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Neuropsychologia 49 (2011) 2673–2684 Contents lists available at ScienceDirect Neuropsychologia jo u rn al hom epa ge : www.elsevier.com/locate/neuropsychologia The neural substrates of script knowledge deficits as revealed by a PET study in Huntington’s disease Philippe Allain a,b,c,, Véronique Gaura d,e , Luciano Fasotti f,g , Valérie Chauviré a,b , Adriana Prundean a , Clarisse Sherer-Gagou a , Dominique Bonneau h , Anne-Catherine Bachoud-Levi i,j,k,l , Frédéric Dubas a,b , Philippe Remy d,e,k,m , Didier Le Gall a,b,c , Christophe Verny a a Département de Neurologie, CHU Angers, France b Centre Mémoire de Ressources et de Recherche, CHU Angers, France c Laboratoire de Psychologie (UPRES EA 2646), Université d’Angers, France d URA CEA-CNRS 2210, Orsay, France e CEA Service hospitalier Frédéric Joliot, DRM, Orsay, France f Sint Maartenskliniek Research, Development and Education, Nimègue, Hollande g Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nimègue, Hollande h Département de Génétique, CHU Angers, France i INSERM U955, Equipe 1, “Neuropsychologie Interventionnelle,” IMRB, Créteil, France j Département d’Etudes Cognitives, ENS, Paris, France k Université Paris-Est XII, Faculté de Médecine, Créteil, France l Service de Neurologie, CHU Henri Mondor, AP-HP, Créteil, France m Département de Neurosciences, CHU Henri Mondor, AP-HP, Créteil, France a r t i c l e i n f o Article history: Received 17 September 2010 Received in revised form 7 April 2011 Accepted 20 May 2011 Available online 30 May 2011 Keywords: Huntington’s disease Script knowledge PET Hypometabolism a b s t r a c t Introduction: Previous neuropsychological investigations have suggested that both the prefrontal cortex and the basal ganglia are involved in the management of script event knowledge required in planning behavior. Methods: This study was designated to map, the correlations between resting-state brain glucose utiliza- tion as measured by FDG-PET (positron emission tomography) and scores obtained by means of a series of script generation and script sorting tasks in 8 patients with early Huntington’s disease. Results: These patients exhibited a selectively greater impairment for the organizational aspects of scripts compared to the semantic aspects of scripts. We showed significant negative correlations between the number of sequencing, boundary, perseverative and intrusion errors and the metabolism of several cortical regions, not only including frontal, but also posterior regions. Conclusion: Our findings suggest that, within the fronto-striatal system, the cortical frontal regions are more crucial in script retrieval and script sequencing than the basal ganglia. © 2011 Elsevier Ltd. All rights reserved. 1. Introduction In cognitive psychology, scripts are defined as a class of organized structures stored as knowledge networks for the rep- resentation of frequent activities undertaken by almost everyone such as “Going to a restaurant” (Schank & Abelson, 1977). They are similar in structure to lexical knowledge, and provide informa- tion about typical actors and their role within the scripts, particular instruments and objects important for the actions in scripts, typical Corresponding author at: Unité de Neuropsychologie, Département de Neurolo- gie, Centre Hospitalier Universitaire, 4 rue Larrey, 49033 Angers Cédex 09, France. Tel.: +33 0 2 41 35 55 46; fax: +33 0 2 41 35 35 94. E-mail address: [email protected] (P. Allain). locations in which scripts are performed, and typical sequences of actions. Over the last 25 years the frontal lobes have been consis- tently shown to play a major role in script events processing. This involvement of frontal regions was reflected in several types of experimental tasks: script generation tasks (the subjects are asked to verbally generate, in the correct temporal order, the sequences of actions corresponding to scripts), script sorting tasks (the sub- jects are asked to select and cluster together, from a larger set, actions belonging to the same script) and/or script sequencing tasks (the subjects are asked to rearrange script actions in the correct temporal order). So, in several studies script generation tasks (Godbout & Doyon, 1995; Fortin, Godbout, & Braun, 2003; Godbout, Cloutier, Bouchard, Braun, & Gagnon, 2004; Sirigu et al., 1995; Zanini, 2008) have 0028-3932/$ see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2011.05.015
Transcript
  • Neuropsychologia 49 (2011) 2673 2684

    Contents lists available at ScienceDirect

    Neuropsychologia

    jo u rn al hom epa ge : www.elsev ier .com/ loca

    The ne citHuntin

    Philippe f,g , Clarisse eriPhilippe a Dpartement b Centre Mmoc Laboratoire dd URA CEA-CNRS 2210, Orsay, Francee CEA Service hospitalier Frdric Joliot, DRM, Orsay, Francef Sint Maartenskliniek Research, Development and Education, Nimgue, Hollandeg Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nimgue, Hollandeh Dpartement de Gntique, CHU Angers, Francei INSERM U955, Equipe 1, Neuropsychologie Interventionnelle, IMRB, Crteil, Francej Dpartement k Universit Pal Service de Neum Dpartement

    a r t i c l

    Article history:Received 17 SeReceived in reAccepted 20 MAvailable onlin

    Keywords:Huntingtons dScript knowledPETHypometaboli

    1. Introdu

    In cognorganized sresentationsuch as Goare similar tion about tinstrument

    Correspongie, Centre HoTel.: +33 0 2 4

    E-mail add

    0028-3932/$ doi:10.1016/j.dEtudes Cognitives, ENS, Paris, Franceris-Est XII, Facult de Mdecine, Crteil, Francerologie, CHU Henri Mondor, AP-HP, Crteil, France

    de Neurosciences, CHU Henri Mondor, AP-HP, Crteil, France

    e i n f o

    ptember 2010vised form 7 April 2011ay 2011e 30 May 2011

    iseasege

    sm

    a b s t r a c t

    Introduction: Previous neuropsychological investigations have suggested that both the prefrontal cortexand the basal ganglia are involved in the management of script event knowledge required in planningbehavior.Methods: This study was designated to map, the correlations between resting-state brain glucose utiliza-tion as measured by FDG-PET (positron emission tomography) and scores obtained by means of a seriesof script generation and script sorting tasks in 8 patients with early Huntingtons disease.Results: These patients exhibited a selectively greater impairment for the organizational aspects of scriptscompared to the semantic aspects of scripts. We showed signicant negative correlations between thenumber of sequencing, boundary, perseverative and intrusion errors and the metabolism of severalcortical regions, not only including frontal, but also posterior regions.Conclusion: Our ndings suggest that, within the fronto-striatal system, the cortical frontal regions aremore crucial in script retrieval and script sequencing than the basal ganglia.

    2011 Elsevier Ltd. All rights reserved.

    ction

    itive psychology, scripts are dened as a class oftructures stored as knowledge networks for the rep-

    of frequent activities undertaken by almost everyoneing to a restaurant (Schank & Abelson, 1977). They

    in structure to lexical knowledge, and provide informa-ypical actors and their role within the scripts, particulars and objects important for the actions in scripts, typical

    ding author at: Unit de Neuropsychologie, Dpartement de Neurolo-spitalier Universitaire, 4 rue Larrey, 49033 Angers Cdex 09, France.1 35 55 46; fax: +33 0 2 41 35 35 94.ress: [email protected] (P. Allain).

    locations in which scripts are performed, and typical sequences ofactions.

    Over the last 25 years the frontal lobes have been consis-tently shown to play a major role in script events processing. Thisinvolvement of frontal regions was reected in several types ofexperimental tasks: script generation tasks (the subjects are askedto verbally generate, in the correct temporal order, the sequencesof actions corresponding to scripts), script sorting tasks (the sub-jects are asked to select and cluster together, from a larger set,actions belonging to the same script) and/or script sequencing tasks(the subjects are asked to rearrange script actions in the correcttemporal order).

    So, in several studies script generation tasks (Godbout & Doyon,1995; Fortin, Godbout, & Braun, 2003; Godbout, Cloutier, Bouchard,Braun, & Gagnon, 2004; Sirigu et al., 1995; Zanini, 2008) have

    see front matter 2011 Elsevier Ltd. All rights reserved.neuropsychologia.2011.05.015ural substrates of script knowledge degtons disease

    Allaina,b,c, , Vronique Gaurad,e , Luciano FasottiSherer-Gagoua , Dominique Bonneauh , Anne-CathRemyd,e,k,m, Didier Le Gall a,b,c, Christophe Vernya

    de Neurologie, CHU Angers, Franceire de Ressources et de Recherche, CHU Angers, Francee Psychologie (UPRES EA 2646), Universit dAngers, Francete /neuropsychologia

    s as revealed by a PET study in

    Valrie Chauvira,b , Adriana Prundeana ,ne Bachoud-Levi i,j,k,l , Frdric Dubasa,b ,

  • 2674 P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684

    been associated with severe frontal pathology due to focal lesions(sequencing errors and/or violation errors and/or perseverations).Similar ndings were reported by Godbout and Bouchard (1999),but only in a backward script generation task. However, nor-mal sequenwith lesion& Shallice, but withouAgar, & Burstudies excpatients weof relevant/formances m(organizatioedge (gener

    Script sotrasting ressorting perpatients wisistently shsingle-caseVorano, & 1996; Zallaonly for novever, opposgroup studycase study studies, we Gall, Etcharwell-localizand withouof executiowith frontahealthy conrejected thexhibited aanalysis revwere consisregion (Brorolandic regregion. Theregion (BA ated with inet al., 2001)conrmed tsequencingevant actioresults foundue to the frontal lobein action selow performproposals rnot examin

    Neuroimtion in heaInvestigatinmagnetic rfound activfrontal gyru(BA 22). Knthese ndinalso Wood,and Kruegetions betweIn a positro

    Sadato, Flitman, and Wild (1996) found that when healthy subjectswere asked to make a judgment about the correct temporal orderof script actions, activations were seen in the right frontal lobe (BA8), the left temporal gyrus (BA 22) and the middle temporal gyrus

    ally (ith th

    eral procanglnizets wits wintaly seqientsso Zthe r

    nonte scrwation.ed ofantlwardoduchan , wepressantlere ctioer, ttoget

    pat pativel tents ed bl andifferealamk, 19

    havmplegenducethat en reGodb

    se efron

    scripn ananglaborae & Bly dis) wilhe Suions ich lingn famanglcing performance has also been reported in patientss mainly involving the frontal lobe (Zanini, Rumiati,2002) and in TBI patients with dysexecutive disorderst focal lesions in frontal regions (Cazalis, Azouvi, Sirigu,nod, 2001). It should be noted however, that in all theseept two (Chevignard et al., 2000; Godbout et al., 2004),re as accurate as healthy controls in terms of the numbercentral actions evoked. This suggests that patients per-ost likely reveal a deterioration of the script sequencen) rather than an inability to access intact script knowl-ation).rting and/or sequencing tasks have also yielded con-ults. Both impaired (Sirigu et al., 1996) and normalformances (Sirigu et al., 1998) have been observed inth frontal lesions. Sequencing tasks were more con-own to be sensitive to frontal lobe lesions in both

    studies (Humphreys & Forde, 1998; Rumiati, Zanini,Shallice, 2001) and group studies (Sirigu et al., 1995,

    et al., 1998; Zanini et al., 2002), although in some casesel scripts (Swain, Polkey, Bullock, & Morris, 1998). How-ite ndings were also reported in the above-mentioned

    with TBI patients (Cazalis et al., 2001) and in the single-(TBI patient JK) of Schwartz et al. (1995). In our ownalso found evidence for some of these ndings (Allain, Lery-Bouyx, Aubin, & Emile, 1999). We asked patients withed frontal lobe damage to sort script actions given witht irrelevant actions, according to their putative ordern. In fact, we found a dual dissociation. Some patientsl lesions made signicantly more sorting errors thantrols and patients with posterior brain damage, but

    e irrelevant actions. Other frontally lesioned patients completely reversed pattern of performances. Lesionealed that three out of ve left lateral frontal regionstently related to sequencing scores: the left prefrontaldmanns area [BA] 8, 9 and 46), the left premotor andion (BA 1, 2, 3, 4 and 6), and the left paraventricular

    left paraventricular region and the left posterior orbital11, 12, 13 and 47) were found to be strongly associ-trusion errors. Later, in a second investigation (Allain, using several script sorting and sequencing tasks, wehe role of the left frontal regions in script information

    and the involvement of the left orbital region in irrel-n processing. Our ndings suggest that the equivocald in the above-mentioned studies might be partially

    neuroanatomical localization of the lesions within the. So, a left lateral lesion would entail low performancesquencing, while a left latero-orbital lesion would lead toances in aberrant action identication. However, our

    emain highly speculative, because some of them wereed by subsequent post-hoc analyses.aging techniques have also shown frontal lobe activa-lthy subjects during the performance of script tasks.g script sequencing in normal subjects with functionalesonance imaging, Crozier et al. (1999) for example,ations predominantly in bilateral middle and medials areas (BA 8, 6, 44, 45) and superior temporal regionsutson, Wood, and Grafman (2004) replicated most ofgs using a very similar script-ordering task (BA 8, 6; see

    Knutson, & Grafman, 2005). Kuchinke, van der Meer,r (2009) found that the processing of sequential rela-en two script events activated the left frontal gyrus.n emission tomography (PET) study, Partiot, Grafman,

    bilatertent w2001).

    Seveventsbasal gto orgapatienpatienthe fro(mainlPD pat(see algated askinggeneratine, fogeneradeprivsignicthe foralso prsions tstudiesnondesignicthey wscript aHowevTaken seen infrontalto unrain patiexplainparallefrom dand th& Stricgangliafor exatheir dand redition has be2007; 2006).

    Thethe prwithinNormabasal gther elShallicitative(scriptFirst, toperatand whSchedutions ibasal gBA 21). The ndings by Partiot et al. (1996) are inconsis-e results of our own clinical studies (Allain et al., 1999,

    neuropsychological studies have shown that scriptessing was also impaired in patients with lesions in theia. Zalla et al. (1998), for instance, studied the ability

    script event sequences given with irrelevant actions inth mild to severe degrees of Parkinsons disease (PD),th frontal lobe lesions and healthy controls. Whereasly lesioned patients manifested severe impairmentsuencing errors and poor processing of distractors), the

    exhibited similarly signicant but less severe decitsalla et al., 2000). Godbout and Doyon (2000) investi-ole of the basal ganglia in the generation of scriptsdemented and nondepressed PD patients to verballyript actions under two experimental conditions; rou-rd script generation and nonroutine, backward script

    PD patients generated scripts that were signicantly contextual elements in the forward condition and madey more sequencing and perseverative errors in both

    and backward conditions than healthy subjects. Theyed a signicantly higher number of irrelevant intru-controls in both conditions. In accordance with these

    showed (Allain et al., 2004) that nondemented anded patients with Huntington disease (HD) committedy more chronological errors than normal controls whenasked to re-establish the sequential order of series ofns in the presence or in the absence of irrelevant actions.heir ability to eliminate aberrant actions was intact.her, these results suggest that script processing decitsients with basal ganglia lesions resemble those seen inents. A neuroanatomical explanation has been proposedhe frontal prole of neuropsychological impairmentswith lesions in the basal ganglia. This prole could bey strong anatomical evidence for the existence of ve, at least partially, segregated circuits, which projectnt areas of the frontal cortex through the basal gangliaus, and back to the frontal lobes (Alexander, Delong,86). Consequently, patients with lesions in the basale particular difculties performing frontal tasks (seee Lawrence et al., 1996; Watkins et al., 2000) becauseerative brain disorders affect fronto-striatal systems

    frontal activity. Normal ageing, which is also a con-reduces frontal lobe activity (Tisserand & Jolles, 2003),ported to impair script events processing (Allain et al.,out, Doucet, & Fiola, 2000; Helmes, Bush, Pike, & Drake,

    ndings also suggest that both the basal ganglia andtal cortex are involved in the organization of eventsts. This idea is consistent with the theory developed byd Shallice (1980) to explain the respective roles of theia and the prefrontal cortex in action planning (for fur-tions, see Cooper & Shallice, 2000; Shallice, 1988, 2002;urgess, 1998). These authors have proposed two qual-tinct processes to determine which particular schemal be activated to establish an appropriate plan of action.pervisory Attentional System (SAS), which modulateswhen situations are non-routine (novel or unusual)depend upon the prefrontal cortex. Second, Contention

    (CS), an automatic process which modulates opera-iliar situations, depending upon the integrity of the

    ia. The model suggests that the frontal lobes are not

  • P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684 2675

    involved in the storage of script information, which is representedin the retro-rolandic cortices that store semantic representations,but that they have a role in script information manipulation condi-tions making extensive demands on executive functions. In Normanand Shalliceinvolve exescript-memtemporal osubjects hawritten on as referenccontinuallyments of thabstract scrfrontal patiimpairmentation in wothe Normancic sequenbut overall the other hglia would (schemas) sufcient to(1982), damformance owould causing irreleva

    In the ligand subcorting impairmlesions, parcessing. Hounderlying cerning thepartially inccortex in scseems relatsuch as the processing have been rin script ma

    In orderease (HD) regions whoknowledge characterizit was thouearly stagesis increasinareas, are aLandwehrmpatients havalready shoscript tasksrole of sub-processing.

    To this emapping (Sglucose utileration andof an activatasks durinstudy frontotion of scripsub-cortica

    Table 1Mean UHDRS executive scores (with standard deviations in parentheses) for HDpatients.

    HD patients Normal

    intery PRVl-digiect in

    s ares ares are

    difds inus stur ine of ifferets (i.euch a20044; P

    mildn, 20uanlinkan, agrateal/syes dihe prl andpothing t

    scri

    rials

    jects

    atient t patierimenrs (SD

    mean wereyearsHDRSal capg mil

    .6). Thtients.5 (SDcognitneurotive fuer, 19ntion 973).

    all th.ench version of the Montgomery and Asberg Depression Rating Scale) was also administered. Patients scored a mean of 10.9 (SD = 3.9). Seven

    scored above the cut-off score of 15 for mild depression and one patient5. HD patients also underwent a clinical assessment interview conducted byatrist, showing that none of them showed signs of signicant depression.tients were receiving small doses of medication at the time of testing in

    reduce motor symptoms (Cyammazine, Tiapride).

    ontrol subjectsthe script sorting tasks, the patient group was compared with a group ofal control volunteers (NC). These subjects were 7 females and 5 maless terms, script sequencing tasks are expected to heavilycutive functions. First, they require subjects to retrieveory representations and to mentally simulate the wholerganization of actions in working memory. Second,ve to create a correspondence between each actiona card and the internal abstract representations usedes. Third, during the sequencing stage, subjects must

    shift attention back and forth from the individual ele-e scripts to the general display dictated by the internalipt representations. Hence, the errors committed byents in script sequencing tasks might reect executivets such as a difculty in maintaining abstract represen-rking memory or a diminished shifting ability. Further,

    and Shallice model would not predict an action spe-cing decit in script tasks following frontal lobe lesions,sequencing decits in task recruiting sequencing. Onand, the same model puts forward that the basal gan-be involved in situations where thought operations

    automatically activated by contention scheduling are carry out the task satisfactorily. According to Shalliceage to the basal ganglia should impair the patients per-n a routine task. More specically, basal ganglia damagee difculties in maintaining the right script and inhibit-nt ones (Godbout & Doyon, 2000).ht of the Norman and Shallice model, both prefrontalical regions seem involved in the script events process-ents observed in patients with frontal or basal ganglia

    ticularly in sequencing errors and poor distractor pro-wever, the precise localization of the neural networksthese impairments remains unclear. First, ndings con-

    role of frontal regions in script event processing areonsistent. In addition, while the role of the prefrontalript generation, script sequencing and script sorting

    ively well established, the role of sub-cortical structuresstriatum and the way they impact on script informationis still poorly understood. Finally, no neuroimaging dataeported yet, showing that the basal ganglia play a rolenagement.

    to clarify these questions, we used Huntington dis-as a model to identify the cortical and sub-corticalse dysfunction is responsible for impairments in scriptprocessing. It is well known that, pathologically, HD ised by neuronal loss and cerebral atrophy. Until recently,ght that the striatum was selectively targeted in the

    of the disease (Aylward et al., 2000). However, thereg evidence that cortical areas, in particular frontallso affected (Henley et al., 2008; Kassubek, Gaus, &eyer, 2004; Rosas et al., 2002), suggesting that early HDe cortical and sub-cortical atrophy. In addition, we havewn (Allain et al., 2004) that HD patients are impaired on. As a result, HD represents a reliable model to study thecortical and cortical areas involved in script information

    nd, we have used FDG-PET with statistical parametricPM) to map the correlation between resting state brainization and the scores obtained in several script gen-

    script ordering tasks in HD patients. Although the usetion paradigm (the execution of more specic script

    g a fMRI session) might have been more appropriate to-striatal dysfunctions in HD patients during the execu-t tasks, in order to discriminate between cortical and

    l contributions to action script processing, such stud-

    StroopFluencSymbo

    corr

    a Normb Normc Norm

    ies aredemanprevioform othe uswith dpatieneases set al., al., 2002010) Reima2009; Hrosis (BRothmof inteneuronsynapsedge, tcorticaWe hybelongexplain

    2. Mate

    2.1. Sub

    2.1.1. PEigh

    this expe38.6 yeawhereasSubjectswas 3.1 Scale (Ufunctionindicatin(SD = 20of the pawas 133

    The prises a of execu& Hamshtive atteSmith, 1range onpatients

    A Fr(MADRSpatientsscored 1a psychiThree paorder to

    2.1.2. CFor

    12 normpublished range

    ference (total correct in 45 s) 25.6 (7.9) >35a

    (total correct in 360 s) 40.2 (13) >56b

    t modalities test (total90 s)

    26.7 (8.1) >37c

    issued from Golden (1978). issued from Cardebat, Doyon, Puel, Goulet, & Joanette (1990). issued from Wechsler (1981).

    cult to perform in these patients since task attentioncrease movement disorders critically. Therefore, as inudies, we relied on resting state metabolic data to per-vestigation. There is an abundant literature reportingFDG-PET in the resting state to measure correlationsnt cognitive and motor tasks in patients, either in HD., Teichmann et al., 2008) or in many other brain dis-s Alzheimers disease (Desgranges et al., 2002; Eustache; Lozza et al., 2004; Mentis et al., 2002; Mosconi etenniello et al., 1995; Piolino et al., 2007; Woo et al.,

    cognitive impairment (Caselli, Chen, Lee, Alexander, &08; Nishi et al., 2010), Parkinsons Disease (Abe et al.,g et al., 2007; Nagano-Saito et al., 2004) or multiple scle-enberg et al., 2000). According to Magistretti, Pellerin,nd Shulman (1999), regional metabolic rate is a markerd local synaptic activity and it is sensitive to both directnaptic damage and secondary functional disruption atstant from the primary site of pathology. To our knowl-esent study is the rst attempt to discriminate between

    subcortical contributions to action script processing.esize that there is a hypometabolism in cerebral areaso cortical-sub-cortical frontal circuits, contributing topt processing impairments.

    and methods

    groupnts with clinical symptoms and genetically identied HD were seen int. The 8 HD patients were 4 females and 4 males whose mean age was

    = 7.5). Their mean number of years of education was 11.1 (SD = 2.2), estimated IQ was 106 (SD = 7.6) on the AVB test (Beauregard, 1971).

    early in the course of their disease: the mean duration of symptoms (SD = 2.9). Mean scores on the Unied Huntingtons Disease Rating; Huntington Study Group, 1996) activities of daily living and totalacity scales were 18.4/25 (SD = 4.9) and 11.7/13 (SD = 2.1) respectively,d functional impairment. The UHDRS total motor score was 33.8/124e mean Mini Mental State Examination score was 26.6 (SD = 1.7; none

    scored below 24) and the mean Mattis Dementia Rating Scale score = 6.7), indicating very mild cognitive impairments.ive part of the UHDRS was also administered to the patients. It com-psychological battery of three subtests that measure several domainsnctioning: spontaneous exibility with a letter uency task (Benton89), inhibition with the Stroop Color-Word Test (Stroop, 1935), selec-and working memory with the Symbol-Digit Modalities Test (SDMT,As can be seen in Table 1, HD patients performed below the normalese measures, suggesting the presence of executive disorders in these

  • 2676 P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684

    whose mean age was 41.5 years (SD = 12.4). Their mean total years of educationwere 11.1 (SD = 3.3) and their mean IQ was 108 (SD = 8.9) on the AVB test. Noneof them reported a history of nervous system disease or psychiatric problems.The HD patients and the NC groups did not differ signicantly with respect toage [t(18) = 0.58, P = 0.56]. The 2 groups were also matched on educational level[t(18) = 0.03, P

    For the scgroup of 9 NC42.1 years (SDwith a mean Imedical illnesThe 2 groups deducational le

    The two gP = 0.89], educ

    Ethical peand the Crtewas obtained the neuropsycperformed in c

    2.2. General p

    Within anropsychologicand a PET mea

    2.3. Neuropsy

    2.3.1. Script gThe subjec

    ties: (1) sewina cup of coffeewich, (7) doinggenerate the severyday activtemporal ordeticipants werescripts had to

    The mean The eight scripby Bower, Blac(1987) and Gobased on a pre2000), which French languaactivities (stan

    The semanon three typevant intrusionthe healthy cothis normativsubsequently trol subjects), actions (mentimet the inclusto the particulsemantic catewas therefore ticular script. C1983) have shor core of theproviding con

    Difcultiesequencing erlogical sequenthe generationpoint) was alsoperseverative a script, were

    2.3.2. Script soWe used th

    to construct twIn the rst

    zation of 2 sccontained 16 aarray of cardswas written ontask. Subjects

    nished laying them on the table. The subjects were then requested to arrange allthe actions of each script in a correct sequential order.

    In the second script sorting task, the subjects were also asked to arrange theactions of 2 different scripts in a correct sequential order, but this time both scriptswere given with 3 aberrant or distractor items consisting of actions belonging to

    ripts. Ttainin

    t distrcript the bif the actort was

    . Subje layingmean

    of disred fo

    scann

    escribigh-rejects

    carritate wous in

    tistica

    ognitivcogniticago, ric Mare tesd and

    tionshng non

    age ages w

    Welrieyalaira8 mm atomy, we ptient wormalative l, a coatienism. Tsholdovide

    wordhan 23metat-valuave thn.

    ults

    ript g

    Sema twoespec) = 21by HDtivel

    as wts (nts e 2. T = 0.97] and IQ [t(18) = 0.31, P = 0.75].ript generation task, the patient group was compared with another. These subjects were 6 females and 3 males whose mean age was

    = 7.2). Their mean number of years of schooling was 10.8 (SD = 8.1)Q of 109 (SD = 9) on the AVB test. All subjects were free of seriouss. None of them had history of neurological and psychiatric illness.id not differ signicantly with respect to age [t(15) = 0.97, P = 0.34],vel [t(15) = 0.18, P = 0.85] and IQ [t(15) = .58, P = 0.56].roups of NC were also matched with respect to age [t(19) = 0.13,ation level [t(19) = 0.14, P = 0.88] and IQ [t(19) = 0.29, P = 0.77].rmission was obtained from the French National Ethics Committeeil University Hospital Ethics Committee. Written informed consentfrom all patients. Normal control volunteers gave their consent tohological study after being extensively informed, and the study wasonformity with the declaration of Helsinki.

    rocedure

    interval of a few days at most, each HD patient underwent a neu-al examination including script generation and script sorting taskssurement of resting CMRGlu.

    chological protocol

    eneration tasksts had to describe how they would accomplish eight everyday activi-g a button again, (2) writing a letter, (3) making an omelet, (4) making

    with milk and sugar, (5) making a green salad, (6) making a ham sand- the washing up and (8) polishing shoes. They were asked to verballyequence of actions (a list of 1020 actions) corresponding to eachity, which was written down by the experimenter. Respect of ther of execution of the actions in each script was also demanded. Par-

    rst given an example (Doing morning routines). The order in whichbe generated was randomized.total number of actions produced in each script was rst considered.ts were then scored according to criteria that have been proposedk, and Turner (1979), Roman, Brownell, Potter, Seibold, and Gardnerdbout and Doyon (2000). The norms used to score our scripts werevious study with 274 francophone healthy control subjects (Allain,

    was conducted in order to establish a corpus of script actions in thege and to quantify four main characteristics of the actions within thedardness, sequence, centrality and distinctiveness).tic aspect of the script was measured using sorting criteria based

    s of actions (major, minor and trivial) and one type of error (rele-). To be included an action had to be mentioned by at least 18% ofntrols subjects of the normative study (Allain, 2000). Consistent withe study (Allain, 2000), actions that met this bottom criterion wereclassied as major (mentioned by more than 60% of the healthy con-minor (mentioned by 4059% of healthy control subjects), or trivialoned by 1839% of control subjects). By contrast, actions that did notion criteria were listed as relevant intrusions, which either belongedar script (relevant) or not (irrelevant). The number of actions in everygory, except for the relevant intrusions, was weighted; this numberdivided by the total number of actions that were generated for a par-ognitive psychologists (Bower et al., 1979; Corson, 1990; Galambos,own that a script consists of major actions that constitute the heart

    semantic aspects of the script, with more minor and trivial actionstext.s in the temporal aspect of the script were evaluated in terms ofrors (Roman et al., 1987), which correspond to a displacement in thece of actions within a script. The presence of boundary errors (when

    of events stops short of the stated endpoint or extends beyond this used to evaluate the temporal dimension of the script. Furthermore,errors, which consist of actions that are repeated more than once inalso measured.

    rting taskse normative data proposed by Bower et al. (1979) and Corson (1990)o types of script sorting tasks.

    one, the subjects were asked to re-establish the sequential organi-ripts (Going shopping and Going to a restaurant). These scriptsnd 21 actions respectively. Subjects were presented with a shufed

    with an action written on each card. The title (header) of the script a separate card and was displayed in front of the subject during thewere allowed to look at and read all cards once the examiner had

    other sceach conaberranfor the sask for actions othe distrthe scripthe tasknished

    The numbereters sco

    2.4. PET

    As dwith a hThe subies wereresting sintraven

    2.5. Sta

    2.5.1. CThe

    Inc., ChparametChi-squagenerateThe relained usi

    2.5.2. ImIma

    (SPM99;1996). Bspace (T8 mm brain an

    Firsteach payears) nconserv

    Thenthe HD pmetabolthis threthat it prIn otherhigher ti.e., hypoa lower do not hcorrectio

    3. Res

    3.1. Sc

    3.1.1. The

    with r[U (15duced respecactions8 scripelemenin Tablhe scripts used were Going to a wedding and Changing a at tire,g 12 actions. The subjects were not informed of the presence of theactors which were stamp a ticket, have a swim, place the jackGoing to a wedding and wipe oneself, install the beach umbrella,ll for the script Changing a at tire. Subjects were presented all thescript and the 3 aberrant distractors written on cards. The actions ands were mixed and displayed on a table in random order. The title of

    also written on a card displayed in front of the subject throughoutcts were allowed to look and read the cards when the examiner had

    them on the table and to arrange the cards in a correct sequence. number of sequencing errors (rst and second task) and the meantractor actions accepted (second task) were the performance param-r each subject.

    ing procedure

    ed elsewhere (Gaura et al., 2004), PET examinations were performedsolution EXACT HR+ tomograph (CTI/Siemens) using a 3D acquisition.head was xed using an individually molded headholder. All stud-ed out in a quiet, dark environment while the patients were in theith the eyes closed. Metabolic images were acquired 3050 min afterjection of 118280 MBq of [18F]uoro-2-deoxy-d-glucose (18FDG).

    l analysis

    e data analysisive data were analyzed using the statistical package SPSS V5.1 (SPSSIL, USA). As these data were not normally distributed, the non-nnWhitney U-test was used to compare HD patients and HC groups.ts were used to compare frequencies (proportions of types of actions

    proportions of subjects making errors in the script generation tasks).ip between cognitive variables obtained in the script tasks was exam--parametric Spearman rank correlations.

    nalysisere analyzed using the statistical parametric mapping softwarecome Department of Cognitive Neurology, London, UK, Friston,, images were transformed into Talairachs standard stereotaxicch & Tournoux, 1988). The images were then smoothed with an8 mm Gaussian lter to compensate for intersubject variability of

    (Friston, 1996).erformed a voxel-by-voxel t-test comparison of brain metabolism ofith the brain metabolism obtained in 17 age-matched (35.8 10.9

    controls. The statistical threshold of each comparison was set at aevel of P < 0.0005.rrelation analysis using a multiple regression model was performed ints to investigate the relationships between cognitive scores and brainhe threshold of the correlation analysis was set at P < 0.005. Although,

    is not corrected for multiple comparisons (Bonferroni), our feeling iss a good compromise considering the exploratory nature of the study.s, a Bonferroni correction would reveal only voxels with a t-value.0 which is highly conservative and might elicit false negative results,bolic regions that are truly associated with cognitive decits but withe. Accordingly, our results should be considered as exploratory ande high degree of condence that would be provided by a Bonferroni

    eneration tasks

    ntic aspect groups did not differ signicantly from each othert to the total number of actions generated per script.0, P = 0.14]. Mean numbers of actions per script pro-

    patients and NC were 10.1 (SD = 3.8) and 10.8 (SD = 2.1)y. The mean percentages of major, minor, and trivialell as relevant intrusions that were generated for the

    umber of elements to a class of action/total number of100) in the HD and normal control groups are reportedhe semantic aspects of the script were examined using

  • P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684 2677

    Table 2Mean percentage (with standard deviations in parentheses) of major, minor, andtrivial actions, as well as relevant intrusions that were generates for each script inthe HD and NC groups.

    Variables HD patients NC subjects P

    Major 62.2 (11.4) 60.2 (7.3) 0.77Minor 11.0 (3.7) 24.4 (5.5) 0.01Trivial 9.6 (4.7) 11.0 (2.9) 0.81Relevant intrusions 14.2 (6.8) 3.4 (1.6) 0.005Irrelevant intrusions 3.0 (1.2) 1.0 (0.2) 0.31

    Chi-square tests. Comparison of proportions of all types of actionsgenerated in both groups revealed a signicant main effect of typeof action [Chi 2 = 13.02, df = 4, P = 0.01], suggesting that the twogroups produced a different semantic organization of the script.Further post hoc analyses comparing the proportions of each type ofactions produced in each group showed that HD patients generateda smaller proportion of minor elements [Chi 2 = 5.8, df = 1, P = 0.01],and a higheP = 0.005]. Tthe proportial element[Chi 2 = 1.02

    3.1.2. TempA signic

    sequence otion of HD signicantlyP = 0.001]. Cnicantly mfar greater generation the HC grouof persever[U (15) = 6.0portion of Hsubjects in df = 1, P = 0.0used in the

    3.2. Script s

    In compacantly more(Going to a r(18) = 6.0, PChanging a

    Howevebetween Hactions (Ta

    Table 3Sequencing, bin parentheses

    Variable

    Sequencing Mean erroNumber o

    Boundary erMean erroNumber o

    PerseverativMean erroNumber o

    Table 4Script sorting task scores (means with standard deviations in parentheses).

    HD patients NC subjects P

    Sequencing errorsGoing to aGoing shoGoing to aChangingTotal

    Irrelevant acGoing to aChangingTotal

    Changing aence emertask.

    rrelaand e

    lyse scrn thtion in s

    gro signencycanin thho =.72, P

    etabo

    le 5 etabd a

    Thisle co0, 1d in , 2, 4

    gniti

    icadataally

    in Tardincingut albilat

    is cntia nigra and the pons, and smaller regions in the prefrontal

    (right middle and superior gyri, left middle and left precen-r proportion of relevant intrusions [Chi 2 = 7.7, df = 1,here was no signicant difference, however, betweenions of major elements [Chi 2 = 0.08, df = 1, P = 0.77], triv-s [Chi 2 = 0.05, df = 1, P = 0.81] and irrelevant intrusions, df = 1, P = 0.31].

    oral aspectant difference was found between HD and NC groups in

    rdering [U (15) = 0.0, P = 0.0005] (Table 3). The propor-patients manifesting sequencing errors (8/8) differed

    from those (2/9) in the NC group [Chi 2 = 10.5, df = 1,ompared to the HC group, HD patients produced sig-ore boundary errors [U (15) = 16.0, P = 0.02]. In fact, aproportion of patients in the HD group (5/8) stoppedof events short of the stated end point, compared top (1/9, [Chi 2 = 4.8, df = 1, P = 0.02). The mean number

    ative errors was signicantly higher in the HD group, P = 0.003]. A statistical analysis comparing the pro-D patients (7/8) making this kind of error to that of

    the HC group (1/9) reached signicance [Chi 2 = 9.92,01]. There was no gender difference in any of the scriptsgeneration task.

    orting tasks

    rison with HC subjects, HD patients, committed signi- errors of sequential organization in all scripts (Table 4)estaurant: [U (18) = 0.0, P = 0.0002]; Going shopping: [U

    = 0.001]; Going to a wedding: [U (18) = 4.5, P = 0.0008];at tire: [U (18) = 10.5, P = 0.003]).r, there was no signicant difference in performanceD patients and HC subjects in inhibiting irrelevantble 3) (Going to a wedding: [U (18) = 44.0, P = 0.75];

    oundary, and perseverative errors (means with standard deviations) in the HD and NC groups.

    HD patients NC subjects P

    errorsr (SD) 7.9 (2.7) 0.1 (0.3) 0.0005

    3.3. Coscores

    Anain bothbetweegeneraduced the HDrelatedthe ua signierrors task (R(Rho =

    3.4. M

    Tabhypomrevealenuclei.multipareas 1area anareas 1

    3.5. Co

    Signnitive principshown

    Regsequengyrus bgyrus erationsubstacortexf subjects 8/8 2/9 0.001

    rorsr (SD) 1.0 (0.9) (0.3) 0.02f subjects 5/8 1/9 0.02

    e errorsr (SD) 4.1 (2.9) 0.2 (0.7) 0.003f subjects 7/8 1/9 0.001

    tral gyri), th(superior anand inferiogeneration)cortex (leftgyrus and errors is co(mainly cun restaurant 3.6 (1.2) 0.3 (0.5) 0.0002pping 2.1 (1.3) 0.2 (0.4) 0.001

    wedding 1.7 (0.7) 0.2 (0.4) 0.0008 a at tire 2.6 (1.7) 0.2 (0.4) 0.003

    10.1 (2.9) 1.1 (0.9) 0.0002

    tions used wedding 0.2 (0.5) 0.2 (0.4) 0.75

    a at tire 0.6 (0.5) 0.5 (0.5) 0.640.9 (0.3) 0.4 (0.8) 0.21

    at tire: [U (18) = 42.0, P = 0.64]). No gender differ-ged in any of the scripts used in the script sorting

    tions between script task scores and between taskxecutive scores

    s of the relationship between script scores computedipt tasks (HD group) revealed a signicant correlatione total number of sequencing errors produced in scripttasks and the total number of sequencing errors pro-cript sorting tasks (Rho = .78, P = 0.03). In addition, inup, sequencing errors in the script sorting task cor-icantly with the total number of words produced in

    task of the UHDRS (Rho = .79, P = 0.02). There was alsot correlation between the total number of sequencinge script generation task and the scores in the uency

    .82, P = 0.01) and in the symbol-digit modalities test = 0.04) of the UHDRS.

    lism results

    and Fig. 1 show the topography and the extent of theolism in patients compared with controls. SPM analysismarked reduction of activity in caudate and putamen

    signicant hypometabolism was also demonstrated inrtical areas: in the prefrontal regions in Brodmanns1, 47, 46, anterior cingulated cortices, parietal inferiorthe sensorimotor and premotor regions, in Brodmanns, 6, 44.

    vemetabolic correlations

    nt correlations (P < 0.005, uncorrected) between cog- and brain regions were numerous and concernedcortical regions. Data produced by the SPM analysis areable 6.g script generation, we showed correlations between

    errors and metabolism of the right middle temporalso with the left precentral gyrus and the inferior frontalerally. The number of boundary errors in script gen-orrelated with the hippocampal region bilaterally, thee cingulate gyrus bilaterally, the left temporal cortexd inferior gyri) and the left parietal cortex (postcentral

    r parietal gyri). Concerning perseverative errors (script, we showed correlations with the bilateral prefrontal

    inferior and right superior gyri) and the right cingulatethe left postcentral gyrus. The number of sequencingrrelated to a hypometabolism of the occipital cortexeus and lingual gyrus) and the inferior frontal gyrus

  • 2678 P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684

    Table 5SPM analysis: local peaks in the whole brain obtained with the t-test comparison.

    Anatomical region Side BA Talairach coordinates Z score Number ofvoxels

    Corrected P(cluster level)

    Corrected P(voxel level)

    x y z

    Caudate L 12 14 2 Inf 2083 0.000 0.000Caudate L 14 6 14 7.79 0.000Caudate R 16 10 10 7.76 1242 0.000 0.000Putamen L 26 4 2 7.17 0.000Putamen R 30 4 2 5.60 0.001Putamen R 26 4 0 5.32 0.005Cingulate gyrus R 24 0 38 2 4.33 174 0.031 0.231Inferior frontal gyrus R 1047 44 42 2 4.64 0.079Middle frontal gyrus R 10 32 50 8 5.56 708 0.000 0.002Middle frontal gyrus R 11 32 36 14 4.72 0.060Middle frontal gyrus L 10 28 46 10 5.19 509 0.000 0.009Middle frontal gyrus L 1046 32 38 20 4.49 0.172Middle frontal gyrus R 44 52 14 10 5.34 513 0.000 0.004Middle frontal gyrus R 6 32 8 46 4.18 0.366Middle front 4.7Superior fro 3.8Superior fro 3.8Superior fro 3.6Precentral g 4.7Precentral g 4.9Postcentral g 4.3Postcentral g 3.7Inferior pari 3.7

    BA = Brodman HD pa(corrected valu

    bilaterally band fusiformand superio

    4. Discussi

    The aimof script prmapping thlization meseveral scripatients wiuse of morhave been min HD patiesubjects sinment disordstudies of dmetabolic dthe cognitiving impairmregions: prietal and ocdiscussed inand the fram

    arac

    resu by pucat

    patiere crent tive ecribe, theipt. T

    thativelyo thoal gyrus L 11 30 38 12 ntal gyrus L 11 10 52 24 ntal gyrus R 11 16 64 20 ntal gyrus R 6 20 6 60 yrus R 6 54 4 10 yrus R 4 46 14 38 yrus R 40 56 18 14 yrus L 12 38 26 40

    etal lobule R 40 40 38 46 n area; x, y, z = coordinates of peaks in Talairachs system; L = left; R = right; n = 8 fores are also in the table).

    ut also small regions in right temporal cortex (middle gyri) and parietal cortex (postcentral gyrus, inferior

    r gyri).

    on

    of the present study was to unravel the neural basesocessing impairments in brain-damaged patients bye correlations between resting-state brain glucose uti-asured by PET and measures of script knowledge acrosspt generation and script sorting tasks in a group ofth HD. As mentioned in the introduction, although thee specic cognitive tasks during a fMRI session might

    ore appropriate to study fronto-striatal dysfunctions

    4.1. Ch

    Thecessingand edby thethey wincoheseverato desomeletper scrgestingis relapared tnts, such studies are difcult to perform with thesece attention demanded by the task increases move-ers to an unacceptable degree. Therefore, as in previousemented or HD patients, we relied on resting stateata to perform our correlations. In the present study,emetabolic correlations revealed that script process-ents were mainly related to the dysfunction of cortical

    marily the lateral frontal cortex, but also temporal, pari-cipital areas, regardless of the task. These results are

    the context of previous clinical and neuroimaging dataework of scripts.

    and consistsmaller proevant intrurelevant intsequencingevents and point (boun

    Script sesorting tasksequencingity to elimin

    Fig. 1. Glassview of the t-test statistical t-map thresholded 154 0.046 0.0647 77 0.251 0.7104 39 0.590 0.7462 35 0.640 0.9251 0.0614 512 0.000 0.0249 0.1956 20 0.835 0.8210 0.879

    tients; n = 17 for healthy controls. Signicant P < 0.0005, uncorrected

    teristics of script impairments in HD patients

    lts of the present study suggest that script event pro-atients with HD is impaired when compared with age-ion-matched controls. Although the scripts generatedents contained a sufcient amount of major actions,haracterized by a lack of detailed information and by ansequential organization, with several boundary and per-rrors. Specically, when patients with HD were asked

    episodes like Sewing a button again or Making anir description consisted of about ten major sub-sectionshis is equivalent to the performance of controls, sug-

    t the general organization of patients script knowledge preserved. However, their descriptions, when com-se of control subjects, were dominated by typical events

    ed of relatively fewer details (HD patients produced aportion of minor elements), with relatively more rel-sions (HD patients produced a higher proportion ofrusions) and perseverative errors. In terms of response, HD patients tended to confuse the sequential order ofto stop the generation of events short of the stated enddary errors).quencing impairments were also observed in the scripts, in which HD patients committed signicantly more

    errors than controls. However, in these tasks, their abil-ate aberrant actions was intact. A signicant correlation

    at P < 0.0005, uncorrected.

  • P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684 2679

    Table 6Negative correlational relationships between metabolism and scores on the script generation and script for the HD patients.

    Cognitive domain Side BA Talairach coordinates Z score Number of voxels

    Anatomical region x y z

    Sequencing errors (script generation)Inferior frontal gyrus L 46/45 42 26 22 3.29 34Inferior frontal gyrus R 46/45 38 28 22 3.10 22Middle temporal gyrus R 21 50 2 16 3.70 154Precentral gyrus L 6 40 0 34 3.35 55Boundary errors (script generation)Middle frontal gyrus R 10 12 64 22 3.19 36Middle frontal gyrus L 10 40 50 22 3.50 22Superior frontal gyrus R 6 20 8 72 4.57 49Superior frontal gyrus R 9 24 62 26 4.00 34Superior frontal gyrus R 6 12 6 58 3.39 74Superior frontal gyrus R 6 10 4 64 3.32Superior temporal gyrus L 28/38 16 12 28 3.16 20Superior temporal gyrus L 28/38 22 8 24 2.62Inferior temporal gyrus L 20 42 18 26 3.33Precentral gyrus L 4 34 20 70 3.36 53Postcentral gyrus L 40 64 24 26 4.43 37Inferior parietal gyrus L 40 60 32 24 2.59Cingulate gyrus R 24 10 4 46 2.74Cingulate gyrus L 24 4 14 24 3.24 35Cingulate gyrus L 24 14 14 28 2.95Cingulate gyrus L 32 10 30 10 3.48 88Hippocampal gyrus R 32 12 16 4.42 73Hippocampal gyrus L 20/38 26 18 36 3.68 256Hippocampal gyrus L 35 16 8 22 3.46 111

    36 18 14 3.69Substancia nigra 10 12 6 3.41Pons 10 12 16 3.11Pons 4 16 38 3.42 165Pons 2 28 34 3.36Pons 2 28 24 2.86

    38 48 20 3.31 28Perseverative errors (script generation)Superior frontal gyrus R 6 10 4 78 3.44 74Superior frontal gyrus R 6 2 8 76 2.61Inferior frontal gyrus L 44/45 42 18 18 3.76 44Postcentral gyrus L 1/2 40 32 58 3.30 36Cingulate gyrus R 24 16 2 44 3.44 43Relevant intrusion (script generation)Superior frontal gyrus L 6 14 0 76 4.19 483

    7 14 54 76 3.82Superior frontal gyrus L 6 4 6 76 3.75Middle frontal gyrus L 11 38 32 16 3.21 27Middle temporal gyrus R 21 72 12 12 3.2 40

    74 24 12 2.97Middle temporal gyrus 21 64 48 4 2.9 20Cingulate gyrus 30/23 0 54 10 3.58Cingulate gyrus/precuneus 23/31 0 56 20 4.87 152Fusiform gyrus R 37 44 50 16 3.72 55Lingual gyrus L 17 8 88 14 4 78Precuneus L 7 6 66 62 3.75 92

    8 58 58 2.719 38 84 16 3.58 79

    Precuneus R 19 20 86 40 3.47 5512 86 38 3.06

    Cuneus L 18 20 100 8 3.96 8524 96 2 3.33

    Cuneus R 18 10 100 10 3.38 100Middle occipital gyus R 18 24 94 22 3.35

    18 98 14 2.95Cerebellum R 42 60 20 2.99Sequencing errors (script sorting)Middle frontal gyrus L 46 44 26 26 3.28 39Inferior frontal gyrus R 46/45 42 30 14 3.78 83Middle temporal gyrus R 21 62 0 20 3.43 30Superior parietal lobule R 7 36 56 48 2.79Inferior parietal gyrus R 40 44 56 44 3.60 53Inferior parietal lobule R 40 52 62 38 2.88Postcentral gyrus R 2 28 34 58 3.33 24Postcentral gyrus R 2 20 38 56 2.73Cuneus R 17 4 80 6 4.35 266Cuneus L 17/18 4 88 2 3.40Cuneus R 17/18 16 96 4 2.84 23Fusiform gyrus R 37 32 50 12 3.62 25Fusiform gyrus R 19 24 76 14 3.56 72Lingual gyrus L 18 16 82 18 3.25 32Cerebellum L 24 56 16 3.14 31

    The table shows regions in which there was a signicant negative correlation between metabolism and scores on the script generation and script sorting. All voxels aresignicant at a threshold of P < 0.005, uncorrected for multiple comparisons across the whole brain volume.

  • 2680 P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684

    indicated than sequencing difculties in script generations taskswere consistent with sequencing problems in script sorting tasksin HD patients.

    The present results suggest that the performance of HD patientsin script geto a deterioity to accescan be arguview that iduce a greasemantic kna two-compcesses frommodel in wthe way in This claim i

    In this thto heavily insition, we exibility (digit modaresembles the same twith Shallicpreestablishtheir script-whole tempduring the stion back athe generalsentations. current stucommitted ing abstractshifting abi

    This patParkinson dfunctioningeral studiesindividual eimpairmenpoor procestasks, and or script geauthors, alsdeprived oferrors and i

    It is inteteristic of bosome discrefrom the tw1998). Firstirrelevant aet al., 2004)patients in patients inctheir scriptdifculties ment of a sinformationparison of ein the actuathat our HDtheir set shtasks, Godbmore irrele

    posed that this type of error was specic to a striatal dysfunctionand consistent with Shallices (1982) theory, in which damage tothe basal ganglia should impair the ability to maintain script actionsactive in memory and to inhibit irrelevant ones. Our HD patients

    t prontainctionis prt soen toifferelitiesedgeript gla etsingions ludintract

    taskscripion sto enlogice ordpresesubstt abo

    patummnt wbasat al.,cingt rsole iith Ssal g

    of srelevcriptcons

    eural

    t, it grouh PEtamtiplensored iet al992;

    foun witcingientseriorntals thces. in st

    scrip009hinkneration and script sorting tasks are most likely dueration of the script organization rather than an inabil-s an intact semantic representation. In other words, ited that the decits described are consistent with then HD patients fronto-striatal lesions selectively pro-ter impairment in the organizational aspects than in theowledge of a script. This nding is more consistent withonent model that dissociates script organizational pro-

    semantic script knowledge than with a one-componenthich all aspects of a script including script content andwhich this content is organized are closely related.s more consistent with Shallices (1982) model.eoretical model, script sequencing tasks are expectedvolve executive functions. Consistent with this propo-have found that sequencing errors correlated withuency task) and working memory measures (symbol-

    lities test) of the UHDRS. This pattern of correlationsthe one we have observed in elderly subjects usingasks (Allain et al., 2007). In this study, and in linees (1982) model, we have suggested that ordering aed sequence of actions requires the subjects to retrievememory representations and to simulate mentally theoral structure of the actions in working memory. Then,equencing stage, subjects must continually shift atten-nd forth from the individual elements of the scripts to

    display dictated by the internal abstract script repre-We think that these suggestions could be applied to thedy. Hence, we can speculate that the sequence errorsby HD patients might reect a difculty in maintain-

    representations in working memory and a diminishedlity.tern of cognitive decits resembles the one seen afterisease (PD), another clinical condition that disrupts

    of the frontostriatal system. As mentioned before, sev- have shown than PD patients have preserved access tovent knowledge required for planning, but signicantts in well-dened aspects of script knowledge retrieval:sing of distractors (Zalla et al., 1998) in script sortingpoor sequencing in script sorting (Zalla et al., 1998)neration tasks (Godbout & Doyon, 2000). The lattero showed that the scripts generated by PD patients were

    contextual elements, and contained more perseverativerrelevant intrusions (Godbout & Doyon, 2000).resting to note that while sequencing errors are charac-th types of patients with basal ganglia lesions, there arepancies between the present HD group and PD patientso previous studies (Godbout & Doyon, 2000; Zalla et al.,, in our script sorting tasks, HD patients discarded all thections. This result ts with our previous ndings (Allain

    in HD patients, but differs from the performance of PDthe study by Zalla et al. (1998). In this last study, the PDluded one or more semantically related distractors in

    arrangements. Zalla et al. (1998) suggested that theseof PD patients with distractors were due to an impair-witching mechanism that is necessary for processing

    in parallel, more precisely to a difculty in on-line com-vent sequences from memory with those to be executedl task. When interpreted in the light of this idea, the fact

    patients discarded most irrelevant actions suggests thatifting ability is intact. Second, in their script generationout and Doyon (2000) found that PD patients producedvant intrusions than normal control subject. They pro-

    did noto maivant awith thin scrip

    Takhave ding abiknowland scthe Zalcompoconditers incand dissortingand 2 evocatasked chronoreversof the These broughand HD

    In scohereof the Zalla esequenThus, ahas a rtent wthe baactionsmost irright sis less

    4.2. N

    Firsin our ies witand puin mulrior, sedescribGaura et al., 1

    WerelatedSequenHD patthe infdle) froconrmsequenfound tion inet al., 2by Kucduce irrelevant intrusions, suggesting that their ability script actions active in memory and to inhibit irrele-s are better preserved than in PD patients. Consistentoposition, our HD patients discarded irrelevant actionsrting protocols.gether, these discrepancies suggest that HD and PDnt consequences on script generation and script sort-. To substantiate this idea, it is useful to compare script

    in PD and HD patients using the same script sortingeneration tasks. This has not been the case to date. In

    al. (2000) study, for example, approximately 20 events 4 independent scripts were presented under different(script events with headers, script events with head-g distractor events and script events without headersors) in the script-event reconstitution task. In our scripts, 2 scripts containing each 12 actions with 3 distractorsts containing 16 or 21 actions were used. In the scripttudy by Godbout and Doyon (2000), PD patients wereumerate the actions of 6 familiar scripts in the correctal order and the actions of 6 other familiar scripts in theer. As mentioned in the materials and methods sectionnt paper, we used 8 scripts in the script evocation task.antial differences in experimental protocols may haveut the variation of performance proles observed in PDients.ary, the behavioral results of the present study are

    ith the data of previous studies in patients with lesionsl ganglia (Allain et al., 2004; Godbout & Doyon, 2000;

    1998), reecting a predominant impairment of script rather than a problem of access to script knowledge.t view, our ndings support the claim that the striatumn script information sequencing. This claim is consis-hallices (1982) model, which implies that damage toanglia impairs the ability to sequentially organize thecripts. However, the fact that our HD patients discardedant action suggests that their ability in maintaining the

    and inhibiting irrelevant ones is preserved. This ndingistent with Shallices ideas.

    bases of script decits in HD patients

    should be noted that the pattern of hypometabolismp of HD patients is in accordance with previous stud-T in HD. The marked reduction of activity in caudateen nuclei, together with a signicant hypometabolism

    areas of prefrontal, anterior cingulated, parietal infe-imotor and premotor corticles have repeatedly beenn these patients (see for example, Furtado et al., 2005;., 2004; Kuhl et al., 1982; Kuwert et al., 1990; Martin

    Mazziotta et al., 1987).d that script generation and script sorting decits cor-h hypometabolism in some of these cortical regions.

    impairments, the most severe decit in our cohort of in both tasks, were associated with hypometabolism in

    frontal gyrus (bilaterally) and the left precentral (mid- gyrus. This nding supports our initial hypothesis ande role of the frontal cortex in the processing of scriptIn fact implications of frontal areas are consistentlyudies investigating the processing of order informa-ts (Crozier et al., 1999; Knutson et al., 2004; Kuchinke; Partiot et al., 1996; Wood et al., 2005). As suggestede et al. (2009), middle frontal gyrus functioning might

  • P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684 2681

    be associated with mental representations of scenes in script basedtasks when participants mentally imagine themselves performingthe proposed actions (Crozier et al., 1999; Knutson et al., 2004).Crozier et al. (1999) and Knutson et al. (2004) had already sug-gested thatof higher leor the sequresults showwith errorsevents.

    The scriwas associa(right middadditional hscript sortintribute to sthat the prodomain is asition, Godbordering imhave also fotasks in pata matter of sive tissue dareas (Braaan fMRI stuprocessing parietal and

    The factcorrelated wwith past esequence le(1995), Graand Ivry (19time of seqof the stimcued). Thus& Seidler, 2resentationgoals of theabstract repScript generfore, we cain script shypometab

    Consequmarily assoet al., 1999of other bret al., 2008and intrusiowith hypomalso consist

    We founcorrelated ter brain re(Henson, CPassinghamwork (Magthat script episodic meation betwemetabolismwork is nee

    Inconsistions betwe

    hypometabolism in the caudate and putamen nuclei. This suggeststhat within the fronto-striatal system, the cortical frontal regionsare more crucial in script processing than the basal ganglia. Sucha nding is consistent with Shallices (1982) theoretical model, in

    the frulatins nhis mifcnes ed i

    lly, r & Solvemtion(199erial

    can deman

    lesioationquenwhicangltientral, ps maddit

    s in Hrefro

    severeserportaeque

    The tientorre999ere a

    werropohe faselecnt seate irmen

    dorsompation

    theed byisean im

    of Loefronecisiefronn abal loein, 1dorsoan th

    loops et the middle frontal gyrus might support the processingvel mental representations responsible for the timingencing of actions. In line with these propositions, our

    that hypometabolism in these regions is correlated in the processing of sequential relations between script

    pt sequencing decit in our cohort of HD patientsted with additional hypometabolism of temporal areasle temporal gyrus) in the script generation task and withypometabolism of parietal and occipital regions in theg task. This suggests that other brain regions may con-

    equencing abilities, thus casting a doubt upon the ideacess of analyzing sequential links in the script action

    specically frontal function. In line with this propo-out et al. (2004) have recently found script temporalpairments in patients with parietal lobe lesions. Weund numerous sequencing errors in script sequencingients with Alzheimers disease (Allain et al., 2008). It iscommon knowledge that these patients have progres-egeneration predominantly affecting temporoparietal

    k & Braak, 1991; Gomez-Isla et al., 1996). Moreover, indy conducted by Crozier et al. (1999), action sequencewas also associated with activation of regions in the

    temporal cortices. that in our script sorting task sequencing errors wereith hypometabolism in the parietal lobe is consistent

    xperiments, showing that this region was engaged forarning. More precisely, Grafton, Hazeltine, and Ivryfton, Hazeltine, and Ivry (1998) or Hazeltine, Grafton,97) have shown that parietal cortex was engaged at theuence encoding and sequence retrieval, independentlyulus cueing characteristics (spatially or symbolically, according to these authors (see also Bo, Peltier, Noll,011), this region is crucial for forming sequence rep-, but at an abstract level that best corresponds to the

    action rather than to specic movements. Scripts areresentations of goal-directed actions of everyday life.ation or sorting tasks require sequence retrieval. There-n speculate that parietal lobe would also be engagedequence processing and that patients with parietalolism would be impaired in script sequencing tasks.ently, while script sequencing tasks have been pri-ciated with frontal lobe functioning until now (Allain; Grafman, 1989; Sirigu et al., 1995), the contributionsain regions should also be considered (see also Allain). The fact that boundary errors, perseverative errorsn errors in our script generation task were correlatedetabolism in frontal and non-frontal brain regions is

    ent with this proposition.d that boundary errors (script generation) were alsowith hippocampal gyrus hypometabolism. This lat-gion has been generally related to memory retrievalansino, Herron, Robb, & Rugg, 2003; Sakai, Rowe, &, 2002), as part of a common memory retrieval net-uire & Mummery, 1999). Therefore, we can speculategeneration might be associated with the activation ofmory representations. On the other hand, the associ-en impaired script generation and hippocampal gyrus

    was relatively weak in the present study and furtherded to conrm this idea.tent with our initial hypotheses, we did not nd correla-en script generation and script sorting impairments and

    which manipfunctioever, tcause devant odiscardtask.

    Fina(Coopecal invcorrelamans managscriptscan beand sefrontalinformrect sescript, basal gHD patemporegion

    In adecitwith ppaper,have pthe impoor s1995).HD pamost cet al., 1lobe wlesionsvant pdata, tited a cohereeliminimpairin theall-encdissociused inobtainof the dbetweeTowereral pron a ddial pris knowneuron& Folstof the lier thcortexWatkinontal lobes have an important role in script informationon conditions making extensive demands on executiveeeded in script generation and script sorting tasks. How-odels prediction that basal ganglia damage should

    ulties in maintaining the right script and inhibiting irrel-is inconsistent with our results. In fact, our HD patientsrrelevant actions, including those of our script sorting

    while the revised model proposed by Shallice (2002)hallice, 2000) implicates a degree of prefrontal corti-ent in routine action processing, cognitivo-metabolic

    s in the current study are more in keeping with Graf-9) (Grafman, Sirigu, Spector, & Hendler, 1993) model of

    knowledge units (MKUs). Grafman (1999) argues thatbe considered as closely related concepts to MKUs, whoned as single units of memory representing syntactictic aspects of event series. Grafman (1999) claims thatns damage the functional network that assembles MKU

    into a correct syntax (that is into a sequentially cor-ce), but not the basic semantic representation of theh is stored in posterior cortical areas, but not in theia. However, the fact that script sequencing decits ins were associated with additional hypometabolism ofarietal and occipital areas suggests that other corticaly contribute to sequencing abilities.ion, our impression is that the pattern of cognitiveD patients is bears similar to the one seen in patientsntal lesions. As mentioned in the introduction of thisral studies have shown that patients with frontal lesionsved access to script knowledge, but poor evaluation ofnce of events (Allain et al., 1999; Sirigu et al., 1995) andncing abilities (Godbout & Doyon, 1995; Sirigu et al.,only difference between frontally lesioned patients ands is that the last group discarded irrelevant actionsctly. The lesion analyses of our past studies (Allain, 2001) revealed that dorsolateral lesions of the frontalssociated with script sequencing decits, while orbitale associated with impairments in eliminating irrele-sitions (Allain et al., 1999, 2001). With regard to thesect that in our script sorting task HD patients exhib-tive impairment in their ability to produce temporallyquences of actions without a decit in their ability torelevant propositions, suggests that script processingts in HD could be better interpreted in terms of changesolateral striato-thalamo-cortical loop rather than inassing striato-thalamo-cortical loop deterioration. The

    of performance observed in the script sorting tasks present study ts well with neuropsychological data

    Watkins et al. (2000) in HD patients early in the coursese. In these patients, these authors found a dissociationpaired performance on a planning test (the one-touchndon), that was strongly associated with the dorsolat-tal cortex in functional imaging, and intact performanceon making task, which was associated to ventrome-tal lesion. Our interpretation is consistent with whatout the neuropathological progression of HD, in whichss progresses in a dorsal-to-ventral direction (Hedreen995). Thereby, the dorsomedial striatum (a componentlateral prefrontal cortex loop circuitry) is affected ear-e ventral striatum (a component of the orbitofrontal

    circuitry). Following Hedreen and Folstein (1995) andal. (2000), it would be very informative to study the per-

  • 2682 P. Allain et al. / Neuropsychologia 49 (2011) 2673 2684

    formance on a script sorting tasks with distractors in later stagesof HD. It could be predicted that decits in inhibiting irrelevantactions would emerge as the disease spreads through the caudatenucleus.

    As a limisize and theresting-statresult, our tion, we didused scriptsof executioSewing a bcuted less oMoll, Zahn,quency modthe human regions of tin processinthe corresprior medialfor low freqhigh frequethat sub-reengaged inhow often Therefore, ent patterninto accounHowever, insequencingfrontal area(Changingwashing upgesting thatno incidencin the scripscripts thatof frequencthis problem

    5. Conclus

    In concllarger impasemantic knscript orderthe decitsdistributedOur ndingbrain imagibecome maFrom a clinmining the progressionmight also life difcult

    Acknowled

    The MIGand AOM 0de Paris) ater involveP. Remy, MP. Maison.

    Dolbeau. The Sites PI are: A.C. Bachoud-Lvi, S. Pal (Crteil), P.Krystkowiak, S. Blond (Lille), J.F. Dmonet, J.C. Sol (Toulouse), C.Verny, P. Menei (Angers), P. Damier, Y. Lajat (Nantes); F. Supiot, M.Levivier (Bruxelles).

    nces

    Fujii, insonptive er, G. ally seroscien. (200t et pde Be., Berre funcing anal Scie., Le Gan of kts. Jou., Le Gt repr., Le Gence ring inropsyc., Vernt de 440., E. H0). Ratingtoard, Aons ScA. L., ciateserg, M. (200itive ltier, or seq. H., B

    hology., & Br. Acta t, D., Dal evoctionR. J., Cg cererters231F., Az

    severety, 7, ard, M0). An496Y. (199hologiR. P., &ities. S., Sir9). Discriptges, Bneuraeimere, F., Pie couesia in., Godits in g. CorK. J. (1ing d

    3633, S., Sotron e. Annatation of our study we have to mention the small sample modest statistical power of our correlations betweene brain glucose utilization and script task scores. As andings should be considered as exploratory. In addi-

    not control for the frequency and/or familiarity of the. Although we selected daily life scripts, their frequencyn may widely vary. For example, an activity such asutton again includes a sequence of actions that are exe-ften than Going Shopping. In a recent study, Krueger,

    Heinecke, and Grafman (1997) showed that event fre-ulates the sequence processing of daily life activities in

    medial prefrontal cortex. The authors revealed that sub-he medial prefrontal cortex were differentially engagedg event sequence knowledge, depending on how oftenonding daily life activities are performed. The ante-

    prefrontal area (BA 10) was differentially activateduency and the posterior medial prefrontal area 10 forncy daily life activities. Krueger et al. (1997) concludedgions of the medial prefrontal cortex are differentially

    processing event sequence knowledge depending onthe activity was reportedly performed in daily life.we can assume that we would have observed differ-s of cognitivo-metabolic correlations if we had takent the variations of frequency/familiarity in our scripts.

    the present work, no correlations emerged between errors and hypometabolism in the anterior medial pre-. In addition, while we used stereotypical male scripts

    a at tire) and stereotypical female scripts (Doing the) in our script task, no gender differences emerged, sug-

    the degree of variation in the execution of an action hase on the likelihood of the subject sequencing it correctlyt. This conclusion is only an hypothesis. A study using

    are based upon tasks that are better controlled in termsy/familiarity would be required in order to disentangle.

    ion

    usion, our ndings provide evidence for a selectivelyirment for the organizational aspects compared toowledge of script in HD patients. Script generation anding are affected early in the course of the disease, and

    observed are correlated with reduced metabolism in a functional network mainly including cortical regions.s should motivate further work, including longitudinalng, in order to clarify when script manipulation decitsnifest and how their brain substrate evolves over time.ical point of view, script tasks may be useful in deter-onset of cognitive involvement and in tracking disease

    in HD. A better understanding of the pattern of decitshave some implications for anticipating the everydayies encountered by HD patients.

    gements

    -HD trial is granted through two PHRC AOM001394021 from the DRCD (Assistance Publique-Hpitauxnd the support of the AFM. The management cen-s: A.C. Bachoud-Lvi (Principal investigator), S. Pal,. Peschanski, P. Hantraye, J.P. Lefaucheur, D. Challine,CROs were: A. Rialland, D. Schmitz. Data manager: G.

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    The neural substrates of script knowledge deficits as revealed by a PET study in Huntington's disease1 Introduction2 Materials and methods2.1 Subjects2.1.1 Patient group2.1.2 Control subjects

    2.2 General procedure2.3 Neuropsychological protocol2.3.1 Script generation tasks2.3.2 Script sorting tasks

    2.4 PET scanning procedure2.5 Statistical analysis2.5.1 Cognitive data analysis2.5.2 Image analysis

    3 Results3.1 Script generation tasks3.1.1 Semantic aspect3.1.2 Temporal aspect

    3.2 Script sorting tasks3.3 Correlations between script task scores and between task scores and executive scores3.4 Metabolism results3.5 Cognitivemetabolic correlations

    4 Discussion4.1 Characteristics of script impairments in HD patients4.2 Neural bases of script deficits in HD patients

    5 ConclusionAcknowledgementsReferences


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