Neuropsycholo`ia\ Vol[ 25\ No[ 6\ pp[ 514Ð530\ 0887Þ 0887 Elsevier Science Ltd[ All rights reserved\ Pergamon Printed in Great Britain

9917Ð2821:87 ,08[99¦9[99PII] S9917Ð2821"86#99057Ð0

Role of the striatum\ cerebellum and frontal lobesin the automatization of a repeated visuomotor

sequence of movements

JULIEN DOYON\�$%' ROBERT LAFORCE JR[\�$ GINETTE BOUCHARD\�$DANIELLE GAUDREAU\�$ JOANNE ROY\�% MARIE POIRIER\% PAUL J[ BEłDARD\%

FERNAND BEłDARD& and JEAN!PIERRE BOUCHARD%

� Groupe de Recherche en Re�adaptation physique\ IRDPQ\ Site Centre Francžois!Charon^ $ E� cole de Psychologie^ % De�partementdes Sciences Neurologiques\ Ho¼pital de l|Enfant!Je�sus^ and & De�partement de Radiologie\ Ho¼pital de l|Enfant!Je�sus\ Universite�

Laval\ Que�bec\ Canada

"Received 14 June 0885^ revised 4 May 0886^ accepted 11 September 0886#

Abstract*Recently\ Doyon et al[ ð19Ł demonstrated that lesions to both the striatum and to the cerebellum in humans produce asimilar de_cit in the learning of a repeated visuomotor sequence\ which occurs late in the acquisition process[ We now report theresults of two experiments that were designed to examine whether this impairment was due to a lack of automatization of therepeating sequence of _nger movements by using a dual!task paradigm and by testing for long!term retention of this skill[ InExperiment 0\ the performance of groups of patients with Parkinson|s disease\ or with damage to the cerebellum or to the frontallobes\ was compared to that of matched control subjects on the Repeated Sequence Test "primary task# and the Brooks| MatricesTest "secondary task#[ These two tests were administered concomitantly in both early and late learning phases of the visuomotorsequence[ Overall\ the groups did not di}er in their ability to execute the primary task[ By contrast\ in accordance with the predictions\patients in Stages 1Ð2 of Parkinson|s disease or with a cerebellar lesion failed to reveal the expected increase in performance on thesecondary task seen with learning\ suggesting that the latter groups of patients did not have access to the same level of residualcognitive resources to complete the matrices compared to controls[ In Experiment 1\ the same groups of patients and control subjectswere retested again 09Ð07 months later[ They were given four blocks of 099 trials each of the repeating sequence task\ followed by aquestionnaire and a self!generation task that measured their declarative knowledge of that sequence[ The results revealed a long!term retention impairment only in patients who changed from Stage I to Stage II of the disease "suggesting further striataldegeneration# during the one!year interval\ or who had a cerebellar lesion[ By contrast\ performance of the three clinical groups didnot di}er from controls on declarative memory tests[ These _ndings suggest that both the striatum and the cerebellum participate tothe automatization process during the late "slow# learning stage of a sequence of _nger movements and that these structures alsoplay a role in the neuronal mechanism subserving long!term retention of such a motor sequence behavior[ Þ 0887 Elsevier ScienceLtd[ All rights reserved[

Key Words] Humans^ procedural memory^ lesion studies^ dual!task paradigm^ long!term retention^ automaticity[

Introduction

A large body of research has demonstrated the exis!tence of a functional dissociation between declarative andprocedural memory systems ð80Ł[ Declarative memorycorresponds to the ability to store events or facts

' Corresponding author] Julien Doyon\ Ph[D[\ Groupe deRecherche en Re�adaptation Physique\ IRDPQ\ Site CentreFrancžois!Charon\ 414\ Boul[ Wilfrid!Hamel\ Local B!66\ Que�!bec "Que�bec#\ Canada\ G0M 1S7[ Fax] "307# 418!2437^ E!mail]julien[doyonÝpsy[ulaval[ca

514

explicitly such that they are available as a conscious rec!ollection[ This memory system is dependent upon theintegrity of the medial temporal "i[e[ the hippocampusand the surrounding cortical areas# and diencephalicstructures ð81\ 82Ł[ By contrast\ procedural memory refersto the capacity to acquire motor\ visuomotor\ vis!uoperceptual\ cognitive or other skills gradually throughpractice ð89Ł[ The anatomical substrate involved in theincremental learning of skilled behaviors still remains asource of debate[ However\ there is increasing evidencefrom both animal and human studies\ which suggest thatthe striatum and the cerebellum\ in concert with associ!ated motor cortical regions of the frontal lobes\ par!

J[ Doyon et al[:Automatization of a visuomotor skill515

ticipate in this type of memory ð8\ 08\ 21\ 25\ 40\ 51\ 83Ð85Ł[

Evidence in favour of a striatal contribution inincremental learning has come from the study of cellphysiology ð02\ 22\ 71Ł and neurochemistry ð5\ 6\ 72Ł\ aswell as from lesion experiments in rodents ð46Ł and non!human primates ð62\ 63\ 85Ł[ Although some scepticismabout the validity of this hypothesis has recently beenexpressed ð16\ 092Ł\ research in patients with either Par!kinson|s or Huntington|s disease ð19\ 11\ 24\ 26\ 27\ 38\51\ 66\ 091Ł and in normal control subjects using modernbrain imaging techniques\ such as positron emission tom!ography "PET# and functional magnetic resonance imag!ing "fMRI#\ have also corroborated the notion that thestriatum plays a critical role in the learning of a varietyof skills ð08\ 10\ 29\ 20\ 25\ 33\ 65\ 74Ł[ Likewise\ evidencein accord with a cerebellar participation in gradual learn!ing after repeated trials has originated from physiologicalð2\ 8\ 31\ 32\ 44\ 55\ 85Ł and ablation studies in animalsð09\ 58\ 76\ 77Ł\ as well as from clinical ð19\ 17\ 60\ 68\ 86Łand brain mapping studies in humans ð08\ 10\ 13\ 14\ 20\33\ 64\ 73\ 74Ł[ Finally\ in addition to the striatum andthe cerebellum\ some researchers have suggested that themotor cortical areas of the frontal cortex "e[g[ pre!SMA\SMA\ premotor cortex and primary motor cortex# areinvolved in skill acquisition as well\ especially thosenecessitating the learning of ordered sequences ð51\ 83\84\ 090Ł[ The latter proposal is supported by anatomicalevidence which shows that the striatum and the cer!ebellum project back to these cortical areas and the pre!frontal cortex ð3\ 47\ 70Ł[ This is also corroborated by aseries of physiological ð34\ 59\ 53\ 54Ł and ablation studiesð50Ł in non!human primates\ as well as by PET and fMRIexperiments in which learning!associated changes in cer!ebral blood ~ow in motor and pre!frontal regions havebeen observed in healthy normal volunteers ð19\ 10\ 29\20\ 25\ 33\ 35\ 61\ 64\ 68\ 73Ł[

Recent investigations in humans have demonstratedthat the striatum and the cerebellum do not only play acritical role in the early "fast# learning stages of a vis!uomotor skill ð14\ 33\ 60Ł in which considerable improve!ment in performance can be seen within a single trainingsession\ but that they may also participate in the {{auto!matization|| process which occurs in the late "slow# phaseof the acquisition process ð08\ 10\ 20\ 33\ 65\ 74Ł[ In thelatter phase of learning during which further gains canbe observed across several sessions "and even weeks# ofpractice ð35\ 36Ł\ it is believed that the execution of thetask becomes automatic\ hence reducing the mental e}ortand attention to be directed in performing the skill aswell as the load on the subjects| working memory capacityð4Ł[ In accordance with this notion\ Doyon et al[ ð19Łhave recently compared the performance of patients withParkinson|s disease\ with a cerebellar lesion\ or with dam!age circumscribed to the frontal lobes on a version of theRepeated Sequence Test ð56Ł[ This test consists of a visualreaction!time task with a _xed embedded sequence of_nger movements[ The subjects received four blocks of

trials "i[e[ 39 presentations of a 09!item sequence# per dayover six training sessions\ which took place once a weekduring six consecutive weeks[ The results revealed thatthe performance of Parkinsonian patients with a bilateralstriatal dysfunction "i[e[ Stages 1Ð2 of the disease accord!ing to Hoehn and Yahr|s scale ð30Ł# and patients withdamage circumscribed to the cerebellum\ but not thosewith a lesion limited to the frontal cortex\ failed toimprove as much as their matched control subjects in thelast three training sessions only[ Moreover\ correlationalanalyses showed that the learning de_cit in patients witheither PD or with a cerebellar lesion was not related to acognitive deterioration\ mood disturbance\ or to a motorde_cit per se[ By contrast\ no signi_cant di}erencebetween the three clinical and control groups was seenwith respect to their level of declarative knowledge ofthe sequence[ Based on these _ndings\ Doyon et al[ ð19Łproposed that\ unlike declarative memory\ the incremen!tal acquisition of a visuomotor skill depends upon theintegrity of the striatum and the cerebellum[ Further!more\ because the impairment was observed in the secondhalf of the training sessions\ they also suggested that thesetwo structures are particularly important in advanced"slow# learning stages of a visuomotor sequence\ possiblyin the {{automatization|| phase\ during which the for!mation of a pattern of response is consolidated ð4Ł[

Several investigators have proposed the use of dual!task methodology to investigate the level of auto!matization of a skill[ This method is thought to test forthe level of attentional resources that subjects can devoteto a second cognitive task as they become more e.cientat performing a learned behavior ð7\ 03\ 04\ 29\ 25\ 42Ł[Indeed\ it has been suggested ð28\ 39\ 75Ł that training ona skill learning task modi_es the performance resourcefunctions of the individual ð69Ł\ such that the capacitiesneeded to execute the task decline with practice henceleaving room for a second task to be executed[ Otherresearchers have proposed that testing for long!termretention of a skill can also be useful to measure thesubjects| level of automatization of that behavior\ as per!formance on tasks that are well learned are less likely todeteriorate due to the simple passage of time ð49\ 42\ 78Ł[In the present study\ these two approaches were used todetermine whether the de_cit seen in Doyon et al[ ð19Ł inPD patients with a bilateral striatal dysfunction and inpatients with a cerebellar lesion\ was indeed due to adi.culty in automatizing a sequence of well!learnedmovements[ It is important to note that the data in thedual!task condition were gathered concomitantly withthose reported in the skill learning study ð19Ł[

Experiment 0] Automatization of a Visuomotor Skill

Assessed Using a Dual!Task Paradigm

In our previous study ð19Ł\ the impairment in learningthe repeating sequence after a bilateral striatal dys!function or damage to the cerebellum was observed only

J[ Doyon et al[:Automatization of a visuomotor skill 516

in late phase of the acquisition process[ Furthermore\the de_cit in these two groups was not related to otherconfounding factors "e[g[ mood disturbance\ motor de_!cit\ or cognitive deterioration#[ The present experimentwas thus designed to examine whether the learningimpairment was due to a lack of automatization of thesequence of _nger movements using a dual!task para!digm[ The performance of the same groups of patientswith Parkinson|s disease\ with a cerebellar lesion\ or withdamage circumscribed to the frontal lobes who par!ticipated in the study by Doyon et al[ ð19Ł\ was comparedto that of their matched control subjects on the Brooks|Matrices test ð09Ł "i[e[ secondary task#\ as they were per!forming concomitantly the Repeated Sequence Test "i[e[primary task#[ These two tasks were administered twice]First\ at the beginning "i[e[ early learning stage# aftersubjects had been exposed 39 times "Session 0# to therepeating sequence^ and second\ at the end "late learningstage# after they had been given 139 repetitions of thesequence and thus had achieved high pro_ciency on thisnew skill "Session 5#[

The automatization phase of a skill constitutes a stageduring which the pattern of responses is consolidatedand the processing resources necessary to execute othercognitive tasks become increasingly available with prac!tice ð4Ł[ It was thus predicted that only the groups ofpatients who showed a learning impairment in late phaseof the learning process "PD patients in Stages 1Ð2 of thedisease and those with a lesion to the cerebellum\ ð19Ł#\would not demonstrate a signi_cant improvement in per!formance across the six training sessions on the Brooks|Matrices Test ð01Ł[ We also expected that such impair!ment would be due to a reduced level of cognitiveresources available to perform the matrices "i[e[ sec!ondary task# because of a lack of automatization of thesequence of movements "i[e[ primary task#[

Method

Subjects

Three groups of patients and of normal control subjects weretested in this dual!task condition "Table 0#[ All of the patientswere recruited via the Departments of Neurological Sciencesand Neuroradiology at the Enfant!Je�sus Hospital in Que�bec\Canada[ By contrast\ the normal control subjects were eitheracquaintances of the experimenters or volunteers from the com!munity[ The patients in each clinical group were screened usinga basic neuropsychological evaluation in order to exclude thoseshowing signs of depression or dementia ð19Ł[ All subjects gaveinformed written consent for their participation in this experi!ment[ This study was approved by the Ethics Review Board ofthe Ho¼pital de l|Enfant!Je�sus\ Qu�ebec\ Canada[

Parkinson|s disease `roup "PD#[ This group was composed of00 patients who had received a diagnosis of idiopathic Par!kinson|s disease "PD# "Table 0#[ They were divided into twosubgroups based on the severity of the disease using Hoehn andYahr|s scale ð30Ł] Stage 0 "n � 5#^ Stages 1Ð2 "n � 4#[ Whenprescribed\ patients were taking optimal levels of levodopamedication at the time of testing[ Patients with drug!induced

Parkinsonism\ multiple system atrophy\ cerebro!vasculardisease\ epilepsy\ history of alcoholism\ head injury or tumor\cerebellar disturbances\ or with disproportionate oculomotorand autonomic dysfunction were excluded from this study[

Cerebellar `roup "CE#[ A group of 00 patients with a radio!logically!documented lesion in the cerebellum was also tested[Eight of them had damage restricted to the cerebellum proper\whilst the rest had lesions extending into the brain stem orspinal cord[ All of these patients had dysarthria\ ataxia anddysmetria\ although the severity of these cerebellar signsdi}ered between patients[

Frontal!lobe `roup "FL#[ A heterogeneous group of nine pat!ients with damage circumscribed to the frontal cortex was alsoseen[ There were 4 patients with left!sided lesions\ 1 with right!sided lesions and 1 with bilateral lesions "Table 0#[

Normal!control `roups "NC#[ Three separate groups ofhealthy control subjects were included to match the clinicalgroups with respect to sex distribution\ mean age and meanlevel of education "Table 0#[ Thus\ groups of 8\ 00 and 03subjects were used as controls for the patients with PD\ with acerebellar lesion or with damage to the frontal cortex\ respec!tively[ None of the control subjects had any positive history ofa psychiatric or neurological disorder[

Materials and procedure

Experimental tasks

The subjects| levels of processing resources available whileexecuting the visuomotor sequence at di}erent stages of thelearning process was measured with a dual!task paradigm usinga version of the Repeated Sequence Test as the primary taskand the Brooks Matrices Test ð01Ł as the secondary task[

Primary task

This task consisted of a short version of the same RepeatedSequence Test that was used in the skill learning aspect of thestudy ð19Ł[ Brie~y\ this test was administered using a responsebox that has four identical lights "stimuli# and four buttons\one below "0[64 cm# each light[ The lights and buttons werearranged horizontally at equidistance from one another[ Thisbox was connected to an IBM PC computer that controlledstimulus presentation and recorded the two measures of interestfor this task] i[e[ the subject|s reaction time and accuracy oneach trial "Fig[ 0#[

The subjects were instructed to use the middle and index_ngers of each hand\ and to keep one _nger on each of the fourkeys[ They were asked to press the button corresponding to thelight that was illuminated as quickly as possible\ while makingas few errors as possible[ The stimulus remained displayed untilthe subject made a response[ After the response\ the light wento} and was immediately followed 499 ms later by the displayof another stimulus[ The location of the stimuli was pro!grammed in a speci_c sequence of 09 positions[ Hence\ if onewere to designate the four possible locations as 0\ 1\ 2 and 3from left to right\ the sequence was the following] 3!1!2!0!2!1!3!2!1!0[ In this dual!task condition\ each block of trials wascomposed of three continuous repetitions of this 09!itemsequence without any pause between them\ so that each blockappeared as a continuous series of 29 trials[ The subjects werenot informed of the presence of the repeating sequence\ nor didthey receive feedback concerning the latencies or accuracy oftheir responses[

J[ Doyon et al[:Automatization of a visuomotor skill517

Table 0[ Subjects characteristics

PD NC Cerebellar NC Frontal NCGroup "n � 00# "n � 8# "n � 00# "n � 00# "n � 8# "n � 03#

Age] Mean years "S[D[# 43[7 "5[2# 42[6 "3[6# 24[5 "7[7# 27[6 "00[5# 39[8 "06[0# 35[2 "00[9#Education] Mean years "S[D[# 02[9 "4[0# 02[6 "1[8# 01[4 "2[2# 02[6 "2[0# 00[2 "2[3# 02[5 "2[0#Sex "female:male#] 5:4 3:4 7:2 3:6 3:4 6:6Diagnostic] VCA] 1 Vasc[ malf[] 1

OPCA] 0 Astrocytoma] 1CA] 5 Meningioma] 2SP] 1 Kystic lesion] 0

Abcess] 0

Stage of the disease0 I] 5II] 1III] 2

Duration of the disease] 9Ð4 years] 2 9Ð4 years] 55Ð09 years] 1 5Ð09 years] 400Ð10 years] 5

Side of lesion Left] 1 Left] 0 Left] 4Right] 2 Right] 0 Right] 1Bilateral] 5 Bilateral] 8 Bilateral] 1

Site of lesion Orbitofrontal] 2Dorsomedial] 0Dorsolateral] 4

Medication L!Dopa] 00Anticholiner!gics

Artane] 2Cogentin] 0Parsitan] 2

VCA] Vascular cerebellar accident^ OPCA] Olivo!ponto!cerebellar atrophy^ CA] Cerebellar atrophy^ SP] Spino cerebellar atrophy^Vasc[ malf[] Vascular malformation[0 Source] Hoehn + Yahr|s Scale "0856#[

Fig[ 0[ Diagram illustrating the materials used and a rep!resentative experimental trial in the dual!task performance situ!

ation[

Secondary task

The Brooks Matrices Test was used as the secondary task inorder to interfere with the visuospatial processing that is elicitedwhile executing the repeating visuomotor sequence[ In this test\subjects were required to keep in mind a visuospatial patternmade of _ve digits in a 3×3 matrix\ the location of each digitbeing dependent upon auditory instructions that were com!municated to them via a cassette player "Fig[ 0#[ They were _rstasked to follow directives\ which instructed them to alwaysplace the _rst digit in the same {{Starting|| box "1nd row\ 1ndcolumn of the matrix# and to position the remaining four digitsin separate\ but connecting boxes[ Following completion of atrial\ subjects were given a template on which a matrix wasillustrated and were then required to indicate the locationof the _ve digits from memory[ A di}erent set of auditoryinstructions representing a unique visuospatial pattern of digitswas administered on each experimental trial[ The dependentmeasure of interest was the number of directional movementsper matrix that were correctly reproduced based on the auditoryinstructions[ A total of 05 di}erent sets of instructions wererecorded and were divided into two groups "A and B#\ whichwere administered on separate occasions "see Experimentaldesign#[

Before the dual!task session began\ the subjects were given

J[ Doyon et al[:Automatization of a visuomotor skill 518

appropriate instructions and a number of practice trials tofamiliarize themselves with the Brooks| matrices task[ First\two trials were given in which a template of the matrix wasplaced in view of the subjects who were required to write downthe digits in the appropriate boxes at the same time as they werehearing the instructions[ Second\ two other practice trials wereadministered in which a template was again placed in view ofthe subjects who were now asked to wait until the end of theauditory instructions before writing the digits in the appropriateboxes[ Finally\ _ve additional trials were given in which thesubjects were required to wait until the end of the auditoryinstructions before writing the digits in the boxes[ This time\however\ the template was hidden from the subjects view duringthe instructions[ Performance in the latter condition was usedas a control measure of the subjects| ability to perform theBrooks| Matrices Test ð01Ł alone[

Experimental design

Both the primary and the secondary tasks were administeredconcurrently in two separate testing sessions\ which were heldafter subjects were given either 39 or 139 repetitions of the 09!item repeating sequence "i[e[ after Sessions 0 and 5 in the pre!vious skill learning study ð19Ł#[ On each experimental trial\ theywere asked to execute a block of 29 trials with the repeatingsequence task\ at the same time as they were completing amatrix[ Eight experimental trials were administered in bothtesting sessions[ Finally\ the order of presentation of the twogroups of instructions "A and B# was counterbalanced withineach group of subjects[

Results

The results of the primary and secondary tasks wereanalysed using mixed!design analyses of variance "ANO!VA|s# for repeated measures[ These analyses were con!ducted comparing the performance of each clinical group"or subgroup in the case of the PD patients# to that oftheir respective group of normal control subjects[ Whennecessary\ post hoc comparisons were performed usingthe NewmanÐKeuls procedure[

Primary task

Accuracy[ Subjects in the three clinical and controlgroups were very accurate on this task\ the mean numberof correct responses per sequence "max�09# rangingfrom 7[78Ð8[89[ Results of separate ANOVA|s revealedthat all the patients| groups made signi_cantly moreerrors than their respective groups of control subjects"PD] F"1\06#�3[61\ P³ 9[94^ CE] F"0\19#�05[16\P³ 9[990^ FL] F"0\10# 05[1\ P³ 9[990#[ Although theGroup main e}ect was signi_cant for the PD patients\the results of post!hoc comparisons conducted on thedata of each subgroup of PD patients did not reachsigni_cance[ The only other signi_cant main e}ect wasthat of Session in the analysis with the CE group andtheir controls\ indicating that these subjects were overallmore accurate on Session 5 than on Session 0[ None of

the double\ nor of the triple interactions were signi_cant[The latter _ndings suggest that patients and control sub!jects did not di}er in their pattern of correct responses[

Reaction time[ Figure 1a\ 1c and 1e illustrate the geo!metric mean RT of all subjects| groups for the two exper!imental conditions "single vs dual tasks# in Sessions 0 and5[ Note that Fig[ 1a shows the performance of the twosubgroups of patients with PD and their matched controlgroup "so that it is possible to compare with the resultsobtained on the secondary task#\ but that the statisticalanalysis was performed using the data from the entiregroup of PD patients[ The reaction times of all subjectswere transformed to logarithms to reduce skewness in thedistribution and the subsequent ANOVA|s were per!formed using this transformation[ These analysesrevealed a main e}ect of Group for the cerebellar!controlcomparison only "F"0\19#�03[4\ P³ 9[990#[ Highly sig!ni_cant e}ects of practice and of experimental conditionwere obtained in the three analyses\ all subjects beingfaster on Session 5 than on Session 0\ while being slowerin the dual than in the single task condition "Session] PD\F"0\06#�57[7\ P³ 9[9990^ CE\ F"0\19#�44[5\P³ 9[9990^ FL\ F"0\10#�67[4\ P³ 9[9990^ Condition]PD\ F"0\06#�099[86\ P³ 9[9990^ CE\ F"0\19#�156[5\P³ 9[9990^ FL\ F"0\10#�134[6\ P³ 9[9990#[ Except fora Session×Group and a Condition×Group interactionin the comparison involving the CE group\ all of theother double and triple interactions did not approachsigni_cance[ These results suggest that\ in general\ theperformance of the subjects| groups was a}ected similarlyby dual!task condition in both testing sessions[

Secondary task[ The results of separate ANOVA|s forrepeated measures on the number of directional move!ments correctly reproduced "Fig[ 1b\ 1d and 1f# revealedthat PD patients "F"1\06#�2[89\ P³ 9[94# and thosewith a cerebellar lesion "F"0\19#�8[62\ P³ 9[90# madesigni_cantly more errors on this test than their controls[In addition\ a signi_cant main e}ect of Session wasobserved in the comparisons between the PD\ CE and FLgroups and their controls "PD] F"1\06#�4[63\ P³ 9[94^CE] F"0\19#�7[38\ P³ 9[90^ FL\ F"0\10#�38[13\P³ 9[9990#\ indicating that subjects in these groupsimproved their performance from Session 0 to Session 5[More importantly and as predicted\ however\ a sig!ni_cant Group×Session interaction was obtained forboth PD and CE groups "PD] F"1\06#�4[61\ P³ 9[91^CE] F"0\19#�02[95\ P³ 9[90#\ but not for the FL group[Subsequent analyses comparing the performance of eachsubgroup of PD patients to the normal control subjectswith a repeated!measures ANOVA yielded a signi_cantinteraction for the patients in Stages 1Ð2 of the diseaseonly "F"0\01#�7[06\ P³ 9[91#[ Further analysesrevealed that the de_cit observed in the groups of patientswith PD "Stages 1Ð2#\ or with damage to the cerebellum\in the secondary task could not be due to an inability toperform the Brooks| Matrices Test for two reasons[ First\there was no di}erence in performance between the clini!cal groups and their respective groups of control subjects

J[ Doyon et al[:Automatization of a visuomotor skill529

Fig[ 1[ Results of the subjects| groups for the Repeated Sequence Test "primary task# "a\ c\ e# and the Brooks Matrices Test "secondarytask# "b\ d\ f #[ The data points in the single condition of the primary task correspond to the mean reaction times of Blocks of trials

0 and 3 that were administered in Session 0 and 5 of the skill learning study ð19Ł[

J[ Doyon et al[:Automatization of a visuomotor skill 520

with respect to the number of directional movementsreproduced in the _ve matrices that were used in theintroduction session to control for the subjects| ability toperform the Brooks| Matrices Test when administeredalone "PD] F"1\06#�1[94\ P�9[05^ CE] F"0\19#�1[34\P�9[02^ FL] F"0\10#�9[93\ P�9[74#[ Second\ no sig!ni_cant group di}erence was obtained "using a one!wayANOVA# when they were compared on Session 0 only\"PD] F"1\06#�9[12\ P�9[68^ CE] F"0\19#�1[35\P�9[02^ FL] F"0\10#�0[87\ P�9[85#\ suggesting thatthe level of performance of the patients did not di}erfrom that of the controls when they were _rst tested inthe dual!task condition[ Also\ the latter _nding suggestthat the patients had a similar level of cognitive resourcesavailable to perform the secondary task at the beginningof learning[

Discussion

The results of the three clinical groups on the primarytask indicate that\ overall\ patients did not di}er from thecontrol subjects in their ability to execute the repeatingsequence when another visuo!spatial task was intro!duced[ Each group showed a signi_cant e}ect ofcondition\ as they were much slower to respond in thedual!task than in the single!task condition[ In addition\this di}erence in performance was still evident on Session5[ This suggests that\ even after 139 repetitions of theembedded sequence\ the patients and control subjects hadnot achieved complete automatization of the sequence ofmovements and thus that they were still in the pro!ceduralization process ð4Ł[ Such a _nding is consistentwith the elegant work of Karni et al[ and his colleaguesð35\ 36Ł who have shown that healthy control subjectscould only reach asymptotic performance of a simple 4!item sequence of _nger movements after 3 weeks of dailypractice "04Ð19 min:day#[ More importantly\ however\the fact that performance of the patients| groups in thedual!task condition did not di}er from that of their mat!ched control subjects\ suggests that the divergence in theresults on the secondary task observed in the PD Stages1Ð2 and the cerebellar groups cannot be due to a di}er!ence in the way subjects were performing the repeatingsequence task[

By contrast\ the results of the present study dem!onstrate that\ as predicted\ patients in Stages 1Ð2 of PDor with damage to the cerebellum\ but not those with afrontal!lobe lesion\ were impaired on the Brook|s Matr!ices Test ð01Ł[ Further analyses showed that this de_citdid not result from an incapacity to perform the matricesper se\ because the performance of patients in both PDand CE groups did not di}er from that of their respectivegroups of control subjects\ both when this task wasadministered alone in the practice session and when itwas _rst given in a dual!task condition "Session 0#[ Fur!thermore\ such an impairment could not be due to adi.culty in attentional capacities\ as the performance of

the clinical and control groups on Brooks| matrices didnot di}er on Session 0[ If a de_cit in dividing attentionfollowing a bilateral striatal dysfunction or damage tothe cerebellum was the source of impairment on the sec!ondary task\ di.culties should have been observed\ notonly on Session 5\ but on Session 0 as well[ Instead\ thefact that only patients in advanced stages of PD and inthe CE group did not improve on Session 5 "i[e[ after 139presentations of the 09!item sequence ð19Ł#\ suggests thatthey did not have the same level of cognitive resources todevote to performing the matrices[ It is important to notethat this impairment was observed in the same groups ofpatients who showed a learning impairment in late phasesof the acquisition process of the repeating visuomotorsequence in our parallel study ð19Ł[ Together\ these resultssupport the hypothesis that the impairment reported byDoyon et al[ ð19Ł in acquiring such a visuomotor skillafter damage to the striatum or the cerebellum was dueto a lack of automatization of the repeated sequence of_nger movements in late "slow# learning phase ð35\ 36Ł[

Such a de_cit can be conceptualized as an inabilityto combine the di}erent _nger movements into a singleintegrated unit with extended practice and thus\ the pre!sent _ndings suggest that both the striatum and the cer!ebellum contribute to the automatization of this co!articulation process[ This does not mean\ however\ thatthe impairment following damage to these structuresresults from the same underlying information processingmechanisms[ Indeed\ Laforce and Doyon ð40Ł haverecently demonstrated a double functional dissociationbetween the striatum and the cerebellum and have sug!gested that the striatum plays a critical role in per!ceptivomotor learning mechanisms based on stimulus!response types of associations\ whereas the cerebellum ispreferentially involved in the ability to integrate separatemovements into a ~uid sequence[ Thus\ although similar\the de_cit observed following damage to both structureswould suggest that the impairment in automatizing thesequence of _nger movements could be due to di}erentcognitive processes[

The notion that the striatum and the cerebellum areinvolved in the automatization phase of a visuomotorskill is consistent with several functional imaging studieswith PET and fMRI\ in which a change in hemodynamicresponses in both of these structures have been associatedwith the learning of a repeating sequence of movementsusing a very similar paradigm ð08\ 10\ 14\ 33\ 65\ 74Ł[ Thisis also in accord with single!cell recording experiments inthe striatum and the cerebellum ð8\ 02\ 22\ 71\ 85Ł\ whichhave demonstrated the existence of highly speci_c _ringpatterns during the learning of a motor skill[ Indeed\ thehypothesized role of the striatum in the automatizationprocess is reminiscent of the work by Shultz et al[ ð71Łwho have described a decrease in the sensitivity of dopa!minergic brain stem neurons to rewarding stimuli as theanimal becomes over!trained on a conditioning para!digm[ This is also consistent with the studies by Graybielet al[ ð23Ł who have demonstrated in the striatum the

J[ Doyon et al[:Automatization of a visuomotor skill521

Fig[ 2[ Results of the subjects| groups on each block of trials of the Repeated Sequence Test in both Session 5 of training and theretention session[ The data points in Session 5 correspond to the mean reaction times of Blocks of trials 0Ð3 that were administered

in Doyon et al[ ð19Ł[

J[ Doyon et al[:Automatization of a visuomotor skill 522

existence of tonically active neurons that begin to signalrewarding stimuli only as a conditioning task becomeswell!learned[ The proposal that the cerebellum par!ticipates as well in the automatization phase of learningis supported by a recent study by Bloedel et al[ ð00Łwho recorded the modulation of multiple single neuronslocated in the di}erent cerebellar nuclei as cats were learn!ing to move a manipulandun through a groove maze[These authors found a signi_cant increase in amplitudeof the cells| response\ which was correlated with animprovement of the cat|s performance on the task[ Theysuggested that the cerebellum is involved actively in theincremental acquisition of a motor skill\ especially inthe process during which the strategy for performing alearned movement becomes established[

Patients with frontal!lobe lesions did not di}er in per!formance from their group of control subjects in bothprimary and secondary tasks[ Further qualitative analy!ses of the performance of the individual patients withinthis group did not reveal any di}erence in the pattern ofresults when the e}ect of side or site of lesion "i[e[ dividingthe patients into those who had damage in the dorso!lateral\ orbitofrontal or medial region of the frontallobes# was analysed[ These results\ together with the factthat the same patients did not reveal any learning impair!ment of the repeating sequence in the skill learning aspectof the study ð19Ł\ implies that the frontal cortex does notplay a signi_cant role in the acquisition of a visuomotorsequence\ nor in its automatization phase[ There is ampleevidence which suggests\ however\ that the frontal lobe\ inparticular\ the primary motor cortex\ the lateral premotorregions and supplementary motor areas\ contributes tothe learning and production of willed sequences of actionsð0\ 18\ 34Ð36\ 61\ 83\ 84\ 86Ł[ Consequently\ the apparentdiscrepancy between the latter results and our _ndingsmay simply be explained by the fact that the patients inthis group had lesions that did not encroach on thesemotor cortical regions[

Experiment 1] Automatization of a Visuomotor Skill

Assessed by Testing for Long!Term Retention

The results of Experiment 0 suggest that the learningimpairment reported by Doyon et al[ ð19Ł following abilateral striatal dysfunction\ or a lesion to the cerebel!lum\ could be due to a di.culty in automatizing therepeating sequence of movements[ In the present study\the {{automatization hypothesis|| was tested again\ butwith a di}erent theoretical approach[ Instead of using adual!task paradigm\ we sought to determine\ for the _rsttime\ whether damage to the striatum and the cerebellumimpairs the long!term retention of a repeated visuomotorsequence[ Patients with either Parkinson|s disease\ orwith damage involving the cerebellum or the frontal cor!tex and their respective groups of normal control subjects\were retested once 7Ð05 months later on the sameRepeated Sequence Test[ The subjects were given four

blocks of 099 trials followed by the administration of twotests "a short questionnaire and a self!generation task#that measured the subject|s declarative knowledge of thesequence[ It was predicted that the groups of patients whoshowed a learning de_cit late in the acquisition process\possibly because of a lack of automatization of thesequence of movements "i[e[ patients in Stages 1Ð2 of PDor with a cerebellar lesion#\ would exhibit an impairmentin long!term retention of this visuomotor skill[ Bycontrast\ the performance of the clinical groups on thedeclarative memory tests would not di}er from their con!trol subjects[

Method

Subjects

Three groups of patients and of normal control subjects wereincluded "Table 1#[ These subjects had participated in the skilllearning study ð19Ł and in Experiment 0 with the dual!taskcondition[ Again\ all subjects gave informed\ written consentfor their participation in this experiment\ which was approvedby the Ethics Review Board of the Ho¼pital de l|Enfant!Je�sus\Que�bec city[

Parkinson|s disease `roup "PD#[ This group consisted of 04patients who had received a diagnosis of idiopathic Parkinson|sdisease "Table 1#[ At the time of testing for retention\ subgroupscomposed of 2 and 6 PD patients\ did not show any sign of asigni_cant clinical deterioration and thus were still consideredto be\ respectively\ in Stage 0 and Stages 1Ð2 of the disease[ Bycontrast\ _ve patients had changed from Stage 0 to Stage 1"called PDÐCS# during the approximate one!year delay period[It is important to note that the clinical status of the PD patientswho showed a motor deterioration during the delay and thosewho did not\ was assessed by a neurologist "Dr P[ J[ Be�dard#associated with our research team using the Hoehn and Yahr|sscale ð30Ł[ On average\ these patients were tested 01[0 months"S[D[ � 9[5# after the last training session in the skill learningstudy ð19Ł[ Again\ when prescribed\ patients were taking optimallevels of levodopa medication at the time of testing[ Patientswith drug!induced Parkinsonism\ multiple system atrophy\ cer!ebro!vascular disease\ epilepsy\ history of alcoholism\ headinjury or tumour\ cerebellar disturbances\ or with dis!proportionate oculomotor and autonomic dysfunction\ werealso excluded from the present experiment[

Cerebellar `roup "CE#[ Twelve patients with a radiologically!documented lesion in the cerebellum were also tested "Table 1#[Eight of them had damage restricted to the cerebellum proper\whilst the rest had lesions extending into the brain stem or thespinal cord[ All of these patients had dysarthria\ ataxia anddysmetria\ although the severity of these cerebellar signsdi}ered between patients[ They were retested on average 02[1months "S[D[] 1[1# after the last training session[

Frontal!lobe `roup "FL#[ A group of 7 patients with di}erentetiologies\ but whose damage was nevertheless circumscribedto the frontal cortex\ were also seen "Table 1#[ There were 3patients with left!sided lesions\ 1 with right!sided lesions and 1with bilateral lesions[ This group was seen on average 09[4months "S[D[ � 9[7# after the last practice session[

Normal control `roups "NC#[ A total of 27 normal controlsubjects were also included in this study[ They were subdividedinto three groups to match the clinical groups with respect tosex distribution\ mean age and mean level of education "Table1#[ The delay between the training and the retention sessionsranged\ on average\ from 00[7Ð02[4 months[

J[ Doyon et al[:Automatization of a visuomotor skill523

Table 1[ Subjects characteristics

PD NC Cerebellar ŁNC Frontal NCGroup "n � 04# "n � 04# "n � 01# "n � 01# "n � 7# "n � 00#

Age] Mean years "S[D[# 45[6 "5[6# 43[2 "7[0# 26[2 "09[2# 39[1 "02[2# 27[8 "05[4# 39[8 "03[5#Education] Mean years "S[D[# 02[4 "3[5# 01[8 "1[7# 01[4 "2[5# 02[2 "1[5# 00[2 "2[3# 02[5 "2[0#Sex "female:male# 6:7 7:6 7:3 6:4 3:3 5:4Delay between training and 01[0 "9[5# 02[4 "2[2# 02[1 "1[1# 01[0 "0[5# 09[4 "9[7# 00[7 "1[2#

retention in months "S[D[#

Diagnostic VCA] 1 Vasc[ Malf[] 1OPCA] 0 Astrocytoma] 1CA] 5 Meningioma] 1CA¦CGP] 0 Kystic lesion] 0SP] 1 Abcess] 0

Stage of the disease0 I] 2IIÐIII] 01

Duration of the disease 9Ð4 years] 9Ð4 years] 65Ð09 years] 2 5Ð09 years] 400Ð10 years] 7

Side of lesion Left] 0 Left] 0 Left] 3Right] 1 Right] 0 Right] 1Bilateral] 01 Bilateral] 09 Bilateral] 1

Site of lesion Orbitofrontal] 2Dorsomedial] 0Dorsolateral] 4

Medication L!Dopa] 04Anticholiner!gics

Artane] 3Cogentin] 0Parsitan] 2

VCA] Vascular cerebral accident^ OPCA] Olivo!ponto!cerebellar atrophy^ CA] Cerebellar atrophy^ CA¦CGP] Cerebellar atrophywith calci_cations of the globus pallidus^ SP] Spinocerebollar atrophy^ Vasc[ Malf[] Vascular malformation[0 Source Hoehn + Yahr|s Scale "0856#[

Experimental tasks

The subjects| levels of retention of a visuomotor skill wasassessed using an identical version of the Repeated SequenceTest to that used by Doyon and colleagues ð19Ł\ whereas theirdeclarative knowledge of the sequence was measured with ashort questionnaire and a self!generated task[

Repeated sequence test] visuomotor skill learnin`[ The materialwas the same as described in Experiment 0[ In this task\ thesubjects were again required to use the middle and index _ngersof each hand and to keep one _nger on each of the four keys[They were asked to press the button corresponding to the lightthat was illuminated as quickly as possible\ while making asfew errors as possible[ The same sequence used by Doyon et al[ð19Ł was repeated again[ The subjects were given four exper!imental blocks of trials in a single retention session[ A shortperiod of rest "89 s# was allowed between each block of trials[

Repeated sequence test] declarative memory tasks[ Followingthe last experimental block of trials of the Repeated SequenceTest\ the subjects| declarative knowledge of the sequence wasassessed in two ways[ First\ they were asked to complete a short

questionnaire that comprised the following three questions] "a#Did you notice anything about the task<\ "b# Did you evernotice any pattern or sequence< and "c# What was the sequence<Subjects were given one point per positive response "total � 2points# on Questions 0 and 1 and were given an additional pointonly if they were able to reproduce the entire sequence of 09stimuli in the right order[ Second\ they were required to com!plete two blocks of 099 trials in a self!generated sequence task[In the latter task\ subjects were told that\ instead of pressingthe button below the light that was illuminated\ they now hadto press the button corresponding to where they thought thenext stimulus should appear in the sequence[ In this task\ accu!racy was more important than speed[ Again\ a rest period of 89s separated the two blocks of trials[

These two tests were always administered after the subjectshad completed four blocks of trials in the repeated sequencecondition in order to warranty that the primary measure ofinterest in this study "i[e[ the long!term retention of the skill#would not be in~uenced by the fact that subjects were reac!quainted with the sequence during the declarative memorytasks[

J[ Doyon et al[:Automatization of a visuomotor skill 524

Results

The dependent variables of interest in the presentexperiment were the mean number of correct responsesand reaction time for the skill learning aspect of theRepeated Sequence Test\ as well as the mean number ofaccurate responses on the two tests measuring the levelof declarative knowledge of the sequence[

Repeated sequence test] visuomotor skill learning

Long!term retention for the repeating sequence wasassessed using three di}erent measures[ First\ subjects|performance taken from the four blocks of trials in Ses!sion 5 of training ð19Ł was compared to that of the fourblocks of trials in the retention session "S5!R#[ Second\data from Session 5 of learning were compared to thoseof the _rst block of trials from the retention session "S5!R[B0#[ Finally\ the results of the fourth block of trialsfrom the training session were compared to those of the_rst block from the retention session "S5[B3!R[B0#[ Foreach of these indices\ separate analyses of variance"ANOVA|s# for repeated measures were conducted con!trasting the results of each clinical group to that of theirrespective groups of normal control subjects[ As for thePD patients\ the analyses were _rst performed using thedata from each subgroup "Stage 0\ ðn�2Ł\ Stages 1Ð2\ðn�01Ł# as they were evaluated clinically at the timeof the retention session[ Subsequent analyses using theresults of the _ve patients who changed from Stage 0 to1 "PDÐCS# within the one!year delay period were alsocarried out in order to examine the e}ects of furthernigrostriatal degeneration on retention of the visuomotorskill[ However\ only the results of the statistical analysescomparing the latter subgroup of PD patients to thegroup of control subjects are reported in Table 2 andFigure 2\ as they were the only subgroup who dem!onstrated a signi_cant di}erent pattern of retention[Three di}erent "instead of a single# measures of retentionwere used to show that the results were robust and notonly a re~ection of the type of retention indices employed[

Accuracy[ Overall\ the subjects in this study were veryaccurate\ the mean number of correct responses within asequence "max[�09# ranging from 7[6Ð8[6[ When thePD patients who stayed in either Stage 0 or Stages 1Ð2during the delay period were _rst compared\ the analyseson each of the dependent measures taken separatelyrevealed main e}ects of Group "S5!R] F"0\14#�00[49\P³ 9[90^ S5!R[B0] F"0\14#�09[54\ P³ 9[90^ S5[B3!R[B0] F"0\14#�8[28\ P³ 9[90# and Session "S5!R[B0]F"0\14#�4[81\ P³ 9[94^ S5[B3!R[B0] F"0\14#�4[80\P³ 9[94# for those in the more advanced group only[However\ there were no signi_cant Group×Sessioninteraction for either group on the dependent measures\suggesting that the PD patients did not di}er from con!trols in the number of errors made over time[ Also\ asreported in Table 2\ comparisons of the PDÐCS\ CE and

FL groups with the control subjects revealed that theydid not di}er with respect to their level of accuracy\ as aunique main e}ect of Group and a single Group×Sessioninteraction were observed\ respectively\ using the S5!Rmeasure with the PDÐCS subgroup "F"0\07#�6[77\P³ 9[94# and the S5[B3!R[B0 indices with the CE group"F"0\11#�5[59\ P³ 9[94#[

Reaction time[ The analyses comparing the reactiontime data of the PD patients who stayed in Stage 0 or inStages 1Ð2 of the disease with those of the control group"Fig[ 2 and Table 2# yielded only a highly signi_cant maine}ect of Session\ which was seen independently of theretention measure used "Stage 0] S5ÐR] F"0\05#�33[61\P³ 9[9990^ S5!R[B0] F"0\05#�34[83\ P³ 9[9990^S5[B3!R[B0] F"0\05#�32[95\ P³ 9[9990^ Stages 1!2]S5!R] F"0\14#�23[27\ P³ 9[9990^ S5!R[B0] F"0\14#�45[95\ P³ 9[9990^ S5[B3!R[B0] F"0\14#�37[67\P³ 9[9990#[ No signi_cant Group×Session interactionwas observed on either measure when the PD patients inStage 0 were compared to control subjects[ Althoughthe latter _ndings are consistent with our expectationsbecause these patients did not show a learning impair!ment in the _rst place ð19Ł\ this lack of _ndings maysimply be due to the small sample size "n�2# in thisgroup[ Contrary to our prediction\ however\ the Groupx Session interaction never reached the level of sig!ni_cance in the PD patients who were in Stages 1Ð2"n�01# at the time of testing[

The results of the PDÐCS\ CE\ FL and their respectivegroups of control subjects in the four blocks of trials forboth Session 5 of training and the retention session areillustrated in Fig 2aÐ2c\ whereas the outcomes of thestatistical analyses using the di}erent dependent mea!sures of retention for each of the groups comparisons aresummarized in Table 2[ As shown in the latter table\ asigni_cant main e}ect of Group was only seen in thecerebellar group "S5!R] F"0\11#�08[76\ P³ 9[990^ S5!R[B0] F"0\11#�05[71\ P³ 9[990^ S5[B3!R[B0]F"0\11#�06[43\ P³ 9[990#\ suggesting that these pat!ients were slower than controls to respond when per!forming the sequence[ All subjects| groups "including theFL group# were also signi_cantly slower to respond inthe retention session compared to the last training session"PDÐCS] S5!R] F"0\07#�22[67\ P³ 9[9990^ S5!R[B0]F"0\07#�75[16\ P³ 9[9990^ S5!B3!R!B0]F"0\07#�84[46\ P³ 9[9990^ CE] S5!R] F"0\11#�24[78\P³ 9[9990^ S5!R[B0] F"0\11#�53[97\ P³ 9[9990^S5[B3!R[B0] F"0\11#�53[66\ P³ 9[9990^ FL] S5!R]F"0\06#�00[51\ P³ 9[90^ S5!R[B0] F"0\06#�10[63\P³ 9[990^ S5[B3!R[B0] F"0\06#�06[06\ P³ 9[990#[Most importantly\ however\ signi_cant Group×Sessioninteractions were observed in both PDÐCS and CE com!parisons "PDÐCS] S5[R] F"0\07#�3[68\ P³ 9[94^ S5!R[B0] F"0\07#�09[4\ P³ 9[90^ S5[B3!R[B0]F"0\07#�02[02\ P³ 9[90^ CE] S5!R] F"0\11#�5[52\P³ 9[94^ S5!R[B0] F"0\11#\ P�9[9415#[ These inter!actions were due to the fact that these patients showed agreater deterioration in performance over time than their

J[ Doyon et al[:Automatization of a visuomotor skill525

Table 2[ Summary of results of the statistical analyses com!paring clinical and normal control groups on the Repeated

Sequence Test

Comparison

PDÐCS vs NC CE vs NC FL vs NCMeasure d[f["0\07# d[f["0\11# d[f["0\06#

AccuracyS5!R G�S5!R!B0S5[B3!R!B0 S� S� G×S�

Reaction timeS5!R S��� G×S� G���S��� S��

G×S�S5!R[B0 S��� G×S$ G���S��� S���

G×S%S5[B3!R!B0 S��� G×S� G���S��� S���

PDÐCS � subgroup of PD patients who changed from Stage 0to Stage 00 of the disease during the one!year delay period[CE � cerebellar group[ FL � frontal!lobe group[ NC � nor!mal control group[ S5FS1Ł� last training session from ourprevious study[ S5[B3 � fourth block of trials in Session 5[R � retention session[ R[B0 � _rst block of trials in the reten!tion session[ G � main e}ect of group[ S � main e}ect ofsession[ G×S � interaction group×session DF � degree offreedom[� P ³ 9[94\ ��P ³ 9[90\ ��� P ³ 9[990\ %P � 9[9415\$ P � 9[9460[

respective groups of control subjects "Figs 2aÐ2c#[ Inter!estingly\ such interactions were also observed for all ofthe di}erent types of retention measures\ except for theS5[B3!R[B0 measure in the CE vs NC comparison whichfailed to reach the level of signi_cance[

Subsequent analyses comparing the subjects| per!formance on Session 5 vs the last block of trials on theretention session "S5!R[B3# were also performed in otherto verify that the loss in speed seen on Block 0 of theretention session was caused by a de_ciency in retentionof the skill rather than by a general slowing of response[The results of all the group comparisons did not revealany signi_cant e}ect of Group\ Session or Group!×Session\ suggesting that di}erence in performance inthe retention session of the PDÐCS and CE groups wasnot due merely to a motor deterioration per se[

Repeated sequence test] declarative memory tasks[Explicit knowledge of the sequence was assessed by com!paring the mean number of correct answers on the shortquestionnaire that were obtained in Session 5 of trainingwith that observed in the retention session using anANOVA for repeated measures[ A similar type ofANOVA for the self!generation task was also performedusing the mean number of accurate responses on thesecond block of trials of the sixth training session "S5[B1#\and those on Block 0 of the retention session "R[B0#[ Theresults of all the comparisons between clinical and controlgroups did not reveal any signi_cant e}ect of Group or

Session\ nor any Group×Session interaction on eithertask "Table 3#[

Discussion

The main _ndings of this study are that\ compared tomatched control subjects\ PD patients who changed fromStage 0 to Stage 1 of the disease "hence suggesting furtherstriatal degeneration#\ as well as those with damage tothe cerebellum\ did not show as much retention of theability to produce the repeating visuomotor sequence\approximately a year after they had been exposed toextensive training of this skill[ Interestingly\ such animpairment in the retention of this skill was observed ina group of patients who had developed a striatal dys!function that was similar to those "in the case of the PDÐCS subgroup#\ or were the exact same patients "in thecase of the CE group#\ who had previously demonstrateda learning de_cit in late phase of the acquisition processð19Ł[ Thus\ similarly to the declarative memory systemthat is critical for both explicit learning and long!termretention of information\ these results suggest that thestriatum and the cerebellum are not only critical for theacquisition of a visuomotor sequence\ but that they mayalso play a role in the neuronal mechanism subservinglong!term retention of such a skill[ Indeed\ the present_ndings suggest that damage to these two structureswould disrupt the consolidation of visuomotor skilledbehaviors and the development of further long!term rep!resentational changes that can occur in both motor cort!ical and subcortical structures with extended practice[The latter notion is in accord with that of Gabrieli et al[ð15Ł who proposed that the striatum and the cerebellumparticipate to the learning of visuomotor skills\ but thatthe long!term representation of this skill would be locatedat a cortical level and not within those structures[ This isalso consistent with a slightly di}erent idea proposed byDoyon ð08Ł who suggested that both the striatum and thecerebellum play a critical role in the automatization phaseof learning of a skill\ but when normal control subjectshave learned an ability and have practiced it until itbecomes automatic and overlearned\ the long!term {{neu!ral representation|| of that skill may then be mediated bya distributed cortical and subcortical system involvingonly the motor related regions "e[g[ M0\ SMA\ pre!motor# of the frontal lobe and the striatum\ but not thecerebellum[

The results of this experiment contrastwith those inwhichintact retention of a visuomotor skill has been reported inamnesic patients with heterogeneous etiologies using eithera very similar version of the Repeated Sequence Test ð37\57Ł or other skill learning tasks ð06\ 07Ł[ Amnesia in humansis known to be produced following bilateral damage tomedial and diencephalic regions ð48\ 80Ł[ By contrast\ node_cit in skill retention is usually observed following lesionsto this neural system\ nor to the frontal lobes[ Thus\ thepresent _ndings reinforce the notion that the striatum and

J[ Doyon et al[:Automatization of a visuomotor skill 526

Table 3[ Results of the declarative memory tasks in Session 5 of training and the retention session for all the subjects| groups on theRepeated Sequence Test

PDÐCS NC Cerebellar NC Frontal NCGroup "n � 4# "n � 04# "n � 01# "n � 01# "n � 7# "n � 00#

Questionnaire "Mean:2 "S[D[##Session 5 1[9 "9[5# 1[0 "9[5# 0[7 "9[6# 0[7 "0[9# 0[5 "9[0# 0[8 "9[6#Retention 1[9 "9[5# 1[0 "9[4# 1[0 "9[6# 1[2 "9[5# 0[7 "9[7# 1[1 "9[5#

Self!generated test "Mean:09 "S[D[##Session 5 5[8 "0[2# 6[0 "1[5# 4[7 "1[2# 5[8 "2[7# 5[6 "1[8# 6[8 "1[3#Retention 5[5 "1[4# 5[1 "1[9# 5[6 "0[8# 4[7 "1[7# 6[9 "1[0# 6[9 "1[3#

the cerebellum are part of a separate neural network\ whichallows a sequence of movements "and possibly\ other skillsas well# to become rapid and automatic with practice\ aswell as to be maintained over long periods of time[

The fact that a retention impairment was found in thePDÐCS group "the same patients who had showed normallearning of the sequence in the skill learning study ð19Ł#\suggests that further dysfunction of the nigro!striatalpathway causes subjects to loose an ability over time[This last _nding would suggest that the striatum doesnot only contribute to the learning and retention of avisuomotor skill\ but that it also constitutes a potentiallyimportant cerebral station within which the motor pro!grams necessary for executing a skill e.ciently could bestored[ Although much conjectural\ such idea would beconsistent with animal work\ which has shown that stri!atal neurons undergo changes in responsiveness duringincremental learning ð02\ 22\ 23\ 71Ł[

Considering that the level of retention of a skill mayconstitute a measure of the degree of automatization ofthat particular ability ð49\ 42\ 78Ł\ the present _ndingssupport the idea that the striatum and the cerebellum areimplicated in this latter phase of learning[ Such interpret!ation is in accord with the results of Experiment 0\ inwhich we have demonstrated a de_cit in the auto!matization of the same repeating visuomotor sequenceusing a dual!task paradigm in the groups of patients withPD "Stages 1Ð2# or with a cerebellar lesion[ This is alsoconsistent with a recent PET imaging study ð10Ł\ in whichwe observed peaks of cerebral blood ~ow "CBF# activityin both the ventral striatum and the cerebellum when therepeating sequence was well learned\ whereas no focalincrease in CBF was seen when subjects were beginningto learn a new sequence[

Finally\ no signi_cant di}erence between each of theclinical group and their respective group of control sub!jects was observed on the declarative memory tasks[These results agrees with our own _ndings ð19Ł\ as wellas those from other studies ð06\ 66Ł\ in which a functionaldissociation between declarative and procedural memorysystems has been reported in similar groups of patients[However\ the last _ndings must be taken with caution asthe declarative memory tests were always administered

after the subjects had terminated the four blocks of trialsin the repeating sequence condition[ It is thus possiblethat the lack of di}erence between groups could be dueto the fact that the subjects| declarative knowledge of thesequence was reactivated while performing the repeatingsequence[

Conclusion

To our knowledge\ the results of Experiment 0 withthe dual!task paradigm constitute the _rst demonstrationin clinical populations\ that an impairment in theincremental learning of a visuomotor skill following adysfunction in the striatum or cerebellum may be due toa di.culty in the automatization process of the skill usinga dual!task paradigm[ Together with _ndings from pre!vious investigations\ which have demonstrated an impair!ment in the early stages of skill acquisition on a varietyof tasks following damage to these two structures ð19\ 11\12\ 66Ł\ the present results suggest that the striatum andthe cerebellum are involved in the automatization phaseof learning a motor sequence[

Finally\ intact retention of a variety of skills has oftenbeen reported after variable delays in normal controlsubjects and amnesic patients ð1\ 05\ 15\ 37\ 52\ 57Ł[ Thisstudy\ however\ constitutes a _rst attempt to test forretention of a visuomotor skill a year later in groups ofpatients who had or had not shown a learning impairmentin the _rst place[ The present results extend those of ourprevious studies and suggest that the striatum and thecerebellum are engaged in neuronal mechanisms that willallow a skill to be maintained in long!term memory[

Acknowled`ements*We would like to express our appreciationto the patients and control subjects who participated in thepresent experiment[ We would also like to thank Rhonda Amselfor her statistical advice\ as well as Dr Morris Moscovitch\ DrAdrian M[ Owen\ Philip Jackson\ Martin La~eur and Marie!Christine Ouellet for their comments on an earlier version ofthis text[

This work served as partial ful_lment for the requirementsof a Ph[D[ degree to R[ Laforce Jr[ and a master degree to G[

J[ Doyon et al[:Automatization of a visuomotor skill527

Bouchard and D[ Gaudreau[ This research was supported inpart by grants to Julien Doyon from the Natural Sciences andEngineering Research Council èOGPIN 901 and the {{Fond!ation de l|Ho¼pital de l|Enfant!Je�sus||\ Que�bec city\ Canada[

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