Path Integration Deficits During Linear Locomotion After Human Medial Temporal Lobectomy

Path Integration Deficits during Linear Locomotion after Human Medial Temporal Lobectomy

John W.Philbeck 1,Marlene Behrmann 2,Lucien Levy 3, Samuel J.Potolicchio 3,andAnthony J.Caputy 3

Abstract

& Animalnavigation studies have implicated structures inand both adecrease inthe consistency ofpath integration and a around the hippocampal formationas crucialin performing systematic underregistration oflinear displacement (and/or path integration (amethod ofdetermining one’s position by velocity) during walking.Moreover, the deficits were observable monitoring internally generated self-motion signals). Less is even when there were virtually no angular acceleration known about the role ofthese structures forhuman path vestibular signals. Theresults suggest that structures inthe integration. We tested path integration inpatients whohad medial temporal lobe participate inhuman path integration undergone left orright medial temporal lobectomy as therapy when individuals walkalong linearpaths and that thisis so to forepilepsy. Thisprocedure removed approximately 50% ofthe agreater extent inright hemisphere structures than left. anterior portion ofthe hippocampus, as wellas the amygdala Thisinformation is relevant forfuture research investigating and lateral temporal lobe. Participantsattempted to walk the neural substrates ofnavigation, not only inhumans without vision to apreviously viewed target 2–6 mdistant. (e.g.,functional neuroimaging and neuropsychological studies), Patients withright, but not left,hemisphere lesions exhibited but also inrodents and other animals. &

INTRODUCTION self-motionsignals is knownas path integration or dead An importantfunction of visionis to facilitate navigation reckoning (Etienne et al.,1996). An updated estimate of from one location to another. As importantas this one’s current positionmay be maintained byintegrating function is,however, visual information is frequently these self-motionsignals over time.Path integration is degraded or made unavailable bythe common occur- formallydistinct from other typesof navigationin which rences of occlusionsand poorlighting conditions. This one usesvision, or someother sensorymodality, to being thecase, itis advantageous for sightedindividuals determine one’s positionrelative toenvironmental fea- toremain able tonavigate withoutvision. Many animals tures (‘‘landmarks’’ )at knownlocations. havethis ability (Etienne, Maurer, &Se´guinot,1996; Effective pathintegration entailsderiving a represen- Wehner, Michel,& Antonsen, 1996), and humansare no tationof thecurrent displacement from one’s last exception. The average humancan sighta target upto knownposition. There isabundant evidence thatthe 20 maway or more,and thenwalk to it quite accurately medialtemporal lobe (MTL) playsan importantrole in whileblindfolded (for areview, see Mittelstaedt& theprocessing of spatialinformation. The firing rate of Mittelstaedt, 2001). The accuracy of thisnonvisual nav- pyramidalcells inthe rodent hippocampusis highly igation isevidence thatthe brain is exquisitely tuned to correlated withthe location of theanimal in space (for sense theself-motion signals generated bywalking and areview of thisextensive literature, see Redish,1999). touse themfor thepurpose of controlling behavior.The One interpretation of sucha resultis that these so- neural processes underlyingnonvisual navigation re- called ‘‘place cells’’ participate inrepresenting the mainpoorly understood, however. layoutof theenvironment (O’ Keefe &Dostrovsky, When navigating withoutvision, the sensory informa- 1971). Consistentwith this view, rodents withlesions tionfor determining one’s positionis restricted to thatdamage thehippocampus or itsconnections tend signalsarising from thevestibular apparatus and signals toperform poorlyon taskssuch as theradial arm maze related to muscularactivity (e.g., proprioceptionand and water maze, whichrequire theanimal to demon- efference copy).The processof determining one’s po- strate itsmemory for locationsit has visited previously sitionon thebasis of internallygenerated (idiothetic) (e. g.,Morris, Garrud, Rawlins,& O’Keefe, 1982). Spatial memorydeficits are manifested after MTLinjury inmonkeys as well,particularly after damage to the 1 TheGeorge Washington University, 2 Carnegie Mellon Uni- parahippocampalgyrus surrounding the hippocampus versity, 3 TheGeorge Washington University Medical Center (Murray &Mishkin,1998).

© 2004Massachusetts Institute ofTechnology Journal ofCognitive Neuroscience 16:4, pp. 510–520 There isevidence thatthe MTL’ s role innavigation muchless research hasfocused directlyon MTLpartic- extends beyondsimply representing spatialinformation ipationin processing human idiothetic self-motion sig- toinclude theassimilation of idiotheticself-motion nals.Observing the behaviorof patientswith MTL signalsinto existing spatial representations. Place cells, damage innonvisual locomotor navigation tasksis a for example, continue toshow location-dependent firing powerful toolfor investigatingthese issues.Walking even when theanimal’ s visionis occluded (Markus, generates strong idiotheticself-motion signals and cre- Barnes, McNaughton, Gladden, &Skaggs, 1994; Quirk, ates asituationin which vestibular and muscularcues are Muller, &Kubie, 1990), suggesting thatthese cells mutuallyconsistent, as they are during real-world navi- participate inthe processing of idiotheticself-motion gation. The occlusionof visionduring locomotionex- signals.In the monkey, some hippocampal cells have cludes landmark-based navigation,thereby providing a been found torespondto whole-body motion (O’ Mara, narrow experimental focus on idiotheticself-motion Rolls,Berthoz, &Kesner, 1994). Several conceptualiza- signals.If theMTL participatesin processing such signals, tionsof hippocampalfunction suggest thatthe MTL’ s MTLinjuryshould result in path integration deficits. role inpath integration (including processingand stor- The MTLdoes seem tobe involvedin these tasks,but ing spatial,temporal, and self-motion information) importantdetails of itsrole remain tobe characterized. emerges aspart of amore general role for subserving Patientswith MTL lesions,particularly in theright hemi- episodicmemory (e.g., Burgess,Maguire, &O’Keefe, sphere,show path integration deficits during whole- 2002; Vargha-Khadem et al.,1997), declarative memory bodyrotations as well as innonvisual walking tasks (e.g., Squire, 1992), relational processing(e.g., Eichen- involvinga combinationof turnsand straightsegments baum& Cohen,2001), or contextual processing(e.g., (Worsleyet al.,2001; Wiest,Mu ¨ller, Glu¨ck,Deecke, & Redish,2001). Baumgartner, 2000). The abilityof suchpatients to Rodents and humansbehave similarlyin water-maze- perform pathintegration along purelylinear pathsis less typenavigation tasks (Hamilton, Driscoll, & Sutherland, clear, however.Worsley et al.(2001) concluded thatthe 2002), butclearly humansuse more sophisticatedrep- pathintegration errors manifested bytheirpatients were resentations tocontrol navigationthan do rodents,at attributable todeficits inrotational updatingonly, but least under certain circumstances (e.g., Wang &Spelke, speculated thattheir methods may not have been suffi- 2002). The extent towhich human navigation within the cientlysensitive to detect deficits inupdatingalong linear local environmentparallels rodent (and monkey)navi- paths.One possiblesource of insensitivitystems from gation isstill poorly understood, however. The need to theiruse of unimodaldistance and route reproduction understand thehomology between rodent and human tasks,in which participants are exposed toa stimulus brainstructures thatparticipate innavigationis particu- pathby walking and thenmust reproduce thatpath, larlypressing, given theenormous body of research that again usingthe walking modality. If participantsperform iscurrently available based on thisanimal model. A host pathintegration similarlyon thestimulus and response of neuropsychological and functional neuroimaging portionsof thepath, systematic errors inthe two seg- studiessupport the view that MTL structures playa mentscould cancel, therebyyielding a potentiallymis- critical role inhuman navigation. Much workhas impli- leading pattern of accurate performance. The possible cated theright hippocampus and/ or parahippocampal impairmentof linear pathintegration after MTL damage gyrusas importantsubstrates for spatialmemory in isimportant to verifyusing more sensitivemethods humans,particularly when informationmust be retained because itstands to elucidate whichsensory inputs to for more thanseveral seconds and lessthan several pathintegration are processed inthe MTLs. Innatural minutes(Pierrot-Deseilligny, Mu ¨ri,Rivaud-Pechoux, Gay- situations,rotating one’s bodyto face another direction mard,& Ploner,2002; Feigenbaum, Polkey,& Morris, generates strong rotational vestibularsignals and arela- 1996; Owen, Milner, Petrides,& Evans,1996; Smith& tivelysmall amount of leg movement.Walking along Milner, 1981). Furthermore, humanswith MTL damage linear paths,meanwhile, produces theopposite pattern. showdeficits intasksthat require navigationto remem- If pathintegration isimpaired during bothlinear and bered locationsin real and virtualenvironments (Astur, rotational locomotionafter MTLdamage, thiswould Taylor,Mamelak, Philpott,& Sutherland, 2002; Spiers indicate thatthe MTL’ s role inpath integration encom- et al.,2001; Skelton, Bukash,Laurance, Thomas,& passessignals from multiplesensory systems rather than Jacobs,2000; Bohbotet al.,1998). Functional neuro- primarilythose arising from thevestibular apparatus. imaging studiesin neurologically intact humanshave Our primarygoal inthe followin gstudywas to alsofound thatthe hippocampus or parahippocampal characterize theeffect of MTLinjuryon pathintegration gyrusbecomes activated as participantsnavigate ina along linear paths.A surgical procedure designed to simulated3-D environment(Gro ¨n,Wunderlich,Spitzer, treat MTL epilepsyprovides a uniqueopportunity to Tomczak, &Riepe, 2000; Maguire et al.,1998; Aguirre, investigate thisissue. This procedure, involvinga partial Detre, Alsop,& D’Esposito,1996). medialtemporal lobectomy,removes approximately two Althoughthese studiessupport the notion that MTL thirdsof theanterior hippocampusand thestructures structures playan importantrole inspatial memory, surroundingit on one sideof thebrain. The lesionsare

Philbecket al.511 too large to allow afine-grained assessmentof localiza- 2001), we anticipated thatdeficits inthe two walking tionof function, butnevertheless providea means of taskswould be more pronounced inthe right MTL addressing our primarygoal of characterizing thepath patientsthan the left. integration deficits thatoccur after MTLdamage. The unilateral nature ofthelesion also permits an analysisof RESULTS apossiblehemispheric specializatio n.This method- ology,then, presents an exceptional opportunityto If tissuethat plays an importantrole inpath integration is investigate thecritical issueof thehomology of function damaged or removed,the remaining structures must between rodent and humanMTL structures. operate on amore sparseset of inputs.This could have We tested patientswith unilateral rightor left hemi- avarietyof effects on signalsprocessed withinthe spheretemporal lobe resections (RTLRand LTLR, residual network, suchas systematicallybiasing the respectively) and neurologically intact control partici- signalsor decreasing thesignal-to-noise ratio. We there- pantsin four behavioraltasks. Two of these tasks fore set outto characterize pathintegration performance evaluated pathintegration: Inthe ‘ ‘target-directed walk- notonly in terms of systematictendencies to over- or ing’’ task,participants attempted towalk without vision underestimate theextent of self-motion(i.e., response toa previewed target. Thistask provides a measure of bias),but also in terms of within-subjectrandom error pathintegration and spatialmemory, as well as a (i.e.,response consistency). To obtaina more robust nonverbal indicationof perceived target distance (Phil- estimate of central tendency ineach participant’s data, beck &Loomis,1997). Thisis a multimodaltask in that outliersmore than4 standard deviationsfrom themean thestimulus distance isspecified byvision and the were removed inthe experimenter-guided and target- responseis indicated viawalking. In the ‘ ‘experimenter- directed walkingtasks. This resulted inthe removal of guided walking’’ task,participants walked withoutvi- approximately5%, 4%, and 3% ofthedata for thecontrol, sionunder theguidance of an experimenter and then LTLR, and RTLR groups,respectively, and caused only verballyestimated thepath length. Thus, the stimulus trivialdifferences inthe statistical analyses relative to and responsephases again entailed different modali- testsperformed on thefull data set.To analyze within- ties—in this case, thestimulus was suppliedby walking subject responseconsistency (i.e., random error), we and theresponse involved verbal estimation.This task usedthe least squarescriterion tofind thebest-fitting providesa separate measure of pathintegration with- straightline through each participant’s responses.Al- outany reliance uponvisual perception. Multimodal thoughwe didnot test nonlinear models,these linear fits tasksare more sensitivethan unimodal tasks to sys- were generally excellent; across thefour tasks,the mean tematic errors inpathintegration because theymitigate squared correlation coefficients were .91, .87, and .87 for against thepossibility that errors incurred during the thecontrol, LTLR and RTLR groups,respectively. We stimulusphase could be canceled bysimilar errors in thentook the standard error of estimate ( SEE) of the theresponse phase. The remaining two taskswere best-fittinglines as a measure of overall consistency.We designed toevaluate visualperception and spatial subjected the SEEstoan analysisof variance (ANOVA), memorywithout drawing uponpath integration ability, with‘ ‘group’’ included asa between-subjects variable given thatthese two processesare alsoimplicated in (control, LTLR and RTLR). Toanalyze group differences target-directed walking:In one of these tests,partic- inconstant error (bias),we performed four ANOVAs on ipantsverbally estimated theegocentric (absolute) thesigned responseerror scores,one for each condition, distance toa visibletarget, and inthe other, they withstimulus distance (2.5 and 5.0 m)included as viewed one target and thenattempted toposition a awithin-subjectvariable. Each participant’s data were second one suchthat it reproduced thedistance ofthe averaged across repetitionbefore analysis. first.The second target inthe distance matchingtask was positionedafter ashortdelay toverify that partic- Visual Perception and Spatial Memory ipantscould remember thetarget location long enough towalk to itif required. Within-Subject RandomError (Consistency) We predicted thatall participantswould be fairly There were no reliable group differences inresponse accurate inthe verbal distance estimationand delayed consistency inthe verbal distance estimation task, distance matchingtasks, given thewell-lit environment as measured byan ANOVA performed on the SEEs, and short(<20 sec) retention intervalsinvolved (Pier- F(2,25) =1.63; SEM = .105; p =.216. The mean SEEs rot-Deseillignyet al.,2002; Bohbotet al.,1998). How- for thecontrol, LTLR and RTLR groupswere .32, .38, and ever, if structures withinthe MTL playa role inpath .52 m,respectively.There was asmallbut reliable effect integration thatencompasses both linear and rotational of group inthe SEEsof thedelayed distance matching self-motion,the patients should show some impairment task, F(2,25) =3.89; SEM = .042; p =.034. Pairwise inthe two tasksthat require pathintegration along planned contrasts ( p =.05) showedthat this effect was linear trajectories relative tocontrol participants.Based due todifferences between theRTLR and control groups on previousresults using similar methods ( Worsleyet al., (mean SEE:.43 mvs..30 mfor RTLRand control,

512Journal ofCognitive Neuroscience Volume 16,Number 4 respectively).The mean SEE for theLTLR group fell between thoseof theother twogroups (.38 m),but did notdiffer reliablyfrom either.Taken together, these data indicate thatthe RTLR procedure isassociated with milddecreases inresponse consistency in tasks requir- ing visualperceptio nand maintenance of asingle target location inmemory for fairly shortdurations (15–20 sec).

Constant Error(Bias) Figure 1. Average indicated distances forthe three groups of Inthe verbal distance estimationcondition, there was a participants (TLR =temporal loberesection). (A) Verbal distance slighttendency for theLTLR group tounderestimate the estimation trials.(B) Delayed distance matching trials.Error bars target distance systematicallyrelative to theother denote ±one standard error ofthe mean calculated across participants. The dashed line indicates accurate performance. groups,but this tendency didnot reach statisticalsignificance (see Table 1and Figure 1A). There were no group differences inconstant error inthe delayed distance matchingcondition and, infact, theresponses perception or inshort-duration spatial memory in the of the two patient groupswere generally accurate patient groups,at least as measured bythese tasks. (Figure 1B). Thus,the RTLR group’s decreased response consistencyin this task was notaccompanied bysystem- Path Integration Tasks atic responsebiases. Taken together, theDistance Esti- mationand Distance Matching testssuggest thatthere Within-Subject RandomError (Consistency) were no strikingsystematic deficits invisual space There were no reliable group differences inthe responseconsistency in the experimenter-guided walking condition, F(2,25) =2.84, SEM = .241, p = .078. The mean SEEsfor thecontrol, LTLR and RTLR groupswere Table 1. Source Tables forAnalyses ofVariance ofMean .53, .33, and .66 m,respectively. However, there was a Signed Responses group effect inthe target-directed walkingcondition, Condition SEM Fratio pvalue F(2,25) =5.04, SEM = .32, p =.014. Inparticular, the responsesof theRTLR patientswere significantlyless Target-directedwalking consistentthan those of theother groups.Pairwise post Group (2,25) 2.47 2.81 .079 hoc contrasts confirmed thatthis effect was primarily due todifferences between theRTLR and control groups Distance (1,25) 111.41 631.92 <.001 (F = 9.99; p =.004); no other contrasts reached Group Distance (2,25) .93 5.28 .012 £ significance. The mean SEE for thecontrol group was .28 m,while the corresponding mean for the RTLR group was more thantwice that(.64 m).The mean Experimenter-guided walking SEE for theLTLR group was intermediate (.49 m).Thus, Group (2,25) 2.81 2.06 .149 one consequence of rightMTL injurymay be increased Distance (1,25) 4.94 18.46 <.001 random error inpath integration processes. Group Distance (2,25) .96 3.60 .042 £ Within-Subject Constant Error(Bias) The participantsgenerally walked quiteaccurately in Verbal distance estimation thetarget-directed walking condition,with the excep- Group (2,25) 3.02 2.28 .123 tionof theRTLR group (Figure 2A). Notably,the RTLR Distance (1,25) 83.62 193.67 <.001 patientstended toovershoot when attempting towalk topreviously viewed targets. Thistendency became Group Distance (2,25) .73 1.70 .203 £ more pronounced for the5-m target (Group Distance interaction, Table 1), when theaverage overwalking£ Delayed distance matching exceeded 15% of thetarget distance. Thisinteraction isto be expected if there are systematicbiases in self- Group (2,25) .52 1.59 .224 motionsensing, as these errors wouldtend toaccumu- Distance (1,25) 67.49 384.41 <.001 late as walked distance increases. Figure 3showsthe mean stoppinglocations for theindividual participants Group Distance (2,25) .28 1.61 .220 £ inwalking tothe 5-m target; althoughthe performance

Philbecket al.513 of several patientsin the RTLR group fall withinthe range of normalperformance, thedistribution of the RTLR group isclearly shiftedtoward positiveconstant errors relative tothe LTLR and control groups.Pairwise planned contrasts showedthat the Group Distance interactionwas drivenby differences between£ the RTLR responsesand each of theother groups(RTLR vs.control : F = 8.43, p =.008; RTLRvs.LTLR: F = 7.07, p =.013). The control and LTLR groupsdid not differ. Inthe experimenter-guided walkingcondition, there was ageneral tendency toward underestimation of walked distances (approximately30% of thestimulus Figure 3. Average walked distances fora target at 5m(target-directed distance; see Figure 2B). The LTLR group’s responses walkingtrials). Each data point isthe mean response forone were somewhatmore underestimated thanthe other participant, collapsed over five orsix measurements; data forall three groups’, particularlyat the5-m stimulus distance (Group participant groups are shown(TLR =temporal loberesection). The Distance interaction, Table 1). Inthis way, the LTLR solidhorizontal line indicates accurate performance. group£ exhibiteda similartendency toward verbal under- estimationas intheverbal distance estimationcondition. Pairwiseplanned contrasts( p =.05) showedthat the calibration for each participantwere knownwith more interaction was drivenby differences between theLTLR certainty. Preliminaryattempts to correct for verbal group and theother groups(LTLR vs.control: F = 6.13, calibration errors inthe experimenter-guided walking p =.02; LTLR vs.RTLR: F = 4.99, p =.035). The control trialsbased on performance inthe verbal distance and RTLR groupsdid not differ from each other.This estimationtrials did not show any striking differences means thatalthough the RTLR group showedthe pattern from theresults presented inTable 1, sowe didnot thatwould be predicted for individualswho underesti- pursueanalyses of thiskind further. mate theirself-motion (overshooting in target-directed walking trialsand underestimating inexperimenter- Absolute (Unsigned) Error guided walkingtrials), they only differed from normal behaviorwhen walking toa previouslyseen target. Analysesof signed error can underestimate systematic Estimatesof walked distance inthe experimenter- biasto the extent thatpositive and negative errors tend guided walking trialswere given verbally.At least some tocancel each other out.Separate ANOVAs were there- of thesystematic bias in these trials,then, could be due fore performed on the absolute errors inthe four toerrors inthe calibration oftheverbal estimates.There experimental conditions.The outcome ofthese analyses were no reliable group differences inthe verbal dis- generally mirrored thoseof thesigned error tests,with tance estimationtrials, and theresponses themselves the following exceptions. Intarget-directed walking were generally fairly accurate. Nevertheless,it may be trials,there were no differences between groups, thatthe analysis of theexperimenter-guided walking F(2,25) =2.052; p =.1496, and no Group Distance data isless sensitive than it might be if theverbal interaction, F(2,25) =2.666; p =.089. Taken£ incon- junction withthe signed error analysis,this suggests that theeffect of righthemisphere MTL lesionson target- directed walking isprimarily manifested interms of overshootingrather thanoverall error. There was amain effect of group inthe experimenter-guided walking condition, F(2,25) =3.725; p =.0384. Pairwiseplanned contracts ( p =.05) suggested thatthis was attributable toa larger amountof overall error inthe LTLR group thanin the other twogroups, which did not differ from each other.The LTLR groups’error was primarilydue to theirunderestimations in this condition, a resultthat is noticeable inFigure 2B.

Figure 2. Average indicated distances forthe three groups of DISCUSSION participants (TLR =temporal loberesection). (A) Target-directed walkingtrials. (B) Experimenter-guided walkingtrials. Error bars As agroup,right hemisphere medial temporal lobec- denote ±one standard error ofthe mean calculated across tomypatients tended toovershoot when attemptingto participants. The dashed line indicates accurate performance. walkwithout vision directly to previouslyseen targets.

514Journal ofCognitive Neuroscience Volume 16,Number 4 Bycontrast, left medial temporal lobectomypatients mated inthe latter. Boththe RTLR and control groups and neurologically intact participantsarrived at the accurately estimated thedistance tovisualtargets when target location more accurately. The overshootingex- no locomotionwas required, soapparently theirunder- hibitedby the RTLR group was accompanied bya estimationsin the experimenter-guided taskwere not twofold increase inthe within-subject variability of simplya resultof poorverbal calibration.Previous work walking responsesrelative to thecontrol participants. hasshown that path integration can be greatly en- When nolocomotion was required, theRTLR patients hanced when an individualhas prior information about were able accurately tomatch target distances after a themagnitude of an upcomingtrajectory before walk- delay (albeit withsomewhat decreased consistency) ing begins(Philbeck, Klatzky, Behrmann,Loomis, & and performed well when verballyjudging thedistance Goodridge, 2001). Visionof thetarget suppliesthis tovisual targets. Good performance on these tasks informationin target-directed walking trials,but there indicates thatneither misperceptionof thetarget’ s isno suchprior knowledge inthe experimenter-guided initialposition nor general deficits inshort-term spatial walking taskbecause participantsdo notknow how far memorycould account for thesystematic tendency theywill be guided on each trial.Thus, the control tooverwalk. Notably, the RTLR patientstended to group mayhave in fact underestimated theextent of verballyunderestimate walked distances when they theirself-motion in experimenter-guided trialsbut per- were guided byan experimenter. Althoughtheir perceived thismotion more accurately intarget-directed formance didnot differ from thecontrol group’s in walking trials.It may be thatthe RTLR surgery inter- thistask, a pointto which we willreturn below,the feres withthe benefit thatis usually afforded toneu- complementary pattern of overshootingin one task rologically intact individualswhen visionof atarget and underestimationin the other showsthat there was isavailable before blindfoldedwalking begins.One no general tendency toproduce too large or too small possibleaccount isthat vision of atarget and the responsesas aresultof rightMTL injury.Instead, we anticipationof walking toit forms the basis of a interpret thispattern as resultingfrom asystematic spatiotemporalcontext for locomotion.When circum- underperception of theextent of self-motionin both stances allow healthyindividuals to establishsuch a tasks.We conclude thatstructures withinthe right contextual framework, itacts tofacilitate theintegra- hemisphereMTL do indeed participate inpath inte- tionof self-motioninformation during thewalk; after gration along linear trajectories. rightMTL injury,however, this benefit does notmate- The LTLR group didnot differ from neurologically rialize because processingof contextual and/orrelation- intact control participantsin terms of theaccuracy and al information isimpaired (Eichenbaum &Cohen, consistencyof target-directed walking whileblind- 2001; Redish,2001). folded. Thisgood performance indicates thatthe LTLR Althoughour resultssuggest thatRTLR patients group was able accurately toperceive and remember showpath integration deficits inlinear paths,Worsley thetarget location. Their good performance on the et al.(2001) didnot find evidence of these errors in Delayed Matching taskcorroborates thisconclusion. In either of theirtwo groupsof patientswith MTL resec- sum,there appears tobe somelateralization of func- tions.Although this apparent discrepancy mightbe due tionof humanpath integration processes;although tosuperficial methodological differences between our our workdoes notrule outleft hemisphereinvolve- twostudies (e.g., our manipulationof walkingspeed ment,right hemisphere structures apparently playthe vs.their use of vocal numberrepetition to discourage more crucial role. Thisconclusion accords well with pace counting), amore likelyexplanation isthat the theresults of Worsleyet al.(2001), and extends that multimodalreproduction tasksused here are more previouswork by confirming thatRTLR surgery dis- sensitiveto path integration errors thanare unimodal ruptspath integration along linear pathsas well as tasks.Interestingly, Worsley et al.also found no evi- pathsthat contain whole-bodyrotations. In addition, dence of deficits inlinear pathintegration intheir we haveshown that right MTL injuryis associated homingvector task,in which blindfolded participants withnot only systematic biases in path integration were guided along two legs of atriangle and then along linear pathsbut also decreases inresponse attempted to return directlyto the origin of locomo- consistency.Importantly, the biases in path integration tion.The authorsused a varietyof stimulustrajectories, associated withRTLR are manifested as errors of under- withthe ideal responsefor each pathentailing the estimationfor bothlinear locomotion(as shownin creation of afinal straightsegment of 2.5 m.Triangle our study)and whole-bodyrotations ( Worsleyet al., completionis an importanttool for characterizing 2001; Wiestet al.,2000). humanpath integration (and indeed, Worsleyet al. Interestingly,whereas theRTLR participantsshowed found thatRTLR patientswere impairedin rotational evidence of underestimating self-motionin both target- pathintegration inthistask); however, its sensitivity for directed walking and experimenter-guided walking detecting pathintegration deficits along linear trajecto- tasks,the neurologically intact control group re- riesmay be limitedwhen there islittle variation in the spondedaccurately inthe former taskbut underesti- required responsepath length. Testing abroader range

Philbecket al.515 of required responsepath lengths promises to increase integration performance, more testingis required to thesensitivity of future studiesinvolving MTL patients resolve thisissue. The possibilityremains that the and toenhance efforts toward computationalmodeling observeddeficits are theresult of more global impair- of humanpath integration (e.g., Klatzky, Beall, Loomis, mentsin relational, temporal,or contextual processing. Golledge, &Philbeck,1999). The critical resultfrom thisstudy is the evidence of We haveused the term MTLadvisedlythroughout deficits inhuman path integration along linear paths thispaper inthat we cannot localize more precisely associated withright hemisphere MTL damage. Rodent theneural region inthese patientsthat mediates the studieshave confirmed thatMTL structures are impli- pathintegration deficit. The surgical resection includes cated innavigation, but this is the first evidence of portionsof thehippocampus, subicular complex and MTLinvolvementin path integration along purely amygdala, partsof theperirhinal and entorhinalcorti- linear pathsin either humansor other animals.Al- ces, theparahippocampal gyrus, and theanterolateral thoughfurther research isneeded to specifythe temporal lobe.In monkeys, the anterolateral temporal relative importance of specific structures withinthe lobe and amygdala appear to be specialized for object MTL inproducing thedeficits, we haveshown that recognition and emotionalprocessing and are notlikely thedeficits are manifested as botha decrease inthe toplay a role inpath integration (Logothetis &Shein- consistencyof pathintegration and alsoas asystematic berg, 1996; Sutherland &McDonald, 1990). Inrodents, underregistration of linear displacement (and/or veloc- therole of thehippocampus proper for pathintegra- ity)during nonvisualwalking. Moreover, thedeficits tionhas been vigorouslydebated (for recent reviews, are observable even whenthere are virtuallyno angu- see Redish,2001; Whishaw,Hines, & Wallace, 2001), but lar acceleration signalscoming from thevestibular there isgeneral agreement thateither thehippocampus apparatus.These findingsnot only clarify thecondi- or structures surroundingit (e.g., thesubicular complex tionsunder whichpath integration deficits can occur or entorhinalcortex) are key.Nevertheless, more re- after unilateral medialtemporal lobectomy,but also the search isneeded tocharacterize theindividual contri- nature of thosedeficits. To theextent thatdamage to butionof theother excised structures,as well asspared thehippocampus and itsassociated structures isin- extratemporal tissue,toward thevarious processes un- deed responsiblefor thepath integration deficits we derlyingpath integration. observed,our resultssupport the notion that these We shouldalso note thatalthough we haveargued structures playa homologousrole for pathintegration for ahemisphericdifference between theRTLR and inhumans and rodents. LTLR groups,another, albeit unlikely,interpretation concerns thefact thatthe LTLR group was tested METHODS somewhatlater after surgery thanthe RTLR group.This difference leaves open thepossibility that systematic Participants biasesin path integratio nmaybe associated with Three groupsof participantsgave theirinformed unilateral damage toeither left or rightMTL structures; consent toparticipate (see Table 2). The experiment inthis view, other brainregions maygradually assume was approvedby the George WashingtonUniversity someof thepath integration functionality.Although (GWU) InstitutionalReview Board. Two groupshad possible,this interpretation isunlikely in view of the undergone unilateral MTLresection as therapyfor hemisphericdifferences inpath integration evinced by intractable epilepsy,whereas athird(the control theage-matched patient groupsdescribed byWorsley group) hadno historyof neurological disorder.An et al.(2001). Similarly,other deficits inspatial process- ANOVA showedno reliable differences inage between ing (e.g., spatialmemory) are knownto be more groups, F(2,25) =2.85, p > .05. stronglyassociated withright rather thanleft hemi- sphereMTL injury(Nunn, Graydon, Polkey,& Morris, Medial Temporal Lobectomy Procedure 1999; Smith& Milner, 1981). Given thateffective pathintegration relies inpart The surgeries were performed byone of theauthors uponthe integrity of spatialmemory, can thedeficits (AJC). Thisstandard procedure consistsof afrontal– observed inthe RTLR group be attributed solelyto temporal craniotomy,which exposes thetemporal memoryimpairments? Our Delayed Matching and Tar- lobe and asmallportion of thefrontal lobe (Caputy get Directed Walking tasksinvolved similar retention &Bejjani, 1999). When these cortical surfaces are intervals,but they did not yield similar differences exposed, an electrocorticography recording array is between theRTLR and control groups.There were only putinto place. The epileptogenic area ismapped smalldifferences inresponse consistency in Delayed and defined, occasionally withthe aid of chemical Matching, whereas there were larger differences inboth (Brevital 20 mg) or electrical stimulation.The area of response consistencyand biasin the walking task. theanterior– lateral temporal lobe tobe resected is Althoughthis suggests that impairments in memory defined byelectrocortographic mapping.Based on this donot completely account for theRTLR group’s path mapping,portions of theanterior and lateral surfaces

516Journal ofCognitive Neuroscience Volume 16,Number 4 Table 2. Demographic Details and Neuropsychological Performance ofthe ThreeParticipant Groups a

Healthy Control Left TLRb Right TLRb Sex (M/F) 6/4 3/5 5/5 Age 35 (20–56) 48 (29–59) 42 (27–58) Handedness (R/L) 10/0 8/0 9/1 Time Testc N/A 5.9 (3.1–10.8) 3.0 (0.6–5.1) Wechsler IQ(premorbid) N/A 106d (85–122) 104e (86–128) Rey Copy (max =36) 31 (28–36) 28 (16–34) 28 (10–35) Rey Delay (max =36) 19 (4–26) 11 (6–20) 14 (8–26) WMS LMIg (max = 50) 25 (5–41) 19 (13–27) 19f (9–25) WMS LMIIg (max = 50) 26 (1–38) 16 (8–23) 18f (5–28) aExcept where indicated, mean values are presented, withthe range in parentheses. bTemporal loberesection. cTime oftesting, postsurgery (years). dn = 7. en = 6. fn = 9. gTotalscore.

of thetemporal lobe are resected untilthe area is language-dominant hemisphere,as is common for this quiescent from an epileptogenic standpoint.The MTL procedure, these hemisphericdifferences were too structures are thenresected, includingthe amygdala smallto reach statisticalsignificance given thesample and anterior portionsof theparahippocampal gyrus size inthis study. and hippocampus.The fornix isspared. The temporal The criteria for inclusionincluded: age 18–75 years, lobe resections are measured whenresection isdeter- 12 or more years of education, absence of dementia or minedto be complete from an electrocorticographic psychiatricdisorder, visual acuity 20/ 100 or better, no standpoint.The measurements are made from the difficultywalking withoutassistance, rare or no seiz- temporal tipin an anterior–rostral toa posterior– ures,and left hemispherelanguage dominance (as caudal direction.Three centimeters of thehippocam- assessedby sodium amobarbital testingprior to sur- puswas removed inall patients.The extent of the gery). All participantswere paida smallstipend to help temporal lobe lesionswas estimated byadding the defray transportation and parking costs.The MTL intraoperative resection measurements along thesupe- patientsall hadpresurgical intelligence quotientsof at rior,middle, and inferior temporal gyri.The resulting least 80 (Wechsler Adult Intelligence Scale—Revised sums(which yield an approximationof thetotal lesion [WAIS-R]) (Wechsler, 1981). Althoughpostsurgical in- area along thecortical surface) averaged 7.9 and 6.4 cm telligence scores were generally notavailable, clinical for theRTLR and LTLR patients,respectively. A two- observationsuggested thatall participantswere suffi- tailed t testperformed on these data showedthere to cientlyintelligent tomeet or exceed ascore of 80 on be no reliable hemisphericdifferences, t(16) = 1.21; theWAIS-R at thetime of testing.A two-tailed t test p =.24. As an additionalcheck, lesionvolumes were showedthat the groups differed interms of when estimated on thebasis of postoperativebrain images testingwas conducted relative tothe medial temporal (computerized tomography).Scans were available for lobectomy, t(16) = 2.67, p =.022, withthe LTLR 10 RTLR and 6LTLR patients.Two neuroradiologists group being tested somewhat¡ later after surgery. independentlyestimated, by visual inspection, the percentage of theentire temporal lobe resected. The Neuropsychological Memory Tests two readings for each patient differed byno more than 10% and anydiscrepancies were averaged. Atwo-tailed The performance of theparticipants on four memory t testperformed on these data again showedno testswere compared inseparate ANOVAs: Logical hemisphericdifferences: mean resection percentage Memory Iand IIsubtests(Total Score measure) of 31%; t(14) = 1.04; p =.31. Thus,although somewhat theWechsler Memory Scale (WMS-III)(Wechsler, lessof thelateral temporal lobe was resected inthe 1997) and the copyand delayed recall measures of

Philbecket al.517 theRey– Osterreith Complex Figure (ROCF) test.The verbal distance estimationand delayed distance match- ROCF testis a commonmeasure of visuospatialmem- ing trials,the stimulus cone was presented at distances ory,involving copying a complex visualfigure and then of 2, 2.5, 3, 4, 5, and 6mthree timesapiece in attemptingto reproduce itby memory after a30-min random order. delay.These testsrequire theretention of information for muchlonger durationsthan are involvedin the Procedure behavioraltasks of thecurrent study,but they are nevertheless standard measures and, therefore, provide Target-DirectedWalking ameans ofcomparing our patientswith similar patients Participantsviewed thetarget cone, thenlowered a described elsewhere. Of these tests,only the WMS-III blindfoldand attempted towalk to thetarget’ s location Logical Memory IIsubtestrevealed asignificant group whileholding onto the experimenter’ s arm for support. difference ( p =.036). Pairwiseplanned contrasts ( p = An assistantremoved thetarget before walking began, .05) showedthat the patient groupsboth performed and theexperimenter kepthis or her eyes closed until significantlymore poorlyon this test than the control thetarget was removed soas toremain blindto the group,but did not differ from each other.One control target distance. Participantswere instructed notto use participantperformed quitepoorly on mostof these apace-counting strategy. Whilewalking withthe par- tests.When hisscores were excluded as outliers,all ticipant,the experimenter imposedone of three pos- analysesexcept for the‘ ‘copy’’ measure of theROCF siblewalking speedson each trial.This prevented testshowed reliable group effects ( p < .05), with veering and ensured consistencyacross participantsin pairwiseplanned contrasts ( p =.05) again showing termsof responsedurations. After responding,partic- thatthe two patient groupsperformed similarlyand ipantswere led back to thestarting location without bothperformed more poorlythan the control group. visionand withouterror feedback. The straight-line Inthe ‘ ‘copy’’ test,the participant can see thesample walked distance was recorded viatape measure. figure whilecopying it, so the lack of agroup effect in thistest suggests that all groupswere approximately equated interms of visuospatialattention. Experimenter-GuidedWalking Participantsviewed theenvironment for several sec- Design and Apparatus onds(without a specified target). Theythen lowered theblindfold and grasped theexperimenter’ s arm.The The experiment tookplace ina well-litclassroom. experimenter walked along astraightpath with a Each observer participated infour blocked conditions length of 2to6 m,using one of thethree possible presented inthe following order: target-directed walk- walkingspeeds. At theend of thepath, the participants ing,experimenter-guided walking,verbal distance esti- verballyestimated thedistance walked from theorigin. mation,and delayed distance matching.The order of Theywere thenguided back tothe starting position trialswithin each of these blockswas randomized. In withouterror feedback. The stimulusdistance imposed thetwo walking conditions,stimulus distances of 2.5 bythe experimenter tended to varyslightly from the and 5mwere presented five timesapiece. Intarget- nominaldistances; these variationswere recorded and directed trials,the stimulus was a23-cm tall cone; in thestatistical analyses were conducted ontheresponse experimenter-guided trials,an experimenter presented errors relative tothe stimulus distance actually pre- thestimulus distance byguiding theblindfolded par- sented on each trial. ticipantalong alinear pathof theappropriate length. To discourage pace-counting strategies, slowand fast walkingpaces (approximately1 and 2m/sec, respec- VerbalDistance Estimation tively)were each imposedon twoof thefive measure- Participantsviewed thetarget and verballyestimated its mentsof each stimulusdistance, witha mediumpace distance from theirfeet. (approximately1.5 m/sec) imposedon thefifth. Pace length increases withwalking speed (Mittelstaedt & DelayedDistance Matching Mittelstaedt, 2001), sothis manipulation makes pace counting an unreliable strategy. Thisdistribution of Participantsviewed astimuluscone (the standard) in walking speedsensured thatsuch an effect wouldnot thelaboratory whilestanding in the laboratory door- systematicallybias the overall pattern of responses.To way;they then walked 1.5 mto asecond viewing providea greater range of distances,stimulus distances location inan adjoining hallwayto see an identical of 2, 3, 4, and 6mwere presented twice apiece. These comparisoncone. The standard was notvisible from distances were randomlypaired withthe slow and fast thesecond viewpoint.At thebeginning ofeach trial,the walking paces for each participant.Because these comparisoncone was placed 6.5 mfrom theobserver’ s distanceswere notsystematically crossed withwalking positionat thesecond viewpoint.Five seconds after the pace, we didnot subsequently analyze these trials.In participantreached thesecond viewpoint,an experi-

518Journal ofCognitive Neuroscience Volume 16,Number 4 menter began to movethe cone towards thepartici- ofthe encoding-error model ofpath integration. Spatial pant.The participantdirected theexperimenter to Cognition and Computation, 1, 31–65. Logothetis, N.K.,&Sheinberg, D.L.(1996). Visualobject movethe comparison cone untilits distance from the recognition. Annual Reviewof Neuroscience,19, participant’s toes matched theremembered distance of 577–621. thestandard cone asseen from thefirst viewpoint. This Maguire, E.A.,Burgess, N.,Donnett, J.G.,Frackowiak, taskimposes far fewer demandson visuospatialmem- R.S.J.,Frith, C. D.,&O’Keefe, J.(1998). Knowing where orythan does the ROCFtest,but is much more and getting there: Ahuman navigation network. Science, 280, 921–924. appropriate for assessingthe memory of atarget loca- Markus, E.J.,Barnes, C.A.,McNaughton, B.L.,Gladden, V.L., tionlong enough towalk to it without vision. &Skaggs, W.E.(1994). Spatial informationcontent and reliabilityof hippocampal CA1neurons: Effects ofvisual input. Hippocampus, 4, 410–421. Acknowledgments Mittelstaedt, M.-L.,& Mittelstaedt, H.(2001). Idiothetic Apreliminaryreport ofthis work was presented inApril, 2002 navigation inhumans: Estimation ofpath length. at the annual meeting ofthe Cognitive Neuroscience Society in Experimental Brain Research,139, 318–332. San Francisco, CA.This work was supported inpart by agrant Morris,R. G.M.,Garrud, P., Rawlins,J. N.P.,&O’Keefe, J. fromthe National Institutes ofMental Health (NIMH54216) to (1982). Place navigation impairedin rats withhippocampal Marlene Behrmann. Theauthors thank KurtRicher, Steven lesions. Nature, 297, 681–683. Brown,Sameer Pandit,J’ aime Hall,Kamil Barker and Jonathan Murray, E.A.,& Mishkin,M. (1998). Object recognition Brigman fortheir assistance inconducting the experiment. and location memory inmonkeys withexcitotoxic lesions ofthe amygdala and hippocampus. 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