtheeffectsofadaptationtoa10°rightwardhorizontaldisplacementoftheirvisualfieldbyprismsin12neglectpatients.Whilewearingtheprismsthepatientsrepeatedlypointed(foronly50trials)totargets10eithersideoftheirbodymidline(butopticallylyingeitherstraightaheador20°totheright(fig3)).Immediatelyafteradaptationtheyfoundthatneglectwasamelioratedacrossallfiveoftheneglectteststheyused;thisimprovementwasevengreaterafterafurthertwohours.Acontrolgroupofneglectpatientsthatunderwentexactlythesameprocedurebutwearingflatlensesshowednosignificantimprovementintheirperformance.Downloadfigure Openinnewtab Downloadpowerpoint Figure3 Adaptationtoarightwarddisplacementinanobserver’svisionproducedbyaprism.Whenviewingascenethroughthewedgeprism,allpointsaredisplacedhorizontallytotherightwithrespecttotheopticalaxisoftheretina(firstpanel).Hence,anobjectatpoint“a”willappeartobelocatedatpoint“b”.Theadaptationprocessrequirestheobservertoreachfortargetsrepeatedlywithinthevisualscene.Atthestartoftheprocess(secondpanel),participantswillmisreachtotherightofthetarget,anerrorreferredtoasthedirecteffect.Theerrorwillswiftlydiminishanddisappearentirelyastheparticipantadaptstothevisualshift(thirdpanel).However,toenabletheparticipanttoadaptfully,approximately50repetitionsshouldbecompleted.Whentheprismsareremovedtheparticipantswillmisreachintheoppositedirectiontothevisualshift(fourthpanel),anerrorreferredtoastheaftereffect.Innormalobserversthisaftereffectwilldisappearafteronlyafewminutes. Frassinettietalfurtherdemonstratedthetherapeuticpotentialofprismadaptationbyshowingthatitcanresultinalongtermameliorationofneglect.31Patientsintheirstudyweregivenbriefprismadaptationtwiceadayfortwoweeksandtheirperformancewascomparedwithamatchedcontrolgroupwhounderwentastandardrehabilitationprogramme.Theparticipantsweretestedonawiderangeofneglectassessments,ecologicallyvalidrealworldtasks,andatdifferentspatialframes(personal,near,andfarspace).Nearlyallthepatientswhohadprismtreatmentshowedasignificantimprovementinneglectafterthefirstsessioninvirtuallyeverytask.Remarkably,thisimprovementincreasedinmagnitudeeachtimethepatientswereassessedupto,andincluding,fiveweeksafterthelastsessionofadaptation.Otherstudieshavealsoshownthatprismadaptationisassociatedwithimprovementsinrepresentationalneglect,119120neglectdyslexia,121posturalimbalanceinhemiparesis,122hapticneglect,123andtactileextinction.124Additionally,McIntoshetalreportedthatthebenefitsofprismadaptationcanextendtoachronicneglectpatienttreatedninemonthsafterherstroke.123 Themechanismsunderlyingtheeffectivenessofprismadaptationarenotyetpreciselyunderstood.However,thegeneralconclusionofthepreviousstudiesisthattheresultscannotbeexplainedmerelybyaleftwardmotoricbiasoftherightarmduringadaptationtoprisms.First,improvementsoccurindomainsthatdonotrequirealimbspecificmotorresponse—forexample,reportingobjectsaroundaroomorrepresentationalneglect.31119120Second,thereisnocorrelationbetweenthedurationoftheimprovementinperformanceintestsofneglectandthedurationofprismaftereffects,measuredbypointingstraightaheadwithoutvisualfeedback.31Thusmoststudieshaveconcludedthatprismadaptationaffectshigherlevelspatialrepresentationsthataredisruptedinneglect.3031Rossettietalclaimedthatthestimulationoflowlevelneuralmechanismsthatmonitorandcorrecterrorsbetweentheactualandexpectedpositionsofthearminprismadaptationmightcorrectthebiasesintroducedbyneglect.30However,asFrassinettietalnote,31analternativeexplanationisthattheimprovementsinneglectreflectchangesinthecontroloftheoculomotorsystem.Ameliorationofneglecthasbeenshownafterinterventionsthatcauseaninvoluntaryshiftofgazeintotheneglectedfield,forexamplevestibularstimulation.107Additionally,previousstudiesofprismadaptationinnormalsubjectshavereportedappreciableoculomotorshifts.125 Thisraisesthegeneralissueoftheappropriatemeasurementoftheeffectsofadaptation.Toourknowledgeallstudiesofprismadaptationandneglecthavemeasuredadaptationbycomparingpointingalongthebodymidlinebeforeandaftertheapplicationofprismsusingtheadaptedarm.However,thisdoesnotmeasurethetotaleffectsofadaptation;nordoesit,ashasbeensuggested,31126measureashiftintheperceivedbodymidlinebutmerelytheadaptiveshiftwithinthehead–armsystem.125Toassesstheeffectsofadaptationonthesagittalbodyaxisitisnecessarytouseameasurethatisindependentofanydirectmotoricadaptation.Unfortunately,theprevalenceofhemiparesisinneglectmeansthattheobvioussolutionofusingthearmnotemployedintheadaptationtaskwouldnotberealisticforthemajorityofpatients.However,theadaptiveaftereffectintheoculomotorsystemcanbereadilymeasuredbysettingthepositionofalineonacomputermonitorsothatitappearstoliedirectlyahead.125Animportantquestionforfutureresearchdirectedtowardsunderstandingwhyprismsareeffectivewouldbetoexaminethemagnitudeandpersistenceofthisaftereffect,andtoassesshowitcorrelateswithimprovedperformancebyneglectpatients.Newdatahavebeguntosuggestthattheeffectivenessofprismtherapyisnotduetoalteringthespatiallylateralisedgradientofattention,atleastinpatientswithmildneglect.127 Treatingnon-spatiallylateraliseddeficits Isitpossibletoamelioratetheseverityofthelateraliseddeficitinneglectusingtreatmentsthattargetnon-spatiallylateralisedimpairments(thatis,thosethataffectbothsidesofspace)?Robertsonandhiscolleaguestestedthishypothesisdirectlybyinvestigatingwhetherincreasingpatients’alertnesswouldleadtoanimprovementintheirspatialbias.128Theyexaminedthresholdsfordetectingwhetherastimulusontheleftprecededorfollowedtheappearanceofacomparableobjectontheright.Onthistask,neglectpatientsshowedastrongspatialbias,typicallyjudgingtheappearanceofbothstimulitobesimultaneouswhentheleftobjectprecededtherightonebyhalfasecond.Remarkably,thisspatialbiaswasabolishedifthestimuliwereprecededbyashorttone,attributedtoaboostinthepatients’alertnessbecausethetonedidnotcontainanyinformationthatwouldpredictwhichobjectwouldcomefirst.Furthermore,theeffectoccurredevenwhenthetoneoriginatedontherightwhich,ifanything,wouldtendtocuethepatientawayfromtheneglectedfield. Abehaviouraltechnique—moreappropriatefortreatingsustainedattentiondeficitsinclinicalsettings—hasalsobeendeveloped.129Neglectpatientswererequiredtocarryoutavarietyoftasksthatrequiredsustainedattention,forexamplesortingcoinsorcards.Whilecarryingoutthetasktheexperimenterwouldintermittentlypromptthemverballytoattend.Patientswerethengraduallytrainedtopromptthemselvessubvocally.Theywerealsomadeawareoftheirsustainedattentionaldeficitdifficultiesandtheimportanceofthisselfalertingprocess.Theeightpatientsshowedconsiderableimprovements,24hoursaftertraining,intestsofsustainedattentionandspatialneglect.However,thenatureoftheinterventionrequirespatientstobeawareoftheirdeficit,aswellasthesituationsinwhichitisnecessarytoalertthemselves.Thedegreetowhichpatientsareabletodothismaylimitthegeneralapplicabilityofthistechnique. Analternativetobehaviouralapproachesforthetreatmentofnon-lateralisedcognitivedeficitsassociatedwithneglectmightbetheuseoftargetedpharmacologicalinterventions.Specifically,ithasbeensuggestedthatimpairedsustainedattentioncouldbetargetedeitherthroughnoradrenergicdrugsknowntomodulatevigilancelevelsinhealthyvolunteers,130orthroughcholinergiccompounds—forexample,acetylcholinesteraseinhibitors—thatarecurrentlyusedtoimprovecognitivefunctioninseveralconditionsincludingAlzheimer’sdiseaseandvasculardementia.131132 Bycontrast,spatialworkingmemorydeficitsacrosssaccades98mightbetargetedusingdopaminergicdrugs.PhysiologicalevidencefromstudiesinrhesusmonkeyssuggeststhatmemoryforthelocationsofsaccadictargetsaremodulatedbydopamineD1receptoragents.133Previousstudiesusingthedopamineagonistbromocriptinehavereportedbothpositiveandnegativeresults.134–136SuchconflictingfindingsmaypartlyreflecttheheterogeneityofpatientsincludedinthestudiesaswellasthefactthatbromocriptineactsmainlyonD2dopaminereceptors.AfuturestudymightprofitablyexaminetheeffectsofanagentthatprimarilytargetsD1receptorsinselectedneglectpatientswhohavebeenshowntohaveaspatialworkingmemorydeficit. CONCLUSIONS Inthisreview,wehavefocusedonclinicalaspectsofneglect.Recentfindingsemphasisethattheneglectsyndromeisaheterogeneousconditionwithdifferentcombinationsofdeficitoccurringindifferentpatients.Whilesomeofthesecomponentsarespatiallylateralised,othersarenot.Treatmentsforneglectareunlikelytobesuccessfulunlesstheyaretailoredtotheunderlyingcognitivedeficitsinindividualpatients.Promisingnewdevelopmentsusingbehaviouralanddruginterventionshavebeguntooffersomenewhopeforthiscommondebilitatingcondition. Acknowledgments Weareextremelygratefultothemanypatientswhohaveparticipatedinourresearch,includingthosefromthestrokeunitsatCharingCrossHospitalandStThomas’Hospitalandtheacutebraininjuryunit,NationalHospitalforNeurologyandNeurosurgery,London.Wewouldalsoliketothankbothreviewersfortheirhelpfulcommentsandsuggestions.ThisworkisfundedbytheWellcomeTrust. 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